Conditions: Narcolepsy Obstructive Sleep Apnea
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 645
Healthy volunteers: no

Brief summary:
This is a Phase 3 study to assess the long-term safety and maintenance of efficacy of JZP-110 in subjects who have completed Study 14-002, 14-003, 14-004, 15-004, 15-005, ADX-N05 201, or ADX-N05 202.

Detailed description:

Arms:
arm 1: Once Daily Dosing

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

Protocol document:
Prot_000.pdf: 
Signature Date: 20161130
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
CONFIDENTIAL 
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Clinical Trial Protocol: 14-005 
Study Title: 
A Long-Term Safety and Maintenance of Efficacy Study of JZP-110 
[(R)-2-amino-3-phenylpropylcarbamate hydrochloride] in the 
Treatment of Excessive Sleepiness in Subjects with Narcolepsy or 
Obstructive Sleep Apnea 
Study Phase: 
3 
Product Name: 
JZP-110 [(R)-2-amino-3-phenylpropylcarbamate hydrochloride] 
IND Number: 
107,203 and 122,590 
EUDRACT 
Number: 
2014-005489-31 
Indication: 
Treatment of excessive sleepiness in adult patients with narcolepsy or 
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: 
18 December 2014 
Amendment 1: 
18 February 2015 
Amendment 2: 
11 September 2015 
Amendment 3: 
02 February 2016 
Amendment 4:    
17 November 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unpublished information contained herein will be published or disclosed without first obtaining written approval 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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SYNOPSIS 
SPONSOR 
Jazz Pharmaceuticals 
PRODUCT 
JZP-110 [(R)-2-amino-3-phenylpropylcarbamate 
hydrochloride] 
TITLE 
A Long-Term Safety and Maintenance of Efficacy Study of 
JZP-110 [(R)-2-amino-3-phenylpropylcarbamate 
hydrochloride] in the Treatment of Excessive Sleepiness in 
Subjects with Narcolepsy or Obstructive Sleep Apnea 
STUDY NUMBER 
14-005 
STUDY PHASE 
Phase 3 
LOCATION 
This trial will be conducted at approximately 110 sites in 
North America and Europe. 
PRIMARY 
OBJECTIVES 
The primary objective of the overall study is to evaluate the 
safety and tolerability of JZP-110 administered once daily for 
up to 52 weeks in doses of 75, 150, and 300 mg. 
The primary objective of the randomized withdrawal period in 
the Maintenance Phase of this study is to evaluate the 
maintenance of efficacy of JZP-110 compared to placebo in 
the treatment of excessive sleepiness in adult subjects with 
narcolepsy or obstructive sleep apnea (OSA) after at least 26 
weeks of daily administration of JZP-110. 
KEY SECONDARY 
OBJECTIVE 
To evaluate the maintenance of efficacy of open-label 
JZP-110 administered once daily for up to 52 weeks in doses 
of 75, 150, and 300 mg in the treatment of excessive 
sleepiness in adult subjects with narcolepsy or OSA. 
DESIGN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This is a Phase 3 study to assess the long-term safety and 
maintenance of efficacy of JZP-110 under open-label and 
double-blind, placebo-controlled conditions, in subjects who 
have completed Study 14-002, 14-003, 14-004, 15-004, 
15-005, ADX-N05 201, or ADX-N05 202. The study will 
consist of a 2-week Titration Phase for all subjects, a 38-week 
Maintenance Phase for subjects who completed Study 14-002 
or 14-003 or a 50-week Maintenance Phase for subjects who 
completed Study 14-004, 15-004, 15-005, ADX-N05 201, or 
ADX-N05 202, and a 2-week Safety Follow-up period. 
During the 2-week Titration Phase, subjects will begin with 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 or 150 mg at any time following a 
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telephone consultation with investigative site staff to achieve 
a maximal dose that is tolerable. After the 2-week Titration 
Phase, subjects will enter the Maintenance Phase at the stable 
dose that was reached at the end of the Titration Phase. After 
entering the Maintenance Phase, only three dose adjustments 
(to doses of 75 mg, 150 mg or 300 mg daily) will be allowed 
during the first 12 weeks of the Maintenance Phase. If the 
dose cannot be successfully adjusted within these parameters, 
the subject will be discontinued from the study. 
Subjects who completed Study 14-002 or 14-003 (Group A) 
will return to the clinic for assessments at the end of the 
2-week Titration Phase and at approximately 14, 27, 29, and 
40 weeks after the start of treatment with JZP-110 in this 
study. Subjects who completed Study 14-004, 15-004, 15-005, 
ADX-N05 201, or ADX-N05-202 (Group B) will return to the 
clinic for assessments at the end of the 2-week Titration Phase 
and at approximately 14, 26, 28, 39, and 52 weeks after the 
start of treatment with JZP-110 in this study. The randomized 
withdrawal period of the Maintenance Phase of the study will 
be conducted from weeks 27-29 in Group A and from weeks 
26-28 in Group B. At the beginning of the randomized 
withdrawal period, subjects will be randomly assigned in a 
1:1 ratio to continue to receive JZP-110 at the dose that they 
are currently receiving or to receive placebo for 2 weeks. At 
the end of the 2-week randomized withdrawal period, subjects 
will receive the same dose that they had been receiving at the 
beginning of the randomized withdrawal period for the 
remainder of the study (a fixed titration of 3 days will be 
included for subjects on the 150 and 300 mg doses).   
When approximately 300 subjects are randomized into the 
randomized withdrawal period, no more subjects will be 
randomized into the period. All subjects who have not entered 
the randomized withdrawal period at that time will receive 
open-label JZP-110 treatment for the remainder of the study. 
All subjects who have entered the randomized withdrawal 
period will complete all scheduled assessments for the period. 
Subjects who completed Study 14-002 or 14-003 (Group A) 
and who are not randomized into the randomized withdrawal 
period will return to the clinic for assessments at the end of 
the 2-week Titration Phase and at approximately 14, 27, and 
40 weeks after the start of treatment with JZP-110 in this 
study. Subjects who completed Study 14-004, 15-004, 15-005, 
ADX-N05 201, or ADX-N05-202 (Group B) and who are not 
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randomized into the randomized withdrawal period will return 
to the clinic for assessments at the end of the 2-week Titration 
Phase and at approximately 14, 26, 39, and 52 weeks after the 
start of treatment with JZP-110 in this study.  
All subjects will be contacted monthly by phone, and the 
investigator will determine whether subjects need to be seen 
in the clinic at any other time(s) during the study to ensure 
their safety. 
Safety will be assessed throughout the study and will include 
the Columbia-Suicide Severity Rating Scale (C-SSRS) 
administered at each clinic visit.  
Open-label maintenance of efficacy will be assessed by the 
Epworth Sleepiness Scale (ESS), Patient Global Impression of 
Change (PGIc), Clinical Global Impression of Change 
(CGIc), and several quality of life and economic measures, 
such as the Functional Outcomes of Sleep Questionnaire 
Short Version (FOSQ-10), 36-Item Short Form Health Survey 
Version 2 (SF-36v2), EuroQoL EQ-5D-5L, and the Work 
Productivity Activity Impairment (WPAI:SHP) 
Questionnaire. Double-blind, placebo-controlled maintenance 
of efficacy in the randomized withdrawal period will be 
assessed by changes on the ESS and FOSQ-10, and ratings on 
the PGIc and CGIc from the beginning to the end of the 2-
week double-blind withdrawal period (from week 27 to 29 or 
from week 26 to 28 in Groups A and B, respectively). 
At the 14 and 40 week visits for subjects in Group A and at 
the 26 and 52 week visits for subjects in Group B, subjects 
will be asked about their healthcare resource utilization over 
the past 3 months in terms of physician visits. 
All subjects will return to the site 2 weeks after the final clinic 
visit of the Maintenance Phase for safety follow-up 
assessments. Unless there are any outstanding safety issues 
that require follow-up, subjects will be discharged from the 
study at that visit. 
ESTIMATED 
DURATION OF 
STUDY 
Subjects may participate for up to 40 (Group A) or 52 (Group 
B) weeks in the current study, with a subsequent safety 
follow-up for 2 weeks following discontinuation of treatment 
(total study participation up to 42 or 54 weeks, respectively). 
It is anticipated that enrollment across all sites will be 
completed in approximately 18 months. 
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STUDY POPULATION Subjects must have completed Study 14-002, 14-003, 14-004, 
15-004, 15-005, ADX-N05 201, or ADX-N05 202 and meet 
the inclusion and exclusion criteria. 
Approximately 600 subjects who meet eligibility 
requirements for this study are planned for enrollment with 
the intention of completing at least 50 subjects with 
narcolepsy and at least 50 subjects with OSA with an 
exposure to JZP-110 of 52 weeks and at least 100 subjects 
with narcolepsy and at least 200 subjects with OSA with an 
exposure to JZP-110 of 26 weeks. 
A sample size of 300 subjects in the randomized withdrawal 
period, with approximately 150 subjects per treatment group, 
will provide at least 95% power to detect a difference of 
3 points in the ESS score from the beginning to the end of the 
2-week randomized withdrawal period. This calculation 
assumes a common standard deviation of 7 points for the ESS 
change during the randomized withdrawal period and a two-
sided significance level of 0.05 using a t-test. 
DIAGNOSIS AND 
MAIN CRITERIA FOR 
INCLUSION 
Inclusion Criteria 
All subjects must meet the following criteria to be enrolled in 
the study. 
1. Subject meets one of the following: 
a. Completed Study 14-002 or 14-003 (Group A) 
b. Completed Study 14-004, 15-004, 15-005, 
ADX-N05 201, or ADX-N05 202 (Group B) 
2. Subject is able, in the opinion of the investigator, to 
take JZP-110 for 40 weeks if continuing from 14-002 
or 14-003 or for 52 weeks if the subject completed 
14-004, 15-004, 15-005, ADX-N05 201, or ADX-N05 
202, and is able to complete all tests and visits 
described in this protocol. 
3. Usual nightly total sleep time of at least 6 hours. 
4. Body mass index from 18 to <45 kg/m2. 
5. 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. 
6. Willing and able to comply with the study design 
schedule and other requirements. 
7. Willing and able to provide written informed consent. 
Exclusion Criteria 
Subjects who demonstrate any of the following will be 
excluded from the study. 
1. Female subjects who are pregnant, nursing, or 
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lactating. 
2. Usual bedtime later than 1 AM (0100 hours). 
3. Occupation requiring nighttime or variable shift 
work. 
4. Experienced any serious adverse event (SAE) in a 
previous study that was deemed related to JZP-110 or 
experienced an AE in a previous study that might 
prevent him/her from safely participating in and 
completing the current study. 
5. Any other clinically relevant medical, behavioral, or 
psychiatric disorder other than narcolepsy or 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. 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. 
8. History of bariatric surgery within the past year or a 
history of gastric bypass procedure. 
9. Presence of renal impairment or calculated creatinine 
clearance <60 mL/min. 
10. Clinically significant ECG abnormality in the opinion 
of the Investigator. 
11. This criterion has been removed. 
12. Presence of significant cardiovascular disease 
including but not limited to: myocardial infarction 
within the past year, unstable angina pectoris, 
symptomatic congestive heart failure (ACC/AHA 
stage C or D), revascularization procedures within the 
past year, ventricular cardiac arrhythmias requiring 
AICD or medication therapy, uncontrolled 
hypertension, or systolic blood pressure ≥155 mmHg 
or diastolic blood pressure ≥95 mmHg at screening or 
Baseline for Group B subjects according to protocol 
specifications; or any history of cardiovascular 
disease or significant cardiovascular condition that in 
the investigator’s opinion may jeopardize subject 
safety in the study. 
13. Laboratory value(s) outside the laboratory reference 
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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 Baseline 
Visit or anticipated excessive use during the study 
defined as >600 mg/day of caffeine. 
15. Use of a monoamine oxidase inhibitor (MAOI) in the 
past 14 days or five half-lives of the drug (whichever 
is longer) prior to the Baseline Visit, or plans to use 
an MAOI during the study. 
16. Received an investigational drug other than JZP-110 
in the past 30 days or five half-lives (whichever is 
longer) before the Baseline Visit, or plans to use an 
investigational drug (other than the study drug) 
during the study. 
17. Current or past (within the past 2 years) diagnosis of 
a moderate or severe substance use disorder 
according to DSM-5 criteria. 
18. Nicotine dependence that has an effect on sleep 
(e.g., a subject who routinely awakens at night to 
smoke). 
19. Current, past (within the past 2 years), or seeking 
treatment for a substance related disorder. 
20. 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. 
21. History of phenylketonuria (PKU) or history of 
hypersensitivity to phenylalanine-derived products. 
22. Group A: Planned use of any over-the-counter 
(OTC) or prescription medications that could affect 
the evaluation of excessive sleepiness at any time 
during the study. 
Group B: Use of any over-the-counter (OTC) or 
prescription medications that could affect the 
evaluation of excessive sleepiness within a time 
period prior to the Baseline Visit corresponding to at 
least five half-lives of the drug(s) or planned use of 
such drug(s) at some point throughout the duration of 
the study. Medications should be discontinued such 
that the subject has returned to his/her baseline level 
of daytime sleepiness at least 7 days prior to the 
Baseline Visit, in the opinion of the Investigator. 
Examples of excluded medications include OTC 
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sleep aids or stimulants (e.g., pseudoephedrine), 
methylphenidate, amphetamines, modafinil, 
armodafinil, sodium oxybate, pemoline, trazodone, 
hypnotics, benzodiazepines, barbiturates, and 
opioids.  
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 
For the randomized withdrawal period, placebo tablets will 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 will be up to 40 weeks for subjects 
who participated in Study 14-002 or 14-003 and up to 
52 weeks for subjects who participated in Study 14-004, 
15-004, 15-005, ADX-N05 201, or ADX-N05 202. 
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 electrocardiograms (ECGs), physical exams, 
and the C-SSRS assessments. 
EFFICACY 
ASSESSMENTS 
 
Efficacy endpoints (ESS, PGIc, CGIc) will be summarized by 
treatment using descriptive statistics. In the randomized 
withdrawal period of the Maintenance Phase, the change in 
ESS from the beginning to the end of the 2-week randomized 
withdrawal period is defined as the primary efficacy endpoint. 
PGIc and CGIc ratings (since the last visit) at the end of the 2-
week randomized withdrawal period will also be evaluated as 
secondary double-blind, placebo-controlled efficacy 
endpoints. The outcome measures in the FOSQ-10, SF-36v2, 
and EQ-5D-5L will be summarized and displayed graphically. 
No adjustment of significance level for multiple testing will 
be employed. 
ECONOMIC 
ASSESSMENTS 
The outcome measures associated with the WPAI:SHP and 
the Resource Utilization Questionnaire will be summarized by 
final dose and time point and displayed graphically. For 
subjects who participated in Study 14-002 or 14-003, the 
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WPAI:SHP measures may also be summarized by the 
previous treatment group. Where applicable, the changes in 
the WPAI:SHP measures from prior study baseline and from 
the endpoint of the prior study will be examined.  
Standard unit costs will be applied to the resources identified 
with the Resource Utilization Questionnaire (as well as to any 
hospitalizations reported as SAEs) in order to calculate the 
mean/median healthcare costs over the one-year period. 
PHARMACOKINETIC 
ASSESSMENTS 
None 
STATISTICAL 
ANALYSIS 
Efficacy and safety data will be summarized using descriptive 
statistics.  
For comparisons between JZP-110 and placebo at the end of 
the randomized withdrawal period in the Maintenance Phase, 
subjects who were randomized to continue on JZP-110 in the 
randomized withdrawal period of the Maintenance Phase will 
be treated as a single group regardless of their diagnosis 
(narcolepsy or OSA) or the dose of JZP-110 that they 
received. Thus, there will be no multiplicity issues with 
respect to multiple doses in the hypothesis testing. A fixed 
sequential testing strategy will be employed to address the 
multiplicity issues in testing the primary and secondary 
endpoints in the randomized withdrawal period.  
For the analysis of the primary efficacy endpoint of the ESS in 
the randomized withdrawal period, an analysis of covariance 
(ANCOVA) model will be used. This model will include 
treatment group and randomization stratification factor as 
fixed effects. The ESS score at the beginning of the 
randomized withdrawal period will be used as the covariate. 
The response variable will be the change in ESS score from 
the beginning to the end of the 2-week randomized 
withdrawal period. 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 chi-squared test will be used to test the hypotheses 
associated with the analysis of the secondary endpoints of 
PGIc and CGIc at the end of the 2-week randomized 
withdrawal period. 
Efficacy data from the open-label period will be summarized 
using descriptive statistics. No formal hypotheses will be 
tested for the open-label efficacy data.  
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DATE OF ORIGINAL 
PROTOCOL 
18 December 2014 
AMENDMENT 1 
18 February 2015 
AMENDMENT 2 
11 September 2015 
AMENDMENT 3 
02 February 2016 
AMENDMENT 4 
17 November 2016 
 
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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
TABLE OF CONTENTS .........................................................................................................11 
LIST OF IN-TEXT TABLES ..................................................................................................15 
LIST OF IN-TEXT FIGURES.................................................................................................15 
LIST OF APPENDIXES..........................................................................................................15 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................17 
1 
INTRODUCTION ...........................................................................................................20 
1.1 
Background and Rationale .....................................................................................21 
1.2 
Nonclinical Experience ..........................................................................................22 
1.3 
Clinical Experience ................................................................................................22 
1.3.1 
Pharmacokinetics of JZP-110 ......................................................................23 
1.3.2 
Efficacy of JZP-110 in Clinical Studies of Narcolepsy ...............................23 
1.3.3 
Safety of JZP-110 in Clinical Studies of Narcolepsy ..................................23 
1.3.4 
Safety of JZP-110 in Clinical Studies of Major Depression and in Healthy 
Subjects ........................................................................................................24 
1.4 
Summary of Potential Benefits and Risks .............................................................26 
2 
STUDY OBJECTIVES ....................................................................................................27 
2.1 
Primary Objectives.................................................................................................27 
2.2 
Secondary Objectives.............................................................................................27 
3 
STUDY DESIGN.............................................................................................................27 
3.1 
Overall Study Design and Plan ..............................................................................27 
3.1.1 
Rationale for Study Design and Control Group ...........................................32 
3.2 
Study Duration and Dates ......................................................................................32 
3.3 
End of Trial ............................................................................................................32 
4 
STUDY POPULATION SELECTION ...........................................................................33 
4.1 
Selection of Study Population ................................................................................33 
4.2 
Inclusion Criteria ...................................................................................................33 
4.3 
Exclusion Criteria ..................................................................................................33 
4.4 
Eligibility ...............................................................................................................35 
5 
STUDY TREATMENT(S) ..............................................................................................35 
5.1 
Description of Treatment(s) ...................................................................................35 
5.1.1 
JZP-110 ........................................................................................................35 
5.1.2 
Placebo .........................................................................................................35 
5.2 
Treatments Administered .......................................................................................35 
5.3 
Selection and Timing of Dose for Each Subject ....................................................36 
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5.4 
Method of Assigning Subjects to Treatment Groups .............................................37 
5.5 
Randomization .......................................................................................................37 
5.6 
Blinding..................................................................................................................37 
5.7 
Prior and Concomitant Therapy .............................................................................37 
5.8 
Restrictions ............................................................................................................38 
5.8.1 
Prior Therapy ...............................................................................................38 
5.8.2 
Fluid and Food Intake ..................................................................................38 
5.9 
Investigational Medicinal Product Treatment Compliance ...................................38 
5.10 
Packaging and Labeling .........................................................................................38 
5.11 
Storage and Accountability ....................................................................................39 
6 
STUDY PROCEDURES .................................................................................................39 
6.1 
Informed Consent...................................................................................................39 
6.2 
Demographics ........................................................................................................39 
6.3 
Medical History .....................................................................................................40 
6.4 
Physical Examination.............................................................................................40 
6.5 
Vital Signs ..............................................................................................................40 
6.6 
Electrocardiography ...............................................................................................41 
6.7 
Columbia-Suicide Severity Rating Scale (C-SSRS) ..............................................41 
6.8 
Clinical Laboratory Tests .......................................................................................41 
6.8.1 
Laboratory Parameters .................................................................................41 
6.8.2 
Estimated Total Blood Volume Required for the Study ..............................44 
6.8.3 
Sample Collection, Storage, and Shipping ..................................................44 
6.9 
Dispensing Study Drug ..........................................................................................45 
6.10 
Efficacy Assessments.............................................................................................45 
6.10.1 
Epworth Sleepiness Scale (ESS) ..................................................................45 
6.10.2 
Clinician Global Impression of Severity (CGIs) .........................................46 
6.10.3 
Clinician Global Impression of Change (CGIc) ..........................................46 
6.10.4 
Patient Global Impression of Change (PGIc) ..............................................46 
6.11 
Functional Outcomes and Quality of Life Endpoints ............................................46 
6.11.1 
Functional Outcomes of Sleep Questionnaire (FOSQ-10) ..........................46 
6.11.2 
36-Item Short Form Health Survey Version 2 (SF-36v2) ...........................47 
6.11.3 
EuroQoL (EQ-5D-5L) .................................................................................47 
6.11.4 
Primary OSA Therapy Use ..........................................................................48 
6.12 
Economic Assessments ..........................................................................................48 
6.12.1 
Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem V2.0 (WPAI:SHP) .........................................................................48 
6.12.2 
Resource Utilization Questionnaire .............................................................48 
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6.13 
Adverse Event Reporting .......................................................................................49 
6.13.1 
Adverse Events (AEs) ..................................................................................49 
6.13.1.1 
Severity Assessment ..........................................................................49 
6.13.1.2 
Serious Adverse Events and Seriousness Assessment .......................50 
6.13.1.3 
Causal Relationship to Study Drug or Procedure ..............................51 
6.13.1.4 
Other Immediately Reportable Experiences ......................................52 
6.13.1.5 
Adverse Events Recording and Reporting .........................................52 
6.13.1.6 
Follow-up of Adverse Events and Serious Adverse Events ..............52 
6.13.2 
Post-Study Reporting Requirements ............................................................53 
6.13.3 
Pregnancy .....................................................................................................53 
6.13.4 
Unblinding of the Treatment Assignment in the Randomized Withdrawal 
Period ...........................................................................................................53 
6.14 
Removal of Subjects from the Trial or Study Drug ...............................................54 
6.14.1 
Handling of Early Terminations ..................................................................54 
6.14.2 
Jazz Pharmaceuticals’ Termination of Study ...............................................55 
6.15 
Appropriateness of Measurements .........................................................................55 
7 
STUDY ACTIVITIES .....................................................................................................56 
7.1 
Group A Study Activities (Subjects from 14-002 or 14-003)................................56 
7.1.1 
Group A – Screening/Baseline Clinic Visit .................................................56 
7.1.2 
Group A – Titration Phase Phone Contacts .................................................57 
7.1.3 
Group A – End of Titration Phase Clinic Visit ............................................57 
7.1.4 
Group A – Maintenance Phase Phone Contacts ..........................................58 
7.1.5 
Group A – Week 14 Maintenance Phase Clinic Visit ..................................59 
7.1.6 
Group A – Week 27 Maintenance Phase Clinic Visit ..................................60 
7.1.7 
Group A – Week 29 Maintenance Phase Clinic Visit ..................................61 
7.1.8 
Group A – Maintenance Phase Final Clinic Visit ........................................62 
7.1.9 
Group A – Safety Follow-up Clinic Visit ....................................................63 
7.2 
Group B Study Activities (Subjects from 14-004, 15-004, 15-005, ADX-N05 201, 
or ADX-N05 202) ..................................................................................................64 
7.2.1 
Group B – Screening Clinic Visit ................................................................64 
7.2.2 
Group B – Baseline Clinic Visit ..................................................................65 
7.2.3 
Group B – Titration Phase Phone Contacts .................................................66 
7.2.4 
Group B – End of Titration Phase Clinic Visit ............................................66 
7.2.5 
Group B – Maintenance Phase Phone Contacts ...........................................68 
7.2.6 
Group B – Week 14 Maintenance Phase Clinic Visit ..................................68 
7.2.7 
Group B – Week 26 Maintenance Phase Clinic Visit ..................................69 
7.2.8 
Group B – Week 28 Maintenance Phase Clinic Visit ..................................71 
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7.2.9 
Group B – Week 39 Maintenance Phase Clinic Visit ..................................72 
7.2.10 
Group B – Maintenance Phase Final Clinic Visit ........................................73 
7.2.11 
Group B – Safety Follow-up Visit ...............................................................74 
7.3 
Early Terminations.................................................................................................74 
7.4 
Discontinuations ....................................................................................................75 
8 
QUALITY CONTROL AND ASSURANCE .................................................................75 
9 
PLANNED STATISTICAL METHODS ........................................................................75 
9.1 
General Considerations ..........................................................................................75 
9.2 
Tests of Hypotheses and Significance Levels ........................................................76 
9.3 
Determination of Sample Size ...............................................................................76 
9.4 
Analysis Populations ..............................................................................................77 
9.5 
Demographics and Baseline Characteristics ..........................................................77 
9.6 
Handling of Dropouts and Missing Data ...............................................................77 
9.7 
Pooling of Investigation Centers ............................................................................78 
9.8 
Placebo-controlled Maintenance of Efficacy Endpoints ........................................78 
9.8.1 
Primary Efficacy Endpoint ..........................................................................78 
9.8.2 
Secondary Efficacy Endpoints .....................................................................78 
9.9 
Efficacy Analyses ..................................................................................................78 
9.9.1 
Double-blind, Placebo-controlled Maintenance of Efficacy Analyses ........78 
9.9.2 
Open-label Maintenance of Efficacy Analyses............................................78 
9.10 
Analysis of Functional Outcomes and Quality of Life Endpoints .........................79 
9.11 
Analysis of Economic Assessments.......................................................................79 
9.12 
Safety Analysis ......................................................................................................79 
9.12.1 
Adverse Event ..............................................................................................79 
9.12.2 
Vital Signs ....................................................................................................80 
9.12.3 
Laboratory Evaluation .................................................................................80 
9.12.4 
Electrocardiograms ......................................................................................80 
9.12.5 
Physical Examinations .................................................................................81 
9.12.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) ....................................81 
9.13 
Subgroup Analyses ................................................................................................81 
9.14 
Interim Analysis and Data Monitoring ..................................................................81 
10 DATA QUALITY ASSURANCE ...................................................................................81 
10.1 
Data Management ..................................................................................................81 
10.2 
Electronic Case Report Forms (eCRFs) .................................................................82 
10.3 
Retention of Data ...................................................................................................82 
10.4 
Data Safety Monitoring Board ...............................................................................82 
11 ADMINISTRATIVE CONSIDERATIONS ....................................................................83 
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11.1 
Investigators and Study Administrative Structure .................................................83 
11.1.1 
Contract Research Organization ..................................................................83 
11.1.2 
Jazz Pharmaceuticals Medical Monitor .......................................................83 
11.1.3 
EU Medical Monitor ....................................................................................83 
11.1.4 
Investigator ..................................................................................................83 
11.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................83 
11.3 
Ethical/Legal Conduct of the Study .......................................................................84 
11.4 
Subject Information and Consent...........................................................................84 
11.5 
Subject Confidentiality ..........................................................................................84 
11.6 
Protocol Adherence – Amendments ......................................................................85 
11.7 
Required Documents ..............................................................................................85 
11.8 
Study Monitoring ...................................................................................................85 
11.9 
Protocol Violations/Deviations ..............................................................................85 
11.10 Access to Source Documentation ..........................................................................86 
11.11 Publication and Disclosure Policy .........................................................................86 
12 REFERENCE LIST .........................................................................................................87 
13 LIST OF UNPUBLISHED STUDY REPORTS .............................................................90 
 
LIST OF IN-TEXT TABLES 
Table 1 
List of Laboratory Tests ...............................................................................43 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Schema for Subjects Randomized into the Randomized  
Withdrawal Period ..........................................................................................30 
Figure 2 
Study Schema for Subjects not Randomized into the Randomized 
Withdrawal Period .......................................................................................31 
 
