A Double-Blind, Placebo-Controlled, Randomized-Withdrawal, Multicenter Study of the Efficacy and Safety of JZP-258 in Subjects With Narcolepsy With Cataplexy
Phase: PHASE3
Conditions: Narcolepsy With Cataplexy
Sponsor: Jazz Pharmaceuticals

JZP-258 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 15-006 Amendment 5 
CONFIDENTIAL 
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Clinical Trial Protocol: 15-006 
Study Title: 
A Double-Blind, Placebo-Controlled, Randomized-Withdrawal, Multicenter 
Study of the Efficacy and Safety of JZP-258 in Subjects with Narcolepsy with 
Cataplexy 
Study Phase: 
Phase 3 
Product Name: 
JZP-258 
EUDRACT Number: 
2016-000426-20 
Indication: 
Treatment of cataplexy in narcolepsy 
Treatment of excessive daytime sleepiness (EDS) in narcolepsy 
Investigators: 
Multicenter 
Sponsor: 
Jazz Pharmaceuticals 
3180 Porter Drive 
Palo Alto, CA 94304 
Tel: +1 650 496 3777 
Sponsor’s Medical Director: 
Contract Research 
Organization: 
Clinical Laboratory: 
Original Protocol: 
25 February 2016 
Amendment 1: 
05 August 2016 
Amendment 2: 
07 November 2016 
Amendment 3 
10 April 2017 
Amendment 4 
15 Dec 2017 
Amendment 5 
15 May 2018 
Confidentiality Statement 
The information in this document is Jazz Pharmaceuticals confidential information. This material may be used 
only for evaluating or conducting clinical investigations; any other proposed use requires written consent from 
Jazz Pharmaceuticals. Acceptance of this document constitutes an agreement by the recipient(s) that no 
unpublished information contained herein will be published or disclosed without first obtaining written approval 
from Jazz Pharmaceuticals, Inc. 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 
FINISHED PRODUCT 
JZP-258, 0.5 g/mL 
STUDY NUMBER 
15-006 
STUDY PHASE 
Phase 3 
TITLE 
A Double-Blind, Placebo-Controlled, Randomized-Withdrawal, Multicenter Study of 
the Efficacy and Safety of JZP-258 in Subjects with Narcolepsy with Cataplexy 
LOCATIONS 
This study will be conducted at multiple international sites 
OBJECTIVES 
Primary objective: 
To evaluate the efficacy of JZP-258 in the treatment of cataplexy in subjects with 
narcolepsy 
Key Secondary objective: 
To evaluate the efficacy of JZP-258 in the treatment of excessive daytime 
sleepiness (EDS) in subjects with narcolepsy 
Secondary objective: 
To evaluate the safety of JZP-258 in the treatment of subjects with narcolepsy 
with cataplexy 
Exploratory objective: 
To characterize the conversion from non-Xyrem anticataplectic treatment 
regimens to JZP-258 in subjects with narcolepsy with cataplexy 
DESIGN 
This is a 2-part study consisting of the MAIN Study (a double-blind, placebo-
controlled, randomized-withdrawal, multicenter study of the efficacy and safety of 
JZP-258) followed by a 24-week Open-Label Extension study.  
 
MAIN STUDY 
The Main Study consists of the following periods, which are described further below: 
• 
Screening Period for up to 30 days 
• 
Optimized Treatment and Titration Period for 12 weeks 
• 
Stable-Dose Period for 2 weeks 
• 
Double-Blind Randomized-Withdrawal Period for 2 weeks 
• 
Safety Follow-up Period for 2 weeks 
 
Subjects are eligible to enter the Main Study if they meet all eligibility criteria and 
their treatment status is: 
• 
Currently treated with a stable dose of Xyrem (sodium oxybate) for at least 
2 months prior to screening 
• 
Currently treated with a stable dose of Xyrem and an additional 
anticataplectic for at least 2 months prior to screening  
• 
Currently treated with an anticataplectic and not treated with Xyrem 
• 
Not currently treated with any anticataplectic at screening. 
 
All subjects will be allowed to continue with their stimulant or non-Xyrem alerting 
agent therapy, if applicable, if doses have been unchanged for 2 months.  
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DESIGN (continued) 
Screening Period (up to 30 days) 
All subjects will be evaluated for eligibility during the Screening Period. 
Rescreening 
Subjects may be allowed to rescreen (one time) if they previously did not meet all 
eligibility requirements at Visit 1. Rescreening may occur following resolution of 
transient exclusionary conditions or stabilization of conditions that were exclusionary 
in the unstable state (e.g., unstable hypothyroidism) and is permitted only with the 
permission of the Medical Monitor. Subjects who are approved for rescreening must 
be re-consented and repeat all screening procedures.  
Optimized Treatment and Titration Period (12 weeks) 
During this period subjects will be transitioned to JZP-258 based on their treatment 
status at study entry. All subjects will begin JZP-258 treatment at the beginning of 
this period and continue through Week 12. They will be treated with JZP-258 alone 
for the final two weeks of this 12-week period. Once the JZP-258 dose has been 
optimized per the Investigator’s judgment, these subjects may enter the 2-week 
Stable-Dose Period with that dose. For the purposes of describing the transition to 
JZP-258, these subjects’ pretreatment status will be defined as Pre-randomization 
Groups 1-4. 
• 
Pre-randomization Group 1(Subjects on Xyrem at study entry): Subjects who 
are only treated with Xyrem as an anticataplectic at study entry will be 
switched from Xyrem gram for gram to JZP-258 and remain on this JZP-258 
dose for a minimum of 2 weeks. If needed, the dose of JZP-258 may then be 
titrated during the subsequent 8 weeks to a stable, tolerable, and effective 
dose. Subjects must be maintained on an unchanged, tolerable, and effective 
dose of JZP-258 for at least 2 weeks prior to entering the Stable-Dose Period.  
• 
Pre-randomization Group 2 (Subjects on Xyrem and an additional 
anticataplectic at study entry): Subjects who enter the study on Xyrem and an 
additional anticataplectic will be switched from Xyrem gram for gram to 
JZP-258 and remain on this JZP-258 dose for a minimum of 2 weeks. 
Following this 2-week period subjects will be tapered off the additional 
anticataplectic over a minimum period of 2 weeks and up to 8 weeks. 
If needed, the dose of JZP-258 may be further titrated to a stable, tolerable, 
and effective dose during this 8-week period. Subjects must be maintained on 
an unchanged, tolerable, and effective dose of JZP-258 alone for at least 2 
weeks prior to entering the Stable-Dose Period.  
• 
Pre-randomization Group 3 (Subjects on a non-Xyrem anticataplectic at study 
entry): Subjects who enter the study on a non-Xyrem anticataplectic and are 
not treated with Xyrem will be titrated to a tolerable dose of JZP-258 over a 
minimum of 2 weeks at the start of this period. After initial titration to 
JZP-258, subjects will be tapered off other anticataplectics over a minimum 
of 2 weeks and up to 8 weeks. If needed, the dose of JZP-258 may be further 
titrated to a stable, tolerable, and effective dose during this 8-week period. 
Subjects must be maintained on an unchanged, tolerable, and effective dose 
of JZP-258 alone for at least 2 weeks prior to entering the Stable-Dose Period. 
• 
Pre-randomization Group 4 (Subjects not treated with an anticataplectic at 
study entry): Subjects who are not treated with any anticataplectic at the study 
entry will be initiated and titrated with JZP-258 over a minimum of 2 weeks 
and up to 8 weeks to achieve a stable, tolerable, and effective dose during this 
period. Subjects must be maintained on an unchanged, tolerable, and effective 
dose of JZP-258 alone for at least 2 weeks prior to entering the Stable-Dose 
Period. 
 
 
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DESIGN (continued) 
Stable-Dose Period (2 weeks) 
All subjects must have been titrated or converted to a tolerable and effective JZP-258 
dose. Subjects will remain on this stable JZP-258 dose, unchanged, during this 
2-week period. The baseline number of weekly cataplectic attacks and baseline EDS 
scores, as well as other secondary endpoints (as applicable), will be determined in 
this period. 
Double-Blind Randomized-Withdrawal Period (2 weeks) 
Subjects are eligible to enter the Double-Blind Randomized-Withdrawal Period if the 
dose of JZP-258 remains unchanged during the Stable-Dose Period and, in the 
judgment of the Investigator, no clinically significant worsening in narcolepsy 
symptoms or clinically significant adverse events (AEs) due to JZP-258 treatment 
have occurred and subjects have completed daily dosing and cataplexy diaries in the 
Stable-Dose Period as described in Section 6.7 and Section 6.12.7. 
Randomization will be stratified based on each subject’s pre-randomization group, as 
defined at study entry. Subjects will be randomized 1:1 to receive one of the 
following two treatments during the 2-week Double-Blind Randomized-Withdrawal 
Period: 
JZP-258: JZP-258 will be continued as a double-blind treatment at the stable dose 
taken in the prior 2 weeks 
JZP-258 Placebo: Placebo will be initiated as a double-blind treatment at a 
volume equivalent to the JZP-258 dose taken in the prior 2 weeks. 
Safety Follow-up Period (2 weeks) 
Subjects who do not enter the open label segment of the study will return for a Safety 
Follow-up visit 2 weeks after the Double-Blind Randomized-Withdrawal Period. The 
Safety Follow-up visit will not take place if the subject directly rolls over into the 
Open-Label Extension at Visit 16. 
 
OPEN-LABEL EXTENSION  
Subjects who complete the double-blind treatment during the Main Study are eligible 
to enter a 24-week Open-Label Extension which consists of the following:  
• 
Open-Label Extension Period for 24 weeks 
• 
Open-Label Safety Follow-up Period for 2 weeks  
 
During this period subjects will receive open-label JZP-258.  
Subjects are eligible to enter the Open-Label Extension if they meet all eligibility 
criteria and their treatment status is: 
• 
Completed double-blind treatment in the Main Study and rolling over into the 
Open-Label Extension 
• 
Completed the Main Study and currently treated with Xyrem alone or Xyrem 
plus an additional anticataplectic 
• 
Completed the Main Study and currently treated with a non-Xyrem 
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anticataplectic  
• 
Completed the Main Study and not currently receiving treatment 
DESIGN (continued) 
Open-Label Extension Period (24 weeks) 
Subjects can enter the Open-Label Extension directly from the Main Study (enter at 
Visit 16) or after completion of the Main Study (enter at Visit 18).  
• 
Rollover Subjects: those who enter the Open-Label Extension at Visit 16 
(i.e., “rollover” directly from the Main Study [after a few additional 
procedures]) (see Section 7.2.1.1). Their Visit 16 has the dual purpose of 
being the last day of the Main Study and Day 1 for the Open-Label Extension. 
• 
Re-entry Subjects: those who enter the Open-Label Extension following 
completion of the Main Study (i.e., require “re-entry” into the study). Their 
Open-Label Extension Day 1 is at Visit 19 and they undergo Open-Label 
screening at Visit 18. 
 
Prior to any study activity informed consent for the Open-Label Extension will be 
obtained.  
Rollover Subjects (enter the Open-Label Extension at Visit 16) 
They will undergo additional procedures from Amendment 4 at Visit 16, including 
study drug dispensing of open-label JZP-258 (see Section 7.2.1.1).  
Re-entry Subjects (enter the Open-Label Extension at Visit 18) 
Those subjects who complete the double-blind treatment prior to regulatory approval 
of Amendment 4 will be required to have the 2-week Safety Follow-up visit and must 
re-enter at the Open-Label Extension prior to the last subject completing the Main 
Study. Subjects re-entering will undergo screening (up to 30 days) and receive Open-
Label JZP-258 at Visit 19. 
 
Open-Label Extension Safety Follow-up Period (2 weeks) 
Subjects will return for a Safety Follow-up visit 2 weeks after the Open-Label 
Extension Period. 
ESTIMATED DURATION 
OF STUDY 
It is anticipated that enrollment will be completed in approximately 18 months. The 
estimated duration of the study (Main Study and Open-Label Extension) is 
approximately 2 ½ years. 
STUDY POPULATION 
The study will enroll subjects who are diagnosed with narcolepsy with cataplexy, and 
who have signed the informed consent form in accordance with local ethics 
committee requirements. Approximately 185 subjects will be enrolled into the study 
from the four therapy groups (pre-randomization groups) described above. An effort 
will be made to include at least 50 subjects previously on Xyrem and 60 subjects 
previously using Xyrem plus other anticataplectics or non-Xyrem anticataplectics 
alone in the study. A minimum of 130 subjects (65 subjects per the two treatment 
groups: JZP-258 and JZP-258 placebo) are planned to be randomized into the 
Double-Blind Randomized-Withdrawal Period. However, due to the potential limited 
availability of study participants (e.g., current Xyrem patients unwilling to interrupt 
therapy for potential placebo therapy), the minimum numbers of subjects in the prior 
therapy groups may be adjusted as necessary to ensure enrollment completion in a 
timely manner. 
 
 
 
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MAIN STUDY 
DIAGNOSIS AND MAIN 
CRITERIA FOR 
INCLUSION 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in the Main Study: 
1. Male or female subjects between 18 and 70 years of age at screening, 
inclusive. 
2. Have a primary diagnosis of narcolepsy with cataplexy that meets 
International Classification of Sleep Disorders-third edition (ICSD-3) criteria 
or Diagnostic and Statistical Manual-Fifth Edition (DSM-5) criteria, and 
currently untreated or treated with or without anticataplectics. 
3. Have a history of having at least 14 cataplexy attacks in a typical 2-week 
period and clinically significant symptoms of EDS prior to any narcolepsy 
treatment. 
4. Treatment status (Pre-randomization Group) at study entry: 
a) Have been taking Xyrem at unchanged doses (twice or thrice nightly 
dosing no higher than a total of 9 g/night), for the treatment of cataplexy 
in narcolepsy for at least 2 months prior to screening; or 
b) Have been taking Xyrem at unchanged doses (twice or thrice nightly 
dosing no higher than a total of 9 g/night), and another anticataplectic 
(tricyclic antidepressant [TCA], serotonin-norepinephrine reuptake 
inhibitor [SNRI], selective serotonin reuptake inhibitor [SSRI], 
atomoxetine, or other) for the treatment of cataplexy in narcolepsy for at 
least 2 months prior to screening; or  
c) Treated with a non-Xyrem anticataplectic (TCA, SNRI, SSRI, 
atomoxetine, or other) and not treated with Xyrem; or 
d) Not treated with any agent with anticataplectic properties. 
5. If currently treated with Xyrem, must have documented clinical 
improvement of cataplexy and EDS per Investigator’s clinical judgment. 
 
6. If applicable, treated with a stimulant or alerting agent at unchanged doses 
for at least 2 months prior to dosing or not treated with a stimulant or 
alerting agent.  
7. Have used a medically acceptable method of contraception for at least 
2 months prior to the first dose of study drug and consent to use a medically 
acceptable method of contraception throughout the entire study period and 
for 90 days after the study is completed. 
8. Willing and able to comply with the study design schedule and other 
requirements. 
9. Willing and able to provide written informed consent. 
MAIN STUDY 
DIAGNOSIS AND MAIN 
CRITERIA FOR 
EXCLUSION 
Exclusion Criteria 
Subjects who demonstrate any of the following will be excluded from the Main 
Study: 
1. Narcolepsy secondary to another medical condition (e.g., central 
nervous system injury or lesion). 
2. Restless leg syndrome (RLS) requiring treatment other than iron 
supplements. 
3. Succinic semi-aldehyde dehydrogenase deficiency (SSADH). 
4. Uncontrolled hypothyroidism. 
5. History of seizures, excluding early childhood non-pathological febrile 
seizures. 
6. History of head trauma associated with loss of consciousness in the past 
5 years or if the event occurred more than 5 years prior to screening and the 
subject has sequelae due to the event. 
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MAIN STUDY 
DIAGNOSIS AND MAIN 
CRITERIA FOR 
EXCLUSION (continued) 
7. Evidence of untreated or inadequately treated sleep-disordered breathing 
including: 
a. 
Presence of clinically significant and untreated obstructive or central 
sleep apnea as determined by the Investigator or documented 
previously;  
or documentation of one of the following: 
b. Apnea index >10 if on obstructive sleep apnea (OSA) treatment or 
untreated; or 
c. 
Clinically significant hypoventilation; or 
d. Noncompliance with primary OSA therapy. (Compliance defined 
as positive airway pressure use of ≥4 hours per night on ≥70% of 
nights [≥5 of 7 nights/week], historical report [with Investigator 
concurrence] of use of an oral appliance on ≥70% of nights [≥5 of 
7 nights/week], or receipt of an effective surgical intervention for OSA 
symptoms.) 
8. Parasomnias (e.g., sleep walking, rapid eye movement [REM] Sleep 
Behavior Disorder, etc.) felt by the investigator to negatively affect the 
conduct of the study. Parasomnia events associated with physical injury to 
the subject (or others) shall be discussed with the Medical Monitor.  
9. Meets criteria for current major depression by clinical interview.  
10. Any other clinically relevant medical, behavioral, or psychiatric disorder 
other than narcolepsy that is associated with excessive sleepiness. 
11. History or presence of bipolar disorder, bipolar related disorders, 
schizophrenia, schizophrenia spectrum disorders, or other psychotic 
disorders according to DSM-5 criteria. 
12. History or presence of any unstable or clinically significant medical 
condition, behavioral or psychiatric disorder (including active suicidal 
ideation), or history or presence of another neurological disorder or surgical 
history that might affect the subject’s safety and/or interfere with the 
conduct of the study in the opinion of the Investigator. 
13. A current electrocardiogram (ECG) with clinically significant deviation(s) 
from normal, or clinically significant physical examination findings, as 
determined by the Investigator at screening. 
14. Any current clinically significant laboratory abnormality as determined by 
the Investigator at screening. 
15. Is a female subject who is pregnant, nursing, or lactating.  
16. A positive urine drug screen for benzodiazepines or drugs of abuse, a 
positive alcohol test, a history of substance abuse including alcohol abuse, or 
unwillingness to refrain from consuming alcohol during the study (if the 
subject takes prescribed amphetamines, a positive result for amphetamines 
will not exclude the subject). 
17. Treatment with any central nervous system sedating agents, including, but 
not limited to, benzodiazepines, non-benzodiazepine anxiolytics/ 
hypnotics/sedatives, neuroleptics, opioids, barbiturates, phenytoin, 
ethosuximide, or the monocarboxylate transporter (MCT) inhibitor valproate 
within 2 weeks prior to enrollment (Day1) (discontinuation for the purpose 
of study enrollment is permitted only if considered safe by the Investigator 
and approved by the Medical Monitor). 
18. Treatment with an antidepressant for cataplexy, if the withdrawal of the 
antidepressant during cross-titration with JZP-258 might be unsafe due to 
prior history of depression. 
19. Current treatment with oral isotretinoin.  
 
 
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MAIN STUDY 
DIAGNOSIS AND MAIN 
CRITERIA FOR 
EXCLUSION (continued) 
20. Received any investigational drug within 30 days or 5 half-lives (whichever 
is longer) before the Screening Visit. 
21. Allergy or sensitivity to malic acid, sucralose or ingredients in the study 
drug formulation or placebo. 
22. Unsafe for the subject to receive placebo treatment for 2 weeks, in the 
opinion of the Investigator. 
OPEN-LABEL EXTENSION 
DIAGNOSIS AND MAIN 
CRITERIA FOR 
INCLUSION 
Inclusion Criteria 
Subjects are reassessed for eligibility if re-entering the study for inclusion in the 
Open-Label Extension (Visits 18 and 19). Rollover Subjects had a screening 
assessment during the Main Study and do not require re-screening for the Open-Label 
Extension. Each re-entering subject must meet the following criteria to be enrolled in 
the Open Label Extension: 
1. Completion of the JZP-258 double-blind treatment and completion of Visit 
16 
2. Is able, in the opinion of the investigator, to take JZP-258 for an additional 
24 weeks 
3. Agrees to continue to use a medically acceptable method of contraception 
throughout the entire study period and for 90 days after the Open-Label 
Extension is completed. 
4. Willing and able to comply with the study design schedule and other 
requirements. 
5. Willing and able to provide written informed consent for Open-Label 
Extension.  
6. If currently being treated with Xyrem, the subject’s total twice nightly 
Xyrem dose must be no higher than 9 g/night 
OPEN-LABEL EXTENSION 
DIAGNOSIS AND MAIN 
CRITERIA FOR 
EXCLUSION  
Exclusion Criteria 
Subjects will be excluded from re-entering the study at the Open-Label Extension if 
they:  
1. Meet Exclusion Criteria 1 through 19 from the Main Study at Visits 18 and 
19.  
2. Received any investigational drug (with the exception of JZP-258) within 
30 days or 5 half-lives (whichever is longer) before the Screening Visit. 
3. Allergy or sensitivity to malic acid, sucralose or ingredients in the study 
drug formulation. 
TEST PRODUCT 
JZP-258 oral solution 0.5 g/mL  
REFERENCE PRODUCT 
JZP-258 Placebo, identical in appearance to JZP-258 
DURATION OF 
TREATMENT 
The maximum treatment duration for each subject who does not enter the Open-Label 
Extension will be up to 16 weeks including 12 weeks Optimized Treatment and 
Titration Period, 2 weeks Stable-Dose Period, 2 weeks Double-Blind Randomized-
Withdrawal Period, and this is followed by a 2 week Safety Follow-up period. The 
treatment period for subjects who do enter the Open-Label Extension will be up to 
40 weeks, which is followed by a 2-week Safety Follow-up Period.  
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EFFICACY ASSESSMENTS Efficacy assessments in general will be comparisons of the measurement(s) made 
during or at the end of the 2 weeks of the Stable-Dose Period compared with the 
2 weeks or the end of the Double-Blind Randomized-Withdrawal Period.  
Primary endpoint:  
Change in weekly number of cataplexy attacks from the two weeks of the Stable-
Dose Period to the two weeks of the Double-Blind Randomized-Withdrawal 
Period 
Key secondary endpoint: 
Change in the Epworth Sleepiness Scale (ESS) score from the end of the Stable- 
Dose Period to the end of the Double-Blind Randomized-Withdrawal Period 
Other secondary endpoints: 
Patient Global Impression of Change (PGIc) for narcolepsy overall at the end of 
the Double-Blind Randomized-Withdrawal Period 
Clinical Global Impression of Change (CGIc) for narcolepsy overall at the end of 
the Double-Blind Randomized-Withdrawal Period 
Change in Quality of Life (QoL) (SF-36) from the end of the Stable-Dose Period 
to the end of the Double-Blind Randomized-Withdrawal Period 
Change in Qol (EuroQol 5 Dimensions Self-Report Questionnaire) from the end 
of the Stable-Dose Period to the end of the Double-Blind Randomized-
Withdrawal Period 
SAFETY ASSESSMENTS 
Safety will be assessed at time points specified in the schedule of events, as well as 
throughout the study. Safety assessments will include the following:  
• Treatment-emergent adverse events (TEAEs) 
• Vital signs 
• Physical examinations (including weight) 
• 12-lead ECGs 
• Clinical laboratory tests (chemistry, hematology, and urinalysis) 
• Columbia-Suicide Severity Rating Scale (C-SSRS) for emergent suicidality 
• Patient Health Questionnaire – 9 (PHQ-9) for emergent depression 
 
During the study all subjects will be carefully monitored for emergent depression and 
suicidality using the PHQ-9 and the C-SSRS. The subject will be evaluated and an 
assessment of risk will be made by a qualified mental health professional if major 
depression is suspected or active suicidal ideation is identified.  
STATISTICAL ANALYSIS A sample size of 65 subjects randomized per treatment group will provide at least 
90% power to assess the difference in the change in mean weekly number of 
cataplexy attacks, from the Stable-Dose Period to the Double-Blind Randomized-
Withdrawal Treatment Period, between JZP-258 and placebo. Assuming a 30% 
dropout rate prior to randomization, up to 185 subjects will be enrolled (including at 
least 50 subjects on Xyrem, and 60 subjects using Xyrem plus other anticataplectics 
or non-Xyrem anticataplectics alone, as applicable) to ensure that a minimum of 
130 subjects enter the Double-Blind Randomized-Withdrawal Period. 
A hierarchical group sequential testing strategy, as described in Section 9.14 and 
Section 9.15, will be used to control the family-wise Type I error rate at the 
0.05 significance level for two-sided testing across the primary and key secondary 
endpoints. 
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STATISTICAL ANALYSIS 
(continued) 
An analysis of covariance (ANCOVA) model will be used to assess the primary 
efficacy endpoint. The model will include treatment group and Pre-randomization 
group as fixed effects. The weekly number of cataplexy attacks during the Stable-
Dose Period will be included in the model as a covariate. The estimate for the 
treatment difference of JZP-258 versus placebo and the 95% confidence intervals will 
be presented. The normality assumption of the ANCOVA model will be examined by 
residual analysis using the Shapiro-Wilk test. If the normality assumption is 
considered violated at the 0.05 significance level, a non-parametric ANCOVA with 
the data replaced by their ranks will be used. 
Analyses of the key secondary efficacy endpoint will be similar to the primary 
endpoint. 
For the other secondary efficacy endpoints, CGIc and PGIc ratings will be analyzed 
as response frequencies using the Cochran-Mantel-Haenszel (CMH) test for the row 
mean score difference. All other non-categorical parameters will be analyzed by 
ANCOVA or non-parametric ANCOVA, similar to the primary endpoint, as 
appropriate.  
Safety analyses will be descriptive in nature, and no formal statistical testing 
performed.  
Final Safety Analysis 
A final safety analysis will be performed once all subjects have completed or 
terminated from the study. 
DATE OF ORIGINAL 
PROTOCOL 
25 February 2016 
AMENDMENT 1 
05 August 2016 
AMENDMENT 2 
07 November 2016 
AMENDMENT 3 
10 April 2017 
AMENDMENT 4 
15 December 2017 
AMENDMENT 5 
15 May 2018 
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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
LIST OF IN-TEXT TABLES ..................................................................................................16 
LIST OF IN-TEXT FIGURES.................................................................................................16 
LIST OF APPENDICES ..........................................................................................................16 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................18 
1 
INTRODUCTION ...........................................................................................................22 
1.1 
Background and Rationale .....................................................................................22 
1.2 
JZP-258 Formulation .............................................................................................23 
1.3 
Summary of Data on Xyrem (sodium oxybate) .....................................................24 
1.3.1 
Pharmacokinetics .........................................................................................24 
1.3.2 
Pharmacodynamics and Mechanism of Action ............................................25 
1.3.3 
Clinical Program in Cataplexy and EDS in Patients with Narcolepsy ........25 
1.3.4 
Safety Data from Clinical Trials in Narcolepsy ...........................................26 
1.3.4.1 
Adverse Reactions Leading to Treatment Discontinuation ...............26 
1.3.4.2 
Commonly Observed Adverse Reactions in Controlled Clinical  
Trials ..................................................................................................26 
1.3.4.3 
Adverse Reactions Occurring at an Incidence of 2% or Greater .......26 
1.3.4.4 
Dose-Response Information...............................................................27 
1.3.5 
Safety Data from Healthy Volunteer Studies ...............................................28 
1.3.5.1 
Xyrem (sodium oxybate) ...................................................................28 
1.3.6 
Postmarketing Experience with Xyrem .......................................................29 
1.4 
Summary of Data on JZP-258 Formulation ...........................................................29 
1.4.1 
Pharmacokinetic Data from Healthy Volunteer Study ................................29 
1.4.2 
Safety Data from Healthy Volunteer Pharmacokinetic Study .....................30 
 
 
2 
STUDY OBJECTIVES ....................................................................................................31 
2.1 
Primary Objective(s) ..............................................................................................31 
2.2 
Secondary Objectives .............................................................................................31 
2.2.1 
Key Secondary Objective: ...........................................................................31 
2.2.2 
Secondary Objective: ...................................................................................31 
2.2.3 
Exploratory Objective ..................................................................................31 
3 
STUDY DESIGN.............................................................................................................32 
3.1 
Overall Study Design and Plan ..............................................................................32 
3.1.1 
Main Study ...................................................................................................32 
3.1.1.1 
Screening Period (up to 30 days) .......................................................32 
3.1.1.2 
Optimized Treatment and Titration Period (12 weeks) .....................33 
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3.1.1.3 
Stable-Dose Period (2 weeks) ............................................................34 
3.1.1.4 
Double-Blind Randomized-Withdrawal Period (2 weeks) ................34 
3.1.1.5 
Safety Follow-up Period (2 weeks) ....................................................34 
3.1.2 
Open-Label Extension .................................................................................36 
3.1.2.1 
Open-Label Extension Period (24 weeks) .........................................36 
3.1.2.2 
Open-Label Extension Safety Follow-up Period (2 weeks) ..............37 
3.1.3 
Rationale for Study Design and Control Group ...........................................39 
3.2 
Study Duration and Dates ......................................................................................40 
3.3 
End of Trial ............................................................................................................40 
4 
STUDY POPULATION SELECTION ...........................................................................41 
4.1 
Selection of Study Population ................................................................................41 
4.2 
Main Study .............................................................................................................41 
4.2.1 
Inclusion Criteria .........................................................................................41 
4.2.2 
Exclusion Criteria ........................................................................................42 
4.3 
Open-Label Extension ...........................................................................................44 
4.3.1 
Inclusion Criteria .........................................................................................44 
4.3.2 
Exclusion Criteria ........................................................................................44 
4.4 
Screening and Randomization Eligibility ..............................................................44 
5 
STUDY TREATMENTS .................................................................................................45 
5.1 
Description of Treatment(s) ...................................................................................45 
5.1.1 
Main Study ...................................................................................................45 
5.1.1.1 
Study Drug .........................................................................................45 
5.1.1.2 
Placebo ...............................................................................................45 
5.1.1.3 
Treatments Administered ...................................................................45 
5.1.2 
Open-Label Extension .................................................................................46 
5.1.2.1 
Study Drug .........................................................................................46 
5.1.2.2 
Treatments Administered ...................................................................46 
5.2 
Selection and Timing of Dose for Each Subject ....................................................47 
5.3 
Method of Assigning Subjects to Treatment Groups .............................................48 
5.4 
Randomization .......................................................................................................48 
5.5 
Blinding..................................................................................................................48 
5.6 
Prior and Concomitant Therapy .............................................................................49 
5.6.1 
Prohibited Concomitant Medications ..........................................................49 
5.6.2 
Permitted Concomitant Medications............................................................49 
5.7 
Restrictions ............................................................................................................50 
5.7.1 
Prior Therapy ...............................................................................................50 
5.7.2 
Fluid and Food Intake ..................................................................................50 
5.7.3 
Other Restrictions ........................................................................................50 
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5.8 
Treatment Compliance ...........................................................................................50 
5.9 
Packaging and Labeling .........................................................................................50 
5.10 
Storage and Accountability ....................................................................................51 
6 
STUDY PROCEDURES .................................................................................................52 
6.1 
Informed Consent...................................................................................................52 
6.2 
Demographics ........................................................................................................52 
6.3 
Medical History .....................................................................................................52 
6.4 
Physical Examination.............................................................................................52 
6.5 
Vital Signs ..............................................................................................................53 
6.6 
Electrocardiography ...............................................................................................53 
6.7 
Study Drug Dosing Diary ......................................................................................53 
6.8 
Columbia-Suicide Severity Rating Scale (C-SSRS) ..............................................54 
6.9 
Patient Health Questionnaire–9 (PHQ-9) ..............................................................54 
6.10 
Clinical Laboratory Tests .......................................................................................54 
6.10.1 
Laboratory Parameters .................................................................................54 
6.10.2 
Sample Collection, Storage, and Shipping ..................................................56 
6.10.3 
Pregnancy Test .............................................................................................56 
6.10.4 
Drug and Alcohol Screens ...........................................................................57 
6.11 
Dispensing Study Drug ..........................................................................................57 
6.12 
Efficacy Assessments .............................................................................................58 
6.12.1 
Epworth Sleepiness Scale (ESS) ..................................................................58 
6.12.2 
Clinician Global Impression of Severity (CGIs) for Narcolepsy Overall ....58 
6.12.3 
Clinical Global Impression of Change (CGIc) for Narcolepsy Overall ......58 
6.12.4 
Patient Global Impression of Change (PGIc) for Narcolepsy Overall ........58 
6.12.5 
36-Item Short Form Health Survey Version 2 (SF-36v2) ...........................59 
6.12.6 
European Quality of Life 5 Dimensions 5 Levels (EuroQol/EQ-5D-5L) ....59 
6.12.7 
Cataplexy Frequency Diary .........................................................................59 
6.13 
Adverse Event Reporting .......................................................................................60 
6.13.1 
Adverse Events (AEs) ..................................................................................60 
6.13.2 
Severity Assessment ....................................................................................61 
6.13.3 
Serious Adverse Events (SAEs) ...................................................................61 
6.13.4 
Causal Relationship to Study Drug or Procedure ........................................63 
6.13.5 
Other Immediately Reportable Experiences ................................................63 
6.13.6 
Adverse Events and Serious Adverse Event Recording and Reporting 
Timeframe ....................................................................................................64 
6.13.7 
Follow-up of Adverse Events and Serious Adverse Events ........................64 
6.13.8 
Pregnancy .....................................................................................................65 
6.13.9 
Emergency Unblinding ................................................................................65 
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6.13.10 Regulatory Reporting ...................................................................................65 
6.14 
Removal of Subjects from the Trial or Study Drug ...............................................66 
6.14.1 
Reasons for Early Terminations...................................................................66 
6.14.2 
Handling of Early Terminations ..................................................................67 
6.14.3 
Jazz Pharmaceuticals’ Termination of Study ...............................................67 
6.15 
Appropriateness of Measurements .........................................................................67 
7 
STUDY ACTIVITIES .....................................................................................................68 
7.1 
MAIN STUDY.......................................................................................................68 
7.1.1 
Screening Period ..........................................................................................68 
7.1.2 
Open-Label Optimized Treatment and Titration Phase ...............................69 
7.1.2.1 
Week 1 to the end of Week 12 (for all subjects 12 weeks) ................69 
7.1.2.2 
Day 1 Visit 2 ......................................................................................70 
7.1.2.3 
Optimized Treatment and Titration Period ........................................71 
7.1.3 
End of Titration Period and Start of Stable-Dose Period .............................74 
7.1.4 
End of Stable-Dose Period/Beginning of the Double-Blind 
Randomized-Withdrawal Period ..................................................................75 
7.1.5 
End of Double-Blind Randomized-Withdrawal Period or Early  
Termination ..................................................................................................76 
7.1.6 
Safety Follow-up Visit .................................................................................77 
7.2 
Open-Label Extension ...........................................................................................77 
7.2.1 
Entrance Period to Open-Label Extension ...................................................78 
7.2.1.1 
Visit 16 (Additional Procedures) – Day 1 of the Open-Label  
Extension (Rollover Subjects only) ...................................................78 
7.2.1.2 
Visit 18 (Screening for Open-Label Extension) – Days –30 
to -1 (Re-entry Subjects only) ............................................................78 
7.2.1.3 
Visit 19 – Day 1 of the Open-Label Extension 
(Re-entry Subjects only) ....................................................................79 
7.2.2 
Open-Label Extension Period (Visits 20 to 32) ...........................................80 
7.2.2.1 
Phone Contact –End of Week 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 ............80 
7.2.2.2 
Clinic Visit 30 – Week 12 ..................................................................80 
7.2.2.3 
Phone Contact –End of Weeks 16 and 20 ..........................................81 
7.2.3 
End of Open-Label Extension or Early Termination ...................................81 
7.2.4 
Safety Follow-up Visit .................................................................................82 
8 
QUALITY CONTROL AND ASSURANCE .................................................................83 
9 
PLANNED STATISTICAL METHODS ........................................................................84 
9.1 
General Considerations ..........................................................................................84 
9.2 
Tests of Hypotheses and Significance Levels ........................................................84 
9.3 
Determination of Sample Size ...............................................................................85 
9.4 
Analysis Populations ..............................................................................................85 
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9.5 
Demographics and Baseline Characteristics ..........................................................85 
9.6 
Handling of Dropouts and Missing Data ...............................................................85 
9.7 
Pooling of Investigation Centers ............................................................................86 
9.8 
Efficacy Endpoints .................................................................................................86 
9.8.1 
Primary Efficacy Endpoint ..........................................................................86 
9.8.2 
Key Secondary Efficacy Endpoint ...............................................................86 
9.8.3 
Other Secondary Efficacy Endpoints ...........................................................86 
9.9 
Safety Endpoints ....................................................................................................86 
9.10 
Efficacy Analyses ..................................................................................................87 
9.10.1 
Primary Efficacy Analysis ...........................................................................87 
9.10.2 
Key Secondary Efficacy Analysis ...............................................................87 
9.10.3 
Other Secondary Efficacy Analysis .............................................................88 
9.11 
Safety Analyses ......................................................................................................88 
9.11.1 
Adverse Event Analyses ..............................................................................88 
9.11.2 
Other Safety Analyses ..................................................................................88 
9.12 
Exploratory Analyses .............................................................................................89 
9.13 
Subgroup Analyses ................................................................................................89 
 
 
9.15 
Final Analysis Testing Procedures .........................................................................93 
10 DATA QUALITY ASSURANCE ...................................................................................94 
10.1 
Data Management ..................................................................................................94 
10.2 
Case Report Forms .................................................................................................94 
10.3 
Retention of Data ...................................................................................................94 
10.4 
Data Safety Monitoring ..........................................................................................95 
11 ADMINISTRATIVE CONSIDERATIONS ....................................................................96 
11.1 
Investigators and Study Administrative Structure .................................................96 
11.1.1 
Contract Research Organization ..................................................................96 
11.1.2 
Jazz Pharmaceuticals’ Medical Director ......................................................96 
11.1.3 
Investigator ..................................................................................................96 
11.1.4 
Clinical Laboratory ......................................................................................96 
11.2 
Ethics Committee (EC) Approval ..........................................................................96 
11.3 
Ethical Conduct of the Study .................................................................................97 
11.4 
Subject Information and Consent...........................................................................98 
11.5 
Subject Confidentiality ..........................................................................................98 
11.6 
Protocol Adherence – Amendments ......................................................................98 
11.7 
Required Documents ..............................................................................................98 
11.8 
Study Monitoring ...................................................................................................98 
 
 
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11.10 Protocol Violations/Deviations ..............................................................................99 
11.11 Access to Source Documentation ..........................................................................99 
11.12 Publication and Disclosure Policy .........................................................................99 
12 REFERENCE LIST .......................................................................................................101 
 
LIST OF IN-TEXT TABLES 
 
 
Table 2 
Adverse Reactions Occurring in ≥2% of Patients and More Frequently 
with Xyrem than Placebo in Three Controlled Trials by Body System  
and Dose at Onset ........................................................................................27 
Table 3 
List of Laboratory Tests ...............................................................................55 
 
 
Table 5 
Adverse Event Severity Definitions.............................................................61 
Table 6 
Boundaries to Reject H0 (p-values) ..............................................................91 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Diagram for Main Study ....................................................................35 
Figure 2 
Study Diagram for the Open-Label Extension .............................................38 
 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events ...........................................................................104 
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Appendix 15 
Signatures of Agreement for Protocol .............................................148 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviation  
Definition 
AASM 
American Academy of Sleep Medicine 
ADL 
Activities of daily living 
AE 
Adverse event 
AI 
Adequate intake 
ALB 
Albumin 
ALK-P 
Alkaline phosphatase 
ALT 
Alanine aminotransferase (SGPT) 
ANCOVA 
Analysis of covariance 
AOR 
Adjusted odds ratio 
AR 
Adverse reaction 
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under the time-concentration curve 
AUC0-inf 
AUC extrapolated to infinity 
AV 
Atrioventricular 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CDC 
Centers for Disease Control 
CEC 
Central ethics committee 
CFR 
Code of Federal Regulations 
CGIc 
Clinical Global Impression of Change 
CGIs 
Clinical Global Impression of Severity 
cGMP 
Current Good Manufacturing Practice 
CI 
Confidence interval 
Cmax 
Peak plasma level 
CMH 
Cochran-Mantel-Haenszel 
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Abbreviation  
Definition 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
CRO 
Contract Research Organization 
DB 
Double-blind 
DMC 
Data Monitoring Committee 
DNS 
Disrupted nighttime sleep 
DSM-IV 
Diagnostic and Statistical Manual-Fourth Edition 
DSM-5 
Diagnostic and Statistical Manual-Fifth Edition 
DRI 
Dietary Reference Intake 
EC 
Ethics committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDS 
Excessive daytime sleepiness 
EFSA 
European Food Safety Authority 
EMA 
European Medicines Agency 
ESS 
Epworth Sleepiness Scale 
EuroQOL  
(EQ-5D-5L) 
European quality of life 5 Dimensions 5 Levels 
EU 
European Union 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GABA 
Gamma-aminobutyric acid 
GABABR 
Gamma-aminobutyric acid receptor 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GHB 
Gamma hydroxybutyrate 
GHBR 
Gamma hydroxybutyrate receptor 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
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Abbreviation  
Definition 
ICSD-3 
International Classification of Sleep Disorders-Third Edition 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
IR 
Immediate release 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LDH 
Lactate dehydrogenase 
MCT 
Monocarboxylate transporter 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSLT 
Multiple sleep latency test 
OLE 
Open-Label Extension 
OSA 
Obstructive sleep apnea 
OTC 
Over-the-counter 
PCP 
Phencyclidine 
PGIc 
Patient Global Impression of Change 
PHQ-9 
Patient Health Questionnaire-9 
PI 
Prescribing information 
PSG 
Polysomnogram 
RDA 
Recommended dietary allowance 
REB 
Research Ethics Board 
Re-entry 
Subjects 
Subjects who enter the Open-Label Extension following completion of the 
Main Study (i.e., require “re-entry” into the study). Day 1 of the Open-Label 
Extension for Re-entry Subjects is at Visit 19; screening for the Open-Label 
Extension is at Visit 18. 
REM 
Rapid eye movement 
RLS 
Restless leg syndrome 
Rollover 
Subjects 
Subjects who enter the Open-Label Extension at Visit 16 (i.e., “rollover” 
directly from the Main Study). Day 1 of the Open-Label Extension is at Visit 
16 for Rollover Subjects (also known as the last day of the Main Study). 
RR 
Respiratory rate 
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Abbreviation  
Definition 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SE 
Standard error 
SF-36 
36-Item Short Form Health Survey Questionnaire 
SGOT 
Serum glutamic oxaloacetic transaminase (AST) 
SGPT 
Serum glutamic pyruvic transaminase (ALT) 
SNRI 
Serotonin-norepinephrine reuptake inhibitor 
SOREMPs 
Sleep onset rapid eye movement periods 
SSADH 
Succinic semi-aldehyde dehydrogenase deficiency 
SSRI 
Selective serotonin reuptake inhibitor 
SUSARs 
Suspected unexpected serious adverse reactions 
Suspected AR 
An AE for which there is a lesser degree of certainty about causality than an 
adverse reaction 
t1/2 
Half-life 
TCA 
Tricyclic antidepressant 
TEAE 
Treatment-emergent adverse events 
Tmax 
Time to peak plasma concentration 
TSH 
Thyroid stimulating hormone 
UA 
Urinalysis 
ULN 
Upper limit of normal 
US 
United States 
V 
Visit 
W, Wk 
Week 
WBC 
White blood cell (count) 
 