LIST OF APPENDIXES 
Appendix 1 
Schedule of Events – Group A...........................................................91 
Appendix 2 
Schedule of Events – Group B ...........................................................94 
Appendix 3 
DSM-5 Criteria for Psychiatric Disorders .........................................99 
Appendix 4 
DSM-5 Substance Use Disorder Diagnostic Criteria .......................106 
Appendix 5 
Epworth Sleepiness Scale (ESS) ......................................................107 
Appendix 6 
Functional Outcomes of Sleep Questionnaire Short Version 
(FOSQ-10) ......................................................................................109 
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Appendix 7 
36-Item Short Form Health Survey Version 2 (SF-36v2) ...............112 
Appendix 8 
EuroQoL EQ-5D-5L ........................................................................119 
Appendix 9 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Baseline/Screening Version ............................................................123 
Appendix 10 
Work Productivity and Activity Impairment Questionnaire: Specific 
Health Problem V2.0 (WPAI:SHP) ................................................127 
Appendix 11 
Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last Visit 
Version ............................................................................................132 
Appendix 12 
Clinical Global Impression of Severity (CGIs) ...............................136 
Appendix 13 
Clinical Global Impression of Change (CGIc) ................................137 
Appendix 14 
Clinical Global Impression of Change (CGIc) - Week 29 (Group A) 
or Week 28 (Group B) ....................................................................138
Appendix 15 
Patient Global Impression of Change (PGIc) ..................................139 
Appendix 16 
Patient Global Impression of Change (PGIc) - Week 29 (Group A) 
or Week 28 (Group B) ....................................................................140 
Appendix 17 
Resource Utilization Questionnaire .................................................141 
Appendix 18 
Signatures of Agreement for Protocol .............................................142 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AASM 
American Academy of Sleep Medicine 
AE 
Adverse event 
ACC 
American College of Cardiology 
AHA 
American Heart Association 
AHI 
Apnea hypopnea index 
AICD 
Automatic implantable cardioverter defibrillator 
ALK-P 
Alkaline phosphatase 
ALT 
Alanine aminotransferase (SGPT) 
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 
Current Good Manufacturing Practices 
Cl 
Chloride 
CPAP 
Continuous positive airway pressure 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
CRF 
Case report form 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
EU 
European Union 
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ESS 
Epworth Sleepiness Scale 
FDA 
Food and Drug Administration 
FOSQ-10 
Functional Outcomes of Sleep Questionnaire Short Version 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practices 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
K 
Potassium 
MedDRA 
Medical Dictionary for Regulatory Activities 
MWT 
Maintenance of Wakefulness Test 
OTC 
Over-the-counter 
PAP 
Positive airway pressure 
PGIc 
Patient Global Impression of change 
PKU 
Phenylketonuria 
PSG 
Polysomnography 
QTc interval 
Q-T interval corrected for heart rate  
QTcB 
Q-T interval corrected for heart rate using Bazett's formula 
QTcF 
Q-T interval corrected for heart rate using Fridericia’s formula 
SAE 
Serious adverse event 
SF-36v2 
36-Item Short Form Health Survey Version 2 
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.  
SGOT 
Serum glutamic oxaloacetic transaminase (AST) 
SGPT 
Serum glutamic pyruvic transaminase (ALT) 
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TEAE 
Treatment emergent adverse event 
ULN 
Upper limit of normal 
UK 
United Kingdom 
US 
United States 
WBC 
White blood cell (count) 
WPAI:SHP 
Work Productivity and Activity Impairment Questionnaire: Specific 
Health Problem V2.0 
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1 
INTRODUCTION 
JZP-110 [(R)-2-amino-3-phenylpropylcarbamate hydrochloride] is a phenylalanine derivative 
(previously known as ADX-N05, R228060, and YKP10A) that is currently being 
investigated as a potential treatment for excessive daytime sleepiness in narcolepsy and 
obstructive sleep apnea (OSA). Nonclinical data indicate that JZP-110 is a wake-promoting 
agent that lacks the noradrenergic releasing effects of amphetamines (EDMS-PSDB-
4956838, EDMS- PSDB-2735318, EDMS-PSDB-5305783) and does not produce rebound 
hypersomnia in rodent models (Hasan et al. 2009). Pharmacologically, JZP-110 appears to be 
a low-potency reuptake inhibitor at dopamine and norepinephrine transporters. 
Narcolepsy is a life-long neurologic disease for which no cure has been identified. It affects 
an estimated 0.02% to 0.067% of the population worldwide, approximately 1 in 
2000 individuals in the United States (Ohayon 2007, Majid & Hirshkowitz 2010), and 4.7 of 
10,000 (0.047%) individuals in the general population of five European countries (United 
Kingdom [UK], Germany, Italy, Portugal, and Spain) (Ohayon et al. 2002). The 
symptomatology of this condition is well described in the literature, with consensus on the 
five core symptoms of narcolepsy: excessive daytime sleepiness, cataplexy, sleep paralysis, 
sleep-related (hypnagogic and hypnopompic) hallucinations, and disrupted nighttime sleep 
(DNS) (Morgenthaler et al. 2007), with excessive daytime sleepiness and cataplexy being the 
most common symptoms. 
Currently approved medications to improve wakefulness and to treat excessive daytime 
sleepiness in narcolepsy include dextroamphetamine (Dexedrine®), methylphenidate 
(Ritalin®), sodium oxybate (Xyrem®), modafinil (Provigil®), and armodafinil (Nuvigil®). 
Each of these medications has limitations, including those related to efficacy and safety. 
Dextroamphetamine and methylphenidate are C-II stimulant medications with high potential 
for abuse. Sodium oxybate is a CNS depressant that requires twice nightly dosing. Modafinil 
and armodafinil do not appear to adequately promote wakefulness throughout the day with 
once daily dosing (Harsh et al. 2006, Schwartz et al. 2003). 
OSA is a sleep-related breathing disorder that is diagnosed 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). 
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. 
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2011). However, the Positive Airway Pressure Task Force of the Standards of Practice 
Committee of the American Academy of Sleep Medicine (AASM) has concluded that 
although continuous positive airway pressure (CPAP) 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).  
Data suggest that, compared to the efficacy of CPAP to reduce the AHI, the efficacy of 
CPAP to reduce subjective and objective measures of excessive sleepiness in all patients is 
limited. For example, in a multicenter study on the relationships between hours of CPAP use 
and measures of sleepiness 34% of subjects with severe OSA still had excessive sleepiness as 
defined by an Epworth Sleepiness Scale (ESS) score >10 after treatment with CPAP and 65% 
of subjects still had excessive sleepiness as defined by a mean sleep latency <7.5 minutes 
after treatment with CPAP (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 CPAP (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. 
In addition, the effectiveness of CPAP in treating objective and subjective sleepiness is 
limited by patient non-compliance or non-adherence to therapy. Non-compliance with CPAP 
is a widely recognized problem that limits its effectiveness (Weaver & Grunstein 2008, 
Weaver & Sawyer 2010, Sawyer et al. 2011). Compliance with CPAP is typically defined as 
the use of CPAP for ≥4 hours per night on ≥70% of nights (Gay et al. 2006). When 
compliance is defined as ≥4 hours of nightly use, it is estimated that 46-83% of patients with 
OSA are non-compliant with their prescribed CPAP therapy (Weaver & Grunstein 2008). 
1.1 
Background and Rationale 
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). 
There are two primary objectives of this study. The primary objective of the overall study is 
to evaluate the safety and tolerability of JZP-110 administered once daily for up to 52 weeks 
in doses of 75, 150, and 300 mg. Long-term safety and tolerability will be examined in 
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narcolepsy patients who have completed one of four controlled clinical trials of JZP-110 
(Study ADX-N05 201, ADX-N05 202, 14-002, or 15-005) or in OSA patients who have 
completed one of three controlled clinical trials of JZP-110 (Study 14-003, 14-004, or 
15-004). The primary objective of the randomized withdrawal period in the Maintenance 
Phase of this study is to evaluate the maintenance of efficacy of JZP-110 compared to 
placebo in the treatment of excessive sleepiness in adult subjects with narcolepsy or OSA 
after at least 26 weeks of daily administration of JZP-110. Given that narcolepsy and OSA 
are chronic health conditions, it is important to know whether controlled data support the 
long-term use of JZP-110 in narcolepsy and OSA. The double-blind, placebo-controlled 
maintenance of efficacy data from the randomized withdrawal period in the Maintenance 
Phase of this study are intended to provide well-controlled evidence of the long-term efficacy 
of JZP-110 to treat excessive sleepiness associated with narcolepsy or OSA. 
1.2 
Nonclinical Experience 
Nonclinical studies have been conducted to characterize primary pharmacology, secondary 
and safety pharmacology, abuse liability, absorption, distribution, metabolism, excretion, and 
toxicology of JZP-110. 
JZP-110 was extensively absorbed and showed high oral bioavailability (71 to 100%) in 
mice, rats, and dogs. In humans, bioavailability was >90% as evidenced by plasma AUC for 
parent drug essentially matching AUC for total radioactivity in a human mass balance study, 
along with urinary recovery of >90% of the dose as unchanged drug. Plasma protein binding 
was low (8 to 17%) in mouse, rat, rabbit, dog, and human plasma. In the in vitro metabolism 
studies, no notable inhibition of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2E1 and CYP3A4 occurred (15%) with concentrations up to 1000 μM. Notable 
inhibition of CYP1A2 (73%) and CYP2D6 (56%) activity was observed only at the highest 
concentration (1000 μM) investigated. However, this level of inhibition is unlikely to result 
in clinically significant drug-drug interactions with CYP1A2 or CYP2D6 substrates. The 
plasma Cmax level after oral administration to humans at 400 mg/day is approximately 7.6 μM 
(1482 ng/mL). JZP-110 (5 to 100 μM) did not inhibit P glycoprotein–mediated transport. 
More detailed information is provided in the JZP-110 Investigators Brochure. 
1.3 
Clinical Experience 
Nine clinical studies (six Phase 1 and three Phase 2a studies) have been conducted in 
262 healthy subjects and 602 subjects (two of whom did not receive study drug) with major 
depressive disorder (MDD). Of these 862 subjects, 555 received JZP-110, 185 received 
placebo, and 122 received paroxetine. Two Phase 2 studies have been conducted in 
126 subjects with narcolepsy, in which 77 subjects received JZP-110 and 49 subjects 
received placebo. 
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1.3.1 
Pharmacokinetics of JZP-110 
JZP-110 is eliminated primarily via the renal route, with at least 90% of the dose being 
excreted as unchanged drug within 48 hours. Following repeated doses administered once or 
twice daily, JZP-110 exposure was dose proportional, absorption (tmax: 1.3 to 2.5 hours) and 
elimination (t½: 6 to 7.6 hours) were rapid, and steady state was reached in 3 days. 
Pharmacokinetics were linear over the multiple-dose (14 day) range of 200 to 1000 mg/day. 
Limited accumulation and no enzyme induction were evident.  
Doses of JZP-110 previously studied in human subjects have ranged from 50 to 1200 mg per 
day in healthy subjects, from 200 to 900 mg per day in subjects with MDD, and have 
included 150 and 300 mg in subjects with narcolepsy.  
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 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, 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 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, 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 AEs (TEAEs) with JZP-110 treatment included nausea (12%), chest 
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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 SAEs, or discontinuations due 
to AEs. Severe TEAEs were limited to two subjects (one with intermittent nausea and one 
with insomnia). JZP-110 treatment was associated with a modest effect on heart rate and 
blood pressure, and TEAEs suggested a profile of effects consistent with those of a wake-
promoting drug (decreased appetite, headache, anxiety, insomnias, and gastrointestinal 
complaints). Palpitations were reported by one subject (3%) and chest pain was reported by 
3 subjects (9%; all reported as non-cardiac pain) while on JZP-110. There were no reports of 
palpitations or chest pain while subjects were on placebo. 
In Study ADX-N05 202, the JZP-110 dose regimen of 150 mg/day for 4 weeks followed by 
300 mg/day for 8 weeks appeared to be safe and well tolerated. The most common TEAEs 
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 
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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). 
• 
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, 
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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 
The potential benefits of JZP-110 to subjects 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 from the MWT and ESS data, 
respectively, from previous studies of JZP-110 in narcolepsy patients. Unlike the controlled 
trials in which subjects will have participated prior to their enrollment in this study, all 
subjects will receive JZP-110 and will undergo titration in an attempt to maximize 
therapeutic efficacy at a dose that is safe and tolerable. 
The risks to subjects in this study who are titrated to the 150 mg or 300 mg doses 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 prior to the 14-003 and 14-004 studies as a part of this 
clinical development program 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; however, in 
all cases subjects will be titrated to a maximal dose that is tolerable. 
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 in vital signs associated 
with JZP-110 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). 
Risks for subjects who are randomized to receive placebo during the 2-week randomized 
withdrawal period in the Maintenance Phase may include those associated with untreated 
symptoms of sleepiness in narcolepsy or OSA and possible discontinuation symptoms of 
JZP-110. 
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2 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
The primary objective of the overall study is to evaluate the safety and tolerability of 
JZP-110 administered once daily for up to 52 weeks in doses of 75, 150, and 300 mg. 
The primary objective of the randomized withdrawal period in the Maintenance Phase of this 
study is to evaluate the maintenance of efficacy of JZP-110 compared to placebo in the 
treatment of excessive sleepiness in adult subjects with narcolepsy or OSA after at least 
26 weeks of daily administration of JZP-110.  
2.2 
Secondary Objectives 
The key secondary objective of this study is to evaluate the open-label maintenance of 
efficacy of JZP-110 administered once daily for up to 52 weeks in doses of 75, 150, and 
300 mg in the treatment of excessive sleepiness in adult subjects with narcolepsy or OSA. 
Another secondary objective is to evaluate the safety and tolerability of JZP-110 compared to 
placebo during the randomized withdrawal period in the Maintenance Phase. 
3 
STUDY DESIGN 
3.1 
Overall Study Design and Plan 
The Schedule of Events is presented in Appendix 1 and Appendix 2 for subjects who have 
completed Study 14-002 or 14-003 (Group A) or Study 14-004, 15-004, 15-005, ADX-N05 
201, or ADX-N05 202 (Group B), respectively. The Study Schema for both Groups is 
presented in Figure 1 and Figure 2. 
This is a Phase 3 study to assess the long-term safety, open-label maintenance of efficacy, 
and double-blind, placebo-controlled maintenance of efficacy of JZP-110 in subjects who 
have completed Study 14-002, 14-003, 14-004, 15-004, 15-005, ADX-N05 201, or 
ADX-N05 202. The study will consist of a 2-week Titration Phase for all subjects, a 38-week 
Maintenance Phase for subjects who completed Study 14-002 or 14-003 or a 50-week 
Maintenance Phase for subjects who completed Study 14-004, 15-004, 15-005, ADX-N05 
201, or ADX-N05 202, and a 2-week Safety Follow-up period. 
During the 2-week Titration Phase, subjects will begin with 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 or 150 mg at any time following a 
telephone consultation with investigative site staff to achieve a maximal dose that is 
tolerable. After the 2-week Titration Phase, subjects will enter the Maintenance Phase at the 
stable dose that was reached at the end of the Titration Phase. After entering the Maintenance 
Phase, only three dose adjustments (to doses of 75 mg, 150 mg or 300 mg daily) will be 
allowed during the first 12 weeks of the Maintenance Phase. If the dose cannot be 
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successfully adjusted within these parameters, the subject will be discontinued from the 
study. 
Subjects who completed Study 14-002 or 14-003 (Group A) will return to the clinic for 
assessments at the end of the 2-week Titration Phase and at approximately 14, 27, 29, and 
40 weeks after the start of treatment with JZP-110 in this study. Subjects who completed 
Study 14-004, 15-004, 15-005, ADX-N05 201, or ADX-N05 202 (Group B) will return to the 
clinic for assessments at the end of the 2-week Titration Phase and at approximately 14, 26, 
28, 39, and 52 weeks after the start of treatment with JZP-110 in this study. The randomized 
withdrawal period of the Maintenance Phase of the study will be conducted from weeks 
27-29 in Group A and from weeks 26-28 in Group B. At the beginning of the randomized 
withdrawal period, subjects will be assigned in a 1:1 ratio to continue to receive JZP-110 at 
the dose that they are currently receiving or to receive placebo for 2 weeks. At the end of the 
2-week randomized withdrawal period, subjects will be titrated to receive the same dose that 
they had been receiving at the beginning of the randomized withdrawal period (a fixed 
titration of 3 days will be included for subjects on the 150 and 300 mg doses). 
When approximately 300 subjects are randomized into the randomized withdrawal period, no 
more subjects will be randomized into the period. All subjects who have not entered the 
randomized withdrawal period at that time will receive open-label JZP-110 treatment for the 
remainder of the study. All subjects who have entered the randomized withdrawal period will 
complete all scheduled assessments for the period. 
Subjects who completed Study 14-002 or 14-003 (Group A) and who are not randomized into 
the randomized withdrawal period will return to the clinic for assessments at the end of the 
2-week Titration Phase and at approximately 14, 27, and 40 weeks after the start of treatment 
with JZP-110 in this study. Subjects who completed Study 14-004, 15-004, 15-005, 
ADX-N05 201, or ADX-N05 202 (Group B) and who are not randomized into the 
randomized withdrawal period will return to the clinic for assessments at the end of the  
2-week Titration Phase and at approximately 14, 26, 39, and 52 weeks after the start of 
treatment with JZP-110 in this study.  
All subjects will be contacted monthly by phone, and the investigator will determine whether 
subjects need to be seen in the clinic at any other time(s) during the study to ensure their 
safety. Safety will be assessed throughout the study and will include the Columbia-Suicide 
Severity Rating Scale (C-SSRS) administered at each clinic visit as indicated in the Schedule 
of Events in Appendix 1 and Appendix 2.  
Open-label maintenance of efficacy will be assessed by the Epworth Sleepiness Scale (ESS), 
Patient Global Impression of Change (PGIc), Clinical Global Impression of Change (CGIc), 
and several quality of life and economic measures, such as the Functional Outcomes of Sleep 
Questionnaire Short Version (FOSQ-10), 36-Item Short Form Health Survey Version 2 
(SF-36v2), EuroQoL EQ-5D-5L, and the Work Productivity Activity Impairment 
(WPAI:SHP) Questionnaire. Double-blind, placebo-controlled maintenance of efficacy in the 
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randomized withdrawal period will be assessed by changes on the ESS and FOSQ-10, and 
ratings on the PGIc and CGIc.  
At the 14- and 40-week visits for subjects in Group A and at the 26 and 52 week visits for 
subjects in Group B, subjects will be asked about their healthcare resource utilization over 
the past 3 months in terms of physician visits. 
All subjects will return to the site 2 weeks after the final clinic visit of the Maintenance Phase 
for safety follow-up assessments. Unless there are any outstanding safety issues that require 
follow-up, subjects will be discharged from the study at that visit.
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Figure 1 
Study Schema for Subjects Randomized into the Randomized Withdrawal Period 
 
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Figure 2 
Study Schema for Subjects not Randomized into the Randomized Withdrawal Period
 
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3.1.1 
Rationale for Study Design and Control Group 
This open-label study will permit an assessment of safety and effectiveness of JZP-110 over 
a longer time period than possible in the double-blind efficacy and safety studies. 
Specifically, data will be collected from at least 100 subjects exposed to JZP-110 for 1 year 
and at least 300 subjects exposed to JZP-110 for 6 months. 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 for Medical Research Involving 
Human Subjects. There is no control group in this study; however, approximately 150 
subjects will be randomized to receive placebo for 2 weeks during the randomized 
withdrawal period of the Maintenance Phase of the study. The purpose of the randomized 
withdrawal period is to evaluate the double-blind, placebo-controlled maintenance of 
efficacy of JZP-110 after at least 26 weeks of daily administration of JZP-110. Given that 
narcolepsy and OSA are chronic health conditions, it is important to know whether controlled 
data support the long-term use of JZP-110 in narcolepsy and OSA. The double-blind, 
placebo-controlled maintenance of efficacy data from the randomized withdrawal period in 
the Maintenance Phase of this study are intended to provide well-controlled evidence of the 
long-term efficacy of JZP-110 to treat excessive sleepiness associated with narcolepsy or 
OSA. 
3.2 
Study Duration and Dates 
Subjects may participate for up to 40 (Group A) or 52  (Group B) weeks in the current study, 
with a subsequent safety follow-up for 2 weeks following discontinuation of treatment (total 
study participation up to 42 or 54 weeks, respectively). It is anticipated that enrollment across 
all sites will be completed in approximately 18 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. 
 
 
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4 
STUDY POPULATION SELECTION 
4.1 
Selection of Study Population 
Subjects must have completed Study 14-002, 14-003, 14-004, 15-004, 15-005, ADX-N05 
201, or ADX-N05 202 and meet the inclusion and exclusion criteria. 
4.2 
Inclusion Criteria 
All subjects must meet the following criteria to be enrolled in the study. 
1. Subject meets one of the following: 
a. Completed Study 14-002 or 14-003 (Group A) 
b. Completed Study 14-004, 15-004, 15-005, ADX-N05 201, or ADX-N05 202 
(Group B) 
2. Subject is able, in the opinion of the investigator, to take JZP-110 for 40 weeks if 
continuing from 14-002 or 14-003 or for 52 weeks if the subject completed 14-004, 
15-004, 15-005, ADX-N05 201, or ADX-N05 202, and is able to complete all tests 
and visits described in this protocol. 
3. Usual nightly total sleep time of at least 6 hours. 
4. Body mass index from 18 to <45 kg/m2. 
5. 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. 
6. Willing and able to comply with the study design schedule and other requirements. 
7. 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. Female subjects who are pregnant, nursing, or lactating. 
2. Usual bedtime later than 1 AM (0100 hours). 
3. Occupation requiring nighttime or variable shift work. 
4. Experienced any serious adverse event (SAE) in a previous study that was deemed 
related to JZP-110 or experienced an AE in a previous study that might prevent 
him/her from safely participating in and completing the current study. 
5. Any other clinically relevant medical, behavioral, or psychiatric disorder other than 
narcolepsy or 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. 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 gastric bypass 
procedure. 
9. Presence of renal impairment or calculated creatinine clearance <60 mL/min. 
10. Clinically significant ECG abnormality in the opinion of the Investigator. 
11. This criterion has been removed. 
12. Presence of significant cardiovascular disease including but not limited to: 
myocardial infarction within the past year, unstable angina pectoris, symptomatic 
congestive heart failure (ACC/AHA stage C or D), revascularization procedures 
within the past year, ventricular cardiac arrhythmias requiring AICD or medication 
therapy, uncontrolled hypertension, or systolic blood pressure ≥155 mmHg or 
diastolic blood pressure ≥95 mmHg at screening or Baseline for Group B subjects 
according to protocol specifications; or any history of cardiovascular disease or 
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 Baseline Visit or anticipated excessive 
use during the study defined as >600 mg/day of caffeine. 
15. Use of a monoamine oxidase inhibitor (MAOI) in the past 14 days or five half-lives 
of the drug (whichever is longer) prior to the Baseline Visit, or plans to use an MAOI 
during the study. 
16. Received an investigational drug other than JZP-110 in the past 30 days or five half-
lives (whichever is longer) before the Baseline Visit, or plans to use an investigational 
drug (other than the study drug) during the study. 
17. Current or past (within the past 2 years) diagnosis of a moderate or severe substance 
use disorder according to DSM-5 criteria. 
18. Nicotine dependence that has an effect on sleep (e.g., a subject who routinely 
awakens at night to smoke). 
19. Current, past (within the past 2 years), or seeking treatment for a substance related 
disorder. 
20. 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. 
21. History of phenylketonuria (PKU) or history of hypersensitivity to phenylalanine-
derived products. 
22. Group A: Planned use of any over-the-counter (OTC) or prescription medications 
that could affect the evaluation of excessive sleepiness at any time during the study. 
Group B: Use of any over-the-counter (OTC) or prescription medications that could 
affect the evaluation of excessive sleepiness within a time period prior to the Baseline 
Visit corresponding to at least five half-lives of the drug(s) or planned use of such 
drug(s) at some point throughout the duration of the study. Medications should be 
discontinued such that the subject has returned to his/her baseline level of daytime 
sleepiness at least 7 days prior to the Baseline visit, in the opinion of the Investigator. 
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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. 
For the purpose of this study, medically acceptable methods of contraception include 
estrogen-progestin oral contraceptive pills, patches, or vaginal ring (if one of these methods 
is chosen it must have been used consistently for 2 months prior to the first dose of study 
drug); progestin implant or injection; diaphragm with spermicide; male condom plus vaginal 
spermicide; surgical sterilization; intrauterine device; post-menopausal (defined as age >50 
and >1 year of amenorrhea); medically documented ovarian failure (defined as age <50 with 
serum estradiol and follicle-stimulating hormone [FSH] levels within the institutional 
postmenopausal range and a negative serum or urine βHCG); vasectomy (>6 months prior to 
baseline); or abstinence. 
4.4 
Eligibility  
Subjects will be considered eligible for study screening if they meet the inclusion criteria and 
do not meet any exclusion criteria. Subjects who do not meet all eligibility criteria will be 
considered screen failures. 
5 
STUDY TREATMENT(S) 
5.1 
Description of Treatment(s) 
5.1.1 
JZP-110 
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. 
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 open-label JZP-110 75, 150, or 300 mg once daily as a single gelatin 
capsule as described above throughout the study except during the 2-week randomized 
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withdrawal period of the Maintenance Phase, when subjects will either receive JZP-110 at 
their current dose or placebo in a double-blind manner. 
Study drug will be dispensed at clinic visits at Baseline, at the end of the Titration Phase, and 
approximately every 3 months thereafter (except during the 2-week randomized withdrawal 
period during which study drug will be dispensed for a 2 week interval) as indicated in the 
Schedule of Events in Appendix 1 and Appendix 2 and, if applicable, at alternative intervals 
specified by State or local regulations. Study drug will be dispensed by qualified study site 
personnel. 
5.3 
Selection and Timing of Dose for Each Subject 
Subjects will be instructed to take a single daily dose of study drug in the morning, on an 
empty stomach and 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. 
During the 2-week Titration Phase of this study, subjects will initially receive a once-daily 
dose of 75 mg of JZP-110 and may be titrated up to a maximum dose of 300 mg of JZP-110. 
Subjects may titrate up one dose level in intervals no shorter than every 3 days. A subject 
may be titrated from 75 mg to 150 mg and then to 300 mg according to this schedule. The 
titration schedule in this protocol is based on the pharmacokinetics of 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). Down-titration directly to 150 or 75 mg is also permitted at any time 
for safety reasons. During the Titration Phase, subjects will be followed by the investigator 
by phone and given titration instructions based on their reported levels of daytime sleepiness 
and their reported tolerability to the study drug. Investigators will be instructed to titrate 
subjects to a maximal dose that is tolerated. After the 2-week Titration Phase subjects will 
enter the Maintenance Phase at the stable dose that was reached at the end of the Titration 
Phase. After entering the Maintenance Phase, up to three dose adjustments will be allowed 
within the first 12 weeks of the Maintenance Phase. If the dose cannot be successfully 
adjusted within these parameters, the subject will be discontinued from the study. During the 
2-week randomized withdrawal period of the Maintenance Phase, subjects will either 
continue to receive JZP-110 at the dose that they are currently receiving or receive placebo 
for 2 weeks. At the end of the 2-week randomized withdrawal period, subjects will receive 
the same dose that they had been receiving at the beginning of the randomized withdrawal 
period. A fixed titration of 3 days will be included for subjects on the 150 and 300 mg doses. 
Subjects who had been receiving 150 mg/day will receive 75 mg/day for the first three days, 
followed by 150 mg/day thereafter. Subjects who had been receiving 300 mg/day will receive 
150 mg/day for the first three days, followed by 300 mg/day thereafter. 
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5.4 
Method of Assigning Subjects to Treatment Groups 
This is an open-label study with a two-week, double-blind, placebo-controlled, randomized 
withdrawal period after at least 26 weeks of JZP-110 administration. At the beginning of the 
study, all eligible subjects will be dispensed JZP-110 and be titrated to a dose of 75, 150, or 
300 mg JZP-110 as described in Section 5.3. At the beginning of the randomized withdrawal 
period of the Maintenance Phase (the week 27 visit for Group A or the week 26 visit for 
Group B), approximately 300 subjects will be randomly assigned in a 1:1 ratio to continue to 
receive JZP-110 at the dose that they are currently receiving or to receive placebo for 
2 weeks.  
The investigator will access an Interactive Voice Response System (IVRS) or an Interactive 
Web Response System (IWRS) to randomize subjects. Subjects will be randomized in a 1:1 
ratio to continue to receive JZP-110 at the dose that they are currently receiving or to receive 
placebo for 2 weeks. The randomization will be stratified on the basis of subjects’ diagnosis 
of narcolepsy or OSA. When approximately 300 subjects have been randomized into the 
randomized withdrawal period, the clinical sites will be notified and the IVRS/IWRS will not 
permit additional randomization. After approximately 300 subjects have been randomized 
into the randomized withdrawal period, use of the IVRS or IWRS will continue for the 
purpose of enrolling subjects, assigning subject identification numbers and tracking open-
label study drug. 
5.5 
Randomization 
A statistician selected by Jazz Pharmaceuticals will prepare and retain the master 
randomization code for the randomized withdrawal period of this study. This statistician will 
not be involved in the analysis of this study. The randomization codes will be generated and 
retained according to Jazz Pharmaceuticals standard operating procedure on the generation, 
distribution, and access to randomization information for clinical studies. Unless there is an 
emergency that requires the release of the subject’s assigned treatment, the code will not be 
broken or released until all study data are collected and accepted for analysis. 
5.6 
Blinding 
A double-blind approach will be used during the 2-week randomized withdrawal period of 
this study 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 2-week randomized withdrawal period. 
5.7 
Prior and Concomitant Therapy 
During the Screening Phase, the prior (30 days) and concomitant medication use and any 
medications used for the treatment of narcolepsy since diagnosis will be recorded on the case 
report form (CRF) for subjects who participated in Study 14-004, 15-004, 15-005,  
ADX-N05 201, or ADX-N05 202. Concomitant medications for subjects who participated in  
14-002 or 14-003 will be captured on the CRF pages in those respective studies. 
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Any medications that are included under the exclusion criteria for entry into the study must 
be discontinued prior to the Baseline visit as specified in Section 4.3 and are prohibited for 
use throughout the study as well. 
Subjects may continue to take their usual medications during the study other than the 
excluded medications described under Section 4.3. All drugs other than study drug that are 
taken during the course of the study (approved or unapproved; prescription, over-the-counter, 
or illicit drugs) will be documented in the concomitant medications 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 under Section 4.3. At the discretion of the investigator, subjects with 
narcolepsy may have anti-cataplectic medications (other than sodium oxybate) reinstituted 
after completion of the previous study. 
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. 
At the final study visit or early termination visit when blood samples are drawn for clinical 
laboratory tests, subjects should report to the clinic in the morning following an overnight 
fast. 
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 on the 3 days prior to the beginning and the 3 days 
prior to the end of the randomized withdrawal period in the Maintenance Phase will be 
recorded. Overall treatment compliance will be calculated at the end of the trial. 
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 
have been overencapsulated in opaque gelatin capsules and packaged in blister cards or 
bottles. 
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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 6.9. 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 unused 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, bottles, 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 
and bottles 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 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. 
6 
STUDY PROCEDURES 
6.1 
Informed Consent 
All subjects will provide their written informed consent before the performance of any study 
related procedures. Subjects will be given a copy of their signed informed consent form 
(ICF).  
Each subject’s chart will include his or her signed ICF. After the conclusion of the study 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 
All demographic information will be collected 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.  
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6.3 
Medical History 
A complete medical history from the time of their previous participation will be collected for 
each subject who completed Study 14-004, 15-004, 15-005, ADX-N05 201, or ADX-N05 
202 (Group B) during the Screening visit. The information will include, but is not limited to, 
symptoms of narcolepsy or OSA, (current or past, including symptoms experienced prior to 
any narcolepsy or OSA treatment); concomitant medication use; any medications or devices 
used for the treatment of narcolepsy or 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 and exclusion criteria. Any updates to the medical history for Group B 
subjects will be assessed at Day -1. The medical history for subjects who completed Study 
14-002 or 14-003 will be re-entered from those study records. 
6.4 
Physical Examination 
A full review of body systems should be obtained at screening for subjects who completed 
Study 14-004, 15-004, 15-005, ADX-N05 201, or ADX-N05 202 (Group B). Findings from 
the physical examination conducted at the final visit of Study 14-002 or 14-003 (Group A) 
will be used for entrance into this study for subjects who participated in those studies. A full 
review of body systems should be obtained at the final visit or early termination for all 
subjects. Physical examinations at screening and final visit or early termination will include a 
full examination of body systems (except genitourinary), height (at screening only), and body 
weight measurements in ordinary indoor clothes without shoes. A qualified investigator or 
sub-investigator should perform the examination. Body weight measurement will also be 
taken at interim clinic visits. 
6.5 
Vital Signs 
Vitals signs (systolic and diastolic blood pressure, pulse, respiratory rate, and body 
temperature) will be obtained at every clinic visit (as indicated in the Schedule of Events, 
Appendix 1 and Appendix 2) after the subject has been resting and seated for at least  
5 minutes. For blood pressure 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 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. 
Vital signs taken at the Screening visit for subjects who completed Study 14-004, 15-004, 
15-005, ADX-N05 201, or ADX-N05 202 (Group B) will be used to meet entrance criteria to 
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the study. For subjects who completed Study 14-002 or 14-003 (Group A), the vital signs that 
were taken at the final study visit in those studies will serve as the vital signs at the 
Screening/Baseline Visit in this study. 
6.6 
Electrocardiography 
A standard 12-lead ECG will be recorded with the subject resting supine for at least 
5 minutes. ECGs will be performed at all clinic visits, as indicated in the Schedule of Events 
(see Appendix 1 and Appendix 2). For subjects who completed Study 14-002 or 14-003 
(Group A), the ECG that is conducted at the final study visit in those studies will serve as the 
ECG at the Screening/Baseline Visit in this study. 
6.7 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
At the Screening Visit, the Baseline/Screening Version of the Columbia Suicide Severity 
Rating Scale (C-SSRS) will be administered to subjects who completed Study 14-004, 
15-004, 15-005, ADX-N05 201, or ADX-N05 202 to exclude any individuals with active 
suicidal ideation or behavior (Appendix 9). 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. Thereafter, the Since Last Visit 
Version of the C-SSRS (Appendix 11) will be administered to all subjects at every clinic 
visit, as indicated in the Schedule of Events (see Appendix 1 and Appendix 2). 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). 
6.8 
Clinical Laboratory Tests 
6.8.1 
Laboratory Parameters 
Subjects will be in a seated or supine position during blood collection. Screening labs may be 
repeated one time. Clinical laboratory tests to be conducted are listed in Table 1. 
The clinical laboratory tests will be performed at a central laboratory. An authorized back-up 
laboratory, as indicated on the Form FDA 1572 or equivalent, may be used if necessary as an 
emergency laboratory. The investigator will supply Jazz Pharmaceuticals or its designee with 
the back-up laboratory’s current licensure and laboratory reference ranges.  
Please note exclusionary clinical laboratory parameters listed in the exclusion criteria 
(Section 4.3). In addition, any laboratory parameter that is out of range and considered 
clinically significant (as determined by the investigator) at the end of treatment must be re-
evaluated. The investigator will provide an explanation of all clinically significant 
observations. These findings will be reported as adverse events. 
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At Screening, the investigator will calculate the estimated creatinine clearance rate using the 
Cockcroft-Gault formula (FDA Guidance Document for Impaired Renal Function 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 for subjects 
who completed Study 14-004, 
15-004, 15-005, ADX-N05 201, or 
ADX-N05 202 (Group B) and 
following a positive urine test for 
all subjects 
- 
Urine (at all other time points 
specified in the Schedule of 
Events) 
*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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6.8.2 
Estimated Total Blood Volume Required for the Study 
The estimated maximum blood volume collected from each subject who completed Study 
14-002 or 14-003 (Group A) will be approximately 30 mL (chemistry 3 x 6 mL and 
hematology 3 x 4 mL), collected at Weeks 14, 27, and the final study visit or Early 
Termination. The estimated maximum blood volume collected from each subject who 
completed Study 14-004, 15-004, 15-005, ADX-N05 201, or ADX-N05 202 (Group B) will 
be approximately 61 mL (chemistry 6 x 6 mL, hematology 6 x 4 mL, and serum pregnancy 
test 1 x 1 mL) if collection at the Baseline Visit is necessary (if the baseline visit occurs 
>28 days after the screening visit) in addition to collection at Screening, Weeks 14, 26, 39, 
and final visit or Early Termination. 
6.8.3 
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. 
For subjects who completed Study 14-002 or 14-003 (Group A), a blood sample for 
hematology and serum chemistry tests will be collected while the subject is fasting at Weeks 
14, 27, and at the final study visit or Early Termination. For these subjects, the hematology 
and serum chemistry tests that are conducted at the final study visit in those studies will serve 
as the hematology and serum chemistry tests at the Screening/Baseline Visit in this study. 
For subjects who completed Study 14-004, 15-004, 15-005, ADX-N05 201, or ADX-N05 
202 (Group B), a blood sample for hematology and serum chemistry tests will be collected 
while the subject is fasting at Screening, Weeks 14, 26, 39, and at the final study visit or 
Early Termination. A blood sample will be collected at the Baseline Visit for Group B only if 
that visit occurs >28 days after the screening visit. 
For subjects who completed Study 14-002 or 14-003 (Group A), a urine sample for urinalysis 
will be collected at Weeks 14, 27, and at the final study visit or Early Termination. For these 
subjects, the urinalysis that is conducted at the final study visit in those studies will serve as 
the urinalysis at the Screening/Baseline Visit in this study. For subjects who completed Study 
14-004, 15-004, 15-005, ADX-N05 201, or ADX-N05 202 (Group B), a urine sample for 
urinalysis will be collected at Screening, Weeks 14, 26, 39, and at the final study visit or 
Early Termination. A urine sample will only be collected at the Baseline Visit for Group B 
only if that visit occurs >28 days after the screening visit. 
A urine sample for a urine drug screen will be collected and analyzed at every clinic visit, as 
indicated in the Schedule of Events (Appendix 1 and Appendix 2). For subjects who 
completed Study 14-002 or 14-003 (Group A), the urine drug screen that is conducted at the 
final study visit in those studies will serve as the urine drug screen at the Screening/Baseline 
Visit in this study. 
A serum pregnancy test for females of childbearing potential will be performed at Screening 
for subjects who completed Study 14-004, 15-004, 15-005, ADX-N05 201, or ADX-N05 202 
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(Group B). Urine pregnancy tests will be performed at Baseline and at the final study visit or 
Early Termination. For subjects who completed Study 14-002 or 14-003 (Group A), the urine 
pregnancy test that is conducted at the final study visit in those studies will serve as the 
pregnancy test at the Screening/Baseline Visit in this study. 
6.9 
Dispensing Study Drug 
Study drug will be dispensed at clinic visits at Baseline, at the end of the Titration Phase, and 
approximately every 3 months thereafter (except during the 2-week randomized withdrawal 
period during which study drug will be dispensed for a 2-week interval), as indicated in the 
Schedule of Events in Appendix 1 and Appendix 2 and, if applicable, at alternative intervals 
specified by State or local regulations. Study drug will be dispensed by qualified study site 
personnel. 
6.10 Efficacy Assessments 
Assessments will be performed at times indicated in the Schedule of Events (Appendix 1 and 
Appendix 2). 
6.10.1 
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). It provides a measure of a 
person’s general level of daytime sleepiness, or their mean sleep propensity in daily life. The 
ESS is a validated measure with high specificity and sensitivity for assessing subjective 
sleepiness (Johns 1991, 2000; Broderick et al. 2013).  
Subjects who are randomized in the randomized withdrawal period will be asked to complete 
the ESS with regard to the level of sleepiness they experienced over approximately the past 7 
days at the following times: 
• For Group A, at Weeks 2, 14, 27, 29, 40, and at Early Termination visits that occur 
after Week 2.  
• For Group B, at Baseline, Weeks 2, 14, 26, 28, 39, 52 and at Early Termination visits 
that occur after Week 2.  
Subjects who are not randomized into the randomized withdrawal period will be asked to 
complete the ESS with regard to the level of sleepiness they experienced over approximately 
the past 7 days at the following times:  
• For Group A: at Weeks 2, 14, 27, 40, and at Early Termination visits that occur after 
Week 2. 
• For Group B: at Baseline, Weeks 2, 14, 26, 39, 52, and Early Termination visits that 
occur after Week 2. 
 