 
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1 
INTRODUCTION 
1.1 
Background and Rationale 
Narcolepsy is a life-long neurologic disease for which no cure has been identified. The 
worldwide prevalence of narcolepsy is estimated to be 0.02% to 0.067% (Ohayon 2007), and in 
the United States (US), the disease afflicts approximately 1 in 2000 individuals (Majid & 
Hirschkowitz 2010). Narcolepsy has been defined as a rapid eye movement (REM) sleep 
disorder resulting from the dysregulation of the sleep-wake cycle (Nishino 2007). It is 
characterized by pathological sleepiness, commonly termed excessive daytime sleepiness, or 
EDS, and includes disrupted nighttime sleep (DNS) and abnormal REM sleep manifestations, 
including cataplexy, sleep paralysis, and hypnagogic or hypnopompic hallucinations (Boscolo-
Berto et al. 2012, Dauvilliers et al. 2013). 
Xyrem® (sodium oxybate) oral solution was approved by the US Food and Drug Administration 
(FDA) in 2002 for the treatment of cataplexy and in 2005 for the treatment of EDS, both in 
patients with narcolepsy (Xyrem US Prescribing Information (PI) 2015): Clinical Program in 
Cataplexy and EDS in Patients with Narcolepsy. In 2005, Xyrem was also approved by Health 
Canada’s Therapeutic Products Directorate for the treatment of cataplexy in patients with 
narcolepsy (Xyrem Canadian Product Monograph 2014), and by the European Agency for the 
Evaluation of Medicinal Products for the European Union (EU; Xyrem EU Summary of Product 
Characteristics 2015) for the treatment of narcolepsy with cataplexy in adult patients and the 
Swiss Agency for Therapeutic Products for the treatment of cataplexy in adult patients with 
narcolepsy.  
Xyrem has been available in the US since 2002, and is the only approved treatment in the US for 
cataplexy in narcolepsy as well as the only approved treatment for both cataplexy and EDS, the 
two primary symptoms of narcolepsy. Since first approval, cumulative exposure to Xyrem in the 
US up to July 16, 2015 is estimated to be over 54,400 unique patients and 75,849 patient-years 
on therapy (data on file).  
Xyrem is dosed at night and has an effective dose range of 6 to 9 g per night, with a 
recommended starting dose of 4.5 g per night. Doses are administered as two equally divided 
doses taken at bedtime and 2.5 to 4 hours later. Section 1.3 provides summaries of information 
about the pharmacokinetics, pharmacodynamics, and safety profile of Xyrem. 
The active ingredient in Xyrem is sodium oxybate, a Schedule III substance and the sodium salt 
of the endogenous neurotransmitter gamma hydroxybutyrate (GHB), which is found in many 
tissues of the body. The sodium salt is used in the current Xyrem formulation because GHB is 
unstable at neutral pH, spontaneously forming its lactone (gamma butyrolactone).  
Although proven to be safe and effective when prescribed according to the recommended 
regimen, the current formulation of Xyrem adds a significant amount of sodium to a patient’s 
diet. Administration of 9 g/night, the maximum recommended dose of Xyrem, results in a daily 
intake of an additional 1.64 g sodium, 109% of the adequate intake (CDC 2010).  
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For patients on a restricted salt diet who are allowed 2 g of sodium a day, the 1.64 g sodium from 
a 9 gram Xyrem dose can pose difficulties. The current prescribing information for Xyrem 
(sodium oxybate) oral solution includes a warning to monitor patients who are sensitive to 
sodium intake (e.g., those with heart failure, hypertension, or impaired renal function). These 
conditions are not uncommon in the narcolepsy population, which is known to have a high 
incidence of cardiovascular comorbidity. In one retrospective study (Ohayon 2013) comparing 
organic diseases in 320 patients with narcolepsy versus age- and sex-matched controls in the 
general population, patients with narcolepsy had a much higher risk of heart diseases (adjusted 
odds ratio [AOR; 95% confidence interval, CI] of 2.07 [range 1.22-3.51] primarily in male 
patients compared to the general population) and a higher risk of hypertension (AOR 1.32 [range 
1.02-1.70]). Epidemiological studies indicate an association of increased risk of morbidity and 
mortality from cardiovascular diseases, including coronary heart disease and stroke, with 
increasing sodium intake (EFSA 2006).  
JZP-258 could provide the known benefits of Xyrem treatment with an improved safety profile, 
particularly for patients with sodium-sensitive conditions but also for any patient concerned 
about sodium intake. It could also enable patients with narcolepsy and cardiovascular, 
hypertensive, or renal conditions to continue on their Xyrem treatment or initiate oxybate 
treatment. 
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1.3 
Summary of Data on Xyrem (sodium oxybate) 
1.3.1 
Pharmacokinetics  
Following oral administration, sodium oxybate oral solution is absorbed rapidly and consistently 
across the clinical dose range, with an absolute bioavailability of 88%. The average peak plasma 
concentrations (1st and 2nd peak) following administration of a 4.5 g total daily dose, divided into 
two equivalent doses given under fasting conditions 4 hours apart, were similar: 84 and 93 
micrograms/milliliter (mcg/mL), respectively. The average time to peak plasma concentration 
(Tmax) ranged from 0.5 to 1.25 hours in eight pharmacokinetic studies. Following oral 
administration, the plasma levels of sodium oxybate increase more than proportionally with 
increasing dose, with blood levels increasing 3.7-fold as dose is doubled from 4.5 to 9 g. 
Administration of sodium oxybate immediately after a high-fat meal resulted in delayed 
absorption (average Tmax increased from 0.75 h to 2.0 h) and reductions in peak plasma level 
(Cmax) by a mean of 58% and systemic exposure (area under the curve; AUC) by a mean of 37%. 
Therefore, patients should allow at least 2 hours after eating before taking the first dose of 
sodium oxybate. Pharmacokinetics is not altered with repeat dosing. In a study of 18 female and 
18 male healthy adult volunteers, no gender differences were detected in the pharmacokinetics of 
sodium oxybate following a single oral dose of 4.5 g. The half-life (t1/2) is typically 0.5 to 1 hour. 
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1.3.2 
Pharmacodynamics and Mechanism of Action 
Sodium oxybate is the sodium salt of GHB, an endogenous compound and metabolite of the 
neurotransmitter gamma-aminobutyric acid (GABA). The primary neural actions of GHB are 
inhibitory (Pardi & Black 2006). Gamma hydroxybutyrate binds to the GHB receptor (GHBR) 
(Snead 2000) and the B subtype of the gamma-aminobutyric acid (GABA) receptor (GABABR) 
(Mathivet et al. 1997, Lingenhoehl et al. 1999).  
Sodium oxybate is a central nervous system depressant. The precise mechanism of action of 
sodium oxybate is not known. It is hypothesized that its effects on cataplexy and EDS are 
mediated through neuropharmacologic, GABABR-mediated actions on noradrenergic and 
dopaminergic neurons, as well as on thalamocortical neurons (Xyrem US PI, Pardi & Black 
2006). Clinical trials have shown that sodium oxybate increases delta (slow-wave or restorative) 
sleep and improves sleep continuity. Other effects include increases in brain acetylcholine, and 
depression of glucose utilization, but not oxygen consumption, in the brain (Pardi & Black 
2006). 
1.3.3 
Clinical Program in Cataplexy and EDS in Patients with Narcolepsy 
The effectiveness of sodium oxybate in the treatment of cataplexy was established in two 
randomized, double-blind, placebo-controlled trials (GHB-2 and SXB-21) in patients with 
narcolepsy. In GHB-2, both the 6 and 9 g/night doses resulted in statistically significant 
reductions in the frequency of cataplexy attacks. In SXB-21, patients randomized to placebo 
after discontinuing long-term open-label sodium oxybate therapy experienced a significant 
increase in cataplexy attacks, providing evidence of long-term efficacy of sodium oxybate.  
The effectiveness of sodium oxybate in the treatment of EDS in narcolepsy was established in 
two randomized, double-blind, placebo-controlled trials (SXB-15 and SXB-22) in patients with 
narcolepsy. In SXB-15, statistically significant improvements were seen on the Epworth 
Sleepiness Scale (ESS) and on the Clinical Global Impression of Change (CGIc) at the 6 and 
9 g/night doses of sodium oxybate. In SXB-22, a statistically significant improvement in the 
Maintenance of Wakefulness Test score was seen in the sodium oxybate and sodium oxybate 
plus modafinil groups. Approximately 80% of subjects used concomitant stimulant therapy 
during the controlled clinical trials.  
In addition, five uncontrolled trials (OMC-SXB-20, OMC-GHB-3, OMC-SXB-6, OMC SXB-7, 
and OMC-SXB-19) provide additional data supporting the use of sodium oxybate in patients 
with narcolepsy. Clinical and postmarketing experience with sodium oxybate in patients with 
narcolepsy is summarized in the Xyrem prescribing information (Xyrem US PI). 
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1.3.4 
Safety Data from Clinical Trials in Narcolepsy 
Xyrem was studied in three placebo-controlled clinical trials (Trials GHB-2, OMC-SXB-15, and 
OMC-SXB-22; Xyrem US PI) in 611 patients with narcolepsy (398 subjects treated with Xyrem, 
and 213 with placebo). A total of 781 patients with narcolepsy were treated with Xyrem in 
controlled and uncontrolled clinical trials. Table 2 presents adverse reactions from three pooled, 
controlled trials (GHB-2, OMC-SXB-15, and OMC-SXB-22) in patients with narcolepsy. 
1.3.4.1 
Adverse Reactions Leading to Treatment Discontinuation 
Of the 398 Xyrem-treated patients with narcolepsy, 10.3% of patients discontinued because of 
adverse reactions compared with 2.8% of patients receiving placebo. The most common adverse 
reaction leading to discontinuation was nausea (2.8%). The majority of adverse reactions leading 
to discontinuation began during the first few weeks of treatment. 
1.3.4.2 
Commonly Observed Adverse Reactions in Controlled Clinical Trials 
The most common adverse reactions (incidence ≥5% and twice the rate seen with placebo) in 
Xyrem-treated patients were nausea, dizziness, vomiting, somnolence, enuresis, and tremor. 
1.3.4.3 
Adverse Reactions Occurring at an Incidence of 2% or Greater 
Table 2 lists adverse reactions that occurred at a frequency of 2% or more in any treatment group 
for three controlled trials and were more frequent in any Xyrem treatment group than with 
placebo. Adverse reactions are summarized by dose at onset. Nearly all patients in these studies 
initiated treatment at 4.5 g per night. In patients who remained on treatment, adverse reactions 
tended to occur early and to diminish over time. 
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Clinical Trial Protocol: 15-006 Amendment 5 
 
  
 
 
 
 
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Table 2 
Adverse Reactions Occurring in ≥2% of Patients and More 
Frequently with Xyrem than Placebo in Three Controlled 
Trials by Body System and Dose at Onset 
System Organ Class /MedDRA 
Preferred Term  
Placebo  
(n=213) % 
Xyrem 4.5g 
(n=185) % 
Xyrem 6g 
(n=258) % 
Xyrem 9g  
(n=178) % 
ANY ADVERSE REACTION 
62 
45 
55 
70 
GASTROINTESTINAL DISORDERS 
Nausea 
3 
8 
13 
20 
Vomiting 
1 
2 
4 
11 
Diarrhea 
2 
4 
3 
4 
Abdominal pain upper 
2 
3 
1 
2 
Dry mouth 
2 
1 
2 
1 
GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS 
Pain 
1 
1 
<1 
3 
Feeling drunk 
1 
0 
<1 
3 
Edema peripheral 
1 
3 
0 
0 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
Pain in extremity 
1 
3 
1 
1 
Cataplexy 
1 
1 
1 
2 
Muscle spasms 
2 
2 
<1 
2 
NERVOUS SYSTEM DISORDERS 
Dizziness 
4 
9 
11 
15 
Somnolence 
4 
1 
3 
8 
Tremor 
0 
0 
2 
5 
Paresthesia 
1 
2 
1 
3 
Disturbance in attention 
0 
1 
0 
4 
Sleep paralysis 
1 
0 
1 
3 
PSYCHIATRIC DISORDERS 
Disorientation 
1 
1 
2 
3 
Anxiety 
1 
1 
1 
2 
Irritability 
1 
0 
<1 
3 
Sleep walking 
0 
0 
0 
3 
RENAL AND URINARY DISORDERS 
Enuresis 
1 
3 
3 
7 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Hyperhidrosis 
0 
1 
1 
3 
Source: Xyrem® (sodium oxybate) oral solution. US Prescribing Information 
MedDRA = Medical Dictionary for Regulatory Activities. 
1.3.4.4 
Dose-Response Information 
In clinical trials in narcolepsy, a dose-response relationship was observed for nausea, vomiting, 
paresthesia, disorientation, irritability, disturbance in attention, feeling drunk, sleepwalking, and 
enuresis. The incidence of all these reactions was notably higher at 9 g per night. In controlled 
trials in narcolepsy, discontinuations of treatment due to adverse reactions were greater at higher 
doses of Xyrem.  
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Clinical Trial Protocol: 15-006 Amendment 5 
 
  
 
 
 
 
CONFIDENTIAL 
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1.3.5 
Safety Data from Healthy Volunteer Studies 
1.3.5.1 
Xyrem (sodium oxybate) 
Xyrem (sodium oxybate) oral solution was studied in 7 studies (one clinical pharmacology study 
and 6 drug-drug interaction studies). No deaths or serious adverse events (SAEs) occurred during 
any of these studies, and no subject was discontinued early for an AE. Overall, the AE profile 
was similar to that seen in patients. 
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Clinical Trial Protocol: 15-006 Amendment 5 
 
  
 
 
 
 
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1.3.6 
Postmarketing Experience with Xyrem  
In addition to those listed in Section 1.3.4, the following AEs that have a likely causal 
relationship to Xyrem exposure have been identified during postmarketing use of Xyrem: 
arthralgia, decreased appetite, fall, fluid retention, hangover, headache, hypersensitivity, 
hypertension, increased libido, memory impairment, nocturia, panic attack, vision blurred, 
aggression, and weight decreased. Because these reactions are reported voluntarily, it is not 
always possible to reliably estimate their frequency. 
1.4 
Summary of Data on JZP-258 Formulation 
1.4.1 
Pharmacokinetic Data from Healthy Volunteer Study 
The JZP-258 formulation was studied in a single-center, open-label, randomized, single dose, 
crossover, study to compare the pharmacokinetics, bioavailability, bioequivalence, and food 
effect of JZP-258 and Xyrem in healthy volunteers. Two formulations of oxybate (JZP-258 and 
Xyrem) were compared under fasting and fed conditions. A total of 36 subjects were enrolled, 
and 30 subjects completed the study and had evaluable pharmacokinetic data. 
Following the administration of single doses of JZP-258 and Xyrem under fasted condition, 
mean concentration-time profiles were generally similar for both treatments. The mean oxybate 
Cmax values were 101.8 µg/mL and 135.7 µg/mL for JZP-258 and Xyrem, respectively, and the 
mean AUC0-inf values were 236.5 µg·h/mL and 265.2 µg·h/mL for JZP-258 and Xyrem, 
respectively. Median Tmax values were 0.75 hour and 0.50 hour for JZP-258 and Xyrem, 
respectively, and mean t1/2 value was 0.57 hour for both treatments. 
Following the administration of single doses of JZP-258 and Xyrem under fed condition, mean 
concentration-time profiles were generally similar for both treatments). The mean oxybate Cmax 
values were 77.4 µg/mL and 84.3 µg/mL for JZP-258 and Xyrem, respectively, and the mean 
AUC0-inf values were 214.8 µg·h/mL and 229.6 µg·h/mL for JZP-258 and Xyrem, respectively. 
Median Tmax values were 0.75 hour for both treatments, and mean t1/2 values were comparable 
with 0.62 hour and 0.57 hour for JZP-258 and Xyrem, respectively. 
Although the mean concentration-time profiles were generally similar for JZP-258 versus Xyrem 
under the fasted condition with similar AUC, Tmax, and t1/2, the FDA-defined bioequivalence 
criteria were met for oxybate plasma AUC (geometric mean ratio of 88.3% with 90% CI of 
84.4%-92.4%) but not for oxybate plasma Cmax (geometric mean ratio of 74.2% with 90% CI of 
67.8%-81.2%), therefore, JZP-258 and Xyrem are not bioequivalent under fasting conditions. 
Under the fed condition, JZP-258 was found to be bioequivalent to Xyrem with regard to Cmax 
(geometric mean ratio of 93.5% with 90% CI of 85.4%-102.4%) and AUC (geometric mean ratio 
of 94.2% with 90% CI of 90.0%-98.6%) after single dose oral administration. 
Presence of food reduced oxybate exposure (Cmax and AUC) for both JZP-258 and Xyrem 
treatments, although the reductions were less pronounced for JZP-258 compared with Xyrem.  
Please refer to current version of the IB for additional information. 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 15-006 Amendment 5 
 
  
 
 
 
 
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1.4.2 
Safety Data from Healthy Volunteer Pharmacokinetic Study 
No SAEs or discontinuations due to AEs occurred during the study. Most AEs were of mild 
severity, none were severe, and most were considered related to study drug or procedure. 
Adverse events reported in ≥5% of subjects included somnolence, dizziness, nausea, headache, 
fatigue, euphoric mood, abdominal pain, feeling of relaxation, hyperhidrosis, vomiting, vision 
blurred, dry mouth, back pain, confusional state, tinnitus, and hyperacusis. Under fasting 
conditions, the incidence of nausea (31.4% versus 47.2%) and vomiting (2.9% versus 13.9%) 
was lower with JZP-258 than with Xyrem, respectively; no other clinically important differences 
in AEs were observed between the JZP-258 formulation and Xyrem. No clinically significant 
trends were noted in the results of clinical laboratory tests, vital signs, oxygen saturation, 
electrocardiograms (ECGs), or physical examinations. 
Please refer to current version of the IB for additional information. 
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Clinical Trial Protocol: 15-006 Amendment 5 
 
  
 
 
 
 
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2 
STUDY OBJECTIVES 
2.1 
Primary Objective(s)  
• To evaluate the efficacy of JZP-258 in the treatment of cataplexy in subjects with 
narcolepsy 
2.2 
Secondary Objectives  
2.2.1 
Key Secondary Objective: 
• To evaluate the efficacy of JZP-258 in the treatment of excessive daytime sleepiness 
(EDS) in subjects with narcolepsy  
2.2.2 
Secondary Objective: 
• To evaluate the safety of JZP-258 in the treatment of subjects with narcolepsy with 
cataplexy 
2.2.3 
Exploratory Objective 
• To characterize the conversion from non-Xyrem anticataplectic treatment regimens 
to JZP-258 in subjects with narcolepsy with cataplexy  
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JZP-258 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 15-006 Amendment 5 
 
  
 
 
 
 
CONFIDENTIAL 
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3 
STUDY DESIGN 
3.1 
Overall Study Design and Plan 
This is a 2-part study consisting of the MAIN Study (a double-blind, placebo-controlled, 
randomized-withdrawal, multicenter study of the efficacy and safety of JZP-258) followed by a 
24-week Open-Label Extension study.  
3.1.1 
Main Study 
The Main Study consists of the following periods, which are further described below: 
• Screening Period for up to 30 days 
• Optimized Treatment and Titration Period for 12 weeks  
• Stable-Dose Period for 2 weeks 
• Double-Blind Randomized-Withdrawal Period for 2 weeks 
• Safety Follow-up Period for 2 weeks 
 
Subjects are eligible to enter the Main Study if they meet all eligibility criteria and their 
treatment status is: 
• Currently treated with a stable dose of Xyrem (sodium oxybate) for at least 2 months 
prior to screening 
• Currently treated with a stable dose of Xyrem and an additional anticataplectic for at 
least 2 months prior to screening 
• Currently treated with an anticataplectic and not treated with Xyrem 
• Not currently treated with any anticataplectic at screening 
 
All subjects will be allowed to continue with their stimulant or non-Xyrem alerting agent 
therapy, if applicable, if doses have been unchanged for 2 months.  
3.1.1.1 
Screening Period (up to 30 days) 
All subjects will be evaluated for eligibility during the Screening Period (up to 30 days). 
Rescreening  
Subjects may be allowed to rescreen (one time) if they previously did not meet all eligibility 
requirements at Visit 1. Rescreening may occur following resolution of transient exclusionary 
conditions or stabilization of conditions that were exclusionary in the unstable state (e.g., 
unstable hypothyroidism) and is permitted only with the permission of the Medical Monitor. 
Subjects who are approved for rescreening must be re-consented and repeat the screening 
procedures described in Section 7.1.1. For subjects who are being rescreened, a repeat 
polysomnogram (PSG) is not required if the results of a previous PSG meet the current 
inclusion/exclusion criteria. 
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JZP-258 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 15-006 Amendment 5 
 
  
 
 
 
 
CONFIDENTIAL 
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3.1.1.2 
Optimized Treatment and Titration Period (12 weeks) 
During this period subjects will be transitioned to JZP-258 based on their treatment status at 
study entry. All subjects will begin JZP-258 treatment at the beginning of this period and 
continue through Week 12. They will be treated with JZP-258 alone for the final two weeks of 
this 12 week period. Once the JZP-258 dose has been optimized per the Investigator’s judgment, 
these subjects may enter the 2 week Stable-Dose Period with that dose. For the purposes of 
describing the transition to JZP-258, these subjects’ pretreatment status will be defined as 
Pre-randomization Groups 1-4. 
Pre-randomization Group 1 
(Subjects on Xyrem at study entry)  
Subjects who are only treated with Xyrem as an anticataplectic at study entry will be switched 
from Xyrem gram for gram to JZP-258 and remain on this JZP-258 dose for a minimum of 
2 weeks. If needed, the dose of JZP-258 may then be titrated during the subsequent 8 weeks to a 
stable, tolerable, and effective dose. Subjects must be maintained on an unchanged, tolerable, 
and effective dose of JZP-258 for at least 2 weeks prior to entering the Stable-Dose Period.  
Pre-randomization Group 2 
(Subjects on Xyrem and an additional anticataplectic at study entry) 
Subjects who enter the study on Xyrem and an additional anticataplectic will be switched from 
Xyrem gram for gram to JZP-258 and remain on this JZP-258 dose for a minimum of 2 weeks. 
Following this 2-week period subjects will be tapered off the additional anticataplectic over a 
minimum period of 2 weeks and up to 8 weeks. If needed, the dose of JZP-258 may be further 
titrated to a stable, tolerable, and effective dose during this 8-week period. Subjects must be 
maintained on an unchanged, tolerable, and effective dose of JZP-258 alone for at least 2 weeks 
prior to entering the Stable-Dose Period.  
Pre-randomization Group 3 
(Subjects on a non-Xyrem anticataplectic at study entry)  
Subjects who enter the study on a non-Xyrem anticataplectic and are not treated with Xyrem will 
be titrated to a tolerable dose of JZP-258 over a minimum of 2 weeks at the start of this period. 
After initial titration to JZP-258, subjects will be tapered off other anticataplectics over a 
minimum of 2 weeks and up to 8 weeks. If needed, the dose of JZP-258 may be further titrated to 
a stable, tolerable, and effective dose during this 8-week period. Subjects must be maintained on 
an unchanged, tolerable, and effective dose of JZP-258 alone for at least 2 weeks prior to 
entering the Stable-Dose Period.  
 
Pre-randomization Group 4 
(Subjects not treated with an anticataplectic at study entry)  
Subjects who are not treated with any anticataplectic at the study entry will be initiated and 
titrated with JZP-258 over a minimum of 2 weeks and up to 8 weeks to achieve a stable, 
tolerable, and effective dose during this period. Subjects must be maintained on an unchanged, 
tolerable, and effective dose of JZP-258 alone for at least 2 weeks prior to entering the Stable-
Dose Period. 
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JZP-258 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 15-006 Amendment 5 
 
  
 
 
 
 
CONFIDENTIAL 
Page 34 of 130 
 
3.1.1.3 
Stable-Dose Period (2 weeks) 
All subjects must have been titrated or converted to a tolerable and effective JZP-258 dose. 
Subjects will remain on this stable JZP-258 dose, unchanged, during this 2-week period. 
The baseline number of weekly cataplectic attacks and baseline EDS scores, as well as other 
secondary efficacy endpoints (as applicable), will be determined in this period. 
3.1.1.4 
Double-Blind Randomized-Withdrawal Period (2 weeks) 
Subjects are eligible to enter the Double-Blind Randomized-Withdrawal Period if their dose of 
JZP-258 remains unchanged during the Stable-Dose Period and, in the judgment of the 
Investigator, no clinically significant worsening in narcolepsy symptoms or clinically significant 
AEs due to JZP-258 treatment have occurred and subjects have completed daily dosing and 
cataplexy diaries in the Stable-Dose Period as described in Section 6.7 and Section 6.12.7. 
Randomization will be stratified based on each subject’s pre-randomization group, as defined at 
study entry. Subjects will be randomized 1:1 to receive one of the following two treatments 
during the 2-week Double-Blind Randomized-Withdrawal Period: 
JZP-258: JZP-258 will be continued as a double-blind treatment at the stable dose taken 
in the prior 2 weeks. 
JZP-258 Placebo: Placebo will be initiated as a double-blind treatment at a volume 
equivalent to the JZP-258 dose taken in the prior 2 weeks. 
3.1.1.5 
Safety Follow-up Period (2 weeks) 
Subjects who do not enter the Open-Label segment of the study will return for a Safety Follow-
up visit 2 weeks after the Double-Blind Randomized-Withdrawal Period. The Safety Follow-up 
visit will not take place if the subject directly rolls over into the Open-Label Extension at Visit 
16.  
A study diagram for the main study is presented in Figure 1. 
 
Confidential
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JZP-258 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 15-006 Amendment 5 
 
  
 
 
 
 
CONFIDENTIAL 
Page 36 of 130 
 
3.1.2 
Open-Label Extension  
Subjects who complete the double-blind treatment during the Main Study are eligible to enter a 
24-week Open Label Extension, which consists of the following: 
• Open-Label Extension Period for 24 weeks 
• Open-Label Safety Follow-up Period for 2 weeks 
 
During this period subjects will receive open-label JZP-258.  
Subjects are eligible to enter the Open-Label Extension if they meet all eligibility criteria and 
their treatment status is:  
• Completed double-blind treatment in the Main Study and rolling over into the Open-
Label Extension 
• Completed the Main Study and currently treated with Xyrem alone or Xyrem plus an 
additional anticataplectic 
• Completed the Main Study and currently treated with a non-Xyrem anticataplectic  
• Completed the Main Study and not currently receiving treatment 
 
3.1.2.1 
Open-Label Extension Period (24 weeks) 
Subjects can enter the Open-Label Extension directly from the Main Study (enter at Visit 16) or 
after completion of the Main Study (enter at Visit 18). 
• Rollover Subjects: those who enter the Open-Label Extension at Visit 16 (i.e., 
“rollover” directly from the Main Study after a few additional procedures [see Section 
7.2.1.1]). Their Visit 16 has the dual purpose of being the last day of the Main Study 
and Day 1 for the Open-Label Extension. 
• Re-entry Subjects: those who enter the Open-Label Extension following completion 
of the Main Study (i.e., require “re-entry” into the study). Their Open-Label 
Extension Day 1 is at Visit 19 and they undergo Open-Label screening at Visit 18. 
 
Prior to any study activity informed consent for the Open-Label Extension will be obtained.  
Confidential
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JZP-258 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 15-006 Amendment 5 
 
  
 
 
 
 
CONFIDENTIAL 
Page 37 of 130 
 
Rollover Subjects (enter the Open-Label Extension at Visit 16) 
They will undergo additional procedures from Amendment 4 at Visit 16, including study drug 
dispensing of open-label JZP-258 (see Section 7.2.1.1).  
Re-entry Subjects (enter the Open-Label Extension at Visit 18) 
Those subjects who complete the double-blind treatment prior to regulatory approval of protocol 
Amendment 4 will need to have the 2 week Safety Follow-up visit and can re-enter the study at 
the Open-Label Extension (e.g., prior to the last subject completing the Main Study). Subjects re-
entering will undergo screening (up to 30 days) and receive Open-Label JZP-258 at Visit 19. 
3.1.2.2 
Open-Label Extension Safety Follow-up Period (2 weeks) 
Subjects will return for a Safety Follow-up visit 2 weeks after completion or early termination 
from the Open-Label Extension Period.  
A study diagram for the Open-Label Extension is presented in Figure 2. 
 
Confidential
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JZP-258 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 15-006 Amendment 5 
 
  
 
 
 
 
CONFIDENTIAL 
Page 39 of 130 
 
 
3.1.3 
Rationale for Study Design and Control Group 
This study is being undertaken to evaluate the efficacy and safety of JZP-258 in the treatment of 
cataplexy in subjects with narcolepsy and treatment of EDS in subjects with narcolepsy. JZP-258 
is being developed in order to provide the same treatment benefits as Xyrem with reduced 
sodium exposure to potentially benefit all patients, particularly those with sodium-sensitive 
conditions. 
A double-blind placebo controlled randomized-withdrawal study of Xyrem in adult narcolepsy 
subjects (OMC-SXB-21) was one of the pivotal studies that supported FDA and European 
Medicines Agency (EMA) approval of Xyrem for the treatment of cataplexy and EDS in subjects 
with narcolepsy. In this Xyrem study, the return of narcolepsy symptoms including cataplexy 
was studied in 55 subjects over a 2-week treatment period following long-term (greater than 
6 months) Xyrem treatment. Relative to subjects who remained on Xyrem, subjects in the 
placebo group had a small, gradual increase in the number of cataplexy attacks during the first 
and the second week of interruption of treatment with Xyrem. The number of subjects reported 
to have AEs, were higher in the group that switched to placebo compared to the group that 
continued with Xyrem therapy in the final 2-week Double-Blind Randomized-Withdrawal 
period, but these differences were not found to be statistically significant. Therefore, this same 
study design, replicating the original Xyrem placebo-controlled registration study, was chosen 
for the current trial (Study 15-006) in the investigation of JZP-258 (a new investigational 
reduced-sodium drug product) and was agreed upon with FDA as an adequate trial for 
registration. 
The inclusion of a placebo control group in this study is necessary to determine the efficacy and 
safety of this new investigational medicinal product. Although effective doses of JZP-258 may 
be observed during Open-Label-Titration and Stable-Dose Periods of the study, the definitive 
efficacy effect can be determined only after double-blind comparison with placebo, considering 
the slightly different pharmacokinetic profile of JZP-258 (lower Cmax versus Xyrem). The risks 
of placebo exposure were taken into consideration during the protocol design. The incorporation 
of a short 2-week, randomized-withdrawal phase into the study may allow the demonstration of 
the efficacy of JZP-258 as measured by the recurrence of cataplexy symptoms without extensive 
placebo burden to the subjects. In this 16 week long study, the maximal time during the Main 
Study that any subject will be exposed to placebo is 2 weeks (12.5% of total exposure time). 
Furthermore, the recurrence of cataplexy during these two weeks, as pointed out above, is 
considered minimal to obtain statistically significant efficacy data compared to placebo. 
Importantly, in the case of emergency situations, as per Section 6.13.9 of the protocol, the 
Investigator will be able to unblind a subject at any time for immediate medical management of 
the subject, if necessary.  
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Jazz has recently modified the protocol (Amendment 4) to include a six month Open-Label 
Extension to the study to allow subjects who have completed the Double-Blind Randomized 
Treatment portion of the study to continue or re-enroll into the study and receive open-label 
JZP-258. This extension period was added to provide additional treatment benefit for subjects as 
well as to assess longer term safety with JZP-258.
 
3.2 
Study Duration and Dates 
It is anticipated that enrollment will be completed in approximately 18 months. The estimated 
duration of the study (Main Study and Open-Label Extension) is approximately 2 ½ years. 
3.3 
End of Trial 
The end of the trial will be the date of the last visit of the last remaining subject in the trial. 
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4 
STUDY POPULATION SELECTION 
4.1 
Selection of Study Population 
The study will enroll subjects who are diagnosed with narcolepsy with cataplexy, and who have 
signed the informed consent form in accordance with local ethics committee requirements. 
Approximately 185 subjects will be enrolled into the study from the four therapy groups (pre-
randomization groups) described in Section 3.1. An effort will be made to include at least 
50 subjects previously on Xyrem and 60 subjects previously using Xyrem plus other 
anticataplectics or non-Xyrem anticataplectics alone in the study. A minimum of 130 subjects 
(65 subjects per the two treatment groups; JZP-258 and JZP-258 placebo) are planned to be 
randomized into the Double-Blind Randomized-Withdrawal Period. However, due to the 
potential limited availability of study participants (e.g., current Xyrem patients unwilling to 
interrupt therapy for potential placebo therapy), the minimum numbers of subjects in the prior 
therapy groups may be adjusted as necessary to ensure enrollment completion in a timely 
manner.
 
4.2 
Main Study 
4.2.1 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in the Main Study: 
1. Male or female subjects between 18 and 70 years of age at screening, inclusive. 
2. Have a primary diagnosis of narcolepsy with cataplexy that meets International 
Classification of Sleep Disorders-Third Edition (ICSD-3) criteria or Diagnostic and 
Statistical Manual-Fifth Edition (DSM-5) criteria (Appendix 2), and currently untreated 
or treated with or without anticataplectics.  
3. Have a history of having at least 14 cataplexy attacks in a typical 2-week period and 
clinically significant symptoms of EDS prior to any narcolepsy treatment. 
4. Treatment status (Pre-randomization Group) at study entry: 
a) Have been taking Xyrem at unchanged doses (twice or thrice nightly dosing no higher 
than a total of 9 g/night), for the treatment of cataplexy in narcolepsy for at least 
2 months prior to screening; or 
b) Have been taking Xyrem at unchanged doses (twice or thrice nightly dosing no higher 
than a total of 9 g/night), and another anticataplectic (tricyclic antidepressant [TCA], 
serotonin-norepinephrine reuptake inhibitor [SNRI], selective serotonin reuptake 
inhibitor [SSRI], atomoxetine, or other) for the treatment of cataplexy in narcolepsy 
for at least 2 months prior to screening; or  
c) Treated with a non-Xyrem anticataplectic (TCA, SNRI, SSRI, atomoxetine, or other) 
and not treated with Xyrem; or 
d) Not treated with any agent with anticataplectic properties. 
5. If currently treated with Xyrem, must have documented clinical improvement of 
cataplexy and EDS per Investigator’s clinical judgment. 
6. If applicable, treated with a stimulant or alerting agent at unchanged doses for at least 
2 months prior to dosing or not treated with a stimulant or alerting agent. 
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7. Have used a medically acceptable method of contraception* for at least 2 months prior to 
the first dose of study drug and consent to use a medically acceptable method of 
contraception throughout the entire study period and for 90 days after the study is 
completed. 
8. Willing and able to comply with the study design schedule and other requirements. 
9. Willing and able to provide written informed consent. 
*For the purpose of this study, medically acceptable methods of contraception include 
estrogen-progestin oral contraceptive pills, patches, or vaginal ring, progestin implant or 
injection, diaphragm with spermicide, male condom plus vaginal spermicide; surgical 
sterilization; intrauterine device; post-menopausal (defined as >1 year of amenorrhea), 
medically documented ovarian failure (defined as 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 (only acceptable when 
this is the subject’s preferred and usual lifestyle).  
4.2.2 
Exclusion Criteria 
Subjects who demonstrate any of the following will be excluded from the Main Study:  
1. Narcolepsy secondary to another medical condition (e.g., central nervous system injury or 
lesion). 
2. Restless leg syndrome (RLS) requiring treatment other than iron supplements. 
3. Succinic semi-aldehyde dehydrogenase deficiency (SSADH). 
4. Uncontrolled hypothyroidism. 
5. History of seizures, excluding early childhood non-pathological febrile seizures.  
6. History of head trauma associated with loss of consciousness in the past 5 years or if the 
event occurred more than 5 years prior to screening and the subject has sequelae due to 
the event. 
7. Evidence of untreated or inadequately treated sleep-disordered breathing including: 
a.  Presence of clinically significant and untreated obstructive or central sleep apnea as 
determined by the Investigator or documented previously;  
or documentation of one of the following:  
b. Apnea index >10 if on obstructive sleep apnea (OSA) treatment or untreated; or 
c. Clinically significant hypoventilation; or 
d. Noncompliance with primary OSA therapy. (Compliance defined as positive airway 
pressure use of ≥4 hours per night on ≥70% of nights [≥5 of 7 nights/week], historical 
report [with Investigator concurrence] of use of an oral appliance on ≥70% of nights 
[≥5 of 7 nights/week], or receipt of an effective surgical intervention for OSA 
symptoms). 
8. Parasomnias (e.g., sleep walking, REM Sleep Behavior Disorder, etc.) felt by the 
investigator to negatively affect the conduct of the study. Parasomnia events associated 
with physical injury to the subject (or others) shall be discussed with the Medical Monitor  
9. Meets criteria for current major depression by clinical interview.  
10. Any other clinically relevant medical, behavioral, or psychiatric disorder other than 
narcolepsy that is associated with excessive sleepiness. 
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11. History or presence of bipolar disorder, bipolar related disorders, schizophrenia, 
schizophrenia spectrum disorders, or other psychotic disorders according to DSM-5 
criteria (Appendix 14). 
12. History or presence of any unstable or clinically significant medical condition, behavioral 
or psychiatric disorder (including active suicidal ideation), or history or presence of 
another neurological disorder or surgical history that might affect the subject’s safety 
and/or interfere with the conduct of the study in the opinion of the Investigator. 
13. A current ECG with clinically significant deviation(s) from normal, or clinically 
significant physical examination findings, as determined by the Investigator at screening. 
14. Any current clinically significant laboratory abnormality as determined by the 
Investigator at screening. 
15. Is a female subject who is pregnant, nursing, or lactating.  
16. A positive urine drug screen for benzodiazepines or drugs of abuse, a positive alcohol 
test, a history of substance abuse including alcohol abuse, or unwillingness to refrain 
from consuming alcohol during the study (if the subject takes prescribed amphetamines, a 
positive result for amphetamines will not exclude the subject). 
17. Treatment with any central nervous system sedating agents including, but not limited to, 
benzodiazepines, non-benzodiazepine anxiolytics/ hypnotics/sedatives, neuroleptics, 
opioids, barbiturates, phenytoin, ethosuximide, or the monocarboxylate transporter 
(MCT) inhibitor valproate within 2 weeks prior to enrollment (Day 1) (discontinuation 
for the purpose of study enrollment is permitted only if considered safe by the 
Investigator and approved by the Medical Monitor). 
18. Treatment with an antidepressant for cataplexy, if the withdrawal of the antidepressant 
during cross-titration with JZP-258 might be unsafe due to prior history of depression. 
19. Current treatment with oral isotretinoin.  
20. Received any investigational drug within 30 days or 5 half-lives (whichever is longer) 
before the Screening Visit. 
21. Allergy or sensitivity to malic acid, sucralose or ingredients in the study drug formulation 
or placebo. 
22. Unsafe for the subject to receive placebo treatment for 2 weeks, in the opinion of the 
Investigator. 
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4.3 
Open-Label Extension 
Subject participation in the Open-Label Extension is optional.  
 
4.3.1 
Inclusion Criteria 
Subjects are reassessed for eligibility if re-entering the study for inclusion in the Open-Label 
Extension (Visits 18 and 19). Rollover Subjects had a screening assessment during the Main 
Study and do not require re-screening for the Open-Label Extension. Each re-entering subject 
must meet the following criteria to be enrolled in the Open-Label Extension: 
1. Completion of the JZP-258 double-blind treatment and completion of Visit 16 
2. Is able, in the opinion of the investigator, to take JZP-258 for an additional 24 weeks 
3. Agrees to continue to use a medically acceptable method of contraception throughout the 
entire study period and for 90 days after the Open-Label Extension is completed. 
4. Willing and able to comply with the study design schedule and other requirements. 
5. Willing and able to provide written informed consent for Open-Label Extension.  
6. If currently being treated with Xyrem, the subject’s total twice nightly Xyrem dose must 
be no higher than 9 g/night 
 
4.3.2 
Exclusion Criteria 
Subjects will be excluded from re-entering the study at the Open-Label Extension if they:  
1. Meet Exclusion Criteria 1 through 19 from the Main Study at Visits 18 and 19. 
2. Received any investigational drug (with the exception of JZP 258) within 30 days or 
5 half-lives (whichever is longer) before the Screening Visit. 
3. Allergy or sensitivity to malic acid, sucralose or ingredients in the study drug 
formulation. 
4.4 
Screening and Randomization Eligibility  
Subjects who do not meet screening criteria will be considered screen failures. Subjects may be 
allowed to rescreen (one time) if they previously did not meet all eligibility requirements 
(Section 3.1). Rescreening in the Main Study may occur following resolution of transient 
exclusionary conditions or stabilization of conditions that were exclusionary in the unstable state 
(e.g., unstable hypothyroidism) and is permitted only with the permission of the Medical 
Monitor. Rescreening is not allowed in Open-Label Extension. 
Subjects will be considered eligible for the Optimized Treatment and Titration Phase of the study 
if they meet the inclusion criteria and do not meet any exclusion criteria. Subjects are eligible to 
enter the Double-Blind Randomized-Withdrawal Period if the dose of JZP-258 remains 
unchanged during the Stable-Dose Period, and in the judgment of the Investigator, no clinically 
significant worsening in narcolepsy symptoms or clinically significant AEs due to JZP-258 
treatment have occurred and subjects have completed daily dosing and cataplexy diaries in the 
Stable-Dose Period as described in Section 6.7 and Section 6.12.7. 
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5 
STUDY TREATMENTS 
5.1 
Description of Treatment(s) 
5.1.1 
Main Study 
5.1.1.1 
Study Drug 
JZP-258 oral solution 0.5 g/mL. 
5.1.1.2 
Placebo  
A matching oral solution to JZP-258 will be provided. The placebo formulation is an aqueous 
solution consisting of sodium citrate, malic acid and sucralose. All ingredients are compendial 
(USP/NF).  
Placebo treatment is applicable to the Double-Blind Randomized-Withdrawal Period only. 
5.1.1.3 
Treatments Administered 
During the Optimized Treatment and Titration Periods all subjects will receive open-label 
JZP-258. 
Pre-randomization Groups 1 and 2 
Subjects entering the study on Xyrem alone or on Xyrem plus an additional anticataplectic 
will be switched from their current dose of Xyrem to JZP-258 on a gram to gram straight 
conversion at the start of the Optimized Treatment and Titration Period and remain on that 
dose for 2 weeks. If further titration is needed, titration will proceed at a rate of 1 or 1.5 g 
per night per week during this period not to exceed a total dose of 9 g per night. 
Pre-randomization Groups 3 and 4 
Subjects entering the study receiving treatment with a non-Xyrem anticataplectic only or 
not treated with any anticataplectic agent will receive an initial dose of JZP-258 4.5 g per 
night at the start of the Optimized Treatment and Titration Period. Dose adjustments will 
proceed at a rate of 1 or 1.5 g per night per week until a tolerable dose of JZP-258 is 
reached over a period of 2 weeks. If needed, the dose of JZP-258 may be further titrated to 
a stable, tolerable, and effective dose that does not exceed a total dose of 9 g per night. 
Pre-randomization Groups 2 and 3 will taper anticataplectics as described in Section 3.1. 
During the Stable-Dose Period subjects will receive open-label JZP-258 at the same unchanged 
dose that they received during the last 2 weeks of the Optimized Treatment and Titration Period. 
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All subjects will receive blinded study drug during the Double-Blind Randomized-Withdrawal 
Period. At the end of the Stable-Dose Period, subjects enter the Double-Blind Randomized-
Withdrawal and will be randomized 1:1 to receive either JZP-258 at the dose taken during the 
last 2 weeks of the Stable-Dose Period or JZP-258 placebo (at a volume equivalent to the 
JZP-258 dose taken in the last 2 weeks of the Stable-Dose Period).
 
 
 
Study drug will be dispensed at clinic visits and, if applicable, at intervals specified by state or 
local regulations or to resolve logistical issues. 
5.1.2 
Open-Label Extension 
5.1.2.1 
Study Drug 
JZP-258 oral solution 0.5 g/mL. 
5.1.2.2 
Treatments Administered 
During the Open-Label Extension all subjects will receive open-label JZP-258. 
Subjects can enter the Open-Label Extension directly from the Main Study (enter at Visit 16) or 
after completion of the Main Study (enter at Visit 18): 
• Rollover Subjects: those who enter the Open-Label Extension at Visit 16 (i.e., 
“rollover” directly from the Main Study [after a few additional procedures]) (see 
Section 7.2.1.1). Their Visit 16 has the dual purpose of being the last day of the Main 
Study and Day 1 for the Open-Label Extension. 
• Re-entry Subjects: those who enter the Open-Label Extension following completion 
of the Main Study (i.e., require “re-entry” into the study). Their Open-Label 
Extension Day 1 is at Visit 19 and they undergo Open-Label screening at Visit 18. 
 