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6.10.2 
Clinician Global Impression of Severity (CGIs)  
The CGIs is a 7-point Likert-type rating scale and a widely used assessment in clinical 
psychopharmacology trials to assess severity of illness (Appendix 12). The responses of this 
investigator-completed scale range from 1 = normal, no signs of illness to 7 = among the 
most extremely ill patients. For Group B subjects, the Investigator will rate his/her 
impression of the severity of the subject’s current condition at Baseline relative to his/her 
experience with this patient population at Baseline. For Group A subjects, this rating will be 
captured at Baseline in the previous study. 
6.10.3 
 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. For the open-label efficacy assessments, investigators will rate 
their impression of any change of the subject’s condition from baseline (before the start of 
treatment in this study for subjects in Group B or before the start of treatment in the prior 
study for subjects in Group A) on a 7-point scale ranging from 1 = very much improved to 
7 = very much worse at Weeks 2, 14, 27, and 40 for subjects in Group A; at Weeks 2, 14, 26, 
39, and 52 for subjects in Group B; and at Early Termination visits that occur after Week 2 
(Appendix 13). For the double-blind, placebo-controlled assessment of the maintenance of 
efficacy, investigators will rate their impression of any change in the subject’s condition from 
the last visit on a 7-point scale ranging from 1 = very much improved to 7 = very much 
worse at Week 29 for subjects in Group A and at Week 28 for subjects in Group B 
(Appendix 14). 
6.10.4 
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. For the open-label efficacy assessments, subjects will rate the 
change in their current overall condition since they started treatment (in this study for 
subjects in Group B or in the prior study for subjects in Group A) on a 7-point scale ranging 
from 1 = very much improved to 7 = very much worse at Weeks 2, 14, 27, and 40 for 
subjects in Group A; at Weeks 2, 14, 26, 39, and 52 for subjects in Group B; and at Early 
Termination visits that occur after Week 2 (Appendix 15). For the double-blind, placebo-
controlled assessment of the maintenance of efficacy, subjects will rate the change in their 
current overall condition since their last visit on a 7-point scale ranging from 1 = very much 
improved to 7 = very much worse at Week 29 for subjects in Group A and at Week 28 for 
subjects in Group B (Appendix 16). 
6.11 Functional Outcomes and Quality of Life Endpoints 
6.11.1 
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 
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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 
affect sizes and pre- and post-treatment differences that are highly correlated with the longer 
version (Chasens et al 2009).  
Subjects who are randomized into the randomized withdrawal period will be asked to 
complete the FOSQ-10 at the following times (Appendix 6): 
• For Group A, at Weeks 14, 27, 29, 40, and at Early Termination visits that occur 
after Week 2.  
• For Group B, at Baseline, Weeks 14, 26, 28, 39, 52, and at Early Termination visits 
that occur after Week 2.  
Subjects who are not randomized into the randomized withdrawal period will be asked to 
complete the FOSQ-10 at the following times (Appendix 6): 
• For Group A: at Weeks 14, 27, 40, and at Early Termination visits that occur after 
Week 2. 
• For Group B: at Baseline, Weeks 14, 26, 39, 52, and Early Termination visits that 
occur after Week 2. 
 
6.11.2 
36-Item Short Form Health Survey Version 2 (SF-36v2) 
The SF-36v2 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-
scale profile of functional health and well-being scores as well as psychometrically-based 
physical and mental health summary measures and a preference-based health utility index 
Hays & Stewart 1992, Ware & Sherbourne 1992) (Appendix 7). Subjects will complete the 
SF-36v2 at Weeks 14, 27, and 40 for subjects in Group A; at Baseline and Weeks 14, 26, 39, 
and 52 for subjects in Group B; and at Early Termination visits that occur after Week 2.  
6.11.3 
EuroQoL (EQ-5D-5L) 
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome that 
includes a descriptive system consisting of 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) and an EQ visual analogue scale (VAS) (EuroQol 
Group, 2013). It is applicable to a wide range of health conditions and treatments, it provides 
a simple descriptive profile and a single index value for health status. The EQ-5D-5L 
includes five levels of severity for each of the 5 dimensions of the descriptive system and 
was developed to improve the instrument’s reliability and sensitivity and to reduce ceiling 
effects. Subjects will complete the EQ-5D-5L at Weeks 14, 27, and 40 for subjects in Group 
A; at Baseline and Weeks 14, 26, 39, and 52 for subjects in Group B; and at Early 
Termination visits that occur after Week 2 (Appendix 8). 
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6.11.4 
Primary OSA Therapy Use 
Subjects who reported using a primary OSA therapy during Study 14-003, 14-004, or 15-004 
will continue to 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, as indicated in the Schedule of Events (see Appendix 1 and Appendix 2), 
from Screening and through the Final Visit of the Maintenance Phase (Week 40 for 14-003 
or Week 52 for 14-004 and 15-004). If a subject’s device usage cannot be extracted from 
his/her device, the subject should be instructed to record whether he/she used his/her primary 
OSA therapy and the estimated duration of use (more than half of the night, less than half of 
the night, or don’t know) on a daily basis from Screening and through the Final Visit of the 
Maintenance Phase (Week 40 for 14-003 or Week 52 for 14-004 and 15-004). Subjects who 
reported not using a primary OSA therapy during Study 14-003, 14-004, or 15-004 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. Subjects will 
be encouraged to stay on their current primary OSA therapy at the same level of use 
throughout the study. 
6.12 Economic Assessments 
6.12.1 
Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem V2.0 (WPAI:SHP) 
The WPAI questionnaire is a 6-item self-administered questionnaire that measures work time 
missed and work and activity impairment because of a specified health problem during the 
past 7 days. The WPAI:SHP will be used with “narcolepsy” or “OSA” as the specified health 
problem. The validity of the WPAI has been established in a number of diseases and it is 
available in multiple languages (Reilly 1993). Subjects will complete the WPAI:SHP at 
Weeks 14, 27, and 40 for subjects in Group A; at Baseline and Weeks 14, 26, 39, and 52 for 
subjects in Group B; and at Early Termination visits that occur after Week 14 (Appendix 10). 
6.12.2 
Resource Utilization Questionnaire 
Patient-reported resource utilization will be assessed at the Week 14 and Week 40 Visits in 
Group A, at the Week 26 and Week 52 Visits in Group B, and at Early Termination visits 
that occur after Week 14. Information about the number of physician visits will be collected 
via questionnaire (Appendix 17). Standard unit costs will be applied to these resources (as 
well as to any hospitalizations reported as SAEs) in order to calculate the mean/median 
healthcare costs over the one-year period. 
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6.13 Adverse Event Reporting 
6.13.1 
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 narcolepsy or OSA are not 
considered as adverse events unless there is an exacerbation of the symptoms from 
baseline. 
• During the study, clinically significant adverse changes in ECGs, routine laboratory 
tests, and physical examinations are considered AEs. Any subject complaint 
associated with such an abnormal finding will also be reported as an AE.  
All AEs, whether observed by the investigator, reported by the subject, determined from 
laboratory findings, or other means, will be recorded on the AE CRF, with each individual 
AE to be listed as a separate entry on the AE CRF. 
Subjects should be questioned in a general way, without asking about the occurrence of any 
specific symptom. The investigator should attempt to establish a diagnosis of the event based 
on signs, symptoms, and/or other clinical information. In such cases, the diagnosis, not the 
individual signs/symptoms, should be documented as the AE.  
Following questioning and evaluation, all AEs, whether believed by the investigator to be 
related or unrelated to the study drug or procedure, must be documented in the subject’s 
medical records, in accordance with the investigator’s normal clinical practice, and on the 
AE CRF. Each AE is to be evaluated for duration, severity, seriousness, and causal 
relationship to the study drug or procedure.  
6.13.1.1 
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. 
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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.  
 
6.13.1.2 
Serious Adverse Events and Seriousness Assessment 
An SAE is an AE that fulfills any of the following criteria, as per Title 21 CFR 312.32 and 
ICH E2A.II.B. Events meeting the following seriousness criteria must be reported to Jazz 
Pharmaceuticals or its designee using the SAE Report form within 24 hours of the site being 
notified of the event. The event must also be entered on the AE CRF. 
• 
Is fatal (results in death) 
• 
Is life-threatening (Note: the term “life-threatening” refers to an event in which the 
subject was at immediate risk of death at the time of the event; it does not refer to an 
event that could hypothetically have caused death had it been more severe) 
• 
Requires inpatient hospitalization or prolongs existing hospitalization 
• 
Results in persistent or significant incapacity or disability, defined as substantial 
disruption of the ability to conduct normal life functions 
• 
Is a congenital anomaly/birth defect 
• 
Is medically significant or requires intervention to prevent one of the outcomes listed 
above   
− Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered an SAE when, based on appropriate 
medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above in the definition 
of an SAE.  
− Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, and the development of 
drug dependency or drug abuse. 
• Suspected transmission of an infectious agent via a medicinal product [for EU sites only; 
EMA Guideline on Good Pharmacovigilance Practices (GVP) Module VI] 
 
Hospitalization is NOT considered an SAE if: 
• 
It is planned prior to subject entering trial 
• 
It is for social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• 
It is elective in nature and not related to worsening of an underlying condition 
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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. 
6.13.1.3 
Causal Relationship to Study Drug or Procedure 
The investigator’s assessment of an AE’s relationship to study drug or procedure is required. 
The relationship or association of the study drug or procedure in causing or contributing to 
the AE will be characterized using the following classification and criteria:  
Related 
or 
Suspected 
to be 
Related 
to Study 
Drug or 
Procedure 
Some temporal relationship exists between the event and the 
administration of the study drug or procedure and the event is 
unlikely to be explained by the subject’s medical condition, other 
therapies, or accident.  
The AE follows a reasonable temporal sequence from administration 
of the study drug or procedure and at least one of the following 
instances of clinical evidence: 
• Follows a known or suspected response pattern to the 
study drug or procedure. 
• Is confirmed by improvement upon stopping the study 
drug or procedure or decreasing the dose (dechallenge). 
• Reappears upon repeated exposure (rechallenge) if 
medically appropriate. 
There is a reasonable possibility that the study drug or procedure 
caused the event—i.e., there is evidence to suggest a causal 
relationship. In such case, the AE is considered an adverse reaction 
(AR). A suspected AR has a lesser degree of certainty about causality 
than an AR. 
Not 
Related 
to Study 
Drug or 
Procedure 
Event can be readily explained by other factors such as the subject’s 
underlying medical conditions, concomitant therapy, or accident; or 
there is no temporal relationship between study drug or procedure 
and the event. 
A reasonable possibility or clinical evidence that the study drug or 
procedure caused the event is lacking. 
 
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6.13.1.4 
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 6.13.1.2), immediately reportable experiences must be reported 
on the SAE Report form, which should be completed as thoroughly as possible and signed by 
the investigator or his/her designee before transmittal to the contact provided on the form. 
The investigator must provide his/her assessment of causality to study drug or procedure at 
the time of the initial report. Where the investigator does not provide causality assessment of 
the SAE at the time of the initial report, the event by default will be presumed “Related.” If 
the investigator’s assessment of causality changes, then a follow-up SAE form must be 
submitted. 
The source document to determine expectedness of an SAE, is the JZP-110 Investigator’s 
Brochure. 
6.13.1.5 
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. 
6.13.1.6 
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. 
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6.13.2 
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 6.13.1.2. 
Any AE or SAE assessed as related to study drug or procedure by the investigator must be 
reported regardless of time after study termination. 
6.13.3 
Pregnancy   
If a subject or a male subject’s partner becomes pregnant any time after the first dose of 
study drug is taken until 30 days after the last dose of study drug is taken, the pregnancy 
form should be used to report the pregnancy to Jazz Pharmaceuticals or its designee. 
Pregnancy of a subject or a male subject’s partner is an immediately reportable event and 
should be reported within 24 hours of first knowledge of the event by study personnel to the 
appropriate Jazz Pharmaceuticals contact or designee. The pregnancy of a subject or a male 
subject’s partner will be followed until the outcome of the pregnancy is known, and in the 
case of a live birth, for 6 months following the birth of the child. The infant follow-up form 
should be used to report information regarding the status of the infant. 
6.13.4 
Unblinding of the Treatment Assignment in the Randomized Withdrawal 
Period 
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 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 6.13.1.2). 
The subject’s treatment assignment may be unblinded for regulatory reporting purposes. 
Notification of the treatment assignment is only made known to those who require it for 
safety reporting and submission processes. All other individuals involved in the study, 
including the investigator, remain blinded to treatment assignment. Subjects for whom the 
blind is broken for this reason will not be withdrawn from the study. 
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6.14 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) 
• 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 7.3. Subjects should be asked to return 
2 weeks later for a safety follow-up visit.  
The specific reason for the discontinuation should be carefully documented on the 
termination CRF. If a subject withdraws informed consent, the specific reason for 
withdrawing the informed consent should be stated. 
Adverse events resulting in termination will be followed to the satisfactory resolution and 
determination of outcome as ascertained by the investigator (and/or Jazz Pharmaceuticals or 
its designee). The data will be recorded on the CRF. 
6.14.1 
Handling of Early Terminations 
If a subject terminates early from the study, either at his or her request or at the investigator’s 
discretion, the investigator will record the reason(s) for early termination on the relevant CRF 
page and notify Jazz Pharmaceuticals immediately. All subjects who terminate from the 
study early should undergo all final study visit assessments. 
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It is vital to obtain follow-up data on any subject who terminated because of an AE, 
abnormal laboratory test, or ECG finding. In any case, every effort must be made to 
undertake safety follow-up procedures. 
6.14.2 
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. 
6.15 Appropriateness of Measurements 
The ESS is a validated measure with high specificity and sensitivity for assessing subjective 
sleepiness (Johns 1991, 2000; Broderick et al. 2013). Additionally, the CGIc, PCIc, SF-36v2, 
FOSQ-10, EQ-5D-5L, and the WPAI:SHP have been used extensively in clinical trials to 
assess efficacy and quality of life. 
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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7 
STUDY ACTIVITIES 
The Schedule of Events for subjects who completed Study 14-002 or 14-003 (Group A) is 
presented in Appendix 1. The Schedule of Events for subjects who completed Study 14-004, 
15-004, 15-005, ADX-N05 201, or ADX-N05 202 (Group B) is presented in Appendix 2. 
Time frames in this section reference the time from the start of this study. 
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.  
7.1 
Group A Study Activities (Subjects from 14-002 or 14-003) 
IF THE SUBJECT IS NOT IN GROUP A, GO TO SECTION 7.2. 
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). 
7.1.1 
Group A – Screening/Baseline Clinic Visit 
Visit 1, Day -1 
Visit 1, Day -1 should occur concurrently with the Final Clinic Visit of Study 14-002 or 
14-003. In the case that a subject agrees to participate in this study after the Final Clinic Visit 
and prior to the Follow-up Visit of Study 14-002 or 14-003, then Visit 1, Day -1 of this study 
should occur concurrently with the Follow-up Visit (Week 14) of Study 14-002 or 14-003. 
• Review the inclusion (Section 4.2) and exclusion (Section 4.3) criteria. 
• If the subject meets the inclusion criteria and does not meet any exclusion criteria, 
access the Interactive Voice Response System (IVRS) or the Interactive Web 
Response System (IWRS) to enroll the subject in the study. 
• If the subject completed Study 14-003, instruct him/her to continue to bring his/her 
device or memory card to the next clinic visit for review of his/her primary OSA 
therapy use or on how to report use (or lack of use) of his/her primary OSA therapy 
as appropriate. Remind these subjects to continue to use their primary OSA therapy 
and to maintain the same level of use as when they entered Study 14-003 
(Section 6.11.4). 
• Dispense study drug, instruct the subject to start dosing on the following day (Day 1) 
(Section 6.9), and review the instructions associated with the different blister cards 
and how they will be used for titration (Section 5.3). 
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• Schedule Phone Contact 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 
(Sections 3.1 and 5.1.2). Schedule the next clinic visit in 2 weeks. 
7.1.2 
Group A – Titration Phase Phone Contacts 
Visits 2-5, Days 3, 6, 9, and 12 (±1) 
• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.13).  
• 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). 
• If the subject uses a primary OSA therapy from which the usage data can be 
extracted, instruct the subject to bring the device or memory card to the next clinic 
visit for review of his/her primary OSA therapy use. If the subject does not use a 
primary OSA therapy from which usage data can be extracted or does not use a 
primary OSA therapy, instruct the subject on reporting use as appropriate 
(Section 6.11.4). 
• Remind subject of next phone contact or clinic visit. 
 
7.1.3 
Group A – End of Titration Phase Clinic Visit 
Visit 6, Day 15 (±2) 
Week 2 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain urine sample for urine drug screen (Section 6.8 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 measurements in 
the seated position, as described in Section 6.5. 
• Obtain a 12-lead ECG (Section 6.6). 
• Administer the following questionnaires to the subject in the order specified below: 
− ESS (Section 6.10.1) 
− PGIc (Section 6.10.4) Since Started Treatment Version (Appendix 15) 
• Administer the C-SSRS Since Last visit version and record results (Section 6.7). 
• If the subject completed Study 14-003, review and record his/her primary OSA 
therapy use from the subject’s device or memory card, or frequency of use (or lack of 
use) as reported by the subject. Remind these subjects to continue to use their primary 
OSA therapy and to maintain the same level of use as when they entered Study 14-
003. If the subject uses a primary OSA therapy from which the usage data can be 
extracted, instruct the subject to bring the device or memory card to the next clinic 
visit for review of his/her primary OSA therapy use. If the subject does not use a 
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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 6.11.4). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken since the last phone contact (Section 5.7). 
• Record all AEs on the AE CRF that occurred since the last phone contact 
(Section 6.13).  
• Collect study drug remaining from the Titration Phase and assess compliance 
(Section 5.9). 
• 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) for the next 12 weeks of the Maintenance Phase (Section 5.3). 
Reminder: After this visit only three dose adjustments to the doses of 75 mg, 150 mg, 
or 300 mg daily will be allowed and subjects will have to return to the clinic for a 
dose adjustment. Dose adjustments will not be allowed after Visit 9 (Week 14). 
• Complete the CGIc (Section 6.10.3) Compared to Baseline Version (Appendix 13). 
• Dispense study drug and provide instruction for how the subject should begin taking 
study drug on the following morning (Sections 5.3 and 5.8.2). No dose adjustments 
are permitted after this visit. 
• Schedule Phone Contact in 4 and 8 weeks (Days 43±7 and 71±7). Schedule the next 
clinic visit in 12 weeks (Day 99±7). 
7.1.4 
Group A – Maintenance Phase Phone Contacts  
 
Visits 
7 
8 
10 
11 
12.1* 
13 
14 
Days 
43±7 
71±7 
127±7 
155±7 
197±3 
218±7 
246±7 
Weeks 
6 
10 
18 
22 
28 
31 
35 
*Visit 12.1 applies only to subjects who are randomized into the randomized withdrawal period.  
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the last visit or phone contact (Section 5.7). 
• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.13).  
• If the subject completed Study 14-003, review and record his/her primary OSA 
therapy use from the subject’s device or memory card, or frequency of use (or lack of 
use) as reported by the subject. Remind these subjects to continue to use their primary 
OSA therapy and to maintain the same level of use as when they entered Study 14-
003. If the subject uses a primary OSA therapy from which the usage data can be 
extracted, instruct the subject to bring the device or memory card to the next clinic 
visit for review of his/her primary OSA therapy use (Section 6.11.4). If the subject 
does not use a primary OSA therapy from which usage data can be extracted or does 
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not use a primary OSA therapy, instruct the subject on reporting use as appropriate 
(Section 6.11.4). 
• Remind subject of next phone contact or clinic visit. 
 
7.1.5 
Group A – Week 14 Maintenance Phase Clinic Visit 
Visit 9, Day 99±7 
Week 14 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain fasting blood samples for serum chemistry and hematology (Section 6.8 and 
Table 1). 
• Obtain urine sample for urinalysis and urine drug screen (Section 6.8 and Table 1). 
• Provide a light breakfast after fasting blood samples are collected. 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure 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 following questionnaires to the subject in the order specified below: 
− ESS (Section 6.10.1) 
− PGIc (Section 6.10.4) Since Started Treatment version (Appendix 15) 
− FOSQ-10 (Section 6.11.1) 
− SF-36v2 (Section 6.11.2) 
− EQ-5D-5L (Section 6.11.3) 
− WPAI:SHP (Section 6.12.1) 
− Resource Utilization Questionnaire (Section 6.12.2) 
• Administer the C-SSRS Since Last Visit version and record results (Section 6.7). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken since the last phone contact or visit (Section 5.7). 
• Record all AEs on the AE CRF that occurred since the last phone contact or visit 
(Section 6.13).  
• Collect study drug and assess compliance (Section 5.9). 
• Complete the CGIc (Section 6.10.3) Compared to Baseline version (Appendix 13). 
• Dispense study drug and provide instruction for how the subject should begin taking 
study drug on the following morning (Sections 5.3 and 5.8.2). No dose adjustments 
are permitted after this visit. 
• If the subject completed Study 14-003, review and record his/her primary OSA 
therapy use from the subject’s device or memory card, or frequency of use (or lack of 
use) as reported by the subject. Remind these subjects to continue to use their primary 
OSA therapy and to maintain the same level of use as when they entered Study 
14-003. If the subject uses a primary OSA therapy from which the usage data can be 
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Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
 
CONFIDENTIAL 
Page 60 of 120 
 
extracted, instruct the subject to bring the device or memory card to the next clinic 
visit for review of his/her primary OSA therapy use. If the subject does not use a 
primary OSA therapy from which usage data can be extracted or does not use a 
primary OSA therapy, instruct the subject on reporting use as appropriate 
(Section 6.11.4). 
• Schedule Phone Contact in 4 and 8 weeks (Days 127±7 and 155±7). Schedule the 
next clinic visit in 13 weeks (Day 190±7). 
 
7.1.6 
Group A – Week 27 Maintenance Phase Clinic Visit 
Visit 12, Day 190±7 
Week 27 – Start of Randomized Withdrawal Period 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain fasting blood samples for serum chemistry and hematology (Section 6.8 and 
Table 1). 
• Obtain urine sample for urinalysis and urine drug screen (Section 6.8 and Table 1). 
• Provide a light breakfast after fasting blood samples are collected. 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure 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 following questionnaires to the subject in the order specified below: 
− ESS (Section 6.10.1) 
− PGIc (Section 6.10.4) Since Started Treatment version (Appendix 15) 
− FOSQ-10 (Section 6.11.1) 
− SF-36v2 (Section 6.11.2) 
− EQ-5D-5L (Section 6.11.3) 
− WPAI:SHP (Section 6.12.1) 
• Administer the C-SSRS Since Last Visit version and record results (Section 6.7). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken since the last phone contact or visit (Section 5.7). 
• Record all AEs on the AE CRF that occurred since the last phone contact or visit 
(Section 6.13).  
• Collect open-label study drug and assess compliance including whether subjects have 
taken study drug on each of the past 3 days (Section 5.9). 
• Complete the CGIc (Section 6.10.3) Compared to Baseline version (Appendix 13). 
• If the subject completed Study 14-003, review and record his/her primary OSA 
therapy use from the subject’s device or memory card, or frequency of use (or lack of 
use) as reported by the subject. Remind these subjects to continue to use their primary 
CONFIDENTIAL
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Signature Date: 20161130
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Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
 
CONFIDENTIAL 
Page 61 of 120 
 
OSA therapy and to maintain the same level of use as when they entered Study 
14-003. 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/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 6.11.4). 
For subjects who are randomized into the randomized withdrawal period: 
• Randomize the subject in the randomized withdrawal period (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 (Sections 5.3 and 5.8.2). 
• Schedule Phone Contact in 1 week (Day 197±3). Schedule next clinic visit in 2 weeks 
(Day 204±7). 
For subjects who are not randomized into the randomized withdrawal period:  
• Dispense open-label study drug and provide instruction for how the subject should 
begin taking study drug on the following morning (Sections 5.3 and 5.8.2). 
• Schedule Phone Contact in 4 and 8 weeks (Days 218±7 and 246±7). Schedule the 
final clinic visit in 13 weeks (Day 281±7). 
 
7.1.7 
Group A – Week 29 Maintenance Phase Clinic Visit 
Visit 12.2, Day 204±7 
Week 29 – End of Randomized Withdrawal Period 
Note: This visit applies only to subjects who are randomized into the randomized withdrawal 
period. 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain urine sample for urine drug screen (Section 6.8 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 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 following questionnaires to the subject in the order specified below: 
− ESS (Section 6.10.1) 
− PGIc (Section 6.10.4) Since Last Visit version (Appendix 16) 
− FOSQ-10 (Section 6.11.1) 
• Administer the C-SSRS Since Last Visit version and record results (Section 6.7). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken since the last phone contact or visit (Section 5.7). 
CONFIDENTIAL
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Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
 
CONFIDENTIAL 
Page 62 of 120 
 
• Record all AEs on the AE CRF that occurred since the last phone contact or visit 
(Section 6.13).  
• Collect double-blind study drug and assess compliance including whether subjects 
have taken study drug on each of the past 3 days (Section 5.9). 
• Complete the CGIc (Section 6.10.3) Compared to Beginning of the Randomized 
Withdrawal Period version (Appendix 14). 
• Dispense open-label study drug and provide instruction for how the subject should 
begin taking study drug on the following morning (Sections 5.3 and 5.8.2). 
• If the subject completed Study 14-003, review and record his/her primary OSA 
therapy use from the subject’s device or memory card, or frequency of use (or lack of 
use) as reported by the subject. Remind these subjects to continue to use their primary 
OSA therapy and to maintain the same level of use as when they entered Study 
14-003. If the subject uses a primary OSA therapy from which the usage data can be 
extracted, instruct the subject to bring the device or memory card to the next clinic 
visit for review of his/her primary OSA therapy use. If the subject does not use a 
primary OSA therapy from which usage data can be extracted or does not use a 
primary OSA therapy, instruct the subject on reporting use as appropriate 
(Section 6.11.4). 
• Schedule Phone Contact in 2 and 6 weeks (Days 218±7 and 246±7). Schedule the 
final clinic visit in 11 weeks (Day 281±7). 
 
7.1.8 
Group A – Maintenance Phase Final Clinic Visit 
Visit 15, Day 281±7 
Week 40 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain fasting blood samples for serum chemistry and hematology 
(Section 6.8, Table 1). 
• Obtain a urine sample for a pregnancy test for all females of childbearing potential 
(Section 6.8.1, see footnote Table 1 for definitions of childbearing potential). 
• Obtain a urine sample for urinalysis and urine drug screens (Section 6.8, Table 1). 
• Provide a light breakfast after fasting blood samples are collected. 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure 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 following questionnaires to the subject in the order specified below: 
− ESS (Section 6.10.1) 
− PGIc (Section 6.10.4) Since Started Treatment version (Appendix 15) 
− FOSQ-10 (Section 6.11.1) 
− SF-36v2 (Section 6.11.2) 
CONFIDENTIAL
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
 
CONFIDENTIAL 
Page 63 of 120 
 
− EQ-5D-5L (Section 6.11.3) 
− WPAI:SHP (Section 6.12.1) 
− Resource Utilization Questionnaire (Section 6.12.2) 
• Administer the C-SSRS Since Last Visit version and record results (Section 6.7). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken since the last phone contact or visit (Section 5.7). 
• Record all AEs on the AE CRF that occurred since the last phone contact or visit 
(Section 6.13).  
• Collect study drug and assess compliance (Section 5.9).  
• Complete the CGIc (Section 6.10.3) Compared to Baseline version (Appendix 13). 
• If the subject completed Study 14-003, review and record his/her 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 6.11.4). 
• Perform a physical examination including a full examination of body systems 
(excluding a full genitourinary exam) and a brief neurological examination 
(Section 6.4). 
• Schedule Safety Follow-up Visit in 2 weeks (Day 295±7). 
 
7.1.9 
Group A – Safety Follow-up Clinic Visit 
Visit 16, Day 295±7 
Week 42 
• Obtain 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 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 6.7). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the last visit or phone contact (Section 5.7). 
• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.13). 
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. 
CONFIDENTIAL
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
 
CONFIDENTIAL 
Page 64 of 120 
 
7.2 
Group B Study Activities (Subjects from 14-004, 15-004, 15-005, 
ADX-N05 201, or ADX-N05 202) 
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).  
7.2.1 
Group B – Screening Clinic Visit  
Visit 1, Day -30 to -2 
• Review the inclusion (Section 4.2) and exclusion (Section 4.3) criteria. 
• Obtain demographic information (Section 6.2). 
• Obtain a complete medical history from the time of previous study participation, 
including current symptoms of narcolepsy or OSA (Section 6.3). 
• Record all prior and concomitant medications, including OTC medications, health, 
and dietary supplements taken during the 30 days before Screening and any 
medications or devices used for the treatment of narcolepsy or OSA since diagnosis 
(Sections 4.3 and 5.7). 
• If there are any ongoing AEs from a previous study, record those AEs on the AE CRF 
(Section 6.13). 
• 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). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure 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 min 
(Section 6.6). 
• Administer the C-SSRS Baseline/Screening version and record the results 
(Section 6.7). 
• Obtain fasting blood samples for serum chemistry and hematology including a serum 
pregnancy test for all females of childbearing potential (Section 6.8.1 and Table 1 for 
definitions of childbearing potential). 
• Obtain a urine sample for urinalysis and urine drug screens (Section 6.8 and Table 1). 
• Provide a light breakfast after blood samples are collected. 
• After screening procedures have been completed and eligibility criteria have been 
confirmed, provide eligible subjects with instructions on how to discontinue any 
excluded medications (Sections 4.3 and 5.7).  
• If the subject completed Study 14-004 or 15-004, instruct him/her to continue to bring 
his/her device or memory card to the next clinic visit for review of his/her primary 
OSA therapy use or on how to report daily use (or lack of use) of his/her primary 
OSA therapy as appropriate. Remind these subjects to continue to use their primary 
CONFIDENTIAL
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Signature Date: 20161130
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Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
 
CONFIDENTIAL 
Page 65 of 120 
 
OSA therapy and to maintain the same level of use as when they entered Study 
14-004 or 15-004 (Section 6.11.4). 
• Schedule a Baseline clinic visit (Visit 2) after the investigator has thoroughly 
reviewed results of all screening procedures and has confirmed all eligibility criteria. 
 
7.2.2 
Group B – Baseline Clinic Visit 
Visit 2, Day -1 
After a subject has successfully completed the screening procedures they will return to the 
investigative site to complete baseline procedures.  
 
• Obtain weight in ordinary indoor clothes (without shoes) (Section 6.4). 
• If the Baseline visit occurs more than 28 days after the Screening visit, obtain fasting 
blood samples for serum chemistry and hematology and a urine sample for urinalysis 
(Section 6.8), and provide a light breakfast after blood samples are taken. 
• Obtain a urine sample for a pregnancy test for all females of childbearing potential 
(Section 6.8.1, Table 1) for definitions of childbearing potential). 
• Obtain urine sample for urine drug screen (Section 6.8 and Table 1). 
• Review the inclusion (Section 4.2) and exclusion (Section 4.3) criteria and medical 
history to determine the subject’s eligibility to continue participating in the study. 
• Update medical history or confirm that no changes have occurred. 
• If the subject meets the inclusion criteria and does not meet any exclusion criteria, 
access the Interactive Voice Response System (IVRS) or the Interactive Web 
Response System (IWRS) to enroll the subject in the study. 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure 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 following questionnaires to the subject in the order specified below: 
− ESS (Section 6.10.1) 
− FOSQ-10 (Section 6.11.1) 
− SF-36v2 (Section 6.11.2) 
− EQ-5D-5L (Section 6.11.3) 
− WPAI questionnaire (Section 6.12.1) 
• Complete the CGIs (Section 6.10.2). 
• Administer the C-SSRS Since Last Visit version and record the results (Section 6.7). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the ICF was signed (Section 5.7). Record the date(s) that excluded 
medications were discontinued. 
CONFIDENTIAL
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Signature Date: 20161130
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Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
 
CONFIDENTIAL 
Page 66 of 120 
 
• Record all AEs on the AE CRF that occurred after the ICF was signed (Section 6.13).  
• If the subject completed Study 14-004 or 15-004, review and record his/her primary 
OSA therapy use from the subject’s device or memory card, or frequency of use (or 
lack of use) as reported by the subject. Remind these subjects to continue to use their 
primary OSA therapy and to maintain the same level of use as when they entered 
Study 14-004 or 15-004. If the subject uses a primary OSA therapy from which the 
usage data can be extracted, instruct the subject to bring the device or memory card to 
the next clinic visit for review of his/her primary OSA therapy use. If the subject does 
not use a primary OSA therapy from which usage data can be extracted or does not 
use a primary OSA therapy, instruct the subject on reporting use as appropriate 
(Section 6.11.4). 
• Dispense study drug and instruct subject on the daily dose administration to begin on 
the following morning (Day 1) (Sections 5.3 and 5.8.2). 
• Schedule Phone Contact for Days 3, 6, 9, and 12 and explain how the clinical titration 
to effect and tolerability will be conducted over the next 2 weeks (Sections 3.1 and 
5.1.2). Schedule the next clinic visit in 2 weeks. 
 
7.2.3 
Group B – Titration Phase Phone Contacts 
Visits 3-6, Days 3±1, 6±1, 9±1, and 12±1 
• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.13). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the last visit or phone contact. 
• 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). 
• If the subject uses a primary OSA therapy from which the usage data can be 
extracted, instruct the subject to bring the device or memory card to the next clinic 
visit for review of his/her primary OSA therapy use. If the subject does not use a 
primary OSA therapy from which usage data can be extracted or does not use a 
primary OSA therapy, instruct the subject on reporting use as appropriate 
(Section 6.11.4). 
• Remind subject of next phone contact or clinic visit. 
 
7.2.4 
Group B – End of Titration Phase Clinic Visit 
Visit 7, Day 15±2 
Week 2 
• Obtain weight in ordinary indoor clothes (without shoes) (Section 6.4). 
• Obtain urine sample for urine drug screen (Section 6.8 and Table 1). 
CONFIDENTIAL
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Signature Date: 20161130
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Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
 
CONFIDENTIAL 
Page 67 of 120 
 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure 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 following questionnaires to the subject in the order specified below: 
− ESS (Section 6.10.1) 
− PGIc (Section 6.10.4) Since Started Treatment version (Appendix 15) 
• C-SSRS Since Last visit version and record the results (Section 6.7). 
• If the subject completed Study 14-004 or 15-004, review and record his/her primary 
OSA therapy use from the subject’s device or memory card, or frequency of use (or 
lack of use) as reported by the subject. Remind these subjects to continue to use their 
primary OSA therapy and to maintain the same level of use as when they entered 
Study 14-004 or 15-004. If the subject uses a primary OSA therapy from which the 
usage data can be extracted, instruct the subject to bring the device or memory card to 
the next clinic visit for review of his/her primary OSA therapy use. If the subject does 
not use a primary OSA therapy from which usage data can be extracted or does not 
use a primary OSA therapy, instruct the subject on reporting use as appropriate 
(Section 6.11.4). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken since the last phone contact or visit (Section 5.7). 
• Record all AEs on the AE CRF that occurred since the last phone contact or visit 
(Section 6.13).  
• Collect study drug remaining from the Titration Phase and assess compliance 
(Section 5.9). 
• 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) for the next 12 weeks of the Maintenance Phase (Section 5.3). 
Reminder: After this visit only three dose adjustments to the doses of 75 mg, 150 mg, 
or 300 mg daily will be allowed and subjects will have to return to the clinic for a 
dose adjustment. Dose adjustments will not be allowed after Visit 10 (Week 14). 
• Complete the CGIc (Section 6.10.3) Compared to Baseline Version (Appendix 13). 
• Dispense study drug for the Maintenance Phase and instruct subject on the daily dose 
administration to begin on the following morning (Sections 5.3 and 5.8.2). 
• Schedule Phone Contact in 4 and 8 weeks (Days 43±7 and 71±7). Schedule the next 
clinic visit in 12 weeks (Day 99±7). 
 
CONFIDENTIAL
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Signature Date: 20161130
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Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
 
CONFIDENTIAL 
Page 68 of 120 
 
7.2.5 
Group B – Maintenance Phase Phone Contacts  
 
Visits 
8 
9 
11 
12 
13.1* 
14 
15 
17 
18 
Days 
43±7 
71±7 
127±7 155±7 190±3 211±7 239±7 302±7 330±7 
Weeks 
6 
10 
18 
22 
27 
30 
34 
43 
47 
*Visit 13.1 applies only to subjects who are randomized into the randomized withdrawal period. 
 
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the last visit or phone contact (Section 5.7). 
• Record all AEs on the AE CRF that occur that occurred since the last visit or phone 
contact and record (Section 6.13).  
• If the subject completed Study 14-004 or 15-004, review and record his/her primary 
OSA therapy use from the subject’s device or memory card, or frequency of use (or 
lack of use) as reported by the subject. Remind these subjects to continue to use their 
primary OSA therapy and to maintain the same level of use as when they entered 
Study 14-004 or 15-004. If the subject uses a primary OSA therapy from which the 
usage data can be extracted, instruct the subject to bring the device or memory card to 
the next clinic visit for review of his/her primary OSA therapy use. If the subject does 
not use a primary OSA therapy from which usage data can be extracted or does not 
use a primary OSA therapy, instruct the subject on reporting use as appropriate 
(Section 6.11.4). 
• Remind subject of next phone contact or clinic visit. 
 
7.2.6 
Group B – Week 14 Maintenance Phase Clinic Visit 
Visit 10, Day 99±7  
Week 14 
• Obtain weight in ordinary indoor clothes (without shoes) (Section 6.4). 
• Obtain fasting blood samples for serum chemistry and hematology (Section 6.8 and 
Table 1). 
• Obtain urine sample for urinalysis and urine drug screen (Section 6.8 and Table 1). 
• Provide a light breakfast after fasting blood samples are collected. 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure 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 following questionnaires to the subject in the order specified below:  
− ESS (Section 6.10.1) 
− PGIc (Section 6.10.4) Since Started Treatment Version (Appendix 15) 
− FOSQ-10 (Section 6.11.1) 
CONFIDENTIAL
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Signature Date: 20161130
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Signature Date:
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
 
CONFIDENTIAL 
Page 69 of 120 
 
− SF-36v2 (Section 6.11.2) 
− EQ-5D-5L (Section 6.11.3) 
− WPAI:SHP (Section 6.12.1) 
• Administer the C-SSRS Since Last Visit version and record the results (Section 6.7). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken since the last phone contact or visit (Section 5.7). 
• Record all AEs on the AE CRF that occurred since the last phone contact or visit 
(Section 6.13).  
• Collect study drug and assess compliance (Section 5.9).  
• Complete the CGIc (Section 6.10.3) Compared to Baseline Version (Appendix 13). 
• Dispense study drug and provide instruction for how the subject should begin taking 
study drug on the following morning (Sections 5.3 and 5.8.2). No dose adjustments 
are permitted after this visit.  
• If the subject completed Study 14-004 or 15-004, review and record his/her primary 
OSA therapy use from the subject’s device or memory card, or frequency of use (or 
lack of use) as reported by the subject. Remind these subjects to continue to use their 
primary OSA therapy and to maintain the same level of use as when they entered 
Study 14-004 or 15-004. If the subject uses a primary OSA therapy from which the 
usage data can be extracted, instruct the subject to bring the device or memory card to 
the next clinic visit for review of his/her primary OSA therapy use. If the subject does 
not use a primary OSA therapy from which usage data can be extracted or does not 
use a primary OSA therapy, instruct the subject on reporting use as appropriate 
(Section 6.11.4). 
• Schedule Phone Contact in 4 and 8 weeks (Days 127±7 and 155±7). Schedule the 
next clinic visit in 12 weeks (Day 183±7). 
7.2.7 
Group B – Week 26 Maintenance Phase Clinic Visit 
Visit 13, Day 183±7 
Week 26 – Start of Randomized Withdrawal Period 
 
• Obtain weight in ordinary indoor clothes (without shoes) (Section 6.4). 
• Obtain fasting blood samples for serum chemistry and hematology (Section 6.8 and 
Table 1). 
• Obtain urine sample for urinalysis and urine drug screen (Section 6.8 and Table 1). 
• Provide a light breakfast after fasting blood samples are collected. 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure 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 following questionnaires to the subject in the order specified below: 
CONFIDENTIAL
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Signature Date: 20161130
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Signature Date:
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JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
 
CONFIDENTIAL 
Page 70 of 120 
 
− ESS (Section 6.10.1) 
− PGIc (Section 6.10.4) Since Started Treatment Version (Appendix 15) 
− FOSQ-10 (Section 6.11.1) 
− SF-36v2 (Section 6.11.2) 
− EQ-5D-5L (Section 6.11.3) 
− WPAI:SHP (Section 6.12.1) 
− Resource Utilization Questionnaire (Section 6.12.2) 
• Administer the C-SSRS Since Last Visit version and record the results (Section 6.7). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken since the last phone contact or visit (Section 5.7). 
• Record all AEs on the AE CRF that occurred since the last phone contact or visit 
(Section 6.13). 
• Collect open-label study drug and assess compliance, including whether subjects have 
taken study drug on each of the past 3 days (Section 5.9). 
• Complete the CGIc (Section 6.10.3) Compared to Baseline version (Appendix 13). 
• If the subject completed Study 14-004 or 15-004, review and record his/her primary 
OSA therapy use from the subject’s device or memory card, or frequency of use (or 
lack of use) as reported by the subject. Remind these subjects to continue to use their 
primary OSA therapy and to maintain the same level of use as when they entered 
Study 14-004 or 15-004. If the subject uses a primary OSA therapy from which the 
usage data can be extracted, instruct the subject to bring the device or memory card to 
the next clinic visit for review of his/her primary OSA therapy use. If the subject does 
not use a primary OSA therapy from which usage data can be extracted or does not 
use a primary OSA therapy, instruct the subject on reporting use as appropriate 
(Section 6.11.4). 
For subjects who are randomized into the randomized withdrawal period: 
• Randomize the subject in the randomized withdrawal period (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 (Sections 5.3 and 5.8.2).  
• Schedule Phone Contact in 1 week (Day 190±3). Schedule the next clinic visit in 
2 weeks (Day 197±7). 
For subjects who are not randomized into the randomized withdrawal period:  
• Dispense open-label study drug and provide instruction for how the subject should 
begin taking study drug on the following morning (Sections 5.3 and 5.8.2).  
• Schedule Phone Contact in 4 and 8 weeks (Days 211±7 and 239±7). Schedule the 
next clinic visit in 13 weeks (Day 274±7). 
 
CONFIDENTIAL
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7.2.8 
Group B – Week 28 Maintenance Phase Clinic Visit  
Visit 13.2, Day 197±7 
Week 28 – End of Randomized Withdrawal Period 
 
Note:  This visit applies only to subjects who are randomized into the randomized withdrawal 
period. 
• Obtain weight in ordinary indoor clothes (without shoes) (Section 6.4). 
• Obtain urine sample for urine drug screen (Section 6.8 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 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 following questionnaires to the subject in the order specified below: 
− ESS (Section 6.10.1) 
− PGIc (Section 6.10.4) Since Last Visit version (Appendix 16) 
− FOSQ-10 (Section 6.11.1) 
• Administer the C-SSRS Since Last Visit version and record the results (Section 6.7). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken since the last phone contact or visit (Section 5.7). 
• Record all AEs on the AE CRF that occurred since the last phone contact or visit 
(Section 6.13). 
• Collect double-blind study drug and assess compliance including whether subjects 
have taken study drug on each of the past 3 days (Section 5.9). 
• Complete the CGIc (Section 6.10.3) Compared to Beginning of the Randomized 
Withdrawal Period version (Appendix 14). 
• Dispense open-label study drug and provide instruction for how the subject should 
begin taking study drug on the following morning (Sections 5.3 and 5.8.2).  
• If the subject completed Study 14-004 or 15-004, review and record his/her primary 
OSA therapy use from the subject’s device or memory card, or frequency of use (or 
lack of use) as reported by the subject. Remind these subjects to continue to use their 
primary OSA therapy and to maintain the same level of use as when they entered 
Study 14-004 or 15-004. If the subject uses a primary OSA therapy from which the 
usage data can be extracted, instruct the subject to bring the device or memory card to 
the next clinic visit for review of his/her primary OSA therapy use. If the subject does 
not use a primary OSA therapy from which usage data can be extracted or does not 
use a primary OSA therapy, instruct the subject on reporting use as appropriate 
(Section 6.11.4). 
• Schedule Phone Contact in 2 and 6 weeks (Days 211±7 and 239±7). Schedule the 
next clinic visit in 11 weeks (Day 274±7). 
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7.2.9 
Group B – Week 39 Maintenance Phase Clinic Visit 
Visit 16, Day 274±7 
Week 39 
• Obtain weight in ordinary indoor clothes (without shoes) (Section 6.4). 
• Obtain fasting blood samples for serum chemistry and hematology (Section 6.8 and 
Table 1). 
• Obtain urine sample for urinalysis and urine drug screen (Section 6.8 and Table 1). 
• Provide a light breakfast after fasting blood samples are collected. 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure measurements in 
the seated position, as described in Section 6.5. 
• Collect study drug and assess compliance (Section 5.9).  
• Obtain a 12-lead ECG after the subject has been resting supine for at least 5 min 
(Section 6.6). 
• Administer the following questionnaires to the subject in the order specified below: 
− ESS (Section 6.10.1) 
− PGIc (Section 6.10.4) Since Started Treatment Version (Appendix 15) 
− FOSQ-10 (Section 6.11.1) 
− SF-36v2 (Section 6.11.2) 
− EQ-5D-5L (Section 6.11.3) 
− WPAI:SHP (Section 6.12.1) 
• Administer the C-SSRS Since Last Visit version and record the results (Section 6.7). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken since the last phone contact or visit (Section 5.7). 
• Record all AEs on the AE CRF that occurred since the last phone contact or visit 
(Section 6.13). 
• Complete the CGIc (Section 6.10.3) Compared to Baseline Version (Appendix 13). 
• Dispense study drug and provide instruction for how the subject should begin taking 
study drug on the following morning (Sections 5.8.2 and 6.9). No dose adjustments 
are permitted after this visit.  
• If the subject completed Study 14-004 or 15-004, review and record his/her primary 
OSA therapy use from the subject’s device or memory card, or frequency of use (or 
lack of use) as reported by the subject. Remind these subjects to continue to use their 
primary OSA therapy and to maintain the same level of use as when they entered 
Study 14-004 or 15-004. If the subject uses a primary OSA therapy from which the 
usage data can be extracted, instruct the subject to bring the device or memory card to 
the next clinic visit for review of his/her primary OSA therapy use. If the subject does 
not use a primary OSA therapy from which usage data can be extracted or does not 
use a primary OSA therapy, instruct the subject on reporting use as appropriate 
(Section 6.11.4). 
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• Schedule Phone Contact in 4 and 8 weeks (Days 302±7 and 330±7). Schedule the 
next clinic visit in 13 weeks (Day 365±7). 
7.2.10 
Group B – Maintenance Phase Final Clinic Visit 
Visit 19 Day 365±7 
Week 52 
• Obtain weight in ordinary indoor clothes (without shoes) (Section 6.4). 
• Obtain fasting blood samples for hematology and serum chemistry tests. 
• Obtain a urine sample for a pregnancy test for all females of childbearing potential 
(Table 1 footnote for definitions of childbearing potential). 
• Obtain a urine sample for urinalysis and urine drug screens (Section 6.8 and Table 1). 
• Provide a light breakfast after blood samples are collected. 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure 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 following questionnaires to the subject in the order specified below: 
− ESS (Section 6.10.1) 
− PGIc (Section 6.10.4) Since Started Treatment Version (Appendix 15) 
− FOSQ-10 (Section 6.11.1) 
− SF-36v2 (Section 6.11.2) 
− EQ-5D-5L (Section 6.11.3) 
− WPAI:SHP (Section 6.12.1) 
− Resource Utilization Questionnaire (Section 6.12.2). 
• Administer the C-SSRS Since Last Visit version and record the results (Section 6.7). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken since the last phone contact or visit (Section 5.7). 
• Record all AEs on the AE CRF that occurred since the last phone contact or visit 
(Section 6.13).  
• Collect study drug and assess compliance (Section 5.9).  
• Complete the CGIc (Section 6.10.3) Compared to Baseline Version (Appendix 13).  
• If the subject completed Study 14-004 or 15-004, review and record his/her 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 6.11.4). 
• Perform a physical examination including a full examination of body systems 
(excluding a full genitourinary exam) and a brief neurological examination 
(Section 6.4). 
• Schedule Safety Follow-up Visit in 2 weeks (Day 379±7). 
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7.2.11 
Group B – Safety Follow-up Visit 
Visit 20 
Day 379±7 (Week 54) 
• Obtain 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 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 6.7). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the last visit or phone contact (Section 5.7). 
• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.13). 
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. 
 
7.3 
Early Terminations 
If a subject withdraws or is withdrawn from the study, after completing the Week 2 Visit 
(Visit 6 for Group A or Visit 7 for Group B) and no more than 3 days have passed since the 
subject’s last dose of study drug was taken, the Maintenance Phase Final Clinic Visit 
procedures should be conducted (Visit 15 for Group A, Section 7.1.8, or Visit 19 for Group 
B, Section 7.2.10). If more than 3 days have passed since the subject’s last dose of study drug 
was taken, only the final safety assessments listed in this section should be conducted (ESS, 
CGIc, PGIc, FOSQ-10, SF-36v2, EQ-5D-5L, WPAI:SHP, and Resource Utilization 
assessments are not required). 
If a subject withdraws or is withdrawn prior to completing the Week 2 Visit (Visit 6 for 
Group A or Visit 7 for Group B), only the final safety assessments listed in this section 
should be conducted (ESS, CGIc, PGIc, FOSQ-10, SF-36v2, EQ-5D-5L,WPAI:SHP, and 
Resource Utilization assessments are not required).  
For any subject who discontinues the study prematurely, also follow procedures in 
Section 7.4. 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain fasting blood samples for serum chemistry and hematology (Section 6.8.1). 
• Obtain a urine sample for a pregnancy test for all females of childbearing potential 
(Section 6.8.1 for definitions of childbearing potential). 
• Obtain a urine sample for urinalysis and urine drug screens (Section 6.8 and Table 1). 
• Provide a light breakfast after fasting blood samples are collected. 
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• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure 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 6.7). 
• Collect Study Drug and assess compliance (Section 5.9). 
• Perform a physical examination including a full examination of body systems 
(excluding a full genitourinary exam) and a brief neurological examination.  
• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.13). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the last visit or phone contact (Section 5.7). 
• Schedule Safety Follow-up Visit in 2 weeks. 
7.4 
Discontinuations 
If a subject is withdrawn before completing the study, the reason for withdrawal will be 
entered on the CRF.  The specific reason for the withdrawal should be carefully documented 
on the CRF. For instance, rather than stating “withdrew informed consent”, the specific 
reason for withdrawing the informed consent should be stated. Whenever possible and 
reasonable, the evaluations that were to be conducted during the final study visit should be 
performed at the time of premature discontinuation as noted above.  
It is vital to obtain follow-up data on any subject who terminated because of an AE, 
abnormal laboratory test, or ECG finding. In any case, every effort must be made to ensure 
safety follow-up procedures are completed. 
8 
QUALITY CONTROL AND ASSURANCE 
The study will be conducted according to GCP guidelines and according to national law. 
Quality Assurance audits may be performed at the discretion of Jazz Pharmaceuticals. 
9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
There are two primary objectives of this study. The primary objective of the overall study is 
to evaluate the safety and tolerability of JZP-110 administered once daily for up to 52 weeks 
in doses of 75, 150, and 300 mg. To achieve this objective all study data will be summarized 
by dose 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 
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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). 
No formal statistical testing will be performed for the open-label analyses; only summary 
statistics will be provided.  
The primary objective of the randomized withdrawal period in the Maintenance Phase of this 
study is to evaluate the maintenance of efficacy of JZP-110 compared to placebo in the 
treatment of excessive sleepiness in adult subjects with narcolepsy or OSA after at least 26 
weeks of daily administration of JZP-110. For the double-blind, placebo-controlled 
maintenance of efficacy data in the randomized withdrawal period, treatment differences 
between JZP-110 and placebo will be tested. 
9.2 
Tests of Hypotheses and Significance Levels 
The primary statistical null hypothesis is that for the ESS score, the mean change from the 
beginning to the end of the 2 week randomized withdrawal period for the JZP-110 group is 
equal to the mean change from the beginning to the end of the 2-week randomized 
withdrawal period for the placebo group. 
For comparisons between JZP-110 and placebo at the end of the randomized withdrawal 
period in the Maintenance Phase, subjects who were randomized to continue on JZP-110 in 
the randomized withdrawal period will be treated as a single group regardless of their 
diagnosis (narcolepsy or OSA) or 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 the primary (ESS) and secondary (PGIc) endpoints. 
To address multiplicity issues in the analysis of the primary and secondary efficacy 
endpoints, a fixed hierarchical testing sequence will be used. Testing will begin with the 
comparison of JZP-110 versus placebo for the primary efficacy endpoint ESS. The primary 
analysis of the ESS endpoint must be significant at or below the 0.05 level for the testing to 
proceed to the comparison of JZP-110 versus placebo for the secondary efficacy endpoints of 
PGIc and CGIc (in that order). Testing will stop if a significance level exceeds 0.05 (p≥0.05). 
This gatekeeping approach will control the family-wise error rate at 0.05. 
9.3 
Determination of Sample Size 
The sample size of this study is based on ICH Guidance on the Extent of Population 
Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of 
Non-Life-Threatening Conditions (E1) and on guidance from FDA. Approximately 600 
subjects are planned for enrollment with the intention of completing at least 50 subjects with 
narcolepsy and at least 50 subjects with OSA with an exposure to JZP-110 of 52 weeks and 
at least 100 subjects with narcolepsy and at least 200 subjects with OSA with an exposure to 
JZP-110 of 26 weeks. A sample size of 300 subjects in the randomized withdrawal period in 
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the Maintenance Phase with approximately 150 subjects per treatment group will provide at 
least 95% power to detect a difference of 3 points in the ESS score from the beginning to the 
end of the 2-week randomized withdrawal period. This calculation assumes a common 
standard deviation of 7 points for the ESS change during the randomized withdrawal period 
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 the safety evaluation and the open-label 
maintenance of efficacy of JZP-110 and will be presented in the tables and listings. All open-
label analyses will be performed for the Safety Population. 
The Modified Intent-to-Treat (mITT) Population for the evaluation of double-blind, placebo-
controlled maintenance of efficacy will include subjects who were randomized in the 2-week 
randomized withdrawal period, who received at least one dose of study medication in the 
2-week randomized withdrawal period, and who have evaluable efficacy data at Week 29 
(Group A) or Week 28 (Group B). 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 mITT subjects who completed the 2-week 
randomized withdrawal period according to protocol specifications without a major violation 
(e.g., lack of compliance on the 3 days prior to the beginning and the 3 days prior to the end 
of the randomized withdrawal period in the Maintenance Phase). 
9.5 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized. The summaries of data will 
include frequency 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 open-label efficacy endpoints at the End of the Maintenance Phase 
(Visit 15 for Group A and Visit 19 for Group B), single or multiple imputation methods will 
be used to impute the missing data in order to assess the sensitivity of the results. For the 
analysis of the double-blind, placebo-controlled efficacy endpoints at the end of the 
randomized withdrawal period at Week 29 (Group A) or Week 28 (Group B), single 
imputation methods will be used to impute the missing data in order to assess the sensitivity 
of the results. 
These missing data imputation 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. 
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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 
Placebo-controlled Maintenance of Efficacy Endpoints 
9.8.1 
Primary Efficacy Endpoint 
• ESS: Change in ESS score from the beginning to the end of the randomized 
withdrawal period  
9.8.2 
Secondary Efficacy Endpoints 
• PGIc: Percentage of subjects reported as worse (minimally, much, or very much) on 
the PGIc at the end of the randomized withdrawal period 
• CGIc: Percentage of subjects reported as worse (minimally, much, or very much) on 
the CGIc at the end of the randomized withdrawal period 
9.9 
Efficacy Analyses 
9.9.1 
Double-blind, Placebo-controlled Maintenance of Efficacy Analyses 
Double-blind, placebo-controlled efficacy endpoints will consist of the change in the ESS 
score from the beginning to the end of the randomized withdrawal period and the percentage 
of subjects reported as worse (minimally, much, or very much) on the PGIc and CGIc at the 
end of the randomized withdrawal period.  
For the analysis of the ESS scores, an analysis of covariance (ANCOVA) model will be used. 
This model will include treatment group and randomization stratification factor as fixed 
effects. The ESS score at the beginning of the randomized withdrawal period will be used as 
the covariate. The response variable will be the change in ESS score from the beginning to 
the end of 2-week randomized withdrawal period. 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 randomized withdrawal 
period. The chi-squared test will be used to test the hypotheses associated with the analysis of 
the secondary efficacy endpoints of PGIc and CGIc. 
9.9.2 
Open-label Maintenance of Efficacy Analyses 
Open-label efficacy endpoints (ESS, PGIc, and CGIc) will be summarized by time point and 
dose, using descriptive statistics and graphical displays. For subjects who participated in 
Study 14-002 or 14-003, ESS may also be summarized by the treatment that was received in 
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the previous study. Where applicable, the changes in ESS from prior study baseline and from 
the endpoint of the prior study will be examined. 
9.10 Analysis of Functional Outcomes and Quality of Life Endpoints 
The outcome measures associated with the FOSQ-10, SF-36v2, EQ-5D-5L, and compliance 
with primary OSA therapy (OSA only) will be summarized by final dose and time point and 
displayed graphically. For subjects who participated in Study 14-002 or 14-003, these 
measures may also be summarized by the previous treatment group. Where applicable, the 
changes in these measures from prior study baseline and from the endpoint of the prior study 
will be examined. Changes in FOSQ-10 score from the beginning to the end of the 
randomized withdrawal period between the JZP-110 and placebo groups will also be 
compared. A similar ANCOVA model as described above will be used as the method of 
analysis for the FOSQ-10 endpoints. 
9.11 Analysis of Economic Assessments 
The outcome measures associated with the WPAI:SHP and the Resource Utilization 
Questionnaire will be summarized by final dose and time point and displayed graphically. 
For subjects who participated in Study 14-002 or 14-003, the WPAI:SHP measures may also 
be summarized by the previous treatment group. Where applicable, the changes in the 
WPAI:SHP measures from prior study baseline and from the endpoint of the prior study will 
be examined. 
9.12 Safety Analysis 
9.12.1 
Adverse Event 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) system to classify events under primary system organ class and preferred term. 
The version of MedDRA dictionary used will be specified in the statistical analysis plan. 
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 dose at the onset of TEAEs. 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 in the maximum 
severity analysis. 
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For all AE summaries, if a subject has more than one AE within a preferred term, the subject 
is counted only once at the maximum severity and with the closest relationship to study drug. 
If a subject has more than one AE within a system organ class, the subject is similarly 
counted once when reporting results for that system organ class. 
All AE data will be listed. The information presented will include subject number, dose at 
AE onset, primary system organ class and preferred term, date of onset, severity, relationship 
to study drug, action taken, and stop date (if available). 
All AE summaries above will be also presented by treatment group during the randomized 
withdrawal period in the Maintenance Phase.  
9.12.2 
Vital Signs 
Abnormal vital signs will be counted by dose. The number and percent of subjects with any 
post-baseline vital sign readings above and/or below specified levels will be presented for 
each dose. In addition, summary statistics (i.e., mean, median, minimum, maximum, standard 
deviation, and number of subjects) will be presented by dose for each vital sign as per 
protocol schedule. An additional listing will be provided of those subjects who have 
clinically significant vital sign values. 
All vital signs summaries above will be also presented by treatment group during the 
randomized withdrawal period in the Maintenance Phase.  
9.12.3 
Laboratory Evaluation 
The number and percent of subjects with abnormal values post-baseline will be tabulated. In 
addition, summary statistics (i.e., mean, minimum, maximum, standard deviation, and 
number of subjects) will be presented for each laboratory parameter as per protocol schedule. 
An additional listing will be provided of those subjects who have clinically significant 
laboratory values. 
9.12.4 
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. 
All ECG summaries above will be also presented by treatment group during the randomized 
withdrawal period in the Maintenance Phase.  
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9.12.5 
Physical Examinations 
A finding identified by the investigator as abnormal on the physical examination at the 
Screening visit will be recorded on the Medical History eCRF. A clinically significant 
adverse change (i.e., worsening) of a physical examination finding after screening will be 
recorded as an AE.  
9.12.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Data from the Since Last Visit Version of the C-SSRS will be summarized according to the 
Columbia Classification Algorithm of Suicide Assessment (C-CASA) (Posner et al. 2007). 
C-SSRS will be also summarized by treatment group during the randomized withdrawal 
phase.  
9.13 Subgroup Analyses 
Adverse events data will be summarized for subjects with narcolepsy or OSA separately, and 
combined. Data may also be summarized by the presence of cataplexy (narcolepsy only) and 
by the level of compliance with primary OSA therapy (OSA only) for exploratory analyses. 
All AE summaries above will be also presented by treatment group during the randomized 
withdrawal period in the Maintenance Phase.  
9.14 Interim Analysis and Data Monitoring 
Interim analyses are planned when the study has approximately 50 subjects with narcolepsy 
and 50 subjects with OSA with an exposure to JZP-110 of 52 weeks and 100 subjects with 
narcolepsy and 200 subjects with OSA with an exposure to JZP-110 of 26 weeks.  
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 
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not limited to a Data Management Overview, Database Contents, annotated CRF, Query 
Contacts, and Consistency Checks. 
10.2 Electronic Case Report Forms (eCRFs) 
Jazz Pharmaceuticals or its designee will supply eCRFs for the recording of all trial data not 
recorded in ECG or generated by laboratory report. 
The principal investigator must review the eCRFs and provide his/her signature certifying 
that he/she has reviewed the data and considers the data accurate to the best of his/her 
knowledge. Regardless of who completes the forms, it is the principal investigator’s 
responsibility to ensure the accuracy of the forms. 
10.3 Retention of Data 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Trial (ICH E6 Good Clinical Practice) and as required by the 
applicable regulatory requirement(s). The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents.  
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period if required by the applicable regulatory requirements or 
by an agreement with Jazz Pharmaceuticals. It is the responsibility of Jazz Pharmaceuticals to 
inform the investigator/institution when these documents no longer need to be retained. 
10.4 Data Safety Monitoring Board 
A data safety monitoring board is not planned for this trial. 
 
 
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Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
 
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11 ADMINISTRATIVE CONSIDERATIONS 
11.1 Investigators and Study Administrative Structure 
11.1.1 
Contract Research Organization  
11.1.2 
Jazz Pharmaceuticals Medical Monitor  
11.1.3 
EU Medical Monitor  
Contact information for the EU Medical Monitor will be provided separately. 
11.1.4 
Investigator 
Multicenter 
11.2 Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) Approval 
The final approved protocol and the informed consent form will be reviewed by the IRB/IEC.  
In addition, the IRB/IEC will review any other written information to be provided to the 
subject, advertisements for subject recruitment (if used), and subject compensation (if any). 
The committee’s decision concerning conduct of the study will be sent in writing to the 
investigator and a copy will be forwarded to Jazz Pharmaceuticals. The investigator agrees to 
make any required progress reports, as well as reports of SAEs, life-threatening problems, 
death, or any significant protocol deviations, as required by the IRB/IEC. 
A list of the IRB/IEC members who actually participated in the review, their respective titles 
(occupational identification), and institutional affiliations or an IRB/IEC assurance number 
must be provided to Jazz Pharmaceuticals. The approval letter or notice must be provided on 
IRB/IEC letterhead and contain the date of the meeting and sufficient information to identify 
the version of the protocol unambiguously (by name and number) and state that the informed 
consent form was also reviewed. 
A clinical trial may not be initiated before the proposed protocol and informed consent form 
have been reviewed and unconditionally approved by an IRB meeting federal regulations. 
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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. Subjects will be given a copy of their signed informed consent 
form. 
Each subject’s chart will have his/her signed ICF for study participation attached to it. When 
the study treatment is completed and the CRF has been monitored, the ICF will be kept in the 
investigator’s central study file. Regulatory authorities may check the existence of the signed 
ICF in this central study folder. 
11.5 Subject Confidentiality  
All reports and communications relating to the subjects in the study will identify each subject 
only by his/her initials and by the subject’s study number. These documents will be treated 
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Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
 
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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. 
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. 
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Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
 
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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 
intended to protect commercial confidential materials (patents, etc.) and not to restrict 
publication.   
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
 
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12 REFERENCE LIST 
American Academy of Sleep Medicine (AASM). International Classification of Sleep 
Disorders-Third Edition (ICSD-3), Darien, IL. American Academy of Sleep Medicine, 2014; 
53-62, 143-155.  
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental 
disorders (5th ed.). Washington, DC. 
Broderick JE, Junghaenel DU, Schneider S, Pilosi JJ, Stone AA. Pittsburgh and Epworth 
sleep scale items: accuracy of ratings across different reporting periods. 2013; Behav Sleep 
Med. 11:173-88. 
Chasens E, Ratcliffe S, Weaver T. Development of the FOSQ-10: A short version of the 
Functional Outcomes of Sleep Questionnaire. 2009; SLEEP 32: 915-919. 
EQ-5D-5L User Guide. 2013. Available at: 
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/UserGuide
_EQ-5D-5L_v2.0_October_2013.pdf.   Accessed November 19, 2014. 
Fietze I, Penzel T, Alonderis A, et al. COST Action B26 Group. Management of obstructive 
sleep apnea in Europe. Sleep Med. 2011; 12:190-7. 
Gasa M, Tamisier R, Launois SH, et al. Scientific Council of the Sleep Registry of the 
French Federation of Pneumology-FFP. Residual sleepiness in sleep apnea patients treated by 
continuous positive airway pressure. J Sleep Res. 2013; 22:389-97. 
Gay P, Weaver T, Loube D, Iber C. Evaluation of positive airway pressure treatment for 
sleep related breathing disorders in adults: A review by the Positive Airway Pressure Task 
Force of the Standards of Practice Committee of the American Academy of Sleep Medicine. 
Sleep. 2006;29:381-401. 
Harsh JR, Hayduk R, Rosenberg R, Wesnes KA, Walsh JK, Arora S, Niebler GE, Roth T. 
The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness 
associated with narcolepsy. Curr Med Res Opin. 2006;22:761-74. 
Hasan S, Pradervand S, Ahnaou A, Drinkenburg W, Tafti M, Franken P. How to keep the 
brain awake? The complex molecular pharmacogenetics of wake promotion. 
Neuropsychopharmacology. 2009;34:1625-1640. 
Hays RD, Stewart AL. (1992b). Construct validity of MOS health measures. In A. L. Stewart 
& J. E. Ware (eds.), Measuring functioning and well-being: The Medical Outcomes Study 
approach (pp. 325-342), Durham, NC: Duke University Press. 
Johns, MW. Sensitivity and specificity of the multiple sleep latency test (MSLT), the 
maintenance of wakefulness test and the epworth sleepiness scale: failure of the MSLT as a 
gold standard J Sleep Res 2000; 9 (1): 5–11. 
Johns, MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. 
Sleep. 1991 Dec;14(6):540-5 
Majid H, Hirshkowitz M. Therapeutics of narcolepsy. Sleep Med Clin 2010; 5:659-673. 
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Morgenthaler TI, Kapur VK, Brown TM, Swick TJ, Alessi C, Aurora RN, Boehlecke B, et 
al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central 
origin. SLEEP 2007; 30:1705-1711. 
Ohayon MM. Epidemiology of narcolepsy. In Narcolepsy and Hypersomnia 2007. C 
Bassetti, M Billiard, E Mignot, eds. New York: Informa Healthcare: pp 125-132. 
Ohayon MM, Priest RG, Zulley J, Smirne S, Paiva T. Prevalence of narcolepsy 
symptomatology and diagnosis in the European general population. Neurology 
2002;58:1826-1833. 
Pépin JL, Viot-Blanc V, Escourrou P, et al. Prevalence of residual excessive sleepiness in 
CPAP-treated sleep apnoea patients: the French multicentre study. Eur Respir J. 2009; 
33:1062-7. 
Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, Jones DW, Kurtz T, Sheps 
SG, Roccella EJ; Subcommittee of Professional and Public Education of the American Heart 
Association Council on High Blood Pressure Research. Recommendations for blood pressure 
measurement in humans and experimental animals: Part 1: blood pressure measurement in 
humans: a statement for professionals from the Subcommittee of Professional and Public 
Education of the American Heart Association Council on High Blood Pressure Research. 
Hypertension. 2005; 45:142-61. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo M, Currier GW, Melvin 
GA, Greenhill L, Shen S, Mann JJ. The Columbia–Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry 2011;168:1266-1277.  
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm 
of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric 
suicidal risk analysis of antidepressants. Am J Psychiatry. 2007;164:1035-1043. 
Randerath WJ, Verbraecken J, Andreas S, et al. Non-CPAP therapies in obstructive sleep 
apnoea. European Respiratory Society task force on non-CPAP therapies in sleep apnoea. 
Eur Respir J. 2011; 37:1000-28. 
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity 
and activity impairment instrument. PharmacoEconomics 1993; 4(5):353-65. 
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. 
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. 
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Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
 
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Ware JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36): I. Conceptual 
framework and item selection. Medical Care. 1992;30: 473-483. 
Weaver TE, Maislin G, Dinges DF, Bloxham T, George CF, Greenberg H, Kader G, 
Mahowald M, Younger J, Pack AI. Relationship between hours of CPAP use and achieving 
normal levels of sleepiness and daily functioning. Sleep. 2007;30:711-719. 
Weaver TE, Grunstein RR. Adherence to continuous positive airway pressure therapy: the 
challenge to effective treatment. Proc Am Thorac Soc. 2008;5:173-178. 
Weaver TE, Sawyer AM. Adherence to continuous positive airway pressure treatment for 
obstructive sleep apnoea: implications for future interventions. Indian J Med Res. 
2010;131:245-258. 
Weaver TE, Laizner AM, Evans LK, et al. An instrument to measure functional status 
outcomes for disorders of excessive sleepiness. Sleep 1997;20:835-43. 
 