Rollover Subjects 
Subjects entering directly from the Main Study will be started at a dose no higher than the dose 
they received at the end of the Stable-Dose Period. A lower starting dose will be allowed at the 
discretion of the Investigator. If further titration is required, it will proceed at a rate of 1 or 1.5 g 
per night per week during this period, not to exceed a total dose of 9 g per night. The maximum 
dose should not be greater than 9 g/night. 
Re-entry Subjects 
Xyrem (alone or with an Additional Anticataplectic): Subjects re-entering the study 
during the Open-Label Extension on Xyrem alone or on Xyrem plus an additional 
anticataplectic will be switched from their current dose of Xyrem to JZP-258 on a gram 
to gram straight conversion at the start of the Open-Label Extension. If further titration is 
needed, titration will proceed at a rate of 1 or 1.5 g per night per week during this period 
not to exceed a total dose of 9 g per night. 
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Non-Xyrem Anticataplectic or Not Currently Receiving Treatment: Subjects re-
entering the study receiving treatment with a non-Xyrem anticataplectic only or not 
treated with any anticataplectic agent will receive an initial dose of JZP 258 4.5 g per 
night at the start of the Open-Label Extension. Dose adjustments will proceed at a rate of 
1 or 1.5 g per night per week until a tolerable dose of JZP-258 is reached. If needed, the 
dose of JZP-258 may be further titrated to a stable, tolerable, and effective dose that does 
not exceed a total dose of 9 g per night.  
Subjects should follow anticataplectic tapering as discussed in Section 5.6 with complete 
removal by Visit 30. 
Study drug will be dispensed at clinic visits and, if applicable, at intervals specified by state or 
local regulations or to resolve logistical issues. 
5.2 
Selection and Timing of Dose for Each Subject 
Sodium oxybate has a t1/2 of approximately 0.5 to 1 hour. Pharmacologic doses of sodium 
oxybate have clinical sedative effects that typically last 2 to 4 hours. Sodium oxybate in divided 
nightly doses has been studied in patients with narcolepsy and patients with fibromyalgia.  
Based on pharmacokinetic data demonstrating the generally similar mean concentration-time 
profiles for JZP-258 and Xyrem under the fasted condition with similar AUC, Tmax and t1/2, and 
FDA defined bioequivalence under fed conditions, the proposed dose range and timing of dosing 
of JZP-258 will be similar to Xyrem. 
With the following exception, all groups should dose with JZP-258 orally in two equally divided 
doses taken at bedtime and again 2.5 to 4 hours later. Subjects who entered the study on Xyrem 
(Pre-randomization Groups 1 and 2) and have used a different nightly dosing regimen prior to 
study entry, may continue their prestudy dosing regimen throughout the study (i.e. the dosing 
regimen may consist of two or three equally or unequally nightly divided doses and dosing may 
begin after the first nightly awakening, however, a once nightly dosing will not be permitted 
during the study). Subjects entering the study on a different nightly dosing regimen may not 
change their regimen during the study. 
Subjects in all groups will be instructed to take each dose while in bed and remain in bed after 
each dose. Subjects should take the first dose of study drug at least 2 hours after eating.  
Investigators should caution subjects about operating hazardous machinery, including 
automobiles or airplanes, until subjects are reasonably certain that study drug does not affect 
them adversely (e.g., impair judgment, thinking, or motor skills). Subjects should not engage in 
hazardous occupations or activities requiring complete mental alertness or motor coordination, 
such as operating machinery or a motor vehicle or flying an airplane or going to school alone, for 
at least 6 hours after taking any dose of study drug. 
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5.3 
Method of Assigning Subjects to Treatment Groups 
Subjects are eligible to enter the Double-Blind Randomized-Withdrawal Period if the dose of 
JZP-258 remains unchanged during the Stable-Dose Period and, in the judgment of the 
Investigator, no clinically significant worsening in narcolepsy symptoms or clinically significant 
AEs due to JZP-258 treatment have occurred and subjects have completed daily dosing and 
cataplexy diaries in the Stable-Dose Period as described in Section 6.7 and Section 6.12.7. At the 
beginning of the Double-Blind Randomized-Withdrawal Period, subjects will be randomized 
with equal allocation to either JZP-258 at the stable dose established in the previous 2 weeks or 
to JZP-258 placebo at a volume equivalent to the JZP-258 dose that was established in the 
previous 2 weeks. Randomization will be stratified by Pre-randomization Group, as defined at 
study entry. 
During the Open-Label Periods (Optimized Treatment and Titration, Stable-Dose, and 
Open-Label Extension) all subjects will receive open-label JZP-258.  
5.4 
Randomization 
A statistician selected by Jazz Pharmaceuticals will prepare and retain the master randomization 
code for the entire study. This statistician will not be involved in the analysis of this study. 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 study data are collected and accepted for 
analysis as described in Section 6.13.9 and Section 9.14.  
The Investigator will access an Interactive Web Response System (IWRS) to randomize subjects.  
5.5 
Blinding 
The Optimized Treatment Titration and Stable-Dose Periods and Open-Label Extension of this 
study will not be blinded to the subjects or the study personnel. A double-blind approach will be 
used during the Double-Blind Randomized-Withdrawal Period. JZP-258 and JZP-258 placebo 
oral solution will be matched in volume, to ensure adequate blinding of the subject and study 
personnel. 
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5.6 
Prior and Concomitant Therapy 
5.6.1 
Prohibited Concomitant Medications 
In this study, the following medications are prohibited: 
a. Treatment with any central nervous system sedating agents including, but not limited to, 
benzodiazepines, non-benzodiazepine anxiolytics/hypnotics/sedatives, neuroleptics, 
opioids, barbiturates, phenytoin, and ethosuximide, or the MCT inhibitor valproate are 
prohibited during the study and must have been discontinued within 2 weeks prior to 
Day 1. (Discontinuation for the purpose of study enrollment is only permitted if 
considered safe by the Investigator and approved by the Medical Monitor.) If a subject 
undergoes short-term out-patient procedures during the study and requires opioids or 
benzodiazepine use, study drug may be held for one night while these drugs are given. If 
opioid or benzodiazepine use is required for multiple days, the subject should be 
discontinued from the study.  
b. Other anticataplectic therapies (e.g., SNRI, SSRI, TCA or atomoxetine) are prohibited 
during the Stable-Dose, Double-Blind, and Open-Label Extension Periods. For the Main 
Study, these therapies must have been tapered and discontinued during the cross titration 
in the Titration Period. (Discontinuation for the purpose of study enrollment is only 
permitted if considered safe by the Investigator and approved by the Medical Monitor.) 
For the Open-Label Extension, tapering and discontinuation must occur by Visit 30. 
c. Oral isotretinoin (Accutane) is prohibited during the study.  
d. Investigational drugs other than study drug are prohibited during the study. 
e. Stimulants or alerting agents are disallowed during the study for subjects who were not 
taking these medications at the start of the study. 
5.6.2 
Permitted Concomitant Medications 
The following concomitant medications are permitted during the study with the following 
stipulations: 
a. Stimulants or alerting agents may be continued during the study if doses were unchanged 
for 2 months prior to dosing and doses remain unchanged throughout the study.  
Note: For subjects who are re-entering the study stimulants must be at a stable dose for 
the preceding 2 weeks before re-entering the study at the Open-Label Extension may be 
continued during the Open-Label Extension. 
b. Vitamins in normal doses may be continued (herbal supplements are prohibited). 
c. Birth control pills, patches, injections, or implants (all hormonal contraceptives) may be 
continued. 
d. Local topical anesthetic agent before any blood draws. 
e. Non-sedating antihistamines. 
f. Anti-inflammatories for pain.  
g. Paracetamol (acetaminophen) for pain 
h. Chronic topical or oral antibiotics for acne. 
i. Over-the-counter (OTC) decongestants. 
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All concomitant medications taken during the study by enrolled subjects will be recorded on the 
Concomitant Medications electronic case report form (eCRF) with indication, total daily dose, 
and dates of drug administration. 
5.7 
Restrictions 
5.7.1 
Prior Therapy 
Subjects who are on Xyrem alone or Xyrem plus an additional anticataplectic at the start of the 
study will be switched to JZP-258 at the start of the Optimized Treatment and Titration Period 
(Main Study) and if applicable, at the start of the Open-Label Extension. Subjects who are on 
any non-Xyrem anticataplectics will have these tapered and discontinued during the Optimized 
Treatment and Titration Period as they are cross titrated to JZP-258 (Main Study) and by Visit 30 
for the Open-Label Extension. 
All subjects may continue prescription and OTC medications with the exception of the 
prohibited medications listed in Section 5.6. For the Main Study and the Open-Label Extension, 
subjects who plan to use an investigational drug (other than the study drug) during the study will 
not be allowed to enter the study. Additionally, subjects in the Main Study and those enrolling 
directly into the Open-Label Extension will not be allowed to enter if they used any other 
investigational drug (other than the study drug) within 30 days or five half-lives (whichever is 
longer) before the Screening Visit for the Main Study (all subjects) or at Visit 18 for the Open-
Label Extension subjects (only those re-entering the study).  
5.7.2 
Fluid and Food Intake  
Subjects should take the first dose of study drug at least 2 hours after eating. No other fluid or 
food restrictions are required. 
5.7.3 
Other Restrictions 
Subjects should take study drug while in bed and lie down immediately after dosing as study 
drug may cause them to fall asleep abruptly without first feeling drowsy.  
5.8 
Treatment Compliance 
The number of bottles of clinical study medication dispensed will be recorded on the 
investigational medicine record by the designated staff member. The volume of solution 
dispensed and returned will be recorded on the investigational medicine record. Treatment 
compliance will be calculated at each applicable clinic visit when drug is expected to be returned 
to the site. 
5.9 
Packaging and Labeling 
Jazz Pharmaceuticals will provide the clinical site with JZP-258 oral solution 0.5 g/mL for use 
during all phases of the study and JZP-258 placebo for use during the Double-Blind 
Randomized-Withdrawal Period.  
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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. 
5.10 Storage and Accountability 
All study medications will be stored, inventoried, reconciled, and retained or destroyed 
according to applicable country and local regulations for a controlled substance and instructions 
from Jazz Pharmaceuticals. Jazz Pharmaceuticals will specify the temperature conditions under 
which each study drug is stored. 
The investigator or designated pharmacist will maintain accurate records of receipt of all study 
drugs, including dates of receipt. Study drug supplies must be kept in a secure area and dispensed 
according to the protocol. Unused (or partially used) supplies must be accounted for on the drug 
inventory record provided by Jazz Pharmaceuticals or the Contract Research Organization 
(CRO). Receipt and dispensing of all study drug must be documented throughout the study and 
reconciled at study completion. Used and unused bottles of study drug will be returned or 
destroyed according to written instructions from Jazz Pharmaceuticals or its designee. For study 
drug returns, the return quantity (per bottle) will be recorded in a Drug Accountability log. A 
difference of 30 mL or more per bottle between the returned volume recorded by the site on the 
Drug Accountability log and the volume measured by the CRA will require a written 
explanation. After review of study drug accountability records at study completion, one copy of 
the drug inventory record will be retained by the CRO and the other will be retained by Jazz 
Pharmaceuticals.  
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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
All subjects will provide their written informed consent before the performance of any study 
related procedures. 
Each subject’s chart will have his or her signed informed consent form (ICF) for study 
participation included. When the study treatment is completed and the eCRF has been monitored, 
the ICF will be kept in the Investigator’s study file. The date of signed consent for enrolled 
subjects will be recorded on the eCRF. Subjects will be given a copy of their signed ICF. 
6.2 
Demographics 
Demographic information will be collected at Screening Visit 1 as permitted by regional or 
national regulations. Demographics will include the subject’s age (as indicated by date of birth, 
month and year of birth, year of birth or age at screening), sex, ethnicity, and race.  
6.3 
Medical History 
A complete medical history for each subject will be collected during the Screening Period. The 
information will include, but is not limited to, symptoms of narcolepsy (current and past, 
including symptoms experienced prior to any narcolepsy treatment); concomitant medication 
use; any medications used for the treatment of narcolepsy 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 (i.e., any conditions 
and surgeries/procedures that occurred prior to the subject signing the informed consent) will be 
assessed at Visit 2 prior to the start of the Optimized Treatment and Titration Period. Conditions 
that occurred after the subject signed the informed consent will be recorded as AEs (Section 
6.13). 
For subjects who re-enter the study at the Open-Label Extension, their previously recorded 
medical history will be reviewed and updated. New medical history (occurring after completion 
of the Main Study and prior to consent for the Open-Label Extension) will be recorded as 
medical history. 
6.4 
Physical Examination 
A review of body systems should be obtained on each subject. Physical examinations will 
include an examination of body systems (except genitourinary examination), brief neurological 
examination (screening, end of Double-Blind Randomized-Withdrawal Period/Early 
Termination, Visit 18 [only for subjects who are re-entering], and Visit 33/Early Termination), 
height (at screening only), and body weight measurements. Height and weight should be 
assessed in ordinary indoor clothes without shoes. A qualified Investigator or designee should 
perform the examination. 
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6.5 
Vital Signs  
Vital signs measurements will include temperature, respiration rate, sitting blood pressure, and 
heart rate. The measurements will be obtained at every clinic visit after the subject has been 
resting and seated for at least 5 minutes. 
6.6 
Electrocardiography 
Standard 12-lead ECGs will be recorded prior to drawing blood samples with the subject resting 
supine for at least 5 minutes. ECGs will be performed for the Main Study during the Screening 
Period and at the end of the Double-Blind Randomized-Withdrawal Period (or at Early 
Termination) and for the Open-Label Extension at Visit 18 (Re-entry Subjects only) and at 
Visit 33 (or at Early Termination).  
Electrocardiograms will be reviewed, initially interpreted, signed, and dated by the Investigator 
after each ECG collection. All ECGs will be transmitted to a designated central ECG laboratory. 
A cardiologist at the central ECG laboratory will conduct full over-read. A report based on data 
from this over-read will be issued to the site. The Principal Investigator or a designated physician 
is responsible for review of all ECGs. 
6.7 
Study Drug Dosing Diary 
Subjects will complete the Study Drug Dosing Diary (Appendix 3) each morning from the start 
of the Open-label Titration Period until the end of the Double-Blind Randomized-Withdrawal 
Period. A Study Drug Dosing Diary will not be completed in the Open-Label Extension. 
Subjects must have completed the Study Drug Dosing Diary on at least 10 out of the 14 days 
during the Stable-Dose Period occurring prior to the start of the Double-Blind Randomized-
Withdrawal Period and must have indicated that they were compliant with dosing on at least 
10 of the 14 days, or they will be discontinued from the study. The study staff will review the 
diary at each study visit and discuss it with the subject at each phone contact. 
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6.8 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
At the Screening Visit for the Main Study, the Baseline/Screening Version of the C-SSRS will be 
administered by a trained rater to subjects to exclude any individuals with active suicidal ideation 
or behavior (Appendix 4). The C-SSRS is a widely used measure of suicidal ideation and 
behavior. The instrument reliably predicts a potential suicide attempt in those who had 
previously attempted suicide and is able to determine clinically meaningful points at which a 
person may be at risk for an impending suicide attempt (Posner et al. 2011). Suicidal ideation 
will be assessed for lifetime and over the past 12 months, and suicidal behavior will be assessed 
for lifetime and over the past 5 years with the Baseline/Screening Version of the C-SSRS.  
The Since Last Visit Version of the C-SSRS will be administered by a trained rater to subjects at 
every clinic visit after their Main Study Screening Visit including the Follow-up Visit (Appendix 
5) for both the Main Study and the Open-Label Extension. 
6.9 
Patient Health Questionnaire–9 (PHQ-9) 
The PHQ-9 is the nine item depression scale developed based on the nine diagnostic criteria for 
major depressive disorder in the DSM-IV (Diagnostic and Statistical Manual Fourth Edition). 
The instrument can be administered in person, by telephone, or can be self-administered and is 
used to facilitate diagnosis of major depression and assessment of symptom severity. It is 
validated and documented in a variety of populations and is available in a variety of languages 
(Appendix 6, Kroenke K et al. 2001). All subjects will be carefully monitored for emergent 
depression and suicidality. The subject will be evaluated and an assessment of risk will be made 
by a qualified mental health professional if major depression is suspected or active suicidal 
ideation is identified. 
6.10 Clinical Laboratory Tests 
6.10.1 
Laboratory Parameters 
Subjects will be in a seated or supine position during blood collection. Clinical laboratory tests 
will include the following as listed in Table 3. Clinical laboratory tests will be performed at the 
times indicated in Appendix 1. 
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Table 3 
List of Laboratory Tests 
Hematology: 
- 
Complete blood count (CBC), 
including platelet count and 
white blood cell count (WBC) 
with differential 
 
Urinalysis:  
- 
Appearance 
- 
Bilirubin 
- 
Color 
- 
Glucose 
- 
Ketones 
- 
Nitrite  
- 
Occult blood 
- 
pH 
- 
Protein 
- 
Specific gravity 
- 
Urobilinogen 
 
 
*Pregnancy Screen:  
Serum at screening  
Urine at start of Titration Period  
 
Drug Screen (urine) 
Alcohol Screen  
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  
- Gamma-glutamyl transferase (GGT) 
- Globulin 
- Glucose 
- Lactate dehydrogenase (LDH) 
- Phosphorus 
- Potassium (K)** 
- Sodium (Na)** 
- Magnesium** 
- Total bilirubin 
- Direct bilirubin 
- Total cholesterol 
- Total protein 
- Triglycerides 
- Uric acid 
- Thyroid stimulating hormone (TSH)(screening only) 
*Pregnancy screening is required for all females of childbearing potential. Female subjects who have undergone 
surgical sterilization, who are post-menopausal (defined as >1 year of amenorrhea), who have medically documented 
ovarian failure (defined as 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. 
** Electrolyte analysis will be performed at the visits indicated in Appendix 1. 
With the exception of the urine pregnancy test done on site, the clinical laboratory tests 
scheduled for this study will be performed at a central laboratory. An authorized local 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 local 
laboratory’s current licensure and laboratory reference ranges. 
Please note exclusionary clinical laboratory parameters listed in the exclusion criteria. 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; clinically significant 
adverse changes from baseline clinical status must be reported as AEs (see Section 6.13.1).  
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6.10.2 
Sample Collection, Storage, and Shipping 
The laboratory will supply detailed instructions and all containers for blood and urine 
investigations. Blood and urine sample volumes will meet the laboratory’s specifications. The 
actual time of blood collection for all samples will be recorded. 
Blood samples for hematology, serum chemistry, and urinalysis will be collected while the 
subject is fasting during the Screening Period, and at the end of the Double-Blind Period or Early 
Termination for the Main Study and during Visit 18 (only subjects who are re-entering) and Visit 
33 (or at Early Termination).
 
 
6.10.3 
Pregnancy Test 
During the Main Study, a serum pregnancy test for females of childbearing potential will be 
performed at screening (Visit 1) and at Visit 18 for Re-entry Subjects (completed the Main 
Study). Urine pregnancy tests for all females of childbearing potential will be performed at the 
beginning of the Optimized Treatment and Titration Period (Visit 2) and at all clinic visits for 
both the Main Study and the Open-Label Extension, and during the Safety Follow-up Periods 
(Visits 17 and 34). 
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6.10.4 
Drug and Alcohol Screens 
For the Main Study, alcohol and urine drug screens will be performed at screening and at the 
beginning of the Titration Period (Day 1) and at each clinic visit through the Double-Blind 
Randomized-Withdrawal Period. For the Open-Label Extension, alcohol and urine drug screens 
will be done at Visits 18, 19, 30, and 33 (or at Early Termination).  
Drug screens will test for the following prohibited substances 
− Amphetamine 
− Barbiturates 
− Benzodiazepines 
− Cannabinoids 
− Cocaine metabolites 
− Opiates 
− Methadone 
− Phencyclidine (PCP) 
Results of the alcohol and drug screens must be determined to be negative at screening and 
before dosing for all subjects. If a subject takes prescribed amphetamines, a positive result for 
amphetamines will not exclude the subject. 
6.11 Dispensing Study Drug 
Study drug will be dispensed during the Main Study by designated study staff to subjects at the 
beginning of the Titration Period (Visit 2) and at each clinic visit (except Visit 3) during the 
Titration Period and at the beginning of the Stable-Dose Phase (Visit 14) and the beginning of 
the Double-Blind Randomized-Withdrawal Period (Visit 15) or at alternative intervals if 
necessary to comply with state and local laws and regulations or to resolve logistical issues 
(see Appendix 1, Schedule of Events). 
Rollover Subjects (entering the Open-Label Extension directly from the Main Study) will receive 
open-label JZP-258 at Visit 16 and Re-entry Subjects (completed the Main Study) will receive 
open-label JZP-258 at Visit 19. All subjects will receive study medication at Visit 30 or at 
alternative intervals (e.g., Visits 23, 27, 31, and 32), if necessary to comply with state and local 
laws and regulations or to resolve logistical issues. 
 