 
 
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Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
 
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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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Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
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Appendix 1 
Schedule of Events – Group A 
Subjects Who Participated in Study 14-002 or 14-003 
Phase 
Screen
-ing/ 
Base-
line 
Titration 
Maintenance 
Early 
Terma 
Follow
-up 
 
 
 
Randomized 
Withdrawal 
Period 
 
 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
12.1* 
12.2* 
13 
14 
15 
16 
Time from Study 
Start 
Day/End of Week 
D -1 
D 3 
±1 
D 6 
±1 
D 9 
±1 
D 
12 
±1 
D 
15 
±2 
Wk 
2 
D 
43 
±7 
Wk 
6 
D 
71 
±7 
Wk 
10 
D 
99 
±7 
Wk 
14 
D 
127 
±7 
Wk 
18 
D 
155 
±7 
Wk 
22 
D 
190 
±7 
Wk 
27 
D 
197 
±3 
Wk 
28 
D 
204 
±7 
Wk 
29 
D 
218 
±7 
Wk 
31 
D 
246 
±7 
Wk 
35 
D 
281 
±7 
Wk 
40 
D 295 
±7  
Wk 42 
Clinic Visit 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
Phone Contact 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
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 
hematology, 
serum chemistry; 
urinalysis 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
 
Light breakfast 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
 
Urine drug screen 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
X 
 
Urine pregnancy 
test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
C-SSRS 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
Enroll via 
IVRS/IWRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomize via 
IVRS/IWRS 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
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Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
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Appendix 1 
Schedule of Events – Group A 
Subjects Who Participated in Study 14-002 or 14-003 
Phase 
Screen
-ing/ 
Base-
line 
Titration 
Maintenance 
Early 
Terma 
Follow
-up 
 
 
 
Randomized 
Withdrawal 
Period 
 
 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
12.1* 
12.2* 
13 
14 
15 
16 
Time from Study 
Start 
Day/End of Week 
D -1 
D 3 
±1 
D 6 
±1 
D 9 
±1 
D 
12 
±1 
D 
15 
±2 
Wk 
2 
D 
43 
±7 
Wk 
6 
D 
71 
±7 
Wk 
10 
D 
99 
±7 
Wk 
14 
D 
127 
±7 
Wk 
18 
D 
155 
±7 
Wk 
22 
D 
190 
±7 
Wk 
27 
D 
197 
±3 
Wk 
28 
D 
204 
±7 
Wk 
29 
D 
218 
±7 
Wk 
31 
D 
246 
±7 
Wk 
35 
D 
281 
±7 
Wk 
40 
D 295 
±7  
Wk 42 
Dispense Study 
Drug 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
Provide 
instructions for 
titration 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect study 
drug/assess 
compliance 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
X 
 
Concomitant meds 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review and 
remind to record 
primary OSA 
therapy use 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ESS 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
CGIc – Compared 
to Baselineb 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
PGIc – Since 
Started Treatmentb 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
CGIc – Compared 
to Beginning of 
RW Periodc 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
PGIc – Since Last 
Visitc 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
FOSQ-10 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
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Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
CONFIDENTIAL 
Page 93 of 120 
 
Appendix 1 
Schedule of Events – Group A 
Subjects Who Participated in Study 14-002 or 14-003 
Phase 
Screen
-ing/ 
Base-
line 
Titration 
Maintenance 
Early 
Terma 
Follow
-up 
 
 
 
Randomized 
Withdrawal 
Period 
 
 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
12.1* 
12.2* 
13 
14 
15 
16 
Time from Study 
Start 
Day/End of Week 
D -1 
D 3 
±1 
D 6 
±1 
D 9 
±1 
D 
12 
±1 
D 
15 
±2 
Wk 
2 
D 
43 
±7 
Wk 
6 
D 
71 
±7 
Wk 
10 
D 
99 
±7 
Wk 
14 
D 
127 
±7 
Wk 
18 
D 
155 
±7 
Wk 
22 
D 
190 
±7 
Wk 
27 
D 
197 
±3 
Wk 
28 
D 
204 
±7 
Wk 
29 
D 
218 
±7 
Wk 
31 
D 
246 
±7 
Wk 
35 
D 
281 
±7 
Wk 
40 
D 295 
±7  
Wk 42 
SF-36v2 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
EQ-5D-5L 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
WPAI:SHP 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
Resource 
Utilization 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Schedule next visit 
or phone contact 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
D=day; Wk=week 
Shaded columns indicate clinic visits. 
 
*When approximately 300 subjects are randomized into the randomized withdrawal period, no more subjects will be randomized into the period. All subjects 
who have not entered the randomized withdrawal period at that time will receive open-label JZP-110 treatment at Visit 12 and will not complete Visits 12.1 and 
12.2. 
a. 
If a subject withdraws or is withdrawn from the study after completing the Week 2 Visit (Visit 6) and no more than 3 days have passed since the subject’s last 
dose of study drug was taken, the Maintenance Phase Final Clinic Visit (Visit 15) procedures should be conducted.  If more than 3 days have passed since the 
subject’s last dose of study drug was taken, only the final safety assessments listed in the Early Termination column should be conducted (ESS, CGIc, PGIc, 
FOSQ-10, SF-36v2, EQ-5D-5L, WPAI:SHP, and Resource Utilization assessments are not required). 
If a subject withdraws or is withdrawn prior to completing the Week 2 Visit (Visit 6), only the final safety assessments listed in the Early Termination column 
should be conducted (ESS, CGIc, PGIc, FOSQ-10, SF-36v2, EQ-5D-5L, WPAI:SHP, and Resource Utilization assessments are not required).  
b.  
CGIc change from baseline version and PGIc change from start of treatment version should be used. 
c. 
CGIc change from the beginning of the randomized withdrawal (RW) period version and PGIc change from the last visit version should be used. 
 
CONFIDENTIAL
Page 93 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
CONFIDENTIAL 
Page 94 of 120 
 
 
Appendix 2 
Schedule of Events – Group B 
Subjects Who Participated in Study 14-004, 15-004, 15-005, ADX-N05 201, or 
ADX-N05 202 
Phase 
Screen-
ing 
Base-
line 
Titration 
Maintenance 
Early 
Terma 
Follow-
up 
 
 
Randomized 
Withdrawal 
Period 
 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
13.1* 
13.2* 
14 
15 
16 
17 
18 
19 
 
20 
Time from 
Study 
Start 
Day/End 
of Week 
D -30  
to -2 
D -1 
D 
3±1 
D 
6 
±1 
D 
9 
±1 
D 
12 
±1 
D 
15 
±2 
Wk 
2 
D 
43 
±7 
Wk 
6 
D 
71 
±7 
Wk 
10 
D 
99 
±7 
Wk 
14 
D 
127 
±7 
Wk 
18 
D 
155 
±7 
Wk 
22 
D 
183 
±7 
Wk 
26 
D 
190 
±3 
Wk 
27 
D 
197 
±7 
Wk 
28 
D 
211 
±7 
Wk 
30 
D 
239 
±7 
Wk 
34 
D 
274 
±7 
Wk 
39 
D 
302 
±7 
Wk 
43 
D 
330 
±7 
Wk 
47 
D 
365 
±7 
Wk 
52 
D 379 
±7  
Wk 54 
Clinic Visit 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
Phone 
Contact 
 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demo-
graphics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Exam-
ination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Instruct 
how to dis-
continue 
excluded 
medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
ECG 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
CONFIDENTIAL
Page 94 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
CONFIDENTIAL 
Page 95 of 120 
 
 
Appendix 2 
Schedule of Events – Group B 
Subjects Who Participated in Study 14-004, 15-004, 15-005, ADX-N05 201, or 
ADX-N05 202 
Phase 
Screen-
ing 
Base-
line 
Titration 
Maintenance 
Early 
Terma 
Follow-
up 
 
 
Randomized 
Withdrawal 
Period 
 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
13.1* 
13.2* 
14 
15 
16 
17 
18 
19 
 
20 
Time from 
Study 
Start 
Day/End 
of Week 
D -30  
to -2 
D -1 
D 
3±1 
D 
6 
±1 
D 
9 
±1 
D 
12 
±1 
D 
15 
±2 
Wk 
2 
D 
43 
±7 
Wk 
6 
D 
71 
±7 
Wk 
10 
D 
99 
±7 
Wk 
14 
D 
127 
±7 
Wk 
18 
D 
155 
±7 
Wk 
22 
D 
183 
±7 
Wk 
26 
D 
190 
±3 
Wk 
27 
D 
197 
±7 
Wk 
28 
D 
211 
±7 
Wk 
30 
D 
239 
±7 
Wk 
34 
D 
274 
±7 
Wk 
39 
D 
302 
±7 
Wk 
43 
D 
330 
±7 
Wk 
47 
D 
365 
±7 
Wk 
52 
D 379 
±7  
Wk 54 
Fasting 
hemat-
ology, 
serum 
chemistry; 
urinalysis 
X 
Xb 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
Light 
breakfast 
X 
Xb 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
Urine drug 
screen 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
 
Serum 
pregnancy 
test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine 
pregnancy 
test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
C-SSRS 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
Dispense 
study drug 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
Enroll via 
IVRS/ 
IWRS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomize 
via IVRS/ 
IWRS 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
Page 95 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
CONFIDENTIAL 
Page 96 of 120 
 
 
Appendix 2 
Schedule of Events – Group B 
Subjects Who Participated in Study 14-004, 15-004, 15-005, ADX-N05 201, or 
ADX-N05 202 
Phase 
Screen-
ing 
Base-
line 
Titration 
Maintenance 
Early 
Terma 
Follow-
up 
 
 
Randomized 
Withdrawal 
Period 
 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
13.1* 
13.2* 
14 
15 
16 
17 
18 
19 
 
20 
Time from 
Study 
Start 
Day/End 
of Week 
D -30  
to -2 
D -1 
D 
3±1 
D 
6 
±1 
D 
9 
±1 
D 
12 
±1 
D 
15 
±2 
Wk 
2 
D 
43 
±7 
Wk 
6 
D 
71 
±7 
Wk 
10 
D 
99 
±7 
Wk 
14 
D 
127 
±7 
Wk 
18 
D 
155 
±7 
Wk 
22 
D 
183 
±7 
Wk 
26 
D 
190 
±3 
Wk 
27 
D 
197 
±7 
Wk 
28 
D 
211 
±7 
Wk 
30 
D 
239 
±7 
Wk 
34 
D 
274 
±7 
Wk 
39 
D 
302 
±7 
Wk 
43 
D 
330 
±7 
Wk 
47 
D 
365 
±7 
Wk 
52 
D 379 
±7  
Wk 54 
Provide 
instructions 
for titration 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect 
study drug 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
 
Concom-
itant Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse 
Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ESS 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
CGIs 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGIc – 
Compared 
to 
Baselined 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
PGIc – 
Since 
Started 
Treatmentd 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
CGIc – 
Compared 
to 
Beginning 
of RW 
Periode 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
PGIc – 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
CONFIDENTIAL
Page 96 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
CONFIDENTIAL 
Page 97 of 120 
 
 
Appendix 2 
Schedule of Events – Group B 
Subjects Who Participated in Study 14-004, 15-004, 15-005, ADX-N05 201, or 
ADX-N05 202 
Phase 
Screen-
ing 
Base-
line 
Titration 
Maintenance 
Early 
Terma 
Follow-
up 
 
 
Randomized 
Withdrawal 
Period 
 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
13.1* 
13.2* 
14 
15 
16 
17 
18 
19 
 
20 
Time from 
Study 
Start 
Day/End 
of Week 
D -30  
to -2 
D -1 
D 
3±1 
D 
6 
±1 
D 
9 
±1 
D 
12 
±1 
D 
15 
±2 
Wk 
2 
D 
43 
±7 
Wk 
6 
D 
71 
±7 
Wk 
10 
D 
99 
±7 
Wk 
14 
D 
127 
±7 
Wk 
18 
D 
155 
±7 
Wk 
22 
D 
183 
±7 
Wk 
26 
D 
190 
±3 
Wk 
27 
D 
197 
±7 
Wk 
28 
D 
211 
±7 
Wk 
30 
D 
239 
±7 
Wk 
34 
D 
274 
±7 
Wk 
39 
D 
302 
±7 
Wk 
43 
D 
330 
±7 
Wk 
47 
D 
365 
±7 
Wk 
52 
D 379 
±7  
Wk 54 
Since Last 
Visite 
FOSQ-10 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
SF-36v2 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
WPAI:SHP 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Resource 
Utilization 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Review 
and remind 
to record 
primary 
OSA 
therapy 
usec 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Schedule 
next visit 
or phone 
contact 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
D=day; Wk=week 
 
Shaded columns indicate clinic visits. 
*When approximately 300 subjects are randomized into the randomized withdrawal period, no more subjects will be randomized into the period. All 
subjects who have not entered the randomized withdrawal period at that time will receive open-label JZP-110 treatment at Visit 13 and will not 
complete Visits 13.1 and 13.2 
 
CONFIDENTIAL
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Signature Date: 20161130
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Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
  
 
 
 
 
CONFIDENTIAL 
Page 98 of 120 
 
a. 
If a subject withdraws or is withdrawn from the study after completing the Week 2 Visit (Visit 7) and no more than 3 days have passed since the 
subject’s last dose of study drug was taken, the Maintenance Phase Final Clinic Visit procedures should be conducted (Visit 19). If more than 3 days 
have passed since the subject’s last dose of study drug was taken, only the final safety assessments listed in the Early Termination column should be 
conducted (ESS, CGIc, PGIc, FOSQ, SF-36 v2, ED-5D-5L, WPAI:SHP and Resource Utilization assessments are not required). 
If a subject withdraws or is withdrawn prior to completing the Week 2 Visit (Visit 7), only the final safety assessments listed in the Early Termination 
column should be conducted (ESS, CGIc, PGIc, FOSQ, SF-36 v2, ED-5D-5L, WPAI:SHP and Resource Utilization assessments are not required).  
b. If the Baseline (Day -1) visit occurs more than 28 days after the Screening visit, obtain fasting blood samples for serum chemistry and hematology and a 
urine sample for urinalysis. Provide a light breakfast for subjects who have their blood drawn. 
c. 
Review and reminders regarding primary OSA therapy use only apply to subjects with OSA from the 14-004 and 15-004 studies. 
d. CGIc change from baseline version and PGIc change from start of treatment version should be used. 
e. 
CGIc change from the beginning of the randomized withdrawal (RW) period version and PGIc change from the last visit version should be used. 
CONFIDENTIAL
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Signature Date: 20161130
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Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
   
 
 
 
 
 
CONFIDENTIAL 
Page 99 of 120 
 
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. 
CONFIDENTIAL
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
   
 
 
 
 
 
CONFIDENTIAL 
Page 100 of 120 
 
2. Decreased need for sleep (e.g., feels rested after only 3 hours of sleep). 
3. More talkative than usual or pressure to keep talking. 
4. Flight of ideas or subjective experience that thoughts are racing. 
5. Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external 
stimuli), as reported or observed. 
6. Increase in goal-directed activity (either socially, at work or school, or sexually) or 
psychomotor agitation. 
7. Excessive involvement in activities that have a high potential for painful 
consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or 
foolish business investments). 
C. The episode is associated with an unequivocal change in functioning that is 
uncharacteristic of the individual when not symptomatic. 
D. The disturbance in mood and the change in functioning are observable by others. 
E. The episode is not severe enough to cause marked impairment in social or occupational 
functioning or to necessitate hospitalization. If there are psychotic features, the episode 
is, by definition, manic. 
F. The episode is not attributable to the physiological effects of a substance (e.g., a drug of 
abuse, a medication, 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. 
1. Depressed mood most of the day, nearly every day, as indicated by either subjective 
report (e.g., feels sad, empty, or hopeless) or observation made by others (e.g., 
appears tearful). (Note: In children and adolescents, can be irritable mood.) 
2. Markedly diminished interest or pleasure in all, or almost all, activities most of the 
day, nearly every day (as indicated by either subjective account or observation). 
3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 
5% of body weight in a month), or decrease or increase in appetite nearly every day. 
(Note: In children, consider failure to make expected weight gain.) 
4. Insomnia or hypersomnia nearly every day. 
5. Psychomotor agitation or retardation nearly every day (observable by others; not 
merely subjective feelings of restlessness or being slowed down). 
6. Fatigue or loss of energy nearly every day. 
7. Feelings of worthlessness or excessive or inappropriate guilt (which may be 
delusional) nearly every day (not merely self-reproach or guilt about being sick). 
8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (either 
by subjective account or as observed by others). 
9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation 
without a specific plan, or a suicide attempt or a specific plan for committing suicide. 
B. The symptoms cause clinically significant distress or impairment in social, occupational, 
or other important areas of functioning. 
C. The episode is not attributable to the physiological effects of a substance or another 
medical condition.  
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
   
 
 
 
 
 
CONFIDENTIAL 
Page 101 of 120 
 
 
Bipolar I Disorder 
A. Criteria have been met for at least one manic episode (Criteria A–D under “Manic 
Episode” above). 
B. The occurrence of the manic and major depressive episode(s) is not better explained 
by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional 
disorder, or other specified or unspecified schizophrenia spectrum and other 
psychotic disorder. 
Bipolar II Disorder 
Diagnostic Criteria 
For a diagnosis of bipolar II disorder, it is necessary to meet the following criteria for a 
current or past hypomanic episode and the following criteria for a current or past major 
depressive episode: 
Hypomanic Episode 
A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood 
and abnormally and persistently increased activity or energy, lasting at least 4 
consecutive days and present most of the day, nearly every day. 
B. During the period of mood disturbance and increased energy and activity, three (or more) 
of the following symptoms have persisted (four if the mood is only irritable), represent a 
noticeable change from usual behavior, and have been present to a significant degree: 
1. Inflated self-esteem or grandiosity. 
2. Decreased need for sleep (e.g., feels rested after only 3 hours of sleep). 
3. More talkative than usual or pressure to keep talking. 
4. Flight of ideas or subjective experience that thoughts are racing. 
5. Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external 
stimuli), as reported or observed. 
6. Increase in goal-directed activity (either socially, at work or school, or sexually) or 
psychomotor agitation. 
7. Excessive involvement in activities that have a high potential for painful 
consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or 
foolish business investments). 
C. The episode is associated with an unequivocal change in functioning that is 
uncharacteristic of the individual when not symptomatic.  
D. The disturbance in mood and the change in functioning are observable by others. 
E. The episode is not severe enough to cause marked impairment in social or occupational 
functioning or to necessitate hospitalization. If there are psychotic features, the episode 
is, by definition, manic. 
F. The episode is not attributable to the physiological effects of a substance (e.g., a drug of 
abuse, a medication or other treatment). 
CONFIDENTIAL
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
   
 
 
 
 
 
CONFIDENTIAL 
Page 102 of 120 
 
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. 
CONFIDENTIAL
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Signature Date: 20161130
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
   
 
 
 
 
 
CONFIDENTIAL 
Page 103 of 120 
 
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). 
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B. An episode of the disorder lasts at least 1 month but less than 6 months. When the 
diagnosis must be made without waiting for recovery, it should be qualified as 
“provisional.” 
C. Schizoaffective disorder and depressive or bipolar disorder with psychotic features 
have been ruled out because either 1) no major depressive or manic episodes have 
occurred concurrently with the active-phase symptoms, or 2) if mood episodes have 
occurred during active-phase symptoms, they have been present for a minority of the 
total duration of the active and residual periods of the illness.  
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). 
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Schizoaffective Disorder 
Diagnostic Criteria 
A. An uninterrupted period of illness during which there is a major mood episode (major 
depressive or manic) concurrent with Criterion A of schizophrenia. 
Note: The major depressive episode must include Criterion A1: Depressed mood. 
B. Delusions or hallucinations for 2 or more weeks in the absence of a major mood 
episode (depressive or manic) during the lifetime duration of the illness.  
C. Symptoms that meet criteria for a major mood episode are present for the majority of 
the total duration of the active and residual portions of the illness. 
D. The disturbance is not attributable to the effects of a substance (e.g., a drug of abuse, 
a medication) or another medical condition. 
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental 
disorders (5th ed.). Washington, DC. 
 
 
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CONFIDENTIAL 
Page 106 of 120 
 
Appendix 4 
DSM-5 Substance Use Disorder Diagnostic Criteria 
The following criteria are adapted from the DSM-5 criteria for substance use disorders and 
are presented as a resource, if needed for screening subjects. The full DSM Edition 5 
(DSM-5) criteria for substance use 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. 
CONFIDENTIAL
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
   
 
 
 
 
 
CONFIDENTIAL 
Page 107 of 120 
 
Appendix 5 
Epworth Sleepiness Scale (ESS) 
 
 
CONFIDENTIAL
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Signature Date: 20161130
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Epworth Sleepiness Scale 
 
 
 
Name:   
 Today’s date:   
 
 
Your age (Yrs):   
 Your  sex (Male = M, Female = F):   
 
 
 
 
How likely are you to doze off or fall asleep in the following situations, in contrast to feeling just 
tired? 
 
This refers to your usual way of life in the past week. 
 
Even if you haven’t done some of these things recently try to work out how they would have affected 
you. 
 
Use the following scale to choose the most appropriate number for each situation: 
 
0  =  would never doze 
1  =  slight chance of dozing 
2  =  moderate chance of dozing 
3  =  high chance of dozing 
 
It is important that you answer each question as best you can. 
 
Situation  
Chance of Dozing (0-3) 
 
 
 
Sitting and reading 
  
 
 
Watching TV 
  
 
 
Sitting, inactive in a public place (e.g. a theatre or a meeting) 
  
 
 
As a passenger in a car for an hour without a break 
  
 
 
Lying down to rest in the afternoon when circumstances permit     
 
 
Sitting and talking to someone     
 
 
Sitting quietly after a lunch without alcohol     
 
 
In a car, while stopped for a few minutes in the traffic    
 
 
 
 
 
THANK YOU FOR YOUR COOPERATION 
 
 M.W. Johns 1990-
97 
CONFIDENTIAL
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JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
   
 
 
 
 
 
CONFIDENTIAL 
Page 108 of 120 
 
Appendix 6 
Functional Outcomes of Sleep Questionnaire Short 
Version (FOSQ-10) 
 
 
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Signature Date: 20161130
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©Weaver, June, 2004 
fosq.97 updated 6/04 
Functional Outcomes of Sleep Questionnaire (FOSQ ) short 
Page 1 
FUNCTIONAL OUTCOMES OF SLEEP QUESTIONNAIRE 
(FOSQ) 
Some people have difficulty performing everyday activities when they feel tired or sleepy.  The 
purpose of this questionnaire is to find out if you generally have difficulty carrying out certain 
activities because you are too sleepy or tired.  In this questionnaire, when the words “sleepy” or 
“tired” are used, it means the feeling that you can’t keep your eyes open, your head is droopy, 
that you want to “nod off”, or that you feel the urge to take a nap.  These words do not refer to 
the tired or fatigued feeling you may have after you have exercised. 
DIRECTIONS: Please put an (X) in the box for your answer to each question.  Select only one 
answer for each question.  Please try to be as accurate as possible.  All information will be kept 
confidential.  
(0) 
I don’t do 
this 
activity 
for other 
reasons 
(4) 
No 
difficulty 
 (3) 
Yes, 
a little 
difficulty 
(2) 
Yes, 
moderate 
difficulty 
(1) 
Yes, 
extreme 
difficulty 
1. Do you have difficulty concentrating on the
things you do because you are sleepy or tired? 
! 
! 
! 
!
2. Do you generally have difficulty
remembering things, because you are sleepy or 
tired? 
! 
! 
! 
!
3. Do you have difficulty operating a motor
vehicle for short distances (less than 100 miles) 
because you become sleepy or tired? 
! 
! 
! 
! 
!
4. Do you have difficulty operating a motor
vehicle for long distances (greater than 100  
miles) because you become sleepy or tired? 
! 
! 
! 
! 
!
CONFIDENTIAL
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Signature Date: 20161130
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©Weaver, June, 2004 
fosq.97 updated 6/04 
Functional Outcomes of Sleep Questionnaire (FOSQ ) short 
Page 2 
(0) 
I don’t do this 
activity for 
other reasons 
(4) 
No 
difficulty 
 (3) 
Yes, 
a little 
difficulty 
(2) 
Yes, 
moderate 
difficulty 
(1) 
Yes, 
extreme 
difficulty 
5. Do you have difficulty visiting with your
family or friends in their home because you 
become sleepy or tired? 
! 
! 
! 
! 
!
6. Has your relationship with family, friends
or work colleagues been affected because you 
are sleepy or tired?
! 
! 
! 
!
!
7. Do you have difficulty watching a movie
or videotape because you become sleepy or 
tired? 
! 
! 
! 
! 
!
8. Do you have difficulty being as active as
you want to be in the evening because you are 
sleepy or tired? 
! 
! 
! 
!
9. Do you have difficulty being as
active as you want to be in the morning 
because you are sleepy or tired? 
! 
! 
! 
!
(0) 
I don’t 
engage in 
sexual 
activity for 
other reasons 
(4) 
No 
(3) 
Yes, 
a 
little 
(2) 
Yes, 
moderately 
(1) 
Yes, 
extremely 
10. Has your desire for intimacy or sex
been affected because you are sleepy or tired? 
!
! 
! 
! 
!
Thank you for completing this questionnaire.
CONFIDENTIAL
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Signature Date: 20161130
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Signature Date:
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JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
   
 
 
 
 
 
CONFIDENTIAL 
Page 109 of 120 
 
Appendix 7 
36-Item Short Form Health Survey Version 2 
(SF-36v2) 
 
 
 
CONFIDENTIAL
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Signature Date: 20161130
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Signature Date:
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SF-36v2™ Health Survey  1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
 
Your Health and Well-Being 
 
 
This survey asks for your views about your health.  This information will help 
keep track of how you feel and how well you are able to do your usual 
activities.  Thank you for completing this survey! 
For each of the following questions, please mark an 
 in the one box that best 
describes your answer. 
1. In general, would you say your health is: 
 
Excellent 
Very good 
Good 
Fair 
Poor 
 
 
 
 
 
  
1 
 
2 
 
3 
 
4 
 
5 
 
2. Compared to one year ago, how would you rate your health in general 
 
now? 
 
Much better 
now than one 
year ago 
Somewhat 
better now 
than one year 
ago 
About the 
same as one 
year ago 
Somewhat 
worse now 
than one year 
ago 
Much worse 
now than one 
year ago 
 
 
 
 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
CONFIDENTIAL
Page 113 of 142


Signature Date: 20161130
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Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
 
SF-36v2™ Health Survey  1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
 
 
 
3. The following questions are about activities you might do during a typical 
day.  Does your health now limit you in these activities?  If so, how much? 
 
Yes, 
limited 
a lot 
Yes, 
limited 
a little 
No, not 
limited 
at all 
 
 
 
 
a  Vigorous activities, such as running, lifting  
 heavy objects, participating in strenuous  
 sports ....................................................................
1...................
2 ..................
3 
 
b   Moderate activities, such as moving a table,  
  pushing a vacuum cleaner, bowling, or  
 playing golf ...........................................................
1...................
2 ..................
3 
 
c   Lifting or carrying groceries ..................................
1...................
2 ..................
3 
 
d  Climbing several flights of stairs............................
1...................
2 ..................
3 
 
e  Climbing one flight of stairs...................................
1...................
2 ..................
3 
 
f  Bending, kneeling, or stooping...............................
1...................
2 ..................
3 
 
g Walking more than a mile ......................................
1...................
2 ..................
3
 
h Walking several hundred yards..............................
1...................
2 ..................
3
 
i Walking one hundred yards ....................................
1...................
2 ..................
3
 
j  Bathing or dressing yourself...................................
1...................
2 ..................
3
 
CONFIDENTIAL
Page 114 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
 
SF-36v2™ Health Survey  1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
 
4. During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of your physical health? 
 
 
All of 
the time
Most of 
the time
Some of 
the time 
A little 
of the 
time 
None of 
the time
 
 
 
 
 
a  Cut down on the amount of time you spent  
on work or other activities.......................................
1.........
2........
3.........
4.........
5 
b  Accomplished less than you would like .................
1.........
2........
3.........
4.........
5 
 
c  Were limited in the kind of work or other  
    activities.................................................................
1.........
2........
3.........
4.........
5 
d  Had difficulty performing the work or other  
  activities (for example, it took extra effort) ...........
1.........
2........
3.........
4.........
5 
 
5. During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of any emotional problems (such as feeling depressed or anxious)? 
 
All of 
the time
Most of 
the time
Some of 
the time 
A little 
of the 
time 
None of 
the time
 
 
 
 
 
 
a  Cut down on the amount of time you spent  
 on work or other activities ....................................
1 .........
2 ........
3..........
4.........
5 
b  Accomplished less than you would like................
1 .........
2 ........
3..........
4.........
5 
 
c  Did work or other activities less carefully  
 than usual...............................................................
1 .........
2 ........
3..........
4.........
5 
 
CONFIDENTIAL
Page 115 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
 
SF-36v2™ Health Survey  1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
6. During the past 4 weeks, to what extent has your physical health or 
emotional problems interfered with your normal social activities with 
family, friends, neighbors, or groups? 
Not at all 
Slightly 
Moderately 
Quite a bit 
Extremely 
 
 
 
 
 
 
1 
 
2 
 
3 
  
4 
 
5 
 
7. How much bodily pain have you had during the past 4 weeks? 
None 
Very mild 
Mild 
Moderate 
Severe 
Very Severe 
 
 
 
 
 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
8. During the past 4 weeks, how much did pain interfere with your normal 
work (including both work outside the home and housework)? 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 
 
 
 
 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
CONFIDENTIAL
Page 116 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
 
SF-36v2™ Health Survey  1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
 
9. These questions are about how you feel and how things have been with you 
during the past 4 weeks.  For each question, please give the one answer that 
comes closest to the way you have been feeling.  How much of the time 
during the past 4 weeks... 
 
All of 
the time
Most of 
the time
Some of 
the time 
A little 
of the 
time 
None of 
the time
 
 
 
 
 
 
 
a   Did you feel full of life? ......................................
1..........
2 ..........
3..........
4 ..........
5
b  Have you been very nervous?..............................
1..........
2 ..........
3..........
4 ..........
5
 
c  Have you felt so down in the dumps  
 that nothing could cheer you up? .........................
1..........
2 ..........
3..........
4 ..........
5
d  Have you felt calm and peaceful?........................
1..........
2 ..........
3..........
4 ..........
5
 
e  Did you have a lot of energy?..............................
1..........
2 ..........
3..........
4 ..........
5
 
f  Have you felt downhearted and  
 depressed?............................................................
1..........
2 ..........
3..........
4 ..........
5
 
g  Did you feel worn out? ........................................
1..........
2 ..........
3..........
4 ..........
5
 
h  Have you been happy?.........................................
1..........
2 ..........
3..........
4 ..........
5
 
i  Did you feel tired?................................................
1..........
2 ..........
3..........
4 ..........
5
 
 
10.  During the past 4 weeks, how much of the time has your physical health  
or emotional problems interfered with your social activities (like visiting 
friends, relatives, etc.)? 
All of the 
time 
Most of the 
time 
Some of the 
time 
A little of the 
time 
None of the 
time 
 
 
 
 
 
 
1 
 
2 
 
3 
  
4 
 
5 
 
CONFIDENTIAL
Page 117 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
 
SF-36v2™ Health Survey  1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
11.   How TRUE or FALSE is each of the following statements for you? 
 
Definitely 
true 
Mostly 
true 
Don't 
know 
Mostly 
false 
Definitely 
false 
 
 
 
 
 
 
a  I seem to get sick a little easier  
 than other people....................................
1............
2 ...........
3 ...........
4 ...........
5 
b  I am as healthy as anybody I know........
1............
2 ...........
3 ...........
4 ...........
5 
c  I expect my health to get worse .............
1............
2 ...........
3 ...........
4 ...........
5 
d  My health is excellent............................
1............
2 ...........
3 ...........
4 ...........
5
 
 
THANK YOU FOR COMPLETING THESE QUESTIONS! 
 
CONFIDENTIAL
Page 118 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
   
 
 
 
 
 
CONFIDENTIAL 
Page 110 of 120 
 
Appendix 8 
EuroQoL EQ-5D-5L 
The version attached is an example. The US English language version will be used in the US.  
CONFIDENTIAL
Page 119 of 142


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Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
   
 
 
 
 
 
CONFIDENTIAL 
Page 111 of 120 
 
Appendix 9 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Baseline/Screening Version 
 
 
 
CONFIDENTIAL
Page 123 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
 
 
 
 
 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS)  
Baseline/Screening Version 
Version 1/14/09 
 
  
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained in 
the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of suicidal 
ideation or behavior depends on the judgment of the individual administering the scale. 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History Form, 
developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
CONFIDENTIAL
Page 124 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to 
question 2 is “yes”, ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete 
“Intensity of Ideation” section below. 
Lifetime: Time 
He/She Felt 
Most Suicidal 
Past __ 
Months 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
If yes, describe: 
 
Yes       No 
□    □ 
 
Yes     No 
□   □ 
2.  Non-Specific Active Suicidal Thoughts 
General non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts 
of ways to kill oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
    Yes       No 
   □    □ 
 
Yes     No 
□   □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a 
specific plan with time, place or method details worked out (e.g.  thought of method to kill self but not a specific plan).  Includes person 
who would say, “I thought about taking an overdose but I never made a specific plan as to when, where or how I would actually do 
it…and I would never go through with it.” 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 
    Yes      No 
 □    □ 
 
Yes     No 
□   □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the 
thoughts but I definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
 
If yes, describe: 
 
 
   Yes      No 
□    □ 
 
Yes     No 
□   □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
   
If yes, describe: 
 
 
   Yes       No 
 □    □ 
 
Yes     No 
□   □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being 
the least severe and 5 being the most severe).  Ask about time he/she was feeling the most suicidal.  
                                   
Lifetime -           Most Severe Ideation:  _______                  ________________________________________ 
                                                                       Type # (1-5)                                                 Description of  Ideation 
 
Past X Months - Most Severe Ideation:  _______                   ________________________________________ 
                                                                      Type # (1-5)                                                 Description of  Ideation 
Most  
Severe 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
 
 
____ 
 
 
____ 
Duration 
When you have the thoughts how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time 
____ 
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts  with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to 
die or acting on thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
____ 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain 
or stop the way you were feeling (in other words you couldn’t go on living with this pain or how you were 
feeling) or was it to get attention, revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain                                                                         living with the pain or  how you were feeling) 
                                                                                                                 (0)  Does not apply 
 
 
____ 
 
 
____ 
 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Baseline/Screening (Version 1/14/09)    
 
 
                             Page 1 of 2     
CONFIDENTIAL
Page 125 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
 
Lifetime 
Past __ 
Years 
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill 
oneself. Intent does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide 
attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in 
mouth but gun is broken so no injury results, this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a 
highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a 
high floor/story). Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or Did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better,  
get sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes     No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
□   □ 
Yes     No 
□   □ 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would 
have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted 
attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once 
they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. 
Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before 
you actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
 
Total # of 
interrupted 
 
______ 
 
Yes     No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-
destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by 
something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
aborted 
 
______ 
Yes     No 
□   □ 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as 
assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a 
suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, 
getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
 
Yes      No 
□   □ 
 
 
Yes     No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Yes     No 
□   □ 
Answer for Actual Attempts Only 
Most Recent 
Attempt 
Date: 
Most Lethal        
Attempt 
Date: 
Initial/First 
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes 
intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree 
burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had 
potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying 
on train tracks with oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Baseline/Screening (Version 1/14/09)    
 
 
                             Page 2 of 2     
CONFIDENTIAL
Page 126 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
   
 
 
 
 
 
CONFIDENTIAL 
Page 112 of 120 
 
Appendix 10 
Work Productivity and Activity Impairment 
Questionnaire: Specific Health Problem V2.0 
(WPAI:SHP) 
For narcolepsy 
 
For OSA 
 
 
 
CONFIDENTIAL
Page 127 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
Work Productivity and Activity Impairment Questionnaire:
Specific Health Problem V2.0 (WPAI:SHP)
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CONFIDENTIAL
Page 128 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
5HLOO\0&=EUR]HN$6'XNHV(7KHYDOLGLW\DQGUHSURGXFLELOLW\RIDZRUNSURGXFWLYLW\DQGDFWLYLW\LPSDLUPHQWPHDVXUH
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Think about days you were limited in the amount or kind of work you could do, days 
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CONFIDENTIAL
Page 129 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
Work Productivity and Activity Impairment Questionnaire:
Specific Health Problem V2.0 (WPAI:SHP)
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CONFIDENTIAL
Page 130 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
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By regular activities, we mean the usual activities you do, such as work around the 
house, shopping, childcare, exercising, studying, etc.  Think about times you were 
limited in the amount or kind of activities you could do and times you accomplished 
less than you would like.  If OSA affected your activities only a little, choose a low 
number.  Choose a high number if OSA affected your activities a great deal.  
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CONFIDENTIAL
Page 131 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
   
 
 
 
 
 
CONFIDENTIAL 
Page 113 of 120 
 
Appendix 11 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Since Last Visit Version 
 
 
 
CONFIDENTIAL
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Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.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 133 of 142


Signature Date: 20161130
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Signature Date:
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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. 
 
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
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Signature Date: 20161130
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Signature Date:
JP: Protocol 14-005 Amendment 4.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 135 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
   
 
 
 
 
 
CONFIDENTIAL 
Page 114 of 120 
 
Appendix 12 
Clinical Global Impression of Severity (CGIs) 
Check if Not Done □ 
 
CGI – SEVERITY 
(Choose only one) 
 
Considering your total clinical experience with this patient population, how ill is the patient at this 
time?  
 
□ 
1. Normal, not at all ill 
□ 
2. Borderline ill 
□ 
3. Mildly ill 
□ 
4. Moderately ill 
□ 
5. Markedly ill 
□ 
6. Severely ill 
□ 
7. Among the most extremely ill patients 
 
 
CONFIDENTIAL
Page 136 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
   
 
 
 
 
 
CONFIDENTIAL 
Page 115 of 120 
 
Appendix 13 
Clinical Global Impression of Change (CGIc) 
Check if Not Done □ 
 
CGI – CHANGE 
Compared to the subject’s condition at BASELINE, 
how much has he/she changed?  
(Choose only one) 
 
□  1. Very much improved 
□  2. Much improved 
□  3. Minimally improved 
□  4. No change 
□  5. Minimally worse 
□  6. Much worse 
□  7. Very much worse 
 
 
 
CONFIDENTIAL
Page 137 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
   
 
 
 
 
 
CONFIDENTIAL 
Page 116 of 120 
 
Appendix 14 
Clinical Global Impression of Change (CGIc) - Week 29 
(Group A) or Week 28 (Group B) 
 
CGI – CHANGE FROM WEEK 27 TO WEEK 29 (Group A) or CHANGE FROM WEEK 26 
TO WEEK 28 (Group B) 
Check if Not Done □ 
 
Compared to the subject’s condition at the BEGINNING OF THE RANDOMIZED 
WITHDRAWAL PERIOD, 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 138 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
   
 
 
 
 
 
CONFIDENTIAL 
Page 117 of 120 
 
Appendix 15 
Patient Global Impression of Change (PGIc) 
Check if Not Done □ 
 
PGI – CHANGE 
(Choose only one) 
 
Since you STARTED study treatment, your OVERALL condition is:  
 
□  1. Very much improved 
□  2. Much improved 
□  3. Minimally improved 
□  4. No change 
□  5. Minimally worse 
□  6. Much worse 
□  7. Very much worse 
 
 
 
 
CONFIDENTIAL
Page 139 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
   
 
 
 
 
 
CONFIDENTIAL 
Page 118 of 120 
 
Appendix 16 
Patient Global Impression of Change (PGIc) - Week 29 
(Group A) or Week 28 (Group B) 
 
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 140 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
   
 
 
 
 
 
CONFIDENTIAL 
Page 119 of 120 
 
Appendix 17 
Resource Utilization Questionnaire 
In the past 3 months, how many times did you visit the following types of physicians for your 
own care (not related to this study): 
Primary care physician 
 
 
 
 
 
 
_____ Visits in past 3 months  
Sleep specialist 
 
 
 
 
 
 
 
 
_____ Visits in past 3 months 
Psychiatrist (for problems other than sleep)  
_____ Visits in past 3 months 
Ear nose and throat specialist  
 
 
 
 
_____ Visits in past 3 months 
Other type of specialist (please specify)  
 
_____ Visits in past 3 months 
________________________________ 
 
 
CONFIDENTIAL
Page 141 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
Signature Date:
JP: Protocol 14-005 Amendment 4.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-005 Amendment 4 
 
   
 
 
 
 
 
CONFIDENTIAL 
Page 120 of 120 
 
Appendix 18 
Signatures of Agreement for Protocol 
Study Title: 
A Long-Term Safety and Maintenance of Efficacy Study of JZP-110 [(R)-
2-amino-3-phenylpropylcarbamate hydrochloride] in the Treatment of 
Excessive Sleepiness in Subjects with Narcolepsy or Obstructive Sleep 
Apnea 
Study Number: 
14-005 
Original Protocol: 
18 December 2014 
Amendment 1: 
18 February 2015 
Amendment 2: 
11 September 2015 
Amendment 3: 
02 February 2016 
Amendment 4: 
17 November 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 142 of 142


Signature Date: 20161130
JP: Protocol 14-005 Amendment 4.pdf
 
 
 
Signature Manifestation 
 

SAP_001.pdf: 
Statistical Analysis Plan 
 
Page 1 of 76 
Sponsor Name:  
Jazz Pharmaceuticals
Protocol Number: 
14-005
Protocol Title:  
A Long-Term Safety and Maintenance of 
Efficacy Study of JZP-110 [(R)-2-amino-3-
phenylpropylcarbamate hydrochloride] in the 
Treatment of Excessive Sleepiness in Subjects 
with Narcolepsy or Obstructive Sleep Apnea 
 
Protocol Version and Date: 
Original protocol, 18 December 2014 
Amendment 1, 18 February 2015 
Amendment 2, 11 September 2015 
 
Amendment 3, 2 February 2016 
Amendment 4, 17 November 2016 
 
 
 
 
SAP Version: 
 1.0
SAP Version Date:  
31 March, 2017
 
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.  
 
 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 2 of 76 
 
Version: 
____1.0_______ 
Version Date: 
_____31 March 2017__________ 
 
I confirm that I have reviewed this document and agree with the content. 
 
 
 
 
APPROVALS
Jazz Pharmaceuticals
 
Approved by:
                      
                      
Date
Approved by:
                      
                      
Date
 
 
 
 
 
 
 
 
 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 3 of 76 
 
 
TABLE OF CONTENTS 
1. 
ABBREVIATIONS........................................................................................ 7 
2. 
PURPOSE .................................................................................................... 9 
3. 
STUDY OBJECTIVES ................................................................................10 
3.1. 
Primary Objective(s) ........................................................................................................... 10 
3.2. 
Secondary Objective(s) ...................................................................................................... 10 
3.3. 
Study Design ....................................................................................................................... 10 
3.4. 
Determination of Sample Size ........................................................................................... 24 
3.5. 
Randomization and Stratification ...................................................................................... 24 
3.6. 
Administration of Study Medication ................................................................................. 25 
4. 
ENDPOINTS ...............................................................................................26 
4.1. 
Placebo-Controlled Randomized Withdrawal Period ...................................................... 26 
4.1.1. 
Efficacy Endpoints ........................................................................................................ 26 
4.1.2. 
Functional Outcomes and Quality of Life Endpoints .................................................... 26 
4.1.3. 
Use of primary OSA therapy ........................................................................................ 26 
4.2. 
Open-label (OL) Phases ..................................................................................................... 26 
4.2.1. 
Efficacy Endpoints ........................................................................................................ 26 
4.2.2. 
Functional Outcomes and Quality of Life Endpoints .................................................... 27 
4.2.3. 
Use of Primary OSA Therapy ....................................................................................... 28 
4.2.4. 
Economic Assessments Endpoints .............................................................................. 28 
4.3. 
Pharmacokinetic Endpoints .............................................................................................. 29 
4.4. 
Pharmacodynamic Endpoints ........................................................................................... 29 
4.5. 
Safety Endpoints ................................................................................................................. 29 


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Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 4 of 76 
5. 
STATISTICAL HYPOTHESES FOR TRIAL OBJECTIVES ........................30 
5.1. 
Maintenance of Efficacy Endpoints from the placebo-controlled randomized 
withdrawal period ............................................................................................................................ 30 
5.2. 
Maintenance of Efficacy Endpoints from the Open-label (OL) phases ......................... 31 
6. 
ANALYSIS POPULATIONS .......................................................................32 
6.1. 
Safety Population ................................................................................................................ 32 
6.2. 
Modified Intent-to-treat Population ................................................................................... 32 
6.3. 
Per-Protocol Population ..................................................................................................... 32 
7. 
EFFICACY ASSESSMENTS ......................................................................33 
7.1. 
Epworth Sleepiness Scale (ESS) ....................................................................................... 33 
7.2. 
Clinician Global Impression of Severity (CGIs) ................................................................ 33 
7.3. 
Clinician Global Impression of Change (CGIc) ................................................................. 34 
7.4. 
Patient Global Impression of Change (PGIc) .................................................................... 34 
7.5. 
Functional Outcomes of Sleep Questionnaire Short Version (FOSQ-10) ..................... 34 
7.6. 
36-Item Short Form Health Survey Version 2 (SF-36v2) ................................................. 35 
7.7. 
EuroQoL (EQ-5D-5L) ........................................................................................................... 35 
7.8. 
Primary OSA Therapy Use ................................................................................................. 36 
7.9. 
Work Productivity and Activity Impairment Questionnaire: Specific Health Problem 
V2.0 (WPAI:SHP) .............................................................................................................................. 36 
7.10. 
Resource Utilization Questionnaire .................................................................................. 36 
8. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS .............................37 
8.1. 
General Methods ................................................................................................................. 37 
8.2. 
Key Definitions .................................................................................................................... 38 
8.2.4. 
JZP-110 Exposure ....................................................................................................... 39 
8.2.5. 
Study Phases and Periods ........................................................................................... 39 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
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8.3. 
Visit Windows ...................................................................................................................... 39 
8.4. 
Missing Data ........................................................................................................................ 43 
8.4.1. 
Placebo-Controlled Randomized Withdrawal Period ................................................... 43 
8.4.2. 
Open-label (OL) Phases .............................................................................................. 43 
8.5. 
Level of Significance and Multiplicity Adjustment .......................................................... 43 
8.6. 
Pooling of Centers and Region ......................................................................................... 44 
8.7. 
Subgroups and Subgroup Analysis .................................................................................. 44 
9. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION ........................................................................................................47 
9.1. 
Subject Disposition and Withdrawals ............................................................................... 47 
9.2. 
Demographic and Other Baseline Characteristics .......................................................... 47 
9.3. 
Medical/Surgical History .................................................................................................... 48 
9.4. 
Medication/Procedure ........................................................................................................ 48 
9.4.1. 
Prior and Concomitant Medication/Procedure ............................................................. 48 
9.4.2. 
Prior Medication ........................................................................................................... 48 
9.4.3. 
Concomitant Medication and Procedure ...................................................................... 49 
9.5. 
Protocol Deviations ............................................................................................................ 49 
10. 
EFFICACY ..................................................................................................50 
10.1. 
ESS Score: Primary Efficacy Endpoint and Analyses .................................................... 50 
10.1.1. 
Placebo-Controlled Randomized Withdrawal Period ................................................... 50 
10.1.2. 
Open-label (OL) Phases .............................................................................................. 53 
10.1.3. 
Subgroup Analyses ...................................................................................................... 53 
10.2. 
CGIc: Clinical Global Impression of change ..................................................................... 54 
10.2.1. 
Placebo-Controlled Randomized Withdrawal Period ................................................... 54 
10.2.2. 
Open-label (OL) Phases .............................................................................................. 54 
10.2.3. 
Subgroup Analyses ...................................................................................................... 54 
10.3. 
PGIc: Patient Global Impression of Change ..................................................................... 54 
10.3.1. 
Placebo-Controlled Randomized Withdrawal Period ................................................... 54 
10.3.2. 
Open-label (OL) Phases .............................................................................................. 55 
10.3.3. 
Subgroup Analysis ....................................................................................................... 55 
10.4. 
Functional Outcomes and Quality of Life Endpoints ...................................................... 56 
10.4.1. 
FOSQ-10: Change in the Total Score .......................................................................... 56 


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Version 1.0 
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10.4.2. 
SF-36v2: Change from Baseline by Domains .............................................................. 57 
10.4.3. 
EQ-5D-5L: EQ-5D Dimensions .................................................................................... 58 
10.4.4. 
EQ VAS: Change in the VAS Score ............................................................................. 58 
10.4.5. 
EQ-5D-5L index: Change in Index Value ..................................................................... 59 
10.4.6. 
Use of Primary OSA Therapy ....................................................................................... 60 
10.5. 
Economic Assessments .................................................................................................... 62 
10.5.1. 
WPAI:SHP .................................................................................................................... 62 
10.5.2. 
Resource Utilization Questionnaire .............................................................................. 63 
10.6. 
Summary of Placebo-Controlled Efficacy Analysis Methods ........................................ 64 
11. 
SAFETY ......................................................................................................66 
11.1. 
Extent of Exposure ............................................................................................................. 66 
11.1. 
Treatment Compliance ....................................................................................................... 66 
11.2. 
Adverse Events ................................................................................................................... 66 
11.2.1. 
Subgroup Analyses ...................................................................................................... 68 
11.3. 
Laboratory Evaluations ...................................................................................................... 68 
11.4. 
Vital Signs ............................................................................................................................ 69 
11.5. 
ECG ...................................................................................................................................... 70 
11.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ......................................................... 70 
11.6.1. 
C-SSRS Outcomes/Composite Endpoints ................................................................... 71 
11.6.2. 
C-SSRS Analyses ........................................................................................................ 72 
12. 
INTERIM ANALYSES .................................................................................74 
13. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ..........................75 
14. 
REFERENCE ..............................................................................................76 
 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 7 of 76 
1. 
ABBREVIATIONS 
Abbreviation 
Description 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
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 
FDA 
Food and Drug Administration 
FOSQ-10 
Functional Outcomes of Sleep Questionnaire Short Version 
ICH 
International Conference on Harmonization 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System  
IXRS 
Interactive Voice/Web Randomization System 
LOCF 
Last Observation Carried Forward 
LOE 
Lack of Efficacy 
LS 
Least Square 
MAR 
Missing at Random 
Max 
Maximum 
MCAR 
Missing Completely at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 8 of 76 
Abbreviation 
Description 
Min 
Minimum 
mITT 
Modified Intent-to-Treat 
MNAR 
Missing Not at Random 
MWT 
Maintenance of Wakefulness Test 
OL 
Open Label 
OSA 
Obstructive Sleep Apnea 
OTC 
Over-the-Counter  
PAP 
Positive airway pressure 
PGIc 
Patient Global Impression of Change  
PP 
Per Protocol 
PT 
Preferred Term 
QTcF 
QT Corrected with Fridericia’s Formula  
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SI 
Single Imputation 
SF-36V2 
36-Item Short Form Health Survey Version 2 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TESAE 
Treatment Emergent Serious Adverse Event 
TLF 
Table, Listing and Figure 
VAS 
Visual Analogue Scale 
WHO 
World Health Organization 
WPAI:SHP 
Work Productivity Activity Impairment Questionnaire: Specific 
Health Problem 
 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 9 of 76 
2. 
PURPOSE 
This Statistical Analysis Plan (SAP) is created based on Protocol 14-005 Amendment 4 (17  
November 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. 
 
 
 
 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 10 of 76 
3. 
STUDY OBJECTIVES 
3.1. 
PRIMARY OBJECTIVE(S) 
The primary objective of this study is to evaluate the safety and tolerability of JZP-110 
administered once daily for up to 52 weeks in doses of 75, 150, and 300 mg. 
The primary objective of the Randomized Withdrawal Period in the Maintenance Phase 
of this study is to evaluate the maintenance of efficacy of JZP-110 compared to placebo 
in the treatment of excessive sleepiness in adult subjects with narcolepsy or obstructive 
sleep apnea (OSA) after at least 26 weeks of daily administration of JZP-110. 
3.2. 
SECONDARY OBJECTIVE(S) 
The key secondary objective of this study is to evaluate the maintenance of efficacy of 
open-label (OL) JZP-110 administered once daily for up to 52 weeks in doses of 75, 150, 
and 300 mg in the treatment of excessive sleepiness in adult subjects with narcolepsy or 
OSA. 
Another secondary objective is to evaluate the safety and tolerability of JZP-110 
compared to placebo during the randomized withdrawal period in the Maintenance 
Phase. 
 
3.3. 
STUDY DESIGN 
The Schedule of Events is presented in Table 1 and Table 2 for subjects who have 
completed Study 14-002 or 14-003 (Group A), or Study 14-004, 15-004, 15-005, ADX-N05 
201 or ADX-N05 202 (Group B), respectively. The Study Schema for both Groups is 
presented in Figure 1 and Figure 2. 
This is a Phase 3 study to assess the long-term safety and maintenance of efficacy of 
JZP-110 under open-label and double-blind, placebo-controlled conditions, in subjects 
who have completed Study 14-002, 14-003, 14-004, 15-004, 15-005, ADX-N05 201, or 
ADX-N05 202. The study will consist of a 2-week Titration Phase for all subjects, a 38-
week Maintenance Phase for subjects who completed Study 14-002 or 14-003 or a 50-
week Maintenance Phase for subjects who completed Study 14-004, 15-004, 15-005, 
ADX-N05 201 or ADX-N05 202, and a 2-week Safety Follow-up Period. 
During the 2-week Titration Phase, subjects will begin with 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 or 150 mg at any time 
following a telephone consultation with investigative site staff to achieve a maximal 
dose that is tolerable. After the 2-week Titration Phase, subjects will enter the 
Maintenance Phase at the stable dose that was reached at the end of the Titration 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 11 of 76 
Phase. After entering the Maintenance Phase, only three dose adjustments (to doses of 
75 mg, 150 mg or 300 mg daily) will be allowed during the first 12 weeks of the 
Maintenance Phase. If the dose cannot be successfully adjusted within these 
parameters, the subject will be discontinued from the study. 
Subjects who completed Study 14-002 or 14-003 (Group A) will return to the clinic for 
assessments at the end of the 2-week Titration Phase and at approximately 14, 27, 29, 
and 40 weeks after the start of treatment with JZP-110 in this study. Subjects who 
completed Study 14-004, 15-004, 15-005, ADX-N05 201, or ADX-N05 202 (Group B) will 
return to the clinic for assessments at the end of the 2-week Titration Phase and at 
approximately 14, 26, 28, 39, and 52 weeks after the start of treatment with JZP-110 in 
this study. The Randomized Withdrawal Period of the Maintenance Phase of the study 
will be conducted from weeks 27-29 in Group A and from weeks 26-28 in Group B. At the 
beginning of the Randomized Withdrawal Period, subjects will be randomly assigned in a 
1:1 ratio to continue to receive JZP-110 at the dose that they are currently receiving or 
to receive placebo for 2 weeks. At the end of the 2-week Randomized Withdrawal 
Period, subjects will receive the same dose that they had been receiving at the 
beginning of the Randomized Withdrawal Period for the remainder of the study (a fixed 
titration of 3 days will be included for subjects on the 150 and 300 mg doses).  
When approximately 300 subjects are randomized into the randomized withdrawal 
period, no more subjects will be randomized into the period. All subjects who have not 
entered the randomized withdrawal period at that time will receive open-label JZP-110 
treatment for the remainder of the study. All subjects who have entered the 
randomized withdrawal period will complete all scheduled assessments for the period.  
Subjects who completed Study 14-002 or 14-003 (Group A) and who are not randomized 
into the randomized withdrawal period will return to the clinic for assessments at the 
end of the 2-week Titration Phase and at approximately 14, 27, and 40 weeks after the 
start of treatment with JZP-110 in this study. Subjects who completed Study 14-004, 15-
004, 15-005, ADX-N05 201, or ADX-N05-202 (Group B) and who are not randomized into 
the randomized withdrawal period will return to the clinic for assessments at the end of 
the 2-week Titration Phase and at approximately 14, 26, 39, and 52 weeks after the 
start of treatment with JZP-110 in this study.  
All subjects will be contacted monthly by phone, and the investigator will determine 
whether subjects need to be seen in the clinic at any other time(s) during the study to 
ensure their safety. 
Safety will be assessed throughout the study and will include the Columbia-Suicide 
Severity Rating Scale (C-SSRS) administered at each clinic visit. 
Open-Label maintenance of efficacy will be assessed by the Epworth Sleepiness Scale 
(ESS), Patient Global Impression of Change (PGIc), Clinical Global Impression of Change 
(CGIc), and several quality of life and economic measures, such as the Functional 
Outcomes of Sleep Questionnaire Short Version (FOSQ-10), 36-Item Short Form Health 
Survey version 2 (SF-36v2), EuroQoL EQ-5D-5L, and the Work Productivity Activity 
Impairment (WPAI:SHP) Questionnaire. Double-blind, placebo-controlled maintenance of 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 12 of 76 
efficacy in the Randomized Withdrawal Period will be assessed by changes on the ESS 
and FOSQ-10, and ratings on the PGIc and CGIc from the beginning to the end of the 2-
week Randomized Withdrawal Period (from Week 27 to 29 or from Week 26 to 28 in 
Groups A and B, respectively) in approximately 300 subjects. 
At the 14 and 40 week visits for subjects in Group A and at the 26 and 52 week visits for 
subjects in Group B, subjects will be asked about their healthcare resource utilization 
over the past 3 months in terms of physician visits. 
All subjects will return to the site 2 weeks after the final clinic visit of the Maintenance 
Phase for safety follow-up assessments. Unless there are any outstanding safety issues 
that require follow-up, subjects will be discharged from the study at that visit. 
Figure 1 Study Schema for Subjects Randomized into the Randomized 
Withdrawal Period 
 
 
 
 
 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 13 of 76 
 
 
 
Figure 2 Study Schema for Subjects not Randomized into the Randomized 
Withdrawal Period 
 
 
 
 


Statistical Analysis Plan 
 
Page 14 of 76 
Table 1 Schedule of Events – Group A 
            Subjects Who Participated in Study 14-002 or 14-003 
Phase 
Scree-
ning/B
aseline 
Titration 
Maintenance 
Early 
Terma 
Follo
w-up 
 
 
Randomized 
Withdrawal 
Period
 
Visit 
1 
2 
3 
4
5
6
7
8
9
10
11
12 
12.1*
12.2*
13
14
15
 
16
Time from 
Study Start 
Day/End of 
Week 
D -1 
D 3 
±1 
D 6 
±1 
D 9 
±1 
D 
12 
±1 
D 
15 
±2 
Wk 
2 
D 
43 
±7 
Wk 
6 
D 
71 
±7 
Wk 
10 
D 
99 
±7 
Wk 
14 
D 
127 
±7 
Wk 
18 
D 
155 
±7 
Wk 
22 
D 
190 
±7 
Wk 
27 
D 197 
±3 
Wk 
28 
D 204 
±7 
Wk 29 
D 
21
8 
±7 
Wk 
31 
D 
246 
±7 
Wk 
35 
D 
281 
±7 
Wk 
40 
D 295 
±7  
Wk 42 
Clinic Visit 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
Phone Contact 
 
X 
X 
X
X
X
X
X
X
 
X
X
X
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
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, 
hematology, 
serum 
chemistry; 
urinalysis 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
 
Light breakfast 
 
 
 
X
X 
X
X
Urine drug 
screen 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
X 
 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 15 of 76 
Phase 
Scree-
ning/B
aseline 
Titration 
Maintenance 
Early 
Terma 
Follo
w-up 
 
 
Randomized 
Withdrawal 
Period
 
Visit 
1 
2 
3 
4
5
6
7
8
9
10
11
12 
12.1*
12.2*
13
14
15
 
16
Time from 
Study Start 
Day/End of 
Week 
D -1 
D 3 
±1 
D 6 
±1 
D 9 
±1 
D 
12 
±1 
D 
15 
±2 
Wk 
2 
D 
43 
±7 
Wk 
6 
D 
71 
±7 
Wk 
10 
D 
99 
±7 
Wk 
14 
D 
127 
±7 
Wk 
18 
D 
155 
±7 
Wk 
22 
D 
190 
±7 
Wk 
27 
D 197 
±3 
Wk 
28 
D 204 
±7 
Wk 29 
D 
21
8 
±7 
Wk 
31 
D 
246 
±7 
Wk 
35 
D 
281 
±7 
Wk 
40 
D 295 
±7  
Wk 42 
Urine 
pregnancy test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
C-SSRS 
 
 
 
X
X
X 
X
X
X
X
Enroll via 
IVRS/IWRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomize via 
IVRS/IWRS 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Dispense Study 
Drug 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
Provide 
instructions for 
titration 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect Study 
Drug/assess 
compliance 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
X 
 
Concomitant 
Meds 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review and 
remind to 
record primary 
OSA therapy 
use 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events 
 
X 
X 
X
X
X
X
X
X
X
X
X 
X
X
X
X
X
X
X
ESS 
 
 
 
X
X
X 
X
X


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 16 of 76 
Phase 
Scree-
ning/B
aseline 
Titration 
Maintenance 
Early 
Terma 
Follo
w-up 
 
 
Randomized 
Withdrawal 
Period
 
Visit 
1 
2 
3 
4
5
6
7
8
9
10
11
12 
12.1*
12.2*
13
14
15
 
16
Time from 
Study Start 
Day/End of 
Week 
D -1 
D 3 
±1 
D 6 
±1 
D 9 
±1 
D 
12 
±1 
D 
15 
±2 
Wk 
2 
D 
43 
±7 
Wk 
6 
D 
71 
±7 
Wk 
10 
D 
99 
±7 
Wk 
14 
D 
127 
±7 
Wk 
18 
D 
155 
±7 
Wk 
22 
D 
190 
±7 
Wk 
27 
D 197 
±3 
Wk 
28 
D 204 
±7 
Wk 29 
D 
21
8 
±7 
Wk 
31 
D 
246 
±7 
Wk 
35 
D 
281 
±7 
Wk 
40 
D 295 
±7  
Wk 42 
CGIc – 
Compared to 
Baselineb 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
PGIc – Since 
Started 
Treatmentb 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
CGIc – 
Compared to 
Beginning of 
RW Periodc 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
PGIc – Since 
Last Visitc 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
FOSQ-10 
 
 
 
X
X 
X
X
SF-36v2 
 
 
 
X
X 
X
EQ-5D-5L 
 
 
 
X
X 
X
WPAI:SHP 
 
 
 
X
X 
X
Resource 
Utilization 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Schedule next 
visit or phone 
contact 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
D=day; Wk=week 
Shaded columns indicate clinic visits. 
 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 17 of 76 
 
*When approximately 300 subjects are randomized into the randomized withdrawal period, no more subjects will be randomized into the 
period. All subjects who have not entered the randomized withdrawal period at that time will receive open-label JZP-110 treatment at 
Visit 12 and will not complete Visits 12.1 and 12.2. 
a. If a subject withdraws or is withdrawn from the study after completing the Week 2 Visit (Visit 6) and no more than 3 days have passed 
since the subject’s last dose of study drug was taken, the Maintenance Phase Final Clinic Visit (Visit 15) procedures should be conducted.  
If more than 3 days have passed since the subject’s last dose of study drug was taken, only the final safety assessments listed in the Early 
Termination column should be conducted (ESS, CGIc, PGIc, FOSQ-10, SF-36v2, EQ-5D-5L, WPAI:SHP, and Resource Utilization assessments 
are not required). 
If a subject withdraws or is withdrawn prior to completing the Week 2 Visit (Visit 6), only the final safety assessments listed in the Early 
Termination column should be conducted (ESS, CGIc, PGIc, FOSQ-10, SF-36v2, EQ-5D-5L, WPAI:SHP, and Resource Utilization assessments 
are not required).  
b. CGIc change from baseline version and PGIc change from start of treatment version should be used. 
c. CGIc change from the beginning of the randomized withdrawal (RW) period version and PGIc change from the last visit version should be 
used. 
 
 
 
 
 
 
 
 
 
 
 
 
 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 18 of 76 
Table 2 Schedule of Events – Group B 
            Subjects Who Participated in Study 14-004, 15-004, 15-005, ADX-N05 201 or ADX-N05 202 
 
Phase 
Scre
e-
ning 
Base
-line 
Titration 
Maintenance 
Early 
Term
a 
Follo
w-up 
 
 
Randomized 
Withdrawal 
Period 
 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
13.
1* 
13.
2* 
14 
15 
16 
17 
18 
19 
 
20 
Time 
from 
Study 
Start 
Day/End 
of Week 
D -30  
to -2 
D -1 
D 
3
±
1 
D 
6 
±1 
D 
9 
±1 
D 
12 
±1 
D 
15 
±2 
Wk 
2 
D 
43 
±7 
Wk 
6 
D 
71 
±7 
Wk 
10 
D 
99 
±7 
Wk 
14 
D 
127 
±7 
Wk 
18 
D 
155 
±7 
Wk 
22 
D 
183 
±7 
Wk 
26 
D 
190 
±3 
Wk 
27 
D 
197 
±7 
Wk 
28 
D 
211 
±7 
Wk 
30 
D 
239 
±7 
Wk 
34 
D 
274 
±7 
Wk 
39 
D 
302 
±7 
Wk 
43 
D 
330 
±7 
Wk 
47 
D 
365 
±7 
Wk 
52 
D 379 
±7  
Wk 54 
Clinic 
Visit 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
Phone 
Contact 
 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion 
/Exclusio
n 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demo-
graphics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Exam-
inations 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Instruct 
how to 
dis-
continue 
excluded 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 19 of 76 
Phase 
Scre
e-
ning 
Base
-line 
Titration 
Maintenance 
Early 
Term
a 
Follo
w-up 
 
 
Randomized 
Withdrawal 
Period 
 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
13.
1* 
13.
2* 
14 
15 
16 
17 
18 
19 
 
20 
Time 
from 
Study 
Start 
Day/End 
of Week 
D -30  
to -2 
D -1 
D 
3
±
1 
D 
6 
±1 
D 
9 
±1 
D 
12 
±1 
D 
15 
±2 
Wk 
2 
D 
43 
±7 
Wk 
6 
D 
71 
±7 
Wk 
10 
D 
99 
±7 
Wk 
14 
D 
127 
±7 
Wk 
18 
D 
155 
±7 
Wk 
22 
D 
183 
±7 
Wk 
26 
D 
190 
±3 
Wk 
27 
D 
197 
±7 
Wk 
28 
D 
211 
±7 
Wk 
30 
D 
239 
±7 
Wk 
34 
D 
274 
±7 
Wk 
39 
D 
302 
±7 
Wk 
43 
D 
330 
±7 
Wk 
47 
D 
365 
±7 
Wk 
52 
D 379 
±7  
Wk 54 
medicati
on 
Weight 
X 
X 
 
 
 
X
X
X
 
X
X
X
X
X
Height 
X 
 
 
 
 
 
Vital 
Signs 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
ECG 
X 
X 
 
 
 
X
X
X
 
X
X
X
X
X
Fasting 
hemat-
ology, 
serum 
chemistry
; 
urinalysis 
X 
Xb 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
Light 
breakfast 
X 
Xb 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
Urine 
drug 
screen 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
 
Serum 
pregnanc
y test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine 
pregnanc
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 20 of 76 
Phase 
Scre
e-
ning 
Base
-line 
Titration 
Maintenance 
Early 
Term
a 
Follo
w-up 
 
 
Randomized 
Withdrawal 
Period 
 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
13.
1* 
13.
2* 
14 
15 
16 
17 
18 
19 
 
20 
Time 
from 
Study 
Start 
Day/End 
of Week 
D -30  
to -2 
D -1 
D 
3
±
1 
D 
6 
±1 
D 
9 
±1 
D 
12 
±1 
D 
15 
±2 
Wk 
2 
D 
43 
±7 
Wk 
6 
D 
71 
±7 
Wk 
10 
D 
99 
±7 
Wk 
14 
D 
127 
±7 
Wk 
18 
D 
155 
±7 
Wk 
22 
D 
183 
±7 
Wk 
26 
D 
190 
±3 
Wk 
27 
D 
197 
±7 
Wk 
28 
D 
211 
±7 
Wk 
30 
D 
239 
±7 
Wk 
34 
D 
274 
±7 
Wk 
39 
D 
302 
±7 
Wk 
43 
D 
330 
±7 
Wk 
47 
D 
365 
±7 
Wk 
52 
D 379 
±7  
Wk 54 
y test 
C-SSRS 
X 
X 
 
 
 
X
X
X
 
X
X
X
X
X
Dispense 
Study 
Drug 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
Enroll via 
IVRS/ 
IWRS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomiz
e via 
IVRS/ 
IWRS 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Provide 
instructio
ns for 
titration 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect 
Study 
Drug 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
 
Concom-
itant 
Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse 
Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 21 of 76 
Phase 
Scre
e-
ning 
Base
-line 
Titration 
Maintenance 
Early 
Term
a 
Follo
w-up 
 
 
Randomized 
Withdrawal 
Period 
 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
13.
1* 
13.
2* 
14 
15 
16 
17 
18 
19 
 
20 
Time 
from 
Study 
Start 
Day/End 
of Week 
D -30  
to -2 
D -1 
D 
3
±
1 
D 
6 
±1 
D 
9 
±1 
D 
12 
±1 
D 
15 
±2 
Wk 
2 
D 
43 
±7 
Wk 
6 
D 
71 
±7 
Wk 
10 
D 
99 
±7 
Wk 
14 
D 
127 
±7 
Wk 
18 
D 
155 
±7 
Wk 
22 
D 
183 
±7 
Wk 
26 
D 
190 
±3 
Wk 
27 
D 
197 
±7 
Wk 
28 
D 
211 
±7 
Wk 
30 
D 
239 
±7 
Wk 
34 
D 
274 
±7 
Wk 
39 
D 
302 
±7 
Wk 
43 
D 
330 
±7 
Wk 
47 
D 
365 
±7 
Wk 
52 
D 379 
±7  
Wk 54 
ESS 
 
X 
 
 
 
X
X
X
 
X
X
X
CGIs 
 
X 
 
 
 
 
CGIc – 
compare
d to 
baselined 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
PGIc – 
Since 
Started 
Treatmen
td 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
CGIc –
Compare
d to 
Beginning 
of RW 
Periode 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
PGIc –
Since 
Last 
Visite 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
FOSQ-10 
 
X 
 
 
 
X
X
 
X
X
X
SF-36v2 
 
X 
 
 
 
X
X
 
X
X
EQ-5D-5L 
 
X 
 
 
 
X
X
 
X
X


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 22 of 76 
Phase 
Scre
e-
ning 
Base
-line 
Titration 
Maintenance 
Early 
Term
a 
Follo
w-up 
 
 
Randomized 
Withdrawal 
Period 
 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
13.
1* 
13.
2* 
14 
15 
16 
17 
18 
19 
 
20 
Time 
from 
Study 
Start 
Day/End 
of Week 
D -30  
to -2 
D -1 
D 
3
±
1 
D 
6 
±1 
D 
9 
±1 
D 
12 
±1 
D 
15 
±2 
Wk 
2 
D 
43 
±7 
Wk 
6 
D 
71 
±7 
Wk 
10 
D 
99 
±7 
Wk 
14 
D 
127 
±7 
Wk 
18 
D 
155 
±7 
Wk 
22 
D 
183 
±7 
Wk 
26 
D 
190 
±3 
Wk 
27 
D 
197 
±7 
Wk 
28 
D 
211 
±7 
Wk 
30 
D 
239 
±7 
Wk 
34 
D 
274 
±7 
Wk 
39 
D 
302 
±7 
Wk 
43 
D 
330 
±7 
Wk 
47 
D 
365 
±7 
Wk 
52 
D 379 
±7  
Wk 54 
WPAI:SHP 
 
X 
 
 
 
X
X
 
X
X
Resource 
Utilizatio
n 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Review 
and 
remind 
to record 
primary 
OSA 
therapy 
usec 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Schedule 
next visit 
or phone 
contact 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
D=day; Wk=week 
 
Shaded columns indicate clinic visits. 
 