 
 
Study drug doses should be prepared with the dosing dispenser (syringe) that is supplied in the 
study drug kit (dosing instructions provided by Jazz Pharmaceuticals). Instructions for dose 
administration of the study drug will be provided to subjects by the site personnel.  
The Investigator or designated pharmacist will maintain accurate records for all study drug 
administered or dispensed. 
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6.12 Efficacy Assessments 
6.12.1 
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 (Appendix 7). Responses range from 
0 = would never doze to 3 = high chance of dozing. Subjects will be asked to complete the ESS 
with regard to the level of sleepiness they experienced over the past 7 days at end of the Stable-
Dose Period (Visit 15) and at the end of the Double-Blind Randomized-Withdrawal Period 
(Visit 16) or Early Termination from the Double-Blind Period. The ESS provides a measure of a 
person’s general level of daytime sleepiness, or their average sleep propensity in daily life. It is a 
validated measure with high specificity and sensitivity for assessing subjective sleepiness (Johns 
1991, Johns 2000, Broderick et al. 2013). 
6.12.2 
Clinician Global Impression of Severity (CGIs) for Narcolepsy Overall  
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 8). The responses of this 
investigator-completed scale range from 1 = normal, no signs of illness to 7 = among the most 
extremely ill subjects. The Investigator, as a trained rater, will rate his/her impression of the 
severity of the subject’s narcolepsy overall at the end of the Stable-Dose Phase (Visit 15) relative 
to his/her experience with this patient population. 
6.12.3 
Clinical Global Impression of Change (CGIc) for Narcolepsy Overall  
The CGIc is a 7-point Likert-type rating scale and a widely used assessment to assess efficacy in 
clinical drug trials. At the end of the Double-Blind Randomized-Withdrawal Period (Visit 16), 
Investigators as trained raters will rate their impression of any change in the severity of the 
subject’s narcolepsy overall (Appendix 9) since the start of the Double-Blind Randomized-
Withdrawal Period (i.e., since the last visit [Visit 15 end of the Stable-Dose Period]) on a 7-point 
scale ranging from 1 = “very much improved” to 7 = “very much worse.” If the subject 
discontinues during the Double-Blind Randomized-Withdrawal Period, the Investigator as a 
trained rater will complete the CGIc for narcolepsy overall at Early Termination (Visit 16).  
6.12.4 
Patient Global Impression of Change (PGIc) for Narcolepsy Overall 
The PGIc is a 7-point Likert-type rating scale and a widely used assessment to assess efficacy in 
clinical drug trials. At the end of the Double-Blind Randomized-Withdrawal Period (Visit 16 or 
Early Termination), subjects will rate the change in their condition on a 7-point scale ranging 
from 1 = “very much better” to 7 = “very much worse’ since the last visit (Visit 15 [end of the 
Stable-Dose Period]) (Appendix 10). If the subject discontinues during the Double-Blind 
Randomized-Withdrawal Period, the subject will complete the PGIc for narcolepsy overall at 
Early Termination (Visit 16). 
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6.12.5 
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). Subjects will complete the SF-36v2 with a one-week recall 
period at the end of the Stable-Dose Period (Visit 15), the end of the Double-Blind Randomized-
Withdrawal Period (Visit 16), or Early Termination from the Double-Blind Period (Appendix 
11). 
6.12.6 
European Quality of Life 5 Dimensions 5 Levels (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 (EuroQol User Guide 
2013). It is applicable to a wide range of health conditions and treatments, it provides a simple 
descriptive profile and a single index value for health status. The EQ-5D-5L includes five levels 
of severity for each of the 5 dimensions of the descriptive system and was developed to improve 
the instrument’s reliability and sensitivity and to reduce ceiling effects. Subjects will complete 
the EQ-5D-5L at the end of the Stable-Dose Period (Visit 15), the end of the Double-Blind 
Randomized-Withdrawal Period (Visit 16), or Early Termination from the Double-Blind Period 
(Appendix 12). 
6.12.7 
Cataplexy Frequency Diary 
Subjects will complete a daily Cataplexy Frequency Diary (Appendix 13) each night prior to 
bedtime, to record the number of cataplexy attacks that they had each day beginning at Visit 2 
through the end of the Double-Blind Randomized-Withdrawal Period. Subjects must have 
completed the Cataplexy Frequency Diary on at least 10 out of the 14 days in the Stable-Dose 
Period occurring prior to the start of the Double-Blind Randomized-Withdrawal Period, or they 
will be discontinued from the study. 
The study staff will review the diary at each study visit and discuss it with the subject at each 
phone contact. 
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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 (defined as Visit 1 and Visit 18 [Re-entry 
Subjects]); (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 narcolepsy are not considered as AEs 
unless there is an exacerbation of the subject’s baseline symptoms at entry into the study. 
(Visit 1 and Visit 18 [subjects who re-enter the study for the Open-Label Extension]). 
• Clinically significant adverse changes from baseline clinical status (Visit 1 and Visit 18 
[subjects who re-enter the study for the Open-Label Extension]) 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 documented. 
For Re-entry Subjects (completed the Main Study), any new clinically significant condition not 
previously recorded as an AE during the Main Study and which occurred prior to obtaining 
informed consent for the Open-Label Extension, is considered medical history and should be 
documented as such (see Section 6.3). 
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. Each AE is to be 
evaluated for duration, severity (Section 6.13.2), seriousness (Section 6.13.3), and causal 
relationship to the study drug or procedure (see Section 6.13.4).  
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6.13.2 
Severity Assessment 
Adverse events will be classified by the Investigator as mild, moderate, severe, life-threatening 
or fatal, as defined below. When the severity of the AE changes over time, the change in severity 
will be recorded on the AE eCRF as a new AE, and the original AE will stop when the new AE 
starts. 
Table 5 
Adverse Event Severity Definitions 
Classification 
Definition 
Mild 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADLa 
Severe 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting age-appropriate self-care 
ADLb  
Life-threatening 
Life-threatening consequences; urgent intervention indicated 
Death 
Death related to AE 
a Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
b Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden 
A Semi-colon indicates ‘or’ within the description of the grade. 
ADL = activities of daily living; AE = adverse event. 
Source: CTCAE, Version [4.03]. 
6.13.3 
Serious Adverse Events (SAEs) 
Serious adverse events (SAEs) must be reported to Jazz Pharmaceuticals or its designee using the 
SAE Reporting form within 24 hours of first knowledge of the event by study personnel. SAE 
Reporting forms and contact information will be provided to the study site. The event must also 
be entered on the AE eCRF in accordance with the eCRF Completion Guidelines. 
An SAE is an AE that fulfills any of the following criteria:  
• 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 in-patient 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 
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• Is an important medical event  
− Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based on appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above in the definition of an SAE.  
− Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in in-patient hospitalization, the development of drug dependency or drug 
abuse, and the occurrence of suicidal ideation. 
− Additionally, any suspected transmission of an infectious agent via a medicinal 
product should be reported as an important medical event. 
 
A hospitalization is NOT considered an SAE if: 
• It is planned prior to subject entering trial or prior to entrance of Open-Label Extension 
(only if subject is re-entering, i.e., completed the main study) 
• It is for social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• It is elective in nature and not related to worsening of an underlying condition 
 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is an SAE.  
“In-patient hospitalization” means the subject has been formally admitted to a hospital for 
medical reasons, for any length of time. Emergency room care without admission to a hospital is 
considered outpatient care.  
Overdose, medication errors, and drug misuse of the study drug are SAEs only if any of the 
seriousness criteria are met.  
The SAE Reporting Form must be completed as thoroughly as possible before transmittal to the 
contact provided on the form. The Investigator should provide his/her assessment of the causality 
(relationship) to study drug and procedure at the time of the 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 Reporting forms must be submitted. 
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6.13.4 
Causal Relationship to Study Drug or Procedure 
The Investigator’s assessment of an AE’s relationship to study drug and to study procedures is 
required. The relationship or association of the study drug or procedure in causing or 
contributing to the AE will be characterized using the following classification and criteria:  
Related or 
Suspected 
to be 
Related to 
Study 
Drug or 
Procedure 
There is a reasonable possibility that the study drug or procedure caused the 
event—i.e., there is evidence to suggest a causal relationship between the study 
drug or procedure and the AE.  
Some temporal relationship exists between the event and the administration of the 
study drug or procedure and the event is unlikely to be explained by the subject’s 
medical condition, other therapies, or accident.  
The event follows a reasonable temporal sequence from administration of the study 
drug or procedure and at least one of the following instances of clinical evidence: 
• 
The event follows a known or suspected response pattern to the study 
drug or procedure. 
• 
The event improves upon stopping the study drug or procedure or 
decreasing the dose (positive dechallenge). 
• 
The event reappears upon repeated exposure, if medically appropriate 
(positive rechallenge). 
Not 
Related to 
Study 
Drug or 
Procedure 
There is not a reasonable possibility or clinical evidence that the study drug or 
procedure caused the event. 
The event can be readily explained by other factors such as the subject’s underlying 
medical conditions, concomitant therapy, or accident; or there is no temporal 
relationship between study drug or procedure and the event. 
 
6.13.5 
Other Immediately Reportable Experiences 
The following immediately reportable experiences may occur during participation in this clinical 
trial and must be reported within 24 hours of first knowledge of the event by study personnel to 
the appropriate Jazz Pharmaceuticals contact or designee: 
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) with a 3-fold or 
greater elevation above the 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 SAEs (Section 6.13.3), the immediately reportable experiences noted above must be 
reported on the SAE Reporting form, which should be completed as thoroughly as possible 
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. These 
experiences must also be entered as AEs on the AE eCRF in accordance with the eCRF 
Completion Guidelines. See Section 6.13.8 for details related to reporting an immediately 
reportable experience of pregnancy. 
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6.13.6 
Adverse Events and Serious Adverse Event Recording and Reporting 
Timeframe 
The Investigator must document all AEs and SAEs that occur during both the Main Study and 
the Open-Label Extension until the Final Study Visit or Early termination, regardless of their 
relationship to study drug or procedure. For those subjects who participate in the Main Study 
only and for Rollover Subject (progress directly into the Open-Label Extension), all AEs and 
SAEs will be documented from the time written informed consent is obtained at Visit 1. For 
Re-entry Subjects (complete the Main Study), all AEs and SAEs for the Open-Label Extension 
will be documented from the time written informed consent is obtained at Visit 18. 
SAEs and immediately reportable experiences must be reported within 24 hours of first 
knowledge of the event by study personnel as described in Section 6.13.3 and Section 6.13.5. 
If an Investigator becomes aware of an SAE within 30 days after the last dose of study drug, the 
event must be documented and reported as described in Section 6.13.3. 
Any SAE assessed as related to study drug or procedure by the Investigator must be reported 
regardless of time after study termination. 
6.13.7 
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. The outcome at the time of the Final Study Visit should be documented. 
If resolved, a resolution date should be provided, and for SAEs, a follow-up SAE Report form 
should 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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6.13.8 
Pregnancy 
Pregnancy of a subject or a male subject’s partner is an immediately reportable experience and 
should be reported within 24 hours of first knowledge of the event by study personnel to the 
appropriate Jazz Pharmaceuticals contact or designee. If a subject or a male subject’s partner 
becomes pregnant any time after the first dose of study drug is taken until 90 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. The pregnancy of a subject or a male subject’s partner should 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. 
6.13.9 
Emergency Unblinding 
A subject’s treatment assignment should only be unblinded when knowledge of the treatment is 
necessary for immediate medical management of the subject. In the case of an immediate 
medical emergency, an Investigator or his/her designee will be able to unblind a subject at any 
time via the IWRS. Every attempt should be made to contact Jazz Pharmaceuticals or its 
designee before unblinding a subject as long as this does not compromise the safety of the 
subject. If a request for unblinding is received from an Investigator, the Medical Monitor will 
discuss with the Investigator the rationale for the request. A comment must be entered in the 
source documentation to specify the reason for unblinding, along with the date on which the code 
was broken and the identity of the person authorizing the unblinding. Subjects for whom the 
blind is broken will be withdrawn from the study. 
6.13.10 Regulatory Reporting 
Jazz Pharmaceuticals or its designee is responsible for reporting relevant SAEs to the relevant 
regulatory authorities, concerned central ethics committees (CECs) and participating 
Investigators, in accordance with ICH guidelines, the US Code of Federal Regulations (CFR), 
the EU Clinical Trial Directive (2001/20/EC) and/or local regulatory requirements. 
The reference safety information for the determination of expectedness for JZP-258 oral solution 
is in the Investigator’s Brochure.  
Suspected unexpected serious adverse reactions (SUSARs) that are fatal or life-threatening will 
be reported to the relevant regulatory authorities, CECs, and participating Investigators no later 
than 7 days after knowledge of such a case, and relevant follow-up information provided within 
an additional 8 days. All other SUSARs (i.e., non-fatal or non-life-threatening) will be reported 
to the relevant regulatory authorities, CECs, and all participating Investigators no later than 
15 days after first knowledge of the event. 
Once a year throughout the study, a report listing of all SUSARs (and SAEs if required by local 
regulation) that have occurred during the period and a report of the subject’s safety will be 
submitted to the applicable authorities and CECs. 
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The subject’s treatment assignment may be unblinded for regulatory reporting purposes. 
Notification of the treatment assignment is only made known to those who require it for safety 
reporting and submission processes. All other individuals involved in the study, including the 
Investigator, will remain blinded to treatment assignment. Subjects for whom the blind is broken 
for this reason will not be withdrawn from the study. 
Reporting of SAEs by the Investigator to his or her local ethics committee will be done in 
accordance with the standard operations procedures and policies of the ethics committee. 
Adequate documentation must be maintained showing that the ethics committee was properly 
notified.  
6.14 Removal of Subjects from the Trial or Study Drug 
6.14.1 
Reasons for Early Terminations 
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 ULN of ALT or 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 > 176 µmol/L 
• Positive alcohol screen 
• Positive urine drug screen 
• Positive pregnancy test 
 