 
 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 23 of 76 
*When approximately 300 subjects are randomized into the randomized withdrawal period, no more subjects will be randomized 
into the period. All subjects who have not entered the randomized withdrawal period at that time will receive open-label JZP-110 
treatment at Visit 13 and will not complete Visits 13.1 and 13.2 
a. If a subject withdraws or is withdrawn from the study after completing the Week 2 Visit (Visit 7) and no more than 3 days have 
passed since the subject’s last dose of study drug was taken, the Maintenance Phase Final Clinic Visit procedures should be 
conducted (Visit 19). If more than 3 days have passed since the subject’s last dose of study drug was taken, only the final safety 
assessments listed in the Early Termination column should be conducted (ESS, CGIc, PGIc, FOSQ, SF-36 v2, ED-5D-5L, WPAI:SHP and 
Resource Utilization assessments are not required). 
If a subject withdraws or is withdrawn prior to completing the Week 2 Visit (Visit 7), only the final safety assessments listed in the 
Early Termination column should be conducted (ESS, CGIc, PGIc, FOSQ, SF-36 v2, ED-5D-5L, WPAI:SHP and Resource Utilization 
assessments are not required).  
b. If the Baseline (Day -1) visit occurs more than 28 days after the Screening visit, obtain fasting blood samples for serum chemistry 
and hematology and a urine sample for urinalysis. Provide a light breakfast for subjects who have their blood drawn. 
c. Review and reminders regarding primary OSA therapy use only apply to subjects with OSA from the 14-004 and 15-004 studies. 
d. CGIc change from baseline version and PGIc change from start of treatment version should be used. 
e. CGIc change from the beginning of the randomized withdrawal (RW) period version and PGIc change from the last visit version 
should be used. 


Statistical Analysis Plan 
 
Page 24 of 76 
 
3.4. 
DETERMINATION OF SAMPLE SIZE 
The sample size of this study is based on ICH Guidance on the Extent of Population 
Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non- 
Life-Threatening Conditions (E1) and on guidance from FDA. Approximately 600 subjects 
are planned for enrollment with the intention of completing at least 50 subjects with 
narcolepsy and at least 50 subjects with OSA with an exposure to JZP-110 of 52 weeks 
and at least 100 subjects with narcolepsy and at least 200 subjects with OSA with an 
exposure to JZP-110 of 26 weeks. A sample size of 300 subjects in the Randomized 
Withdrawal Period in the Maintenance Phase with approximately 150 subjects per 
treatment group will provide at least 95% power to detect a difference of 3 points in the 
ESS score from the beginning to the end of the 2-week Randomized Withdrawal Period. 
This calculation assumes a common standard deviation of 7 points for the ESS change 
during the Randomized Withdrawal Period and a two-sided significance level of 0.05 
using a t-test. 
3.5. 
RANDOMIZATION AND STRATIFICATION 
At the beginning of the Randomized Withdrawal Period of the Maintenance Phase (the 
Week 27 visit for Group A or the Week 26 visit for Group B), subjects will be randomly 
assigned in a 1:1 ratio to continue to receive JZP-110 at the dose that they are currently 
receiving or to receive placebo for 2 weeks in a double-blind manner. The investigator 
will access an Interactive Voice Response System (IVRS) or an Interactive Web Response 
System (IWRS) to randomize subjects. The randomization will be stratified on the basis 
of subjects’ diagnosis of narcolepsy or OSA. When approximately 300 subjects have been 
randomized into the randomized withdrawal period, the clinical sites will be notified 
and the IVRS/IWRS will not permit additional randomization. After approximately 300 
subjects have been randomized into the randomized withdrawal period, use of the IVRS 
or IWRS will continue for the purpose of enrolling subjects, assigning subject 
identification numbers and tracking open-label study drug. 
A statistician selected by Jazz Pharmaceuticals will prepare and retain the master 
randomization code for the Randomized Withdrawal Period of this study. This 
statistician will not be involved in the analysis of this study. The randomization codes 
will be generated and retained according to Jazz Pharmaceuticals standard operating 
procedure on the generation, distribution, and access to randomization information for 
clinical studies. 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. 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 25 of 76 
3.6. 
ADMINISTRATION OF STUDY MEDICATION 
Subjects will receive open-label JZP-110 75, 150, or 300 mg once daily throughout the 
study except during the 2-week Randomized Withdrawal Period of the Maintenance 
Phase, when subjects will either receive JZP-110 at their current dose or placebo in a 
double-blind manner. 
Study drug will be dispensed at clinic visits at Baseline, at the end of the Titration 
Phase, and approximately every 3 months thereafter (except during the 2-week 
Randomized Withdrawal Period during which study drug will be dispensed for a 2 week 
interval), as indicated in the Schedule of Events in Table 1 and Table 2 and, if 
applicable, at alternative intervals specified by State or local regulations. Study drug 
will be dispensed by qualified study site personnel. 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 26 of 76 
4. 
ENDPOINTS 
4.1. 
PLACEBO-CONTROLLED RANDOMIZED WITHDRAWAL PERIOD 
4.1.1. 
Efficacy Endpoints 
 
Primary efficacy endpoint: 
o ESS: Change in ESS score from the beginning to the end of the 
Randomized Withdrawal Period 
 
Second efficacy endpoints: 
o PGIc: Percentage of subjects reported as worse (minimally, much, or very 
much) on the PGIc at the end of the Randomized Withdrawal Period 
o CGIc: Percentage of subjects reported as worse (minimally, much, or very 
much) on the CGIc at the end of the Randomized Withdrawal Period  
4.1.2. 
Functional Outcomes and Quality of Life Endpoints 
o FOSQ-10: Change in total score and 5 subscale score from the beginning 
to the end of the Randomized Withdrawal Period  
4.1.3. 
Use of primary OSA therapy 
Use of primary OSA therapy for the randomized subjects from study 14-003, 14-004, and 
15-004 in the Randomized Withdrawal Period of the Maintenance Phase will be 
summarized as follows: 
 
 
For Group A and B 
 
o Percentage of nights that subjects use their primary OSA therapy in the 
Randomized Withdrawal Period 
o Change in the percentage of nights that the primary OSA therapy is used 
from the visit before Randomized Withdrawal Period to the Randomized 
Withdrawal Period 
4.2. 
OPEN-LABEL (OL) PHASES 
4.2.1. 
Efficacy Endpoints 
 
For Group A: 
o ESS: Change from the baseline in the previous study over time 


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Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 27 of 76 
o ESS: Change from the last assessment in the previous study over time 
 
For Group B: 
o ESS: Change from the study baseline over time 
 
For Group A and B: 
o CGIc: Percentage of subjects reported as improved (minimally, much, or 
very much) at each time point 
o PGIc: Percentage of subjects reported as improved (minimally, much, or 
very much) at each time point 
4.2.2. 
Functional Outcomes and Quality of Life Endpoints 
For all functional outcomes (FOSQ-10 total score and 5 subscales) and quality of life 
endpoints (SF-36v2 8 subscale scores, Physical and Mental Health Component summary 
scores, EQ-5D-5L Index, and EQ VAS), the following changes will be summarized: 
 
For Group A: 
o Change from the baseline in the previous study over time 
o Change from the last assessment in the previous study over time 
 
For Group B: 
o Change from the study baseline over time 
EuroQoL (EQ-5D-5L) will be summarized as follows: 
o EQ-5D Dimensions 
 
Number and percentage of subjects in each of the 5 levels of severity 
(e.g., no problem, slight problem, moderate problem, severe 
problem, unable) for each of the 5 dimensions (e.g., mobility, self-
care) over time 
 
Number and percentage of subjects reporting any problems (levels 2-
5) for each of the 5 dimensions (e.g., mobility, self-care) over time 
o EQ-5D-5L Index  
o EQ VAS  


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 28 of 76 
4.2.3. 
Use of Primary OSA Therapy 
Use of primary OSA therapy for the subjects from the study 14-003, 14-004, and 15-004 
will be summarized as follows: 
 
 
For Group A  
o Change in the percentage of nights that the primary OSA therapy is used 
from the Screening period in the previous study to each time point   
o Change in the percentage of nights that the primary OSA therapy is used 
from the last period in the previous study to each time point 
 
For Group B 
o Change in the percentage of nights that the primary OSA therapy is used 
from the Screening period (e.g., all available data prior to the first dose 
date of study drug in this study) to each time point  
 
 
For Group A and B 
 
o Percentage of nights that subjects use their primary OSA therapy will be 
summarized by visit and treatment group 
4.2.4. 
Economic Assessments Endpoints 
 Data from the economic assessments will be summarized over time. 
 
Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem V2.0 (WPAI:SHP):  
o Percent work time missed due to problem  
o Percent impairment while working due to problem  
o Percent overall work impairment due to problem  
o Percent activity impairment due to problem  
 
Resource Utilization Questionnaire:  
o Number of visits in past 3 months 
o Mean/median healthcare costs over the one-year period based on 
standard unit costs and any hospitalizations reported as SAEs. 
The following changes will be summarized for the WPAI:SHP: 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 29 of 76 
 
For Group A: 
o Change from the baseline in the previous study over time 
o Change from the last assessment in the previous study over time  
 
For Group B: 
o Change from the study baseline over time 
 
4.3. 
PHARMACOKINETIC ENDPOINTS 
Not applicable 
4.4. 
PHARMACODYNAMIC ENDPOINTS  
Not applicable 
 
4.5. 
SAFETY ENDPOINTS  
To evaluate the safety and tolerability evaluations as determined by the occurrence of 
and/or changes in: 
 
Treatment-emergent adverse events (TEAEs) 
 
Clinical laboratory tests (chemistry, hematology, and urinalysis) 
 
Vital signs 
 
12-lead electrocardiograms (ECGs) 
 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
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Page 30 of 76 
5. 
STATISTICAL HYPOTHESES FOR TRIAL OBJECTIVES 
5.1. 
MAINTENANCE OF EFFICACY ENDPOINTS FROM THE PLACEBO-
CONTROLLED RANDOMIZED WITHDRAWAL PERIOD 
The primary hypothesis, corresponding to the primary efficacy variable (ESS), is the 
following: 
 
JZP-110 is superior to placebo as measured by the change in the ESS score from 
the beginning to the end of the 2-week Randomized Withdrawal Period  
The statistical null hypothesis is that for the ESS score, the mean change from the 
beginning to the end of the 2-week Randomized Withdrawal Period for the JZP-110 
group is the same as the mean change from the beginning to the end of the 2-week 
Randomized Withdrawal Period for the placebo group. 
In addition to the primary hypothesis, the secondary hypotheses are: 
 
JZP-110 is superior to placebo as measured by the Patient Global Impression of 
Change (PGIc) at the end of the Randomized Withdrawal Period (Week 29 for 
subjects in Group A and Week 28 for subjects in Group B) 
The statistical null hypothesis is that for the PGIc, the percentage of subjects 
reported as worse (minimally, much, or very much) at the end of the 2 week 
Randomized Withdrawal Period compared to the beginning of the Randomized 
Withdrawal Period for the JZP-110 group is the same as the percentage of subjects 
reported as worse (minimally, much, or very much) at the end of the 2-week 
Randomized Withdrawal Period for the placebo group.  
 
JZP-110 is superior to placebo as measured by the Clinical Global Impression of 
Change (CGIc) at the end of the Randomized Withdrawal Period (Week 29 for 
subjects in Group A and Week 28 for subjects in Group B) 
The statistical null hypothesis is that for the CGIc, the percentage of subjects 
reported as worse (minimally, much, or very much) at the end of the 2 week 
Randomized Withdrawal Period compared to the beginning of the Randomized 
Withdrawal Period for the JZP-110 group is the same as the percentage of subjects 
reported as worse (minimally, much, or very much) at the end of the 2-week 
Randomized Withdrawal Period for the placebo group. 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 31 of 76 
5.2. 
MAINTENANCE OF EFFICACY ENDPOINTS FROM THE OPEN-
LABEL (OL) PHASES 
To evaluate the maintenance of efficacy of OL JZP-110 administered once daily for up 
to 52 weeks, no formal statistical testing will be performed; only summary statistics will 
be provided. 
 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 32 of 76 
6. 
ANALYSIS POPULATIONS 
6.1. 
SAFETY POPULATION 
The Safety Population will include all subjects who received at least one dose of study 
medication in this study. This population will be analyzed for the safety evaluation and 
the open-label maintenance of efficacy of JZP-110 and will be presented in the tables 
and listings. All open-label analyses will be performed on the Safety Population. 
 
6.2. 
MODIFIED INTENT-TO-TREAT POPULATION 
The Modified Intent-to-Treat (mITT) Population for the evaluation of Double-Blind, 
Placebo-Controlled maintenance of efficacy in the Randomized Withdrawal Period will 
include subjects who were randomized in the 2-week Randomized Withdrawal Period, 
who received at least one dose of study medication in the 2-week Randomized 
Withdrawal Period, and who have evaluable efficacy data at Week 29 (Group A) or Week 
28 (Group B). 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. 
 
 
6.3. 
PER-PROTOCOL POPULATION 
The Per-Protocol Population will include mITT subjects who completed the 2-week 
Randomized Withdrawal Period according to protocol specifications without a major 
protocol 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 in the study 
protocol deviation report.   
 
The categories of major protocol deviation 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 primary and 
secondary efficacy endpoints.  
 
 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 33 of 76 
7. 
EFFICACY ASSESSMENTS 
7.1. 
EPWORTH SLEEPINESS SCALE (ESS)  
The ESS provides a measure of a person’s general level of daytime sleepiness, or their 
mean sleep propensity in daily life. It 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 (see Protocol Appendix 5). It provides a measure of a person’s general level of 
daytime sleepiness, or their mean sleep propensity in daily life. The ESS is a validated 
measure with high specificity and sensitivity for assessing subjective sleepiness.  
 
Subjects who are randomized in the randomized withdrawal period will be asked to 
complete the ESS with regard to the level of sleepiness they experienced over 
approximately the past 7 days at the following times:  
 
For Group A, at Weeks 2, 14, 27, 29, 40, and at Early Termination visits that 
occur after Week 2.  
 
For Group B, at Baseline, Weeks 2, 14, 26, 28, 39, 52 and at Early Termination 
visits that occur after Week 2.  
 
Subjects who are not randomized into the randomized withdrawal period will be asked 
to complete the ESS with regard to the level of sleepiness they experienced over 
approximately the past 7 days at the following times: 
 
 
For Group A: at Weeks 2, 14, 27, 40, and at Early Termination visits that occur 
after Week 2.  
 
For Group B: at Baseline, Weeks 2, 14, 26, 39, 52, and Early Termination visits 
that occur after Week 2.  
 
 
7.2. 
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 the severity of illness (see Protocol Appendix 12). 
The responses of this investigator-completed scale range from 1 = normal, no signs of 
illness to 7 = among the most extremely ill patients. For Group B subjects, the 
Investigator will rate his/her impression of the severity of the subject’s current 
condition at baseline relative to his/her experience with this patient population at 
Baseline. For Group A subjects, this rating will be captured at baseline in the previous 
study. 
 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 34 of 76 
7.3. 
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. For the open-label efficacy assessments, investigators will 
rate their impression of any change of the subject’s condition from baseline (before the 
start of treatment in this study for subjects in Group B or before the start of treatment 
in the previous study for subjects in Group A) on a 7-point scale ranging from 1 = very 
much improved to 7 = very much worse. Subjects in Group A will be assessed at Weeks 
2, 14, 27, and 40; subjects in Group B will be assessed at Weeks 2, 14, 26, 39, and 52. 
All subjects will be assessed at early termination visits that occur after Week 2 (see 
Protocol Appendix 13). For the double-blind, placebo-controlled assessment of the 
maintenance of efficacy, investigators will rate their impression of any change in the 
subject’s condition from the beginning of the Randomized Withdrawal Period on a 7 
point scale ranging from 1 = very much improved to 7 = very much worse at Week 29 
(for subjects in Group A) or at Week 28 (for subjects in Group B). For additional 
information, see Appendix 14 of the Protocol. 
 
7.4. 
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. For the open-label efficacy assessments, subjects will 
rate the change in their current overall condition since they started treatment (in this 
study for subjects in Group B or in the previous study for subjects in Group A) on a 7-
point scale ranging from 1 = very much improved to 7 = very much worse. Group A 
subjects will provide ratings at Weeks 2, 14, 27, and 40; Group B subjects will provide 
ratings at Weeks 2, 14, 26, 39, and 52. All subjects will provide ratings at early 
termination visits that occur after Week 2 (see Protocol Appendix 15). For the double-
blind, placebo-controlled assessment of the maintenance of efficacy, subjects will rate 
the change in their current overall condition since their last visit on a 7-point scale 
ranging from 1 = very much improved to 7 = very much worse at Week 29 (for subjects in 
Group A) or at Week 28 (for subjects in Group B).  For additional information, see 
Appendix 16 of the Protocol. 
 
7.5. 
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, effect sizes, 


Jazz Pharmaceuticals 
Protocol: 14-005 
Version 1.0 
Statistical Analysis Plan 
 
Page 35 of 76 
and pre- and post-treatment differences that are highly correlated with the longer 
version. 
 
Subjects who are randomized into the randomized withdrawal period will be asked to 
complete the FOSQ-10 at the following times (see Protocol Appendix 6):  
 
For Group A, at Weeks 14, 27, 29, 40, and at Early Termination visits that occur 
after Week 2.  
 
For Group B, at Baseline, Weeks 14, 26, 28, 39, 52, and at Early Termination 
visits that occur after Week 2.  
 
Subjects who are not randomized into the randomized withdrawal period will be asked 
to complete the FOSQ-10 at the following times (see Protocol Appendix 6):  
 
For Group A: at Weeks 14, 27, 40, and at Early Termination visits that occur after 
Week 2.  
 
For Group B: at Baseline, Weeks 14, 26, 39, 52, and Early Termination visits that 
occur after Week 2.  
 
7.6. 
36-ITEM SHORT FORM HEALTH SURVEY VERSION 2 (SF-36V2) 
The SF-36v2 is a multi-purpose, short-form health survey with 36 questions. It yields an 
8-scale profile of functional health and well-being scores as well as psychometrically-
based physical and mental health summary measures and a preference-based health 
utility index (see Protocol Appendix 7). Group A subjects will complete the SF-36v2 at 
Weeks 14, 27, and 40; Group B subjects will complete the questionnaire at baseline and 
Weeks 14, 26, 39, and 52. All subjects will complete the questionnaire at early 
termination visits that occur after Week 2. 
 
7.7. 
EUROQOL (EQ-5D-5L) 
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome that 
includes a descriptive system consisting of 5 dimensions (mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression) and an EQ visual analogue scale 
(VAS). It is applicable to a wide range of health conditions and treatments and provides 
a simple descriptive profile and a single index value for health status. The EQ-5D-5L 
includes five levels of severity (1=no problem, 2=slight problem, 3=moderate problem, 
4=severe problem, 5=unable) for each of the 5 dimensions of the descriptive system and 
was developed to improve the instrument’s reliability and sensitivity and to reduce 
ceiling effects. Group A subjects will complete the EQ-5D-5L at Weeks 14, 27, and 40; 
Group B subjects will complete the questionnaire at baseline and Weeks 14, 26, 39, and 
52. All subjects will complete the questionnaire at early termination visits that occur 
after Week 2 (see Protocol Appendix 8). 
 


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Page 36 of 76 
7.8. 
PRIMARY OSA THERAPY USE 
Subjects who reported using a primary OSA therapy during Study 14-003, 14-004, or 15-
004 will continue to 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 through the final visit of the 
Maintenance Phase (Week 40 for 14-003 or Week 52 for 14-004 and 15-004). If a 
subject’s device usage cannot be extracted from his/her device, the subject should be 
instructed to record whether he/she used his/her primary OSA therapy 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 through the final visit of the Maintenance 
Phase (Week 40 for 14-003 or Week 52 for 14-004 and 15-004). Subjects who reported 
not using a primary OSA therapy during Study 14-003, 14-004, or 15-004 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.  
 
Subjects will be encouraged to stay on their current primary OSA therapy at the same 
level of use throughout the study. 
 
7.9. 
WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT 
QUESTIONNAIRE: SPECIFIC HEALTH PROBLEM V2.0 
(WPAI:SHP) 
The WPAI questionnaire is a 6-item self-administered questionnaire that measures work 
time missed and work and activity impairment because of a specified health problem 
during the past 7 days. The WPAI:SHP will be used with “narcolepsy” or “OSA” as the 
specified health problem. The validity of the WPAI has been established in a number of 
diseases and it is available in multiple languages (Reilly 1993). Group A subjects will 
complete the WPAI:SHP at Weeks 14, 27, and 40 for ; Group B subjects will complete 
the questionnaire at baseline and Weeks 14, 26, 39, and 52. All subjects will complete 
the questionnaire at early termination visits that occur after Week 14 (Protocol 
Appendix 10). 
7.10. 
RESOURCE UTILIZATION QUESTIONNAIRE 
Patient-reported resource utilization will be assessed at the Week 14 and Week 40 visits 
in Group A, at the Week 26 and Week 52 visits in Group B, and for all subjects at early 
termination visits that occur after Week 14. Information about the number of physician 
visits will be collected via questionnaire (Protocol Appendix 17). Standard unit costs will 
be applied to these resources (as well as to any hospitalizations reported as SAEs) in 
order to calculate the mean/median healthcare costs over the one-year period. 


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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 the 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%; 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 separately by open-label study phases and 
Randomized Withdrawal Period. All data will be summarized in the following manner, 
unless specified otherwise. 
 
In the open label phases, the analyses will be summarized overall and by modal 
dose level (e.g., JZP-110 75 mg, 150 mg, or 300 mg).  
 
In the Randomized Withdrawal Period, the analyses will be summarized by 
treatment group (Placebo or Combined JZP-110), and the analyses will be also 
summarized by dose level (e.g., JZP-110 75 mg, 150 mg, or 300 mg).   
For Group A, additional summary tables will be provided by the treatment received in 
the previous studies.  
Graphical presentations will be provided based on subject’s modal dose to evaluate 
efficacy, functional outcomes and quality of life measures, and economic data over time 
in this study.  
Data collected in this study will be presented in by-subject listings.    
All analyses and outputs will be generated using SAS® version 9.3 (or higher). 


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8.2. 
KEY DEFINITIONS 
8.2.1. 
Baseline  
8.2.1.1. 
Placebo-Controlled Randomized Withdrawal Period 
o For subjects who were randomized in the randomized withdrawal period, 
non-missing measurements taken at the beginning of the double-blind 
Randomized Withdrawal Period (Week 27 for Group A and Week 26 for 
Group B) will be used as the ‘efficacy baseline’ of the Randomized 
Withdrawal period. 
 
8.2.1.2. 
Open-label (OL) Phases  
 
For Group A: 
o The baseline measurement for subjects is defined as the last non-missing 
value up to week 12 from the previous study, 14-002 or 14-003.  
o The baseline in the previous study will be also used as a reference for 
summary analysis (parent study baseline). 
 
For Group B: 
o The baseline measurement for subjects is defined as the last non-missing 
value from the baseline visit measured prior to the first dose of study 
drug in this study. If a subject has repeated measurements from the 
baseline visit, then the last non-missing value will be used. If there is no 
value from the scheduled baseline visit, the last non-missing value from 
other screening or unscheduled visits measured prior to the first dose of 
the study drug will be used.  
 
8.2.2. 
Study Day 
Study day will be assigned as follows: 
 
The first dose of study drug in this study 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 visits 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.  


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8.2.3. 
Modal Dose 
The modal dose is defined as the dose level that the subject received most frequently in 
the study. If there is a tie between the two dose levels, the lower dose will be used. 
8.2.4. 
JZP-110 Exposure 
JZP-110 exposure is defined as the number of days that a dose of JZP-110 is taken, 
regardless of the JZP-110 dose level. 
8.2.5. 
Study Phases and Periods 
The following study phases and period are defined for analyses: 
 
For subjects who are randomized into the randomized withdrawal period: 
o The open label phases (Titration and Maintenance Phases) are from the first 
day that study drug is taken (Day 1) in this study up to end of Week 27 (Group 
A) or Week 26 (Group B), or to the ET date for the subjects who discontinue 
without reaching the end of Week 27 (Group A) or Week 26 (Group B) and 
after the end of Week 29 (Group A) or Week 28 (Group B) up to the end of 
date in the study, or to the ET date for the subjects who discontinue without 
completing the study. 
 
For subjects who are not randomized into the randomized withdrawal period: 
o The open label phases are from the first day that study drug is taken (Day 1) 
in this study up to the end of date in the study, or to the ET date for the 
subjects who discontinue without completing the study. 
 
The Randomized Withdrawal Period is from the end of Week 27 (Group A) or 
Week 26 (Group B) to the end of Week 29 (Group A) or Week 28 (Group B), or to 
the ET date for the subjects who discontinue without reaching the end of 
Randomized Withdrawal Period.  
 
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 for determining study day 
and then study day will then 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 


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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, 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 visit will be used.  
The unscheduled or early termination (ET) visit will be mapped to a scheduled visit 
before the imputation methods are used for handling dropouts and missing data for the 
efficacy endpoints.  
The data not flagged as an “analyzed record” will be listed in subject listings. 


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Group A Visit Windows: 
 
Study Day Window 
Scheduled Study Day  
Scheduled Visit/Week
Day (-1) 
Day -1
Visit 1/Screening/Baseline
Day  1 – 4 
Day 3
Visit 2/Day 3 
Day  5 – 7 
Day 6
Visit 3/Day 6 
Day  8 – 10 
Day 9
Visit 4/Day 9 
Day 11 – 13 
Day 12
Visit 5/Day 12 
Day 14 – 29 
Day 15
Visit 6/Week 2 
Day 30 – 57 
Day 43
Visit 7/Week 6 
Day 58 – 85 
Day 71
Visit 8/Week 10 
Day 86 – 113 
Day 99
Visit 9/Week 14 
Day 114 – 141 
Day 127
Visit 10/Week 18 
Day 142 – 173 
Day 155
Visit 11/Week 22 
Non-randomized subjects: 
Day 174 – 193 
 
Randomized subjects: 
Day 174 – day of 
randomization date 
Day 190
Visit 12/Week 27 
Randomized subjects: 
Day 1 - 10 after the 
randomization date 
Day 197
Visit 12.1/Week 28 
Randomized subjects: 
Day 11 - 20 after the day 
of randomization date 
Day 204
Visit 12.2/Week 29 
Non-randomized subjects: 
Day 194 to 232 
 
Randomized subjects:  
(Day after Visit 12.2/Week 
29 or Day > 20 after the 
day of randomization date 
if missing week 29  
) - 232 
Non-randomized subjects: 
Day of Visit 12/Week 27 + 2 
weeks 
 
Randomized subjects:  
Day 218  
Visit 13/Week 31 
Day 233 -264 
Day 246
Visit 14/Week 35 
Day 265 -288 
Day 281
Visit 15/Week 40 
Day >=289  
Day 295
Visit 16/Week 42 
  


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Group B Visit Windows: 
Study Day Window 
Scheduled Study Day
Scheduled Visit/Week
Day (-30) - (-2) 
Day -2
Visit 1/Screening 
Day (-1) 
Day -1
Visit 2/Baseline 
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 - 29  
Day 15
Visit 7/Week 2 
Day 30 – 57 
Day 43
Visit 8/Week 6 
Day 58 – 85 
Day 71
Visit 9/Week 10 
Day 86 – 113 
Day 99
Visit 10/Week 14 
Day 114 – 141 
Day 127
Visit 11/Week 18 
Day 142 - 169 
Day 155
Visit 12/Week 22 
Non-randomized subjects: 
Day 170 – 186 
 
Randomized subjects: 
Day 170 – day of 
randomization date 
Day 183
Visit 13/Week 26 
Randomized subjects: 
Day 1 – 10 after the 
randomization date  
Day 190
Visit 13.1/Week 27 
Randomized subjects: 
Day 11 – 20 after the 
randomization date 
Day 197
Visit 13.2/Week 28 
Non-randomized subjects: 
Day 187 to 225  
 
Randomized subjects:  
Day > 20 after the 
randomization date   
Non-randomized subjects: 
Date of Visit 13/Week 26 
 
Randomized subjects:  
Day 211  
Visit 14/Week 30 
Day 226 – 257 
Day 239
Visit 15/Week 34 
Day 258 – 288 
Day 274
Visit 16/Week 39 
Day 289 – 316 
Day 302
Visit 17/Week 43 
Day 317 – 348 
Day 330
Visit 18/Week 47 
Day 349 – 372 
Day 365
Visit 19/Week 52 
Day >= 373 
Day 379
Visit 20/Week 54 
 
 
 
 


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8.4. 
MISSING DATA 
8.4.1. 
Placebo-Controlled Randomized Withdrawal Period 
ESS: 
For the primary analysis, missing data will be imputed using a single imputation 
approach (SI) the last observation carried forward (LOCF, i.e. the last-observation 
during the Randomized Withdrawal Period). Another single imputation approach (SI) - 
mean imputation will be used to assess the potential impact of missing data as a 
sensitivity analysis as described in section 10.1.1.3.1.  Additional sensitivity analyses 
will be conducted to investigate the robustness of the primary analysis method; the 
details are described in section 10.1.1.3.2.  
 
The algorithm for calculating of the total ESS score is described in Section 10.1.   
 
PGIc: 
For the primary analysis, missing data will be imputed using a single imputation 
approach (SI) – the last observation carried forward (LOCF, i.e. the last-observation 
during the Randomized Withdrawal Period). 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.  
 
CGIc: 
For the primary analysis, missing data will be imputed using a single imputation 
approach (SI) – the last observation carried forward (LOCF, i.e. the last-observation 
during the Randomized Withdrawal Period). 
 
Missing items on the functional outcomes and quality of life measures will be handled as 
described in Section 10.4. 
 
8.4.2. 
Open-label (OL) Phases  
Missing data for the efficacy parameters ESS, CGIc, PGIc will be imputed using an LOCF 
approach.  
 
8.5. 
LEVEL OF SIGNIFICANCE AND MULTIPLICITY ADJUSTMENT 
For comparisons between JZP-110 and placebo at the end of the Randomized 
Withdrawal Period, subjects who were randomized to continue on JZP-110 in the 
Randomized Withdrawal Period will be treated as a single group regardless of their 
diagnosis (narcolepsy or OSA) or dose of JZP-110 that they received. Thus, there will be 
no multiplicity issues with respect to multiple doses in the hypothesis 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 primary and secondary endpoints. 


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To address the multiplicity issues in the analyses of the primary and 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 primary efficacy endpoint ESS. 
The p-value of the primary analysis of the ESS endpoint must be less than 0.05 before 
testing can proceed to the comparison of combined JZP-110 versus placebo for the 
secondary efficacy endpoints PGIc and CGIc (in that order). Testing will stop when the 
significance level exceeds 0.05 (p≥0.05). This gate-keeping approach will control the 
family-wise error rate at 0.05. 
 
8.6. 
POOLING OF CENTERS AND REGION 
Due to 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 investigational centers will be pooled for the 
primary analyses.  
Data will also be summarized by region (North America and Europe) for specified  
analyses.  
8.7. 
SUBGROUPS AND SUBGROUP ANALYSIS 
Exploratory analyses of the key efficacy and safety endpoints will be conducted in the 
following subgroups of subjects:  
 
Subjects with narcolepsy (from study 14-002, 15-005, ADX-N05 201, or ADX-N05 
202)  
 
Subjects with OSA (from study 14-003, 14-004, or 15-004) 
 
Subjects with narcolepsy who report the presence or absence of cataplexy at 
randomization in a previous study (Group A subjects) or at baseline in this study 
(Group B subjects) 
 
Subjects with compliant or non-compliant use of a primary OSA therapy at 
randomization in a previous study (14-003 and 14-004) or at baseline in this study 
(15-004) 
 
Region (North America and Europe) 
The following endpoints will be included in the subgroup analyses: 
 
ESS: Change from the beginning to the end of the Randomized Withdrawal Period 
 
ESS: Change from the study baseline (Group B) 
 
ESS: Change from the last assessment in the previous study (Group A)  
 
ESS: Change from the baseline in the previous study (Group A) 


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 
FOSQ-10: Change in total score and 5 subscale scores from the beginning to the 
end of the Randomized Withdrawal Period 
 
FOSQ-10: Change in total score and 5 subscale scores from the study baseline 
(Group B) 
 
FOSQ-10: Change in total score and 5 subscale scores from the last assessment in 
the previous study (Group A) 
 
FOSQ-10: Change in total score and 5 subscale scores from the Baseline in the 
previous study (Group A) 
 
PGIc: Percentage of subjects reported as improved in the OL Phases at each time 
point (Group A and B) 
 
CGIc: Percentage of subjects reported as improved in the OL Phases at each time 
point (Group A and B) 
 
PGIc: Percentage of subjects reported as worse at the end of Randomized 
Withdrawal Period 
 
CGIc: Percentage of subjects reported as worse at the end of Randomized 
Withdrawal Period  
 
TEAEs 
 
EQ-5D-5L: 
o Number and percentage of subjects in each of the 5 levels (e.g., no 
problem, slight problem, moderate problem, severe problem, unable) for 
each dimension at study Baseline and each post-baseline time point 
(Group B) 
o Number and percentage of subjects in each of the 5 levels (e.g., no 
problem, slight problem, moderate problem, severe problem, unable) for 
each dimension at last assessment and baseline in the previous study and 
each post-baseline time point (Group A) 
o Number and percentage of subjects reporting any problems (levels 2-5) 
for each dimension at study Baseline and each post-baseline time point 
(Group B) 
o Number and percentage of subjects reporting any problems (levels 2-5) 
for each dimension at last assessment and baseline in the previous study 
and each post-baseline time point (Group A) 
o EQ VAS score at each time point and change from study Baseline to each 
post-baseline time point (Group B) 


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o EQ VAS score at each time point and change from baseline in the 
previous study (Group A) 
o EQ VAS score at each time point and change from the last assessment in 
the previous study (Group A) 
 
  


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9. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
9.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
The number of all enrolled subjects and the number and percentage of subjects in the 
each analysis population will be presented. For Group A, data will also be summarized 
by previous study treatment. In addition, the number of subjects who 
completed/prematurely discontinued and the reason for discontinuation will also be 
presented by study phases and period.  Disposition information will be summarized for 
the Safety and mITT population and for the subgroups of subjects by region. 
The summary of disposition over time will show the number of subjects terminating the 
study in each week 
For the Group A subjects, disposition information will be also summarized by treatment 
group from the previous study.  
For screen failure subjects in Group B, reasons for screen failure will be summarized 
separately.   
9.2. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline characteristics will be summarized for the safety, mITT, Per-
Protocol populations, and subgroups of subjects by region. 
Demographic information will be collected for subjects who completed Study 14-004, 
15-004, 15-005, ADX-N05 201, or ADX-N05 202 (Group B). Demographic information for 
subjects who completed Study 14-002 or 14-003 (Group A) will be obtained from those 
study databases. 
For Group A subjects, demographic and baseline characteristics will be also summarized 
by treatment group from the previous study.  
Demographic and baseline characteristics include age, gender, race, ethnicity, region, 
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 screen failure subjects in Group B, demographic data will be summarized 
separately.   
In addition, the following variables will be summarized: 
 
Baseline disease severity: total ESS score and clinical global impression of 
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 
Randomization stratification factors from previous studies: narcolepsy and OSA, 
presence of cataplexy, and primary OSA therapy use (compliant, non-compliant) 
for Group A 
 
Efficacy endpoints at the beginning of Randomized Withdrawal Period: total ESS 
score, CGIc, and PGIc 
 
9.3. 
MEDICAL/SURGICAL HISTORY 
A complete medical/surgical history from the time of participation in Study 14-004, 15-
004, 15-005, ADX-N05 201, or ADX-N05 202 (Group B) will be collected for each subject 
during the Screening visit. Any updates to the medical/surgical history for Group B 
subjects will be assessed at Day -1. The medical history for subjects who completed 
Study 14-002 or 14-003 will be re-entered from those study records. 
Medical/surgical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA), Version 18.0. 
Medical/surgical 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 and Concomitant Medication/Procedure 
During the Screening Phase, prior (30 days or more) and concomitant medication use 
and any medications used for the treatment of narcolepsy or OSA (including devices 
used for OSA) since diagnosis will be recorded on the case report form (CRF) for subjects 
who participated in Study 14-004, 15-004, 15-005, ADX-N05 201, or ADX-N05 202 (Group 
B). Concomitant medications for subjects who participated in 14-002 or 14-003 (Group 
A) will be captured on the CRF pages in those respective studies.  
9.4.2. 
Prior Medication 
Prior medication will be defined as any medication (except for investigational product in 
one of the prior studies) with a start date prior to the first dose of study drug in this 
study.  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. 


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Prior medications will be summarized by anatomical therapeutic chemical (ATC) level 3 
term and preferred term based on the Safety Population. 
9.4.3. 
Concomitant Medication and Procedure 
Concomitant medication will be defined as any medication 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 in this study. A 
medication with complete missing use dates or partial missing use dates without 
evidence that the medication 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 will be summarized by ATC level 3 term and preferred term 
based on safety population. Procedures will be summarized by MedDRA SOC and PT. The 
summaries will be based on the Safety Population. 
 
9.5. 
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 
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 Per-Protocol 
population and the reason for exclusion from 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 study phases and period based on the 
Safety Population. Major protocol deviations will also be summarized by randomized 
treatment group for the Randomized Withdrawal Period based on the mITT Population. 


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10. 
EFFICACY 
Observed data at each time point and change from baseline to each post-baseline time 
point during each phases and period will be summarized as described below. For 
categorical data, frequency counts and percentages will be presented in a similar 
manner. 
10.1. 
ESS SCORE: PRIMARY EFFICACY ENDPOINT AND ANALYSES 
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. 
Placebo-Controlled Randomized Withdrawal Period  
10.1.1.1. 
Primary Analysis 
For the primary analysis of the ESS score, an analysis of covariance (ANCOVA) model will 
be used. The response variable will be the change from the beginning to the end of 
Randomized Withdrawal Period The model will include the following fixed effects: 
 
Treatment group (with 2 levels: Combined JZP-110 and Placebo) 
 
Randomization stratification factor (narcolepsy vs. OSA) 
 
‘Efficacy Baseline’, defined as the ESS total score at the beginning of the 
Randomized Withdrawal Period  
SAS procedure 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 
interval will be presented. The LOCF approach will be used for subjects who 
discontinued early in the Randomized Withdrawal Period.   
The analysis will be based on the mITT Populations.  
 


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10.1.1.2. 
Secondary Analysis 
For 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. 
10.1.1.3. 
Sensitivity Analysis 
This section describes analyses to explore the potential impact of missing data.  
Importantly, the analyses described in Section 10.1.1.1 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.  
10.1.1.3.1. 
Sensitivity Analyses using Single Imputation (SI) Approach 
The ANCOVA model described in Section 10.1.1.1 will be used to evaluate the change in 
in the ESS score from the beginning to the end of the Randomized Withdrawal Period 
using the SI approach described below.   
The mean imputation approach assumes missing completely at random, meaning that 
the probability of observed data being missing does not depend on observed data or on 
unobserved data. For each subject, missing data at the beginning to the end of 
Randomized Withdrawal Period will be replaced with the corresponding treatment group 
mean.  
10.1.1.3.2. 
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 for the placebo-controlled maintenance of 
efficacy of the ESS score analysis.  
For missing data due to dropouts, pattern mixture imputation will be considered based 
on 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 


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Scenario 2: 
MNAR (missing not at random):  
 
dropout due to adverse event (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 reasons (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 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.    
 
If the missing data in the combined JZP-110 treatment group falls into a MNAR pattern, 
the analysis will assume the treatment differences over the missing visit (e.g., Week 29 
(Group A) or Week 28 (Group B)) 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 the primary endpoint of ESS 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 JZP-110 treatment group that fall 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 
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the JZP-110 treatment groups, dropout due to AE in the JZP-110 treatment group, and 
dropout due to LOE or AE in the 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 10.1.1.1. 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.   
 
10.1.2. 
Open-label (OL) Phases 
For the OL maintenance of efficacy analyses, ESS scores will be summarized by time 
point as following:   
 
For Group A: 
o Change in ESS score from the baseline in the previous study  
o Change in ESS score from the last assessment in the previous study  
For the Group A, the ESS analysis will also be summarized by the treatment in the 
previous study.  
 
For Group B: 
o Change in ESS score from the study baseline  
The analysis will be based on the Safety Population.  
 
 
10.1.3. 
Subgroup Analyses 
The approach described in the primary analysis in Section 10.1.1.1 will also be used for 
the subgroup analyses. The analysis will be performed for the Randomized Withdrawal 
Period (based on the mITT Population) and the OL Phases (based on the Safety 
Population) separately. The primary analysis in Section 10.1.1.1 will be used for the 
subgroup analyses, however the randomization stratification factor (with 2 levels, 
narcolepsy vs. OSA) will be removed from the model for analysis the subgroup of 
subjects with narcolepsy or OSA at randomization. Similar analyses will be conducted for 


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the subgroups listed in Section 8.7. No formal statistical testing will be performed for 
the open-label analyses; only summary statistics will be provided. 
 
10.2. 
CGIC: CLINICAL GLOBAL IMPRESSION OF CHANGE 
 
10.2.1. 
Placebo-Controlled Randomized Withdrawal Period 
10.2.1.1. 
Primary Analysis 
The percentage of subjects reported as worse on the CGIc at the end of Randomized 
Withdrawal Period will be calculated and summarized by treatment group. Comparison 
between combined JZP-110 doses and placebo will be performed using a chi-square test. 
95% confidence intervals for the difference in percentages will be calculated. Missing 
data at the end of Randomized Withdrawal Period will be imputed using LOCF. The 
analysis will be based on the mITT population. 
10.2.2. 
Open-label (OL) Phases 
The percentage of subjects reported as improved on the CGIc at each time point will be 
summarized and presented graphically.  LOCF will be used to impute data for subjects 
with missing post-baseline assessments. The summaries will be based on the Safety 
Population.  
10.2.3. 
Subgroup Analyses 
The approach described in the primary analysis in Section 10.2.1.1 will also be used for 
the subgroup analyses. The analysis will be performed for the Randomized Withdrawal 
Period (based on the mITT Population) and the OL Phases (based on the Safety 
Population) separately.  No formal statistical testing will be performed for the open-
label analyses; only summary statistics will be provided. 
 
10.3. 
PGIC: PATIENT GLOBAL IMPRESSION OF CHANGE 
10.3.1. 
Placebo-Controlled Randomized Withdrawal Period 
10.3.1.1. 
Primary Analysis 
The percentage of subjects reported as worse on the PGIc at the end of Randomized 
Withdrawal Period will be calculated and summarized by treatment group. Comparison 
between combined JZP-110 doses and placebo will be performed using a chi-square test. 
95% confidence intervals for the difference in percentages will be calculated.  Missing 


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data at the end of Randomized Withdrawal Period will be imputed using LOCF. The 
analysis will be based on the mITT population. 
10.3.1.2. 
Secondary Analysis 
The analysis of the secondary endpoint will be performed using the same statistical 
method as the primary analysis based on the PP population instead of the mITT 
population 
10.3.1.3. 
Sensitivity Analyses 
Missing data at the end of the Randomized Withdrawal Period 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 Randomized Withdrawal Period due to lack of 
efficacy or adverse events will be considered worsened (minimally, much, or very much) 
at the end of Randomized Withdrawal Period. Subjects with missing data at the end of 
the RW Period for other reasons will be imputed using LOCF.  
Approach 2 – SI by the Worst-Case  
All subjects with missing data the end of the Randomized Withdrawal Period 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 the treatment groups will be calculated. These analyses will be based on the 
mITT population.  
 
10.3.2. 
Open-label (OL) Phases 
The percentage of subjects reported as improved on the PGIc at each time point will be 
summarized and presented graphically.  LOCF will be used to impute data for subjects 
with missing post-baseline assessments in the Open label Phases. The summaries will be 
based on the Safety Population.  
10.3.3. 
Subgroup Analysis 
The approach described in the primary analysis in Section 10.3.1 will also be used for 
the subgroup analyses. The analysis will be performed for the Randomized Withdrawal 
Period (based on the mITT Population) and the OL Phases (based on the Safety 


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Population) separately.  No formal statistical testing will be performed for the open-
label analyses; only summary statistics will be provided. 
 
10.4. 
FUNCTIONAL OUTCOMES AND QUALITY OF LIFE ENDPOINTS 
Outcome measures associated with the FOSQ-10, SF-36v2, EQ-5D-5L, and compliance 
with primary OSA therapy (OSA only) will be summarized by study phases and period. 
These results will also be displayed graphically over time. Changes (as described in 
Section 4.2) in these measures from the baseline and from the last assessment in the 
previous study will be examined.  
10.4.1. 
FOSQ-10: Change in the Total Score  
The 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.  
10.4.1.1. 
Placebo-Controlled Randomized Withdrawal Period 
Change in the FOSQ-10 total score from the beginning to the end of the Randomized 
Withdrawal Period will be analyzed using a similar ANCOVA model as the primary 
analysis of primary efficacy endpoint (Section 10.1.1.1). 
Changes in the FOSQ-10 total score and the 5 subscale scores from the beginning to the 
end of the Randomized Withdrawal Period will be summarized.  
The analysis will be based on the mITT Population.  
10.4.1.2. 
Open-label (OL) Phases 
FOSQ-10 scores will be summarized by time point as following:   
For Group A: 
 
Change in FOSQ-10 total score and the 5 subscale scores from the baseline in the 
previous study 
 
Change in FOSQ-10 total score and the 5 subscale scores from the last 
assessment in the previous study 
For Group B: 
 
Change in FOSQ-10 total score and the 5 subscale scores from baseline in this 
study.  


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Analyses will be based on the Safety Population. 
10.4.1.3. 
Subgroup Analysis 
The approach described in the primary analysis in Section 10.4.1 will also be used for 
the subgroup analyses. The analysis will be performed for the Randomized Withdrawal 
Period (based on the mITT Population) and the OL Phases (based on the Safety 
Population) separately.  No formal statistical testing will be performed for the open-
label analyses; only summary statistics will be provided. 
 
10.4.2. 
SF-36v2: Change from Baseline by Domains 
The SF-36v2 is composed of 8 domains/scales: physical functioning (PF), role-physical 
(RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role-
emotional (RE), and mental health (MH). From the eight domains, a physical component 
summary (PCS) (aggregate of the PF, RP, BP and GH scales) and mental component 
summary (MCS) (aggregate of the VT, SF, RE and MH scales) are derived.  
 
10.4.2.1. 
Open-label (OL) Phases 
SF-36 items and scales are scored so that a higher score indicates a better health state. 
Scoring the SF-36 involves several steps. First, 10 items are reverse-coded and an 
algorithm for an algebraic summation of item scores is applied to produce domain-
specific raw scales that accounts for missing item responses. Domain-specific raw scales 
are then transformed to a 0 to a 100 range, after which a norm-based (T-score) 
transformation is applied so that each scale ranges from 0 to 100, with a mean of 50 and 
a standard deviation of 10 in the 1998 general U.S. population (Ware et al 2000). A 
norm-based transformation is applied so that domain-specific scales can be meaningfully 
compared between each other.  
 
The mental and physical component summary scores (MCS/PCS) are computed by 
aggregating domain scores using factor score coefficients from the 1998 general U.S. 
population (Ware et al 2000). The aggregated summary scores are standardized to have 
a mean of 50 with a standard deviation of 10 in the general 1998 U.S. population (Ware 
et al 2000). 
 
When calculating the raw domain scores, if at least half the item scores for a domain 
are non-missing, the missing item scores will be replaced with the average of the non-
missing scores for the domain. Otherwise the raw domain score and corresponding norm-
based domain scores will be set to missing. 
Domain scores and component summary scores will be calculated using the Quality 
Metric (QM) Certified Scoring software and provided by Optum, Inc.  


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SF-36v2 analysis in domain scores (norm-based), the physical component summary (PCS) 
score, and mental component summary (MCS) score will be summarized by time point as 
following:   
For Group A: 
 
Change from the baseline in the previous study 
 
Change from the last assessment in the previous study 
For Group B: 
 
Change from the study baseline 
The analysis above will be based on the Safety Population.  
10.4.3. 
EQ-5D-5L: EQ-5D Dimensions  
10.4.3.1. 
Open-label (OL) Phases 
EQ-5D-5L has 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression). Each dimension has 5 levels of response (e.g., 1=no problem, 
2=slight problem, 3=moderate problem, 4=severe problem, 5=unable). 
If multiple levels of response are checked for a single dimension, then the level of 
response will be treated as a “missing value” for the dimension.  
The following categories will be summarized for EQ-5D-5L by time point : 
 
Number and percentage of subjects in each of the 5 levels of severity (e.g., no 
problem, slight problem, moderate problem, severe problem, unable) for each of 
the 5 dimension (e.g., mobility, self-care) 
 
Number and percentage of subjects reporting any problems (levels 2-5) for each 
dimension  
Similar analyses will be conducted for the subgroups listed in Section 8.7. 
The analyses above will be based on the Safety Population.   
10.4.4. 
EQ VAS: Change in the VAS Score  
10.4.4.1. 
Open-label (OL) Phases 
The EQ VAS score ranges from 0 to 100, with a higher score indicating a better health 
condition.  


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For Group A: 
 
EQ VAS score and change from the baseline in the previous study 
 
EQ VAS score change from the last assessment in the previous study 
For Group B: 
 
EQ VAS score change from this study baseline  
Similar analyses will be conducted for the subgroups listed in Section 8.7. 
The analysis above will be based on the Safety Population.  
10.4.5. 
EQ-5D-5L index: Change in Index Value 
10.4.5.1. 
Open-label (OL) Phases 
Health states in the EQ-5D-5L can be converted into a single index value, where index 
values are presented in the country specific value sets to facilitate the calculation of 
quality-adjusted life years (QALYs). EQ-5D-5L value sets can be used to obtain the EQ-
5D-5L index values based on the crosswalk for the respective countries: Denmark, 
France, Germany, Japan, the Netherlands, Spain, Thailand, UK, US, Zimbabwe. 
References: http://www.euroqol.org/about-eq-5d/valuation-of-eq-5d/eq-5d-5l-value-
sets.html; van Hout B, Janssen MF, et al. Interim scoring for the EQ-5D-5L: Mapping the 
EQ-5D-5L to EQ-5D-3L value sets. Value in Health 2012 Jul-Aug; 15(5):708-15. 
For Group A: 
 
Change in the EQ-5D-5L index value from the baseline in the previous study 
 
Change in the EQ-5D-5L index value from the last assessment in the previous 
study   
For Group B:  
 
Change from the study baseline.  
Similar analyses will be conducted for the subgroups listed in Section 8.7. 
The analysis above will be based on the Safety Population.  


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10.4.6. 
Use of Primary OSA Therapy 
Subjects who reported using a primary OSA therapy during Study 14-003, 14-004, or 15-
004 will continue to record information regarding whether they used their device each 
night and the duration of nightly use. These data will be extracted from the data 
download from their device or memory card from screening through the final visit of the 
Maintenance Phase (Week 40 for 14-003 or Week 52 for 14-004 and 15-004). Subjects 
who do not have electronically retrievable data from their OSA therapy device will 
record their usage of their OSA therapy device using a daily diary.  
Compliance with primary OSA therapy for the subjects from the study 14-003, 14-004, 
and 15-004 will be summarized by visit. 
 
If daily data for primary OSA therapy use are missing, the missing daily data will be 
imputed using the LOCF method between each visit. LOCF will be applied up to the 
early termination date or the last date prior to the next visit, whichever is earlier. 
Otherwise these data will not be imputed.  
10.4.6.1. 
Placebo-Controlled Randomized Withdrawal Period 
Compliance with primary OSA therapy for the randomized subjects in the Randomized 
Withdrawal Period will be summarized as follows: 
 
 
Percentage of nights that subjects use their primary OSA therapy in the 
Randomized Withdrawal Period 
 
Change in the percentage of nights that the primary OSA therapy is used from 
the visit before Randomized Withdrawal Period to the Randomized Withdrawal 
Period 
The change in the percentage of nights that the primary OSA therapy is used from the 
visit before the Randomized Withdrawal Period to the Randomized Withdrawal Period 
will be analyzed using a Wilcoxon-Mann-Whitney test to compare the treatment 
difference between combined JZP-110 with placebo. 
 
For subjects who have electronically retrievable data,  
 
Average number of hours that a subject used the OSA device per night at each 
visit will be calculated as:  
o Total number of hours that a subject used the OSA device between visits/ 
total number of nights that the subject used the OSA device between 
visits. The nights that the subject did not use an OSA device will not be 
included in the calculation.   


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For subjects who do not have electronically retrievable data: 
 
 
Percentage of nights that subjects used an OSA device more than half of the 
night  
 
Percentage of nights that subjects used an OSA device less than half of the night  
 
Percentage of nights that subjects used an OSA device with unknown duration 
 
10.4.6.2. 
Open-label (OL) Phases 
Compliance with primary OSA therapy in the Open-label Period will be summarized as 
follows: 
 
 
For Group A and B 
 
o Percentage of nights that subjects use the primary OSA therapy in the 
Open label Phases  
 
 
For Group A  
o Change in the percentage of nights that the primary OSA therapy is used 
in the screening period in the previous study to each time point 
o Change in the percentage of nights that the primary OSA therapy is used 
in the last period in the previous study to each time point 
 
For Group B 
o Change in the percentage of nights that the primary OSA therapy is used 
from the Screening Period (e.g., all available data prior to the first dose 
date of study drug in this study) to each time point  
In addition, the following exploratory summary analyses will be conducted:  
 
 
For subjects who have electronically retrievable data : 
 
o Average number of hours that a subject used OSA device per night in each 
period, will be calculated as: Total number of hours that a subject used 
the OSA device in a period/ total number of nights that the subject used 
OSA device in that period. The nights that the subject did not use an OSA 
device will not be included in the calculation.   
 
 
For subjects who do not have electronically retrievable data : 
 


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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 
 
The analyses above will be based on the Safety Population.  
10.5. 
ECONOMIC ASSESSMENTS 
10.5.1. 
WPAI:SHP   
10.5.1.1. 
Open-label (OL) Phases 
The outcome measures associated with the WPAI:SHP will be summarized overall and by 
modal dose and time point as described in Section 8. Results will also be displayed 
graphically. No missing data imputation will be performed. 
The WPAI questionnaire is a 6-item self-administered questionnaire that measures work 
time missed and work and activity impairment due to a specified health problem during 
the past 7 days. The WPAI:SHP will be used with “narcolepsy” or “OSA” as the specified 
health problem. Subjects will complete the WPAI:SHP at Weeks 14, 27, and 40 for 
subjects in Group A; at baseline and Weeks 14, 26, 39, and 52 for subjects in Group B; 
and at early termination visits that occur after Week 14 (see Protocol Appendix 10). 
 
Questions: 
1 = currently employed 
2a = hours missed from work due to problem 
2b = hours missed from work other reasons 
3 = hours actually worked 
4 = degree problem affected productivity while working 
5 = degree problem affected regular activities 
Endpoints and Scoring: 
The following four endpoints will be developed for the evaluation of work 
productivity and activity impairment. Multiply scores by 100 to express in percentages. 
 
Percentage of work time missed due to problem: Score = Q2a/(Q2a+Q2b+Q3) 
 
Percentage impairment while working due to problem: Score = Q4/10 
 
Percentage of overall work impairment due to problem:  


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 Score = (Q2a+Q2b)/(Q2a+Q2b+Q3) + {(1-(Q2a+Q2b)/(Q2a+Q2b+Q3)) x Q4/10 
 
Percent of activity impairment due to problem: Score = Q5/10  
Where applicable, the changes in the WPAI:SHP measures from the previous study 
baseline and from the last assessment of the previous study will be examined for the 
following categories:  
 
Percentage of work time missed due to problem 
 
Percentage of impairment while working due to problem 
 
Percentage of overall work impairment due to problem  
 
Percentage of activity impairment due to problem 
 
The analyses above will be performed based on the Safety Population. 
 
10.5.2. 
Resource Utilization Questionnaire  
10.5.2.1. 
Open-label (OL) Phases 
The outcome measures associated with the Resource Utilization Questionnaire will be 
summarized overall and by stable dose and time point as described in Section 8. Results 
will also be displayed graphically. No missing data imputation will be performed. 
A patient-reported Resource Utilization Questionnaire will be administered at the Week 
14 and Week 40 visits in Group A, at the Week 26 and Week 52 Visits in Group B, and at 
early Termination visits that occur after Week 14. Information about the number of 
physician visits will be collected via questionnaire (see Protocol Appendix 15). Standard 
unit costs will be applied to these resources (as well as to any hospitalizations reported 
as SAEs) in order to calculate the mean/median healthcare costs over the one-year 
period. 
Questions: 
In the past 3 months, how many times did you visit the following types of physicians for 
your own care (not related to this study):  
 
Primary care physician  
 
Sleep specialist  
 
Psychiatrist (for problems other than sleep)  
 
Ear nose and throat specialist  
 
Other type of specialist (please specify)  
The statistical summary will include the number of visits for each type of visit in past 3 
months. Mean/median healthcare costs over the one-year period will be summarized.  


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For Group A, resource utilization data will also be summarized by treatment in the 
previous study. 
The analysis above will be performed based on the Safety Population.  
10.6. 
SUMMARY OF PLACEBO-CONTROLLED EFFICACY ANALYSIS 
METHODS 
Endpoint 
Group A 
Time Point
Group B
Time point
Analysis/ 
Population 
Method 
Missing Data 
Imputation 
Primary 
Change from 
beginning to end of 
RW Period in ESS   
Week 29 
Week 28
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
Secondary 
Worsening in PGIc,  
at end of RW 
Period 
Week 29  
Week 28 
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
Worsening in CGIc,  
at end of RW 
Period 
Week 29 
Week 28
Primary/
mITT 
Chi-
square 
SI: LOCF
 
 
Subgroup/
mITT 
Chi-
square 
SI: LOCF
Functional outcomes and quality of life
Change from 
beginning to end of 
RW Period in FOSQ-
10 
Week 29  
Week 28 
Primary /
mITT 
ANCOVA 
 
 
 
Subgroup/
ANCOVA 
 


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Endpoint 
Group A 
Time Point
Group B
Time point
Analysis/ 
Population 
Method 
Missing Data 
Imputation 
mITT
Change in the 
percentage of 
nights that the 
primary OSA 
therapy is used 
from the 
Maintenance Phase 
before RW Period 
to the RW Period 
Week 29  
Week 28 
Primary /
mITT 
Wilcoxon 
rank sum 
 


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11. 
SAFETY 
Safety analyses will be based on the Safety Population. No inferential statistics will be 
performed; 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 the Open label Phases and the 
Randomized Withdrawal Period. Exposure to study drug (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. In additional, overall exposure 
to JZP-110 (in days) is calculated as last dose date of study drug – first dose date of 
study drug + 1 regardless of the JZP-110 dose level. 
Study drug exposure will also be summarized based on the treatment received in the 
previous study for Group A. 
11.1. 
TREATMENT COMPLIANCE  
Study drug compliance (%) during a specific period and overall is calculated as: 100 x 
(total number of capsules dispensed – total number of capsules returned)/ total number 
of tablets expected to be taken during the specific period (once daily). 
Compliance will be summarized for the Open label Phases and the Randomized 
Withdrawal Period. In addition, the number and percentage of subjects in the following 
compliance categories (< 80%, 80-100%, >100%, and >120%) will be summarized similarly. 
Overall Compliance will also be summarized across study phases and period, regardless 
of dose level. 
 
11.2. 
ADVERSE EVENTS 
Adverse events will be coded using MedDRA 18.0 to classify events under primary system 
organ class (SOC) and preferred term (PT). 
 
A TEAE is defined as an AE that began after the first dose of study drug or worsened 
after the first dose of study drug.   
AE and TEAE will be summarized by study phases and period (e.g., Open label Phases, 
Randomized Withdrawal Period) 


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An overview of all AEs, the incidence of TEAEs, and the incidence of serious TEAEs will 
be summarized across the study phases or period, respectively.  
TEAEs will be summarized by SOC and PT, the sorting will be based on alphabetical 
order for the SOC and frequency count (descending order) for the PT.  In addition, 
incidence of all TEAEs and serious TEAEs will be summarized by PT, the sorting is based 
on the frequency count (descending order).  
 
For the Open label Phases, the TEAEs will be summarized by Overall, JZP-110 dose level 
(75 mg, 150 mg, and 300 mg).   
In the Randomized Withdrawal Period, TEAEs will be presented by randomized 
treatment (placebo, combined JZP-110) and by JZP-110 dose level (75 mg, 150 mg, and 
300 mg).  
In the Open label Phases and the Randomized Withdrawal Period, TEAEs will be 
summarized by JZP-110 dose level (placebo is considered as JZP-110 dose of 0) at the 
time of onset during JZP-110 exposure in the study. In addition, this analysis will also be 
summarized by previous treatment group (Placebo in Group A) versus other subject 
(Combined JZP-110 in Group A and all subjects in Group B). 
An overview of adverse events will include the number and percentage of subjects who 
had at least one TEAE, Serious TEAE, TEAE related/suspected to be related to study 
drug, TEAE related/suspected to be related to study procedure, study drug withdrawn 
due to TEAE, TEAE of maximum severity, and TEAE with fatal outcome. 
Multiple occurrences of an AE are counted only once per subject per system organ class 
(SOC) and preferred term (PT) in the 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 as specified by 
investigators 
 
Incidence of TEAEs related/suspected to be related to study procedure as 
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 subject withdrawn from 
study 
 
Incidence of TEAEs in which the outcome is fatal 


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Incidence of TEAEs occurring in ≥ 5% and ≥ 10% of subjects in 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. 
11.2.1. 
Subgroup Analyses 
The following analyses will be also 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 as 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  
 
The above analysis will be summarized by the study period and across the study periods, 
respectively.  
 
11.3. 
LABORATORY EVALUATIONS 
If a continuous laboratory value is reported as below or above the limits of 
quantification, the qualifiers should be dropped and the numeric value will be used in 
the analysis (e.g., “< 3” should be “3” and “> 200” should be “200”). 
For Group A: 
Observed data at each time point and the change from the last assessment from the 
previous study will be summarized by treatment in the previous studies.  
For Group B:  
Observed values at each time point and the change from baseline at each post-baseline 
time point 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 and abnormal. 
Frequency counts and percentages will be presented for these categorical data. 
Additional information on clinical significance will also be included in the listing of lab 
values. 


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11.4. 
VITAL SIGNS  
Vital signs will be summarized by observed value and change from baseline by visit.  
For Group A: 
 
The last assessment/baseline in the previous study will be used as a reference.   
For Group B: 
 
The baseline assessment in this study will be used as a reference. 
For Group A and B: 
The assessment at the beginning of Randomized Withdrawal Period will be used as 
reference for the analysis in the Randomized Withdrawal Period.  
The number and percentage of subjects change from the reference in blood pressure 
and heart rate at the each time point 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).  In addition, shifts in categories from the reference at the each time point 
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 
 
An additional listing will be provided of those subjects who have clinically significant 
vital sign values. 


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11.5. 
ECG  
Observed data and change in each ECG parameters [HR, RR, PR, QRS, QT and QT 
corrected with Fridercia’s formula (QTcF)]from baseline to each time point and from 
the beginning of the Randomized Withdrawal Period to the end of the Randomized 
Withdrawal Period will be summarized. 
 
For Group A: 
 
The last assessment/baseline in the previous study will be used as a reference.  
 For Group B: 
 
The baseline assessment in this study will be used as a reference. 
For Group A and B: 
The assessment at the beginning of the Randomized Withdrawal Period will be used as 
reference for the analysis in the Randomized Withdrawal Period.  
The number and percentage of patients with QT and QTcF values falling into the 
following categories will be summarized within each study phases and period  
 
 
Change from reference of 30 – 60 msec in QT and QTcF. 
 
Change from reference of >60 msec in QT and QTcF 
 
Post- reference value > 480 msec and reference value <= 480 msec in QT and 
QTcF 
 
Post- reference value > 500 msec and reference value <= 500 msec in QT and 
QTcF 
 
 
The subjects with other clinically significant ECG findings will also be listed. 
 
Additional information on clinical significance will also be included in the listing 
of ECG measurements. 
 
11.6. 
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
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.   


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11.6.1. 
C-SSRS Outcomes/Composite Endpoints 
The following C-SSRS outcomes/composite endpoints have binary responses (yes/no).  
 
Suicidal Ideation (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 (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.  
 
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 


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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. 
 
If there is no “yes” answer to any of the ten suicidal or behavior questions, the 
composite scores will be set to 0. 
 
11.6.2. 
C-SSRS Analyses  
The number and percentage of subjects having a response of ‘Yes’ to the above 
outcomes/composite endpoints during each phases and period will be summarized by 
category.  
 
In addition, to evaluate potential treatment emergent in C-SSRS, the following variables 
will be summarized: 
 
 
 
For Group A  
 
o Shift to the most serious outcome in the C-SSRS outcomes (No suicidal 
ideation or behavior, Suicidal Ideation, and Suicidal Behavior) from the 
last assessment in the previous study to each subsequent visit, from the 
baseline in the previous study to each subsequent visit, and from the 
beginning to the end of the Randomized Withdrawal Period 
o Shift to the maximum score in each of the C-SSRS composite score 
(Suicidal Ideation score, Suicidal Behavior score,  Suicidal ideation or 
behavior score) from the last assessment in the previous study to each 
subsequent visit, from the baseline in the previous study to each 
subsequent visit, and from the beginning to the end of the Randomized 
Withdrawal Period  
 
 
For Group B 
 
o Shift to the most serious outcome in C-SSRS outcomes (No suicidal 
ideation or behavior, Suicidal Ideation, and Suicidal Behavior) from the 
study baseline to each subsequent visit, and from the beginning to the 
end of the Randomized Withdrawal Period 
o Shift to the maximum score in each of the C-SSRS composite scores 
(Suicidal Ideation score, Suicidal Behavior score, Suicidal Ideation or 
Behavior score) from the study baseline to each subsequent visit, and 
from the beginning to the end of the Randomized Withdrawal Period 


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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 
Interim analyses are planned when the study has approximately 50 subjects with 
narcolepsy and 50 subjects with OSA with an exposure to JZP-110 of 52 weeks and 
100 subjects with narcolepsy and 200 subjects with OSA with an exposure to JZP-110 of 
26 weeks. 


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13. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
Changes from analysis planned in protocol include the following: 
Item 
Section 
Category 
Protocol
SAP
1 
9.10 
Functional 
outcomes 
and quality 
of Life 
endpoints 
The outcome measures 
associated with the 
FOSQ-10, SF-36v2, EQ-5D-
5L, and compliance 
with primary OSA therapy 
(OSA only) will be 
summarized by final dose 
and time point and 
displayed graphically 
The outcome measures 
associated with the 
FOSQ-10, SF-36v2, EQ-
5D-5L, and compliance 
with primary OSA 
therapy (OSA only) will 
be summarized by modal 
dose and time point and 
displayed graphically 
 
 


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14. 
REFERENCE 
1. Rubin D.B.: Multiple Imputation for Nonresponse in Surveys. New York: John Wiley 
and Sons, 1987 
 
2. Schafer: Analysis of Incomplete Multivariate Data. Chapman & Hall, New York, 1997 
 
3. Ware JE: SF-36 Health Survey update.  Spine, 25(24):3130–3139, 2000 
 
4. Carpenter, J. R. and Kenward, M. G. (2013), Multiple Imputation and Its Application, 
New York: John Wiley & Sons. 
5. van Buuren, S. (2012), Flexible Imputation of Missing Data, Boca Raton, FL: Chapman 
& Hall/CRC.