For all subjects who prematurely discontinue from the Main Study, an attempt should be made to 
perform all early termination assessments (same assessments as those performed at the final 
study visit). Subjects should be asked to return 2 weeks later for a safety follow-up visit.  
The specific reason for the discontinuation should be documented on the termination eCRF. If a 
subject withdraws informed consent, the specific reason for withdrawing the informed consent 
should be stated. 
Adverse events resulting in termination will be followed to the satisfactory resolution and 
determination of outcome as ascertained by the Investigator (and/or Jazz Pharmaceuticals or its 
designee). The data will be recorded on the appropriate eCRF. 
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For all subjects who prematurely discontinue from the Open-Label Extension, an attempt should 
be made to perform all early termination assessments (same assessments as those performed at 
the final study visit). Subjects should be asked to return 2 weeks later for a safety follow-up visit. 
6.14.2 
Handling of Early Terminations 
If a subject terminates early from the study, either at his or her request or at the Investigator’s 
discretion, the Investigator will record the reason(s) for early termination on the relevant eCRF 
page and notify Jazz Pharmaceuticals immediately. All subjects who terminate from the study 
early should undergo all final study visit assessments. Early termination subjects from the Main 
Study should complete Visits 16 and 17. While early termination subjects from the Open-Label 
Extension should complete Visits 33 and 34. 
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. 
6.14.3 
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 in narcolepsy (Johns 1991, Johns 2000; Broderick et al. 2013). Additionally, the 
CGIc, PGIc, SF-36v2, and the EQ-5D-5L 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-258. 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) and the PHQ-9 has been shown 
to facilitate monitoring and the assessment of symptom severity (Kroenke K et al. 2010). 
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7 
STUDY ACTIVITIES 
7.1 
MAIN STUDY 
Procedures for all visits and phone contacts are provided in this section and also detailed in 
Appendix 1.1. The Investigator may opt to have the subject attend an unscheduled visit, if 
deemed necessary, at any time during the study. 
7.1.1 
Screening Period 
Visit 1 – Days –30 to -1 (The Screening Visit window may be extended for an additional 
2 weeks to complete all screening activities, with permission of the Medical Monitor.)  
Prior to any study activity informed consent (ICF) will be obtained. 
• Review the inclusion and exclusion criteria. 
• Obtain demographics and a medical history, including past (prior to any narcolepsy 
treatment) and current symptoms of narcolepsy.  
• Record all prior and concomitant medications, including OTC medications, health, and 
dietary supplements taken during the 30 days before screening; also record any 
medications used for the treatment of narcolepsy since diagnosis. 
• Perform a physical examination including a full examination of body systems (excluding 
a full genitourinary exam) and a brief neurological examination. 
• Record height and weight in ordinary indoor clothes (without shoes).  
• Obtain vital signs (systolic and diastolic blood pressure, heart rate and respiratory rate, 
and body temperature) in the seated position after the subject has been resting for 
5 minutes. 
• Obtain a 12-lead ECG after the subject has been resting supine for at least 5 minutes. 
• Administer the: 
− C-SSRS Baseline/screening version. 
− PHQ-9. 
• Obtain fasting blood samples for serum chemistry, hematology and thyroid stimulating 
hormone (TSH) tests including a serum pregnancy test for all females of childbearing 
potential (see Table 3 footnote [Section 6.10.1] for definitions of childbearing potential). 
• Obtain a urine sample for urinalysis. 
• Perform alcohol screen and urine drug screen. 
• Provide a light breakfast after blood samples are collected (optional depending on 
screening procedure scheduling). 
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• When necessary, a PSG may be performed, with the approval of the Jazz 
Pharmaceuticals’ Medical Monitor, to evaluate the subject for evidence of sleep 
disordered breathing, if the subject has not been adequately evaluated prior to study 
entry. In addition, a PSG and multiple sleep latency test (MSLT) may also be performed, 
if necessary, with approval of the Jazz Pharmaceuticals’ Medical Monitor for diagnosis 
of narcolepsy. The PSG and MSLT will be performed according the study center’s 
standard procedures. 
• After screening procedures have been completed and eligibility criteria have been 
confirmed, provide eligible subjects with instructions on how to discontinue any excluded 
medications.  
• Schedule the Day 1 visit after the Investigator has thoroughly reviewed results of all 
screening procedures and has confirmed all eligibility criteria. 
Rescreening 
In the Main Study, subjects may be allowed to rescreen (one time) if they previously did not 
meet all eligibility requirements. Rescreening may occur following resolution of transient 
exclusionary conditions or stabilization of conditions that were exclusionary in the unstable state 
(e.g., unstable hypothyroidism) and is permitted only with the permission of the Medical 
Monitor. 
Subjects who are approved for rescreening must be re-consented and repeat the screening 
procedures described above in Section 7.1.1. For subjects who are being rescreened, a repeat 
PSG is not required (if previously done) providing the results of the previous PSG meet the 
current inclusion/exclusion/criteria. 
7.1.2 
Open-Label Optimized Treatment and Titration Phase 
7.1.2.1 
Week 1 to the end of Week 12 (for all subjects 12 weeks) 
For the purposes of describing the procedures during this phase of the study the subject’s 
cataplexy treatment status at study entry will be designated as follows: 
• Pre-randomization Group 1: Subjects treated with Xyrem alone at study entry.  
• Pre-randomization Group 2: Subjects treated with Xyrem and an additional 
anticataplectic at study entry.  
• Pre-randomization Group 3: Subjects treated with a non-Xyrem anticataplectic at study 
entry.  
• Pre-randomization Group 4: Subjects not being treated with any agent with 
anticataplectic properties at screening.  
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7.1.2.2 
Day 1 Visit 2  
After a subject has successfully completed the screening procedures, they will return to the 
investigative site after washout of any excluded medications. 
• Assess if there are any updates to the subject’s medical history (Section 6.3).  
• Review inclusion and exclusion criteria. 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain a blood sample for electrolytes (Na, K, Ca, and Mg). 
• Obtain a urine sample for a pregnancy test for all females of childbearing potential (see 
Table 3 footnote [Section 6.10.1] for definitions of childbearing potential). 
• Perform drug (urine) and alcohol screen.  
• Obtain vital signs (systolic and diastolic blood pressure, heart rate and respiratory rate, 
and body temperature), in the seated position after the subject has been resting for 
5 minutes. 
• Record all AEs that occurred since the last visit. 
• Record all concomitant medications that were taken since the last visit. 
• Record the date(s) that excluded medications were discontinued on the concomitant 
medication eCRF (for enrolled subjects). 
• Administer: 
− C-SSRS Since Last Visit version. 
− PHQ-9. 
• Dispense Cataplexy Frequency Diary and instruct on use. 
• Dispense study drug and provide dosing instruction for conversion/titration 
(Section 5.1.1.3):  
− 
Pre-randomization Groups 1 and 2: gram to gram straight conversion from Xyrem to 
JZP-258. Subjects are required to be on this dose for a minimum of 2 weeks. 
− 
Pre-randomization Group 3 and 4: begin titration of JZP-258.  
• Dispense Dosing Diary. 
• Schedule the next clinic visit in 1 week. 
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7.1.2.3 
Optimized Treatment and Titration Period 
Pre-randomization Groups 1 and 2 will have a phone contact at Week 1 unless the Investigator 
elects to assess the subject in the clinic; if a clinic visit is elected all applicable clinic visit 
procedures listed below under Clinic Visit 3 will be performed. Pre-randomization Groups 3 
and 4 will be assessed at a clinic visit at Week 1. 
PHONE CONTACT VISIT 3 – END OF WEEK 1 FOR PRE-RANDOMIZATION GROUPS 1 AND 2 
• Record all AEs that occurred since the last visit on the AE eCRF. 
• Record all concomitant medications that were taken since the last visit on the 
concomitant medications eCRF. 
• Discuss the frequency of cataplexy attacks with the subject and confirm that the 
Cataplexy Frequency Diary is being completed. 
• Discuss dosing with the subject and confirm compliance; confirm that the Dosing Diary 
is being completed. 
• Confirm that anticataplectic medication usage is being completed on the concomitant 
medications eCRF (Group 2 only). Assess control of cataplexy, EDS and tolerability to 
current dose. 
• Instruct subjects to continue the same JZP-258 dose for the next week. 
• Schedule the Week 2 Phone Contact (Visit 4). 
CLINIC VISIT 3 – END OF WEEK 1 FOR PRE-RANDOMIZATION GROUPS 3 AND 4 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain vital signs (systolic and diastolic blood pressure, heart rate and respiratory rate, 
and body temperature), in the seated position after the subject has been resting for 
5 minutes. 
• Obtain a urine pregnancy test for all females of childbearing potential (Section 6.10.1). 
• Perform alcohol screen and urine drug screen.  
• Record all AEs that occurred since the last visit on the AE eCRF. 
• Record all concomitant medications that were taken since the last visit on the 
concomitant medications eCRF. 
• Administer C-SSRS Since Last Visit version.  
• Review Cataplexy Frequency Diary for completeness. 
• Review the Dosing Diary for compliance with dosing. 
• Assess control of cataplexy, EDS and tolerability to current dose. 
• Provide instructions for continued dosing with JZP-258 until the next phone contact. 
 (If Pre-randomization Groups 1 and 2 attend a clinic visit at Week 1: instruct subjects 
to continue the same JZP-258 dose for the next week.) 
 Pre-randomization Groups 3 and 4: continue to titrate JZP-258 dose, as needed. 
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• Schedule the Week 2 Phone Contact (Visit 4). 
PHONE CONTACT –END OF WEEK 2, 3, 5, 6, 7, 9 
Visits 4, 5, 7, 8, 9, and 11 
• Record all AEs that occurred since the last visit or phone contact on the AE eCRF. 
• Record all concomitant medications that were taken since the last visit or phone contact 
on the concomitant medications eCRF. 
• Administer the PHQ-9 (Weeks 2, and 6 only). 
• Discuss the frequency of cataplexy attacks with the subject and confirm that the 
Cataplexy Frequency Diary is being completed. 
• Discuss dosing with the subject and confirm compliance; confirm that the Dosing Diary 
is being completed. 
• Discuss tapering of anticataplectics with the subject (Groups 2 and 3 only). 
• Assess control of cataplexy, EDS and tolerability to current dose. 
− All Pre-randomization Groups: If needed, continue titration of JZP-258 and provide 
instructions for dosing (titration up or down or staying on the current dose) until the 
next phone contact or clinic visit. JZP-258 dose adjustments are not allowed after 
Week 10. 
− Pre-randomization Groups 2 and 3: If further JZP-258 titration is not needed and the 
subject has remained on the same JZP-258 dose for the previous 2 weeks begin taper 
of the non-indicated anticataplectic.  
− Pre-randomization Groups 2 and 3: When taper of non-Xyrem anticataplectic is 
initiated, assess taper progress and advise subject on taper instructions, as appropriate. 
Anticataplectic taper must be completed by Week 10. 
• Schedule the next phone contact or clinic visit. 
CLINIC VISITS - END OF WEEK 4 AND 8 – VISITS 6 AND 10 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain vital signs (systolic and diastolic blood pressure, heart rate and respiratory rate, 
and body temperature), in the seated position after the subject has been resting for 
5 minutes.  
• Obtain a blood sample for electrolytes (Na, K, Ca, and Mg). 
• Obtain a urine pregnancy test for all females of childbearing potential (Section 6.10.1). 
• Perform alcohol screen and urine drug screen. 
• Record all AEs that occurred since the last phone contact on the AE eCRF. 
• Record all concomitant medications that were taken since the last phone contact on the 
concomitant medications eCRF. 
• Administer: 
− C-SSRS Since Last Visit version.  
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− PHQ-9. 
• Review Cataplexy Frequency Diary for completeness. 
• Review the Dosing Diary for compliance with dosing. 
• Assess control of cataplexy, EDS and tolerability to current dose. 
− If needed, continue titration of JZP-258 and provide instructions for dosing (titration 
up or down or staying on the current dose) until the next phone contact or clinic visit. 
− Pre-randomization Groups 2 and 3 only: 
− If the subject’s dose of JZP-258 has been determined as optimized over the 
previous 2 weeks, begin the taper of anticataplectic medication over the following 
2 weeks. 
− When initiated, assess taper of non-Xyrem anticataplectic and advise subject on 
taper instructions as appropriate.  
• Collect study drug and assess compliance.  
• Dispense study drug.  
• Schedule the next phone contact. 
PHONE CONTACT – END OF WEEK 10  
Visit 12 
• Record all AEs that occurred since the last visit or phone contact on the AE eCRF 
• Record all concomitant medications that were taken since the last visit or phone contact 
on the concomitant medications eCRF. 
• Administer the PHQ-9.  
• Discuss the frequency of cataplexy attacks with the subject and confirm that the 
Cataplexy Frequency Diary is being completed. 
• Assess control of cataplexy, EDS and tolerability to current dose. 
• Discuss dosing with the subject and confirm compliance; confirm that the Dosing Diary 
is being completed. 
• Confirm that the anticataplectic has been discontinued (Groups 2 and 3 only); if the 
anticataplectic has not been discontinued by Week 10, schedule the subject for an Early 
Termination visit. 
• Instruct the subject to continue the current dose of JZP-258 for the next 2 weeks. 
• Schedule the Week 11 (Visit13) phone contact. 
PHONE CONTACT –END OF WEEK 11 
Visit 13 
• Record all AEs that occurred since the last visit or phone contact on the AE eCRF. 
• Record all concomitant medications that were taken since the last visit or phone contact 
on the concomitant medications eCRF. 
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• Discuss the frequency of cataplexy attacks with the subject and confirm that the 
Cataplexy Frequency Diary is being completed. 
• Assess control of cataplexy, EDS and tolerability to current dose. 
• Confirm that the subject has not taken anticataplectics since the last phone contact. 
• Discuss dosing with the subject and confirm compliance; confirm that the Dosing Diary 
is being completed. 
• Confirm that the subject has continued on an unchanged JZP-258 dose over the past week 
and instruct the subject to continue the current dose of JZP-258 for the next week. 
• Schedule Visit 14 (Week 12) clinic visit to begin the Stable-Dose Period. 
7.1.3 
End of Titration Period and Start of Stable-Dose Period 
End of Week 12 – Visit 14 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain vital signs (systolic and diastolic blood pressure, heart rate and respiratory rate, 
and body temperature), in the seated position after the subject has been resting for 
5 minutes. 
• Obtain a urine pregnancy test for all females of childbearing potential (Section 6.10.1). 
• Obtain a blood sample for electrolytes (Na, K, Ca, and Mg). 
• Perform alcohol screen and urine drug screen. 
• Administer: 
− C-SSRS Since Last Visit version.  
− PHQ-9. 
• Review Cataplexy Frequency Diary for completeness. 
• Review the Dosing Diaries for compliance with dosing. 
• Record all AEs that occurred since the last visit or phone contact on the AE eCRF 
(Section 6.13).  
• Record all concomitant medications that were taken since the last visit or phone contact 
on the concomitant medications eCRF. 
• Collect any remaining study drug from the Titration Phase and assess compliance. 
• Confirm that a stable dose has been reached (i.e., a dose that achieves an optimal clinical 
benefit with adequate control of cataplexy and EDS while maintaining tolerability) and 
has remained unchanged for the last 2 weeks of the Optimized Treatment and Titration 
Period. 
• Dispense study drug for the Stable-Dose Phase and provide instruction for how the 
subject should begin taking study drug on that evening. 
• Schedule the next Clinic Visit (Visit 15). 
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7.1.4 
End of Stable-Dose Period/Beginning of the Double-Blind Randomized-
Withdrawal Period 
End of Week 14 – Visit 15 
• Record weight in ordinary indoor clothes (without shoes). 
• Obtain vital signs (systolic and diastolic blood pressure, heart rate and respiratory rate, 
and body temperature) after the subject has been resting for at least 5 minutes. 
• Obtain a blood sample for electrolytes (Na, K, Ca, and Mg). 
• Obtain a urine pregnancy test for all females of childbearing potential (Section 6.10.1). 
• Perform alcohol screen and urine drug screen. 
• Review Cataplexy Frequency Diary for completeness. Subjects must have completed the 
Cataplexy Frequency Diary on at least 10 out of the 14 days in the Stable-Dose Period, or 
they will be discontinued from the study.  
• Review the Dosing Diaries for completeness and compliance with dosing. Subjects must 
have completed the Study Drug Dosing Diary on at least 10 out of the 14 days in the 
Stable-Dose Period and must have indicated that they were compliant with dosing on at 
least 10 of the 14 days, or they will be discontinued from the study. 
• Collect remaining study drug from Stable-Dose Period and assess compliance versus 
Dosing Diary. 
• Record all AEs that occurred since the last visit on the AE eCRF.  
• Record all concomitant medications that were taken since the last visit on the 
concomitant medications eCRF. 
• Complete CGIs for narcolepsy overall (current condition).  
• Administer the following:  
− ESS  
− SF-36 
− EuroQoL 
− PHQ-9 
− C-SSRS Since Last Visit version.  
• Randomize subject or assign open-label JZP-258 (access IWRS for assignment). 
− Note: subjects will not require randomization if Jazz decides to stop enrollment 
and randomization based on DMC recommendation as all subjects will be 
assigned open-label JZP-258 during the Double-Blind Randomized-Withdrawal 
Period. 
• Dispense study drug and provide instructions for dose administration.  
• Schedule the next visit (Visit 16) in 2 weeks. 
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7.1.5 
End of Double-Blind Randomized-Withdrawal Period or Early Termination 
End of Week 16 – Visit 16 
• Record weight in ordinary indoor clothes (without shoes). 
• Obtain vital signs (systolic and diastolic blood pressure, heart rate and respiratory rate, 
and body temperature) after the subject has been resting for at least 5 minutes. 
• Perform a physical examination including a full examination of body systems (excluding 
a full genitourinary exam) and a brief neurological examination. 
• Obtain fasting blood samples for serum chemistry (including Na, K, Ca, and Mg), 
hematology. 
• Collect urine for urinalysis and perform urine drug screen. 
• Perform alcohol screen. 
• Provide for a light breakfast, if needed. 
• Obtain a 12-lead ECG after the subject has been resting supine for at least 5 minutes. 
• Complete CGIc for narcolepsy overall.  
• Have subject complete the PGIc. 
• Obtain a urine pregnancy test for all females of childbearing potential (Section 6.10.1). 
• Administer the following:  
− ESS  
− SF-36 
− EuroQoL 
− PHQ-9 
− C-SSRS Since Last Visit version. 
• Review Cataplexy Frequency Diary for completeness. 
• Review the Dosing Diaries for completeness and compliance with dosing. 
• Collect remaining study drug from Double-Blind Randomized-Withdrawal Period and 
assess compliance versus Dosing Diary. 
• Record all AEs that occurred since the last visit on the AE eCRF.  
• Record all concomitant medications that were taken since the last visit on the 
concomitant medications eCRF. 
• Schedule the Safety Follow-up Visit in 2 weeks if not enrolling into the Open-Label 
Extension. 
• Instruct subject to follow-up with their healthcare provider regarding the resumption of 
any medications that were discontinued prior to study participation if not enrolling into 
the Open-Label Extension. 
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If a subject is withdrawn before completing the study, the reason for withdrawal will be entered 
on the appropriate eCRF. The specific reason for the withdrawal should be documented on the 
eCRF. For instance, rather than stating “withdrew informed consent”, the specific reason for 
withdrawing the informed consent should be stated. Whenever possible and reasonable, the 
evaluations that were to be conducted during the final study visit should be performed at the time 
of premature discontinuation.  
It is vital to obtain follow up data on any subject who terminated because of an AE, abnormal 
laboratory test, or ECG finding. In any case, every effort must be made to ensure safety follow 
up procedures are completed. 
7.1.6 
Safety Follow-up Visit 
End of Week 18 – Visit 17 
Visit is not required if subject is enrolling directly into Open-Label Extension at Visit 16. 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain vital signs (systolic and diastolic blood pressure, heart rate and respiratory rate, 
and body temperature) after the subject has been resting for at least 5 minutes. 
• Obtain a urine pregnancy test for all females of childbearing potential (Section 6.10.1). 
• Administer:  
− C-SSRS Since Last Visit version 
− PHQ-9. 
• Record all AEs that occurred since the last visit on the AE eCRF. 
• Record all concomitant medications that were taken after the last visit on the concomitant 
medications eCRF. 
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.  
7.2 
Open-Label Extension 
Procedures for all visits and phone contacts are provided in this section and also detailed in 
Appendix 1.2. The Investigator may opt to have the subject attend an unscheduled visit, if 
deemed necessary, at any time during the study. 
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7.2.1 
Entrance Period to Open-Label Extension 
Prior to any study activity informed consent (ICF) for the Open-Label Extension will be 
obtained.  
Rollover subjects (entering directly into the Open-Label Extension from the Main Study) 
will have additional procedures done at Visit 16 (Day 1 of the Open-Label Extension) (see 
Section 7.2.1.1). Re-entry subjects (completed the Main Study and are re-entering the study at 
the Open-Label Extension) will undergo screening at Visit 18 and Day 1 procedures for the 
Open-Label Extension at Visit 19.  
7.2.1.1 
Visit 16 (Additional Procedures) – Day 1 of the Open-Label Extension 
(Rollover Subjects only) 
This visit is only for those subjects entering directly into the Open-Label Extension from the 
Main Study. They will undergo the following additional Visit 16 procedures: 
• Dispense study drug and provide instructions for dose administration.  
• Schedule the next weekly (Visit 20) phone call. 
7.2.1.2 
Visit 18 (Screening for Open-Label Extension) – Days –30 to -1 
(Re-entry Subjects only) 
(The Screening Visit window may be extended for an additional 2 weeks to complete all 
screening activities, with permission of the Medical Monitor.) This visit is for those subjects who 
are re-enrolling after completing the Main Study. 
• Review the inclusion and exclusion criteria. 
• Reconfirm medical history, including past (prior to any narcolepsy treatment) and current 
symptoms of narcolepsy. Any new clinically significant condition not previously 
recorded as an AE during the Main Study and which occurred prior to obtaining informed 
consent for the Open-Label Extension will be recorded as medical history. 
• Review all prior and concomitant medications, including OTC medications, health, and 
dietary supplements taken and any medications used for the treatment of narcolepsy since 
completion of the Main Study. 
• Perform a physical examination including a full examination of body systems (excluding 
a full genitourinary exam) and a brief neurological examination. 
• Obtain weight in ordinary indoor clothes (without shoes).  
• Obtain vital signs (systolic and diastolic blood pressure, heart rate and respiratory rate, 
and body temperature) in the seated position after the subject has been resting for at least 
5 minutes. 
• Obtain fasting blood samples for serum chemistry, hematology and TSH  
• Obtain a urine sample for urinalysis. 
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• Perform alcohol screen and urine drug screen. 
• Obtain a serum pregnancy test for all females of childbearing potential (Section 6.10.1). 
• Obtain a 12-lead ECG after the subject has been resting supine for at least 5 minutes. 
• Provide a light breakfast after blood samples are collected (optional depending on 
screening procedure scheduling). 
• Administer the: 
− C-SSRS Since Last Visit version. 
− PHQ-9. 
• After screening procedures have been completed and eligibility criteria have been 
confirmed, provide eligible subjects with instructions on how to discontinue any excluded 
medications.  
• Record all concomitant medications that were taken since the last visit on the 
concomitant medications eCRF. 
• Schedule the Day 1 visit after the Investigator has thoroughly reviewed results of all 
screening procedures and has confirmed all eligibility criteria. 
7.2.1.3 
Visit 19 – Day 1 of the Open-Label Extension (Re-entry Subjects only) 
This visit is only for those subjects who completed both Visits 16 and 17 during the Main Study. 
• Review the inclusion and exclusion criteria. 
• Reconfirm medical history, including past (prior to any narcolepsy treatment) and current 
symptoms of narcolepsy.  
• Obtain weight in ordinary indoor clothes (without shoes).  
• Obtain vital signs (systolic and diastolic blood pressure, heart rate and respiratory rate, 
and body temperature) in the seated position after the subject has been resting for at least 
5 minutes. 
• Obtain a blood sample for electrolytes (Na, K, Ca, and Mg).  
• Perform alcohol screen and urine drug screen. 
• Obtain a urine pregnancy test for all females of childbearing potential (Section 6.10.1). 
• Administer the: 
− C-SSRS Since Last Visit version. 
− PHQ-9. 
• Record all AEs that occurred since the last visit on the AE eCRF.  
• Record all concomitant medications that were taken since the last visit on the 
concomitant medications eCRF. 
• Dispense study drug and provide instructions for dose administration.  
• Schedule the next phone contact in 1 week. 
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7.2.2 
Open-Label Extension Period (Visits 20 to 32) 
Subjects will include: 
• Subjects who enter the Open-Label Extension directly from the Main Study (at Visit 16) 
• Subjects who enter the Open-Label Extension after completion of the Main Study 
(at Visit 18) on Xyrem (alone or with an additional anticataplectic) 
• Subjects who enter the Open-Label Extension after completion of the Main Study 
(at Visit 18) on non-Xyrem anticataplectic or not currently receiving treatment 
7.2.2.1 
Phone Contact –End of Week 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 
Visits 20, 21, 22, 23, 24, 25, 26, 27, 28, and 29 
• Assess tolerability, discuss dosing, and confirm compliance 
• Record all AEs that occurred since the last visit or phone contact on the AE eCRF. 
• Record all concomitant medications that were taken since the last visit or phone contact 
on the concomitant medications eCRF. 
• Schedule the next phone contact or clinic visit. 
7.2.2.2 
Clinic Visit 30 – Week 12 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain vital signs (systolic and diastolic blood pressure, heart rate and respiratory rate, 
and body temperature), in the seated position after the subject has been resting for at least 
5 minutes. 
• Obtain a blood sample for electrolytes (Na, K, Ca, and Mg). 
• Perform alcohol screen and urine drug screen.  
• Collect any remaining study drug from prior visits and assess compliance. 
• Assess tolerability, discuss dosing. 
• Dispense study drug and provide instructions for dose administration. 
• Obtain a urine pregnancy test for all females of childbearing potential (Section 6.10.1). 
• Administer the:  
− C-SSRS Since Last Visit version. 
− PHQ-9 
• Record all AEs that occurred since the last visit or phone contact on the AE eCRF. 
• Record all concomitant medications that were taken since the last visit or phone contact 
on the concomitant medications eCRF. 
• Schedule the Week 16 and 20 Phone Contacts (Visits 31 and 32). 
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7.2.2.3 
Phone Contact –End of Weeks 16 and 20 
Visits 31 and 32 
• Assess tolerability, discuss dosing, and confirm compliance 
• Record all AEs that occurred since the last visit or phone contact on the AE eCRF. 
• Record all concomitant medications that were taken since the last visit or phone contact 
on the concomitant medications eCRF. 
• Schedule the next phone contact or clinic visit. 
7.2.3 
End of Open-Label Extension or Early Termination 
End of Week 24 – Visit 33 (or Early Termination) 
• Perform a physical examination including a full examination of body systems (excluding 
a full genitourinary exam) and a brief neurological examination. 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain vital signs (systolic and diastolic blood pressure, heart rate and respiratory rate, 
and body temperature) after the subject has been resting for at least 5 minutes. 
• Obtain fasting blood samples for serum chemistry (including Na, K, Ca, and Mg), 
hematology. 
• Collect urine for urinalysis and perform urine drug screen. 
• Perform alcohol screen. 
• Provide for a light breakfast, if needed. 
• Obtain a 12-lead ECG after the subject has been resting supine for at least 5 minutes. 
• Obtain a urine pregnancy test for all females of childbearing potential (Section 6.10.1). 
• Administer the:  
− C-SSRS Since Last Visit version. 
− PHQ-9 
• Record all AEs that occurred since the last visit or phone contact on the AE eCRF.  
• Record all concomitant medications that were taken since the last visit on the 
concomitant medications eCRF. 
• Collect remaining study drug from Open-Label Extension and assess compliance. 
• Instruct subject to follow-up with their healthcare provider regarding the resumption of 
any medications that were discontinued prior to study participation. 
• Schedule the Safety Follow-up Visit in 2 weeks. 
If a subject is withdrawn before completing the study, the reason for withdrawal will be entered 
on the appropriate eCRF. The specific reason for the withdrawal should be documented on the 
eCRF. For instance, rather than stating “withdrew informed consent”, the specific reason for 
withdrawing the informed consent should be stated. Whenever possible and reasonable, the 
evaluations that were to be conducted during the final study visit should be performed at the time 
of premature discontinuation.  
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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 ensure safety follow 
up procedures are completed. 
7.2.4 
Safety Follow-up Visit 
End of Week 26 – Visit 34 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain vital signs (systolic and diastolic blood pressure, heart rate and respiratory rate, 
and body temperature) after the subject has been resting for at least 5 minutes. 
• Obtain a urine pregnancy test for all females of childbearing potential (Section 6.10.1). 
• Administer:  
− C-SSRS Since Last Visit version 
− PHQ-9. 
• Record all AEs that occurred since the last visit on the AE eCRF. 
• Record all concomitant medications that were taken since the last visit on the 
concomitant medications eCRF.  
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.  
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8 
QUALITY CONTROL AND ASSURANCE 
The study will be conducted according to GCP guidelines and according to national law. Quality 
audits may be performed at the discretion of Jazz Pharmaceuticals. 
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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
Analyses may be provided either across the study or by study period (i.e., Optimized Treatment 
and Titration, Stable-Dose, Double-Blind Randomized-Withdrawal, and Open-Label Extension 
Periods) as appropriate to describe the efficacy and safety of JZP-258, and will be detailed in the 
statistical analysis plan (SAP). In general, for the Optimized Treatment and Titration, Stable-
Dose, and Open-Label Extension Periods, results will be summarized by Pre-randomization 
Group and overall, and for the Double-Blind Randomized-Withdrawal Period results will be 
summarized by treatment group.  
Categorical variables will be reported as frequency and percent. Continuous variables will 
be reported as number of subjects, mean, standard deviation (SD), or standard error (SE), 
median, minimum and maximum. All summaries, statistical analyses, and individual subject data 
listings described below will be completed using Version 9.3 or later of the SAS Statistical 
Analysis System (SAS Institute, Inc. Cary, NC). 
9.2 
Tests of Hypotheses and Significance Levels 
The primary objective of this study is to evaluate the efficacy of JZP-258 compared to placebo 
on the change in weekly cataplexy attacks from the two weeks of the Stable-Dose Period to the 
two weeks of the Double-Blind Randomized-Withdrawal Period. The key secondary objective is 
to evaluate the efficacy of JZP-258 compared to placebo on the change in ESS score from the 
end of the Stable-Dose Period to the end of the Double-Blind Randomized-Withdrawal Period. 
Subjects who are randomized to continue JZP-258 in the Double-Blind Randomized-Withdrawal 
Period will be treated as a single group regardless of the dose of JZP-258 received. Thus, there 
will be no multiplicity issues with respect to multiple doses for hypotheses testing. 
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A hierarchical group sequential testing strategy will be used to test the primary and key 
secondary endpoints during the 
 analyses as described in Section 9.14 and 
Section 9.15, with the family-wise Type I error rate controlled at 0.05 for two-sided testing 
across both endpoints. 
9.3 
Determination of Sample Size 
Up to 185 subjects will be enrolled in the study to ensure a minimum of 130 subjects (65 subjects 
per treatment group) enter the Double-Blind Randomized-Withdrawal Period. This includes at 
least 50 subjects on Xyrem, and 60 subjects using Xyrem plus other anticataplectics or non-
Xyrem anticataplectics alone, as applicable. 
A sample size of 65 subjects randomized per treatment group will provide at least 90% power to 
detect a difference in the change in mean weekly cataplexy attacks, from the Stable-Dose Period 
to the Double-Blind Randomized-Withdrawal Period, of 17.5 between JZP-258 and placebo. 
This assumes common SD of 30 and a two-sided significance level of 0.05 using a t-test. 
Assuming a 30% dropout rate prior to randomization, approximately 185 subjects will be 
enrolled to ensure that a minimum of 130 subjects enter the Double-Blind Randomized-
Withdrawal Period. Assumptions were conservatively based on previously completed Xyrem 
studies GHB-2, OMC-SXB-15, and OMC-SXB-21 and account for study design. From these 
3 studies, the mean weekly reduction in cataplexy attacks of Xyrem compared to placebo 
(common SD) ranged from approximately 10 (30) to 16 (28). 
9.4 
Analysis Populations 
The Safety Population will include all subjects who took at least one dose of study medication. 
Safety populations will also be defined for each study period (i.e., Optimized Treatment and 
Titration, Open-Label Stable-Dose, Double-Blind Randomized-Withdrawal, and Open-Label 
Extension periods) for by-period analyses. These populations will be used for safety evaluations 
and efficacy summaries.  
The Efficacy Population will include all subjects who are randomized to JZP-258 or placebo, 
who received at least 1 dose of study drug during the Double-Blind Randomized-Withdrawal 
Period and have at least one set of post-baseline efficacy assessments. This population will be 
used as the main analysis population for the primary and secondary efficacy endpoints. 
9.5 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized descriptively for the 
Safety Population, Efficacy Population, and the Safety Population from the Open-Label 
Extension period. For the Efficacy Population, results will be provided by randomized treatment 
group.  
9.6 
Handling of Dropouts and Missing Data 
Subjects who drop out of the study will not be replaced. Methods of addressing missing efficacy 
data are described in Section 9.10. 
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9.7 
Pooling of Investigation Centers 
Data from all investigational centers will be pooled. Data may also be pooled by region as 
appropriate for exploratory analyses. 
9.8 
Efficacy Endpoints 
9.8.1 
Primary Efficacy Endpoint 
• Change in weekly number of cataplexy attacks from the two weeks of the Stable-Dose 
Period to the two weeks of the Double-Blind Randomized-Withdrawal Period 
9.8.2 
Key Secondary Efficacy Endpoint 
• Change in the ESS score from the end of the Stable-Dose Period to the end of the 
Double-Blind Randomized-Withdrawal Period 
9.8.3 
Other Secondary Efficacy Endpoints 
• PGIc for narcolepsy overall at the end of the Double-Blind Randomized-Withdrawal 
Period 
• CGIc for narcolepsy overall at the end of the Double-Blind Randomized-Withdrawal 
Period 
• Change in QoL (SF-36) from the end of the Stable-Dose Period to the end of the Double-
Blind Randomized-Withdrawal Period 
• Change in QoL (EuroQol 5 Dimensions Self-Report Questionnaire) from the end of the 
Stable-Dose Period to the end of the Double-Blind Randomized-Withdrawal Period 
9.9 
Safety Endpoints 
The safety and tolerability evaluations will be assessed by the occurrence of and/or changes in: 
• Treatment-emergent adverse events (TEAEs) 
• Vital signs 
• Physical examinations (including weight) 
• 12-lead ECGs 
• Clinical laboratory tests (chemistry, hematology, and urinalysis) 
• C-SSRS for emergent suicidality 
• PHQ-9 for emergent depression 
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9.10 Efficacy Analyses 
Efficacy analyses will be performed with the Efficacy Population by randomized treatment 
group.  
Efficacy assessments in general will be comparisons of the measurement(s) made during or at the 
end of the 2 weeks of the Stable-Dose Period compared with the 2 weeks or the end of the 
Double-Blind Randomized-Withdrawal Period.  
A hierarchical group sequential testing strategy, described in Section 9.14 and Section 9.15, will 
be used to control the family-wise Type I error rate at the 0.05 significance level for two-sided 
testing across the primary and key secondary endpoints. All other efficacy endpoints will be 
tested without multiplicity adjustments and nominal p-values provided. 
Sensitivity analyses including use of imputation methods, such as multiple imputations for 
missing data, on the primary and key secondary efficacy endpoints will be used to assess 
robustness. These analyses and methods will be described in the SAP. 
9.10.1 
Primary Efficacy Analysis 
For the primary endpoint, the change in the weekly number of cataplexy attacks from the 
2 weeks of the Stable-Dose Period to the 2 weeks of the Double-Blind Randomized-Withdrawal 
Period will be assessed. For subjects with at least one day of cataplexy attack data, the weekly 
number of cataplexy attacks will be the average number of daily attacks from days with non-
missing data within the 2 week period, and then multiplied by 7.  
An analysis of covariance (ANCOVA) model will be used to assess the endpoint. The SAS 
procedure PROC GLM will be used to carry out the analysis. The model will include treatment 
group and Pre-randomization group as fixed effects. The weekly number of cataplexy attacks 
during the Stable-Dose Period will be included in the model as a covariate. The estimate for the 
treatment difference of JZP-258 versus placebo and the 95% CIs will be presented. The 
normality assumption of the ANCOVA model will be examined by residual analysis using the 
Shapiro-Wilk test. If the normality assumption is considered violated at the 0.05 significance 
level, a non-parametric ANCOVA with the data replaced by their ranks will be used. 
The number of cataplexy attacks will be summarized by week.  
9.10.2 
Key Secondary Efficacy Analysis 
For the key secondary efficacy endpoint, the change in ESS score from the end of the 
Stable-Dose Period to the end of the Double-Blind Randomized-Withdrawal Period will be 
assessed. Analyses will be similar to the primary endpoint. 
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9.10.3 
Other Secondary Efficacy Analysis 
Other secondary efficacy endpoints of PGIc and CGIc for narcolepsy overall will be assessed at 
the end of the Double-Blind Randomized-Withdrawal Period. The change in score from the end 
of the Stable-Dose Period to the end of the Double-Blind Treatment Period will be assessed for 
SF-36, and EuroQol 5. 
For the other secondary efficacy endpoints, CGIc and PGIc ratings will be analyzed as response 
frequencies using the Cochran-Mantel-Haenszel (CMH) test for the row mean score difference. 
All other non-categorical parameters will be analyzed by ANCOVA or non-parametric 
ANCOVA, similar to the primary endpoint, as appropriate. 
9.11 Safety Analyses 
Safety analyses will be performed using the Safety Population. For the Double-Blind 
Randomized-Withdrawal Period, results will be summarized by the actual treatment. Analyses 
will be descriptive in nature, and no formal statistical testing will be performed. 
9.11.1 
Adverse Event Analyses 
Adverse events will be mapped to system organ classes and preferred terms using the Medical 
Dictionary for Regulatory Activities (MedDRA).  
The subject incidence of TEAEs, TEAEs related to study drug, SAEs, AEs leading to 
discontinuation, and fatal AEs will be summarized. This overall summary will also provide 
TEAEs by maximum severity. 
The subject incidence of TEAEs, TEAEs related to study drug, AEs, and AEs leading to 
discontinuation will also be presented by system organ class and preferred term. Preferred term 
summaries may also be provided. 
A TEAE is defined as an AE that either began after the first study drug dose or worsened after 
the first dose. In summarizing the subject incidence of AEs, multiple events with the same 
preferred term or with increases in severity will only be counted as one AE and summarized at 
the maximum severity. Subject incidence is similarly defined for multiple events within the same 
system organ class. Summaries by period will be based on AEs considered emergent within a 
period. 
Adverse events occurring after a subject has completed the Main Study and prior to the Open-
Label Extension Period will be recorded as medical history. Adverse events occurring after first 
dose of study drug in the Open-Label Extension Period will be considered treatment emergent. 
9.11.2 
Other Safety Analyses 
Vital Signs 
For each vital sign parameter, summary statistics will be provided for observed and change from 
baseline values by scheduled visit.  
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Physical Examinations 
Observed and change from baseline values for weight will be summarized descriptively by 
scheduled visit.  
12-lead ECG 
Observed and change from baseline values for ECG intervals will be summarized descriptively. 
QT abnormalities will be assessed; the number and percent of subjects with values or change 
from baseline values exceeding certain thresholds will be tabulated.  
Laboratory Evaluations 
Observed and change from baseline laboratory evaluations will be summarized descriptively.  
C-SSRS 
C-SSRS parameters will be tabulated by scheduled visit. 
PHQ-9 
Depression severity based on PHQ-9 will be summarized by scheduled visit. 
9.12 Exploratory Analyses 
To address the exploratory objective of characterizing the conversion to JZP-258 from 
non-Xyrem anticataplectic treatments, analyses including subjects from Pre-randomization 
Groups 2, 3, and combined will be provided. Analyses will include, but are not limited to, 
summaries of anticataplectic use, titration and duration of anticataplectics, as well as JZP-258 
titration during the Optimized Treatment and Titration Period. 
9.13 Subgroup Analyses 
Subgroup analyses for the efficacy and key safety endpoints (including, but not limited to, AEs 
during the Double-Blind Randomized-Withdrawal Period) will be provided by 
Pre-randomization Group. 
Additional subgroup analyses by sex or other characteristics will be provided for efficacy and 
key safety endpoints as appropriate. 
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10 DATA QUALITY ASSURANCE 
Steps to assure the accuracy and reliability of data include the selection of qualified Investigators 
and appropriate study sites, review of protocol procedures with the Investigator and associated 
personnel prior to the study, and periodic monitoring visits by Jazz Pharmaceuticals or its 
designee. Data 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 of Jazz Pharmaceuticals or the CRO. A comprehensive Data Management Plan will 
be developed, which will describe the processes and procedures for collecting, reviewing, and 
reconciling data throughout the trial. 
10.2 Case Report Forms 
Jazz Pharmaceuticals or its designee will supply electronic case report forms (eCRFs) for the 
recording of all trial data not recorded in subject diaries, 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. 
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10.4 Data Safety Monitoring  
A data safety monitoring board is not planned for this trial. 
A multi-functional team led by Jazz Drug Safety and Pharmacovigilance department will review 
the accumulating safety data, including, but not limited to, all AE and SAEs from Jazz-sponsored 
clinical trials of JZP-258 (data from blinded studies will be blinded) and information derived 
from any clinical or epidemiologic investigations, foreign or domestic, including epidemiological 
studies or pooled analysis of multiple studies and animal or in vitro studies, that may have a 
bearing on the safety of JZP-258. This review is done on a periodic basis, but additional ad hoc 
meetings may be called as required. Reports of safety findings (from either single events or 
based on aggregate review) that suggest a significant risk to humans will be distributed to all 
participating Investigators and to the relevant regulatory authorities and CECs. 
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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 Director 
11.1.3 
Investigator 
Multicenter 
11.1.4 
Clinical Laboratory  
11.2 Ethics Committee (EC) Approval 
The final approved protocol and the informed consent form will be reviewed by an ethics 
committee (e.g. Institutional Review Board [IRB], Independent Ethics Committee [IEC], or 
Research Ethics Board [REB]). In addition, the ethics committee will review any other written 
information to be provided to the subject, advertisements for subject recruitment (if used), and 
subject compensation (if any). The committee’s decision concerning conduct of the study will be 
sent in writing to the Investigator and a copy will be forwarded to Jazz Pharmaceuticals. The 
Investigator agrees to make any required progress reports, as well as reports of SAEs, life 
threatening problems, death, or any significant protocol deviations, as required by the ethics 
committee. 
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A list of the ethics committee members who actually participated in the review, their respective 
titles (occupational identification), and institutional affiliations or an ethics committee assurance 
number must be provided to Jazz Pharmaceuticals. The approval letter or notice must be 
provided on ethics committee letterhead and contain the date of the meeting and sufficient 
information to identify the version of the protocol unambiguously (by name and number) and 
state that the informed consent form was also reviewed. 
A clinical trial may not be initiated before the proposed protocol and informed consent form 
have been reviewed and unconditionally approved/given favorable opinion by the ethics 
committee, meeting country or local regulations. The clinical study remains subject to continuing 
review by the ethics committee. Jazz Pharmaceuticals or its designee will supply all necessary 
data for the Investigator to submit to the ethics committee. Jazz Pharmaceuticals will not ship 
clinical supplies to an investigational site until written signed approval/favorable opinion from 
the site’s ethics committee has been received by Jazz Pharmaceuticals. 
The Investigator is responsible for ensuring initial and continued review and approval of the 
clinical trial by the ethics committee at his/her site. The Investigator must also ensure that he/she 
will promptly report to the ethics committee and Jazz Pharmaceuticals all changes in the research 
activity and all unanticipated problems involving risk to human subjects or others, and that 
he/she will not make any changes in the research without ethics committee approval/favorable 
opinion, except where necessary to eliminate apparent hazards to human subjects. If the trial 
remains in progress for more than 1 year, documentation of annual renewal must be submitted to 
Jazz Pharmaceuticals or its designee. Within 3 months of trial completion or termination, a final 
report must be provided to the ethics committee by the clinical site. 
11.3 Ethical Conduct of the Study 
The study will be conducted in accordance with applicable local regulations relating to Good 
Clinical Practice (GCP) and with the Standard Operating Procedures of the CRO or Jazz 
Pharmaceuticals, as applicable. These standards respect the following guidelines or laws: 
• Integrated Addendum to ICH E6 (R1): Guideline for Good Clinical Practice E6(R2) 
• 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.” 
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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 
(ICF). 
Each subject’s chart will have his/her signed ICF for study participation attached to it. When the 
study treatment is completed and the eCRF has been monitored, the ICF will be kept in the 
Investigator’s central study file.  
11.5 Subject Confidentiality  
All reports and communications relating to the subjects in the study will identify each subject 
only by his/her initials and by the subject’s study number. These documents will be treated with 
strict adherence to professional standards of confidentiality and will be filed at the study site 
under adequate security and restricted access.  
Portions of the subject’s medical records pertinent to the study will be reviewed by Jazz 
Pharmaceuticals personnel or its designee and possibly by governmental agency personnel to 
ensure adequate source documentation, accuracy, and completeness of the eCRFs. The ethics 
committee has the authority to review subject records. 
11.6 Protocol Adherence – Amendments 
The protocol must be read thoroughly and the instructions must be followed exactly.  
Any changes in the protocol will require a formal amendment. Such amendments will be agreed 
upon and approved in writing by the Investigator and the Jazz Pharmaceuticals designees. The 
ethics committee will be notified of all amendments to the protocol. Amendments to the protocol 
will not be implemented until written ethics committee approval has been received.  
11.7 Required Documents 
The Investigator must provide Jazz Pharmaceuticals or its designee with the applicable 
regulatory documents before the enrollment of any subject (copies should be kept by the 
Investigator in the Investigator’s regulatory document binder).  
11.8 Study Monitoring 
Throughout the course of the study, the study monitor will make frequent contacts with the 
Investigator. This will include telephone calls and onsite visits. During the onsite visits, the 
eCRFs will be reviewed for completeness and adherence to the protocol. As part of the data 
audit, source documents will be made available for review by the site. The study monitor will 
also perform drug accountability checks and may periodically request review of the Investigator 
study file to assure completeness of documentation in all respects of clinical trial conduct. 
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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. 
11.10 Protocol Violations/Deviations 
All protocol violations/deviations will be reviewed at interim monitoring visits. Protocol 
violations/deviations will be reported to the sites ethics committee as required by that ethics 
committee. It is the responsibility of the Principal Investigator to ensure proper reporting to the 
ethics committee. Reports of protocol violations/deviations will be reported to Jazz 
Pharmaceuticals, as defined in the monitoring plan. 
11.11 Access to Source Documentation  
The Investigator/institution will permit trial-related monitoring (Section 11.8), audits conducted 
by the Clinical Quality Assurance Department of Jazz Pharmaceuticals or designee, ethics 
committee review and regulatory inspections by providing direct access to source data and 
documents for the trial. 
11.12 Publication and Disclosure Policy  
Please refer to individual site contracts for specific contractual obligations and requirements. 
All information concerning oxybate mixed-salt oral solution, 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. Electronic 
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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 oxybate mixed-salt oral solution, and 
therefore may disclose this information as required to other Jazz Pharmaceuticals Investigators; 
appropriate international regulatory agencies; or others. In agreeing to participate in this study, 
the Investigator understands that he/she has an obligation to provide complete test results and all 
data developed during this trial to Jazz Pharmaceuticals. Jazz Pharmaceuticals requires that 
permission to publish details of this study must be obtained in writing as further detailed in the 
Clinical Study Agreement signed by the Investigator and/or institution. It is intended that the 
results of this trial be published in scientific literature. The conditions noted here are intended to 
protect commercial confidential materials (patents, etc.) and not to restrict publication. 
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12 REFERENCE LIST 
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. 
Boscolo-Berto R, Viel G, Montagnese S, Raduazzo DI, Ferrara SD, Dauvilliers Y. Narcolepsy 
and effectiveness of gamma-hydroxybutyrate (GHB): A systematic review and meta-analysis of 
randomized controlled trials. Sleep Med Rev 2012; 16:431-443. 
Broderick JE, Junghaenel DU, Schneider S, Pilosi JJ, Stone AA. Pittsburgh and Epworth sleep 
scale items: accuracy of ratings across different reporting periods. Behav Sleep Med., 2013; 
11:173-188. 
Centers for Disease Control (CDC) Sodium: the facts. 2010. Accessed 8/2/2103. At: 
http://www.cdc.gov/salt/pdfs/Sodium_Fact_Sheet.pdf 
CTCAE, Version [4.03] Accessed at: 04.03_2010-06-14_QuickReference_8.5x11.pdf. 
Dauvilliers Y, Jennum P, Plazzi G. Rapid eye movement sleep behavior disorder and rapid eye 
movement sleep without atonia in narcolepsy. Sleep Med 2013; 14:775-781. 
European Food Safety Authority (EFSA). Opinion of the Scientific Panel on Dietetic Products, 
Nutrition and Allergies on a Request from the Commission Related to the Tolerable Upper 
Intake Level of Sodium in Tolerable Upper Intake Levels for Vitamins and Minerals. Scientific 
Committee on Food Scientific Panel on Dietetic Products, Nutrition and Allergies, 2006: 429-
446 (http://www.efsa.eu.int). 
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. 
Glimm E, Maurer W, and Bretz F. Hierarchical testing of multiple endpoints in group-sequential 
trials. Stat Med. 2010; 29: 219-228.  
Hays RD, Stewart AL. Construct validity of MOS health measures. In A L Stewart & J E Ware 
(eds.), Measuring functioning and well-being: The Medical Outcomes Study approach. Sleep 
Measures Duke University Press, Durham NC. 1992; 325-342. 
Hwang IK, Shih WJ, and DeCani JS. Group sequential designs using a family of type I error 
probability spending functions. Stat Med. 1990; 9:1439–1445. 
Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. 
Sleep 1991; 14 (6): 540–545. 
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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: 5-11. 
Kroenke K, Spitzer RL, Williams JB, Löwe B. The Patient Health Questionnaire somatic, 
anxiety, and depressive symptom scales: a systematic review. Gen Hosp Psychiatry 2010; 
32:345-359.  
Kroenke K, Spitzer RL, Williams JB. The PHQ-9: Validity of a brief depression severity 
measure. J Gen Intern Med 2001;16:606-613.  
Lingenhoehl K, Brom R, Heid J, Beck P, Froestl W, Kaupmann K, Bettler B, Mosbacher J. 
Gamma-hydroxybutyrate is a weak agonist at recombinant GABA(B) receptors. 
Neuropharmacology 1999; 38(11):1667-73.  
Majid H, Hirshkowitz M. Therapeutics of narcolepsy. Sleep Med Clin 2010; 5:659-673. 
Mathivet P, Bernasconi R, De Barry J, Marescaux C, Bittiger H. Binding characteristics of 
gamma-hydroxybutyric acid as a weak but selective GABAB receptor agonist. Eur J Pharmacol 
1997; 321(1):67-75. 
Nishino S. Clinical and neurobiological aspects of narcolepsy. Sleep Med 2007; 8:373-399. 
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. Narcolepsy is complicated by high medical and psychiatric comorbidities: a 
comparison with the general population. Sleep Med (2013), 
http://dx.doi.org/10.1016/j.sleep.2013.03.002. 
Pardi, D, Black J. Gamma-Hydroxybutyrate/sodium oxybate: neurobiology, and impact on sleep 
and wakefulness. CNS Drugs 2006; 20(12):993-1018. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, 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.  
Snead OC. Evidence for a G protein-coupled gamma-hydroxybutyric acid receptor. J Neurochem 
2000;75:1986-96. 
Ware JE, Jr, Sherbourne CD. The MOS 36-Item Short-Form Health Survey (SF-36): I. 
Conceptual Framework and Item Selection. Med Care 1992;, 30:473-483. 
Xyrem® (sodium oxybate) oral solution. Canadian Product Monograph, Valeant Canada Ltd, 
2014.  
Xyrem® (sodium oxybate) oral solution. US Prescribing Information (April 2015), Jazz 
Pharmaceuticals, Palo Alto, CA.  
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Xyrem® 500 mg/mL oral solution. European Union Summary of Product Characteristics, UCB 
Pharma Ltd, November 2015. 
 
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Appendix 1 
Schedule of Events  
Appendix 1.1 
Screening, Optimized Treatment and Titration, Stable-Dose, Double-Blind 
Randomized-Withdrawal, and Safety Follow-up Periods 
 
Screen-
ing 
 
Optimized Treatment and Titration 
Stable-
Dose 
Period 
DB Randomized-
Withdrawal Period 
Safety 
Follow-
up 
Period 
 
Events 
Study 
Entry 
Switch to 
or Start 
JZP-258 
Begin Titration 1 
End 
Titration 
Begin 
Stable-Dose 
End of 
Stable-Dose 
Begin DB 
Treatment 
End of DB 
Treatment or 
Early 
Termination 
Visits 2 
Phone contacts are shaded 
except for Wk 1 (see footnote) 
V1 
V2 
V3 
Clinic 
Visit 
Call 5 
V4 
V5 
Call 
V6 
V7 
V8 
V9 
Call 
V10 
V11 
Call 
V12 
Call 
V13 
Call 
V14 
V15 
V16 
V17 
End of Week (W) 
Day -30 
to -1 
Day 1 
(+ 3 days) 
(+ 3 days) 
(+ 3 days) 
(+ 3 days) 
(+ 3 days) 
W1 
W2, W3 W4 
W5, W6, W7 
W8 
W9 
W10 
W11 
W12 
W14 
W16 
W18 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
Vital Signs (BP, HR, body 
temperature, RR) 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
PSG/MSLT 3, if necessary 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting chemistry, hematology, 
UA;TSH (screening only) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Electrolytes 4 
 
X 
 
 
X 
 
X 
 
 
 
X 
X 
X 
 
Urine Drug Screen  
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
 
Alcohol Screen 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
 
Serum Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
12 Lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Provide light breakfast 
(optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
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Appendix 1.1 
Screening, Optimized Treatment and Titration, Stable-Dose, Double-Blind 
Randomized-Withdrawal, and Safety Follow-up Periods 
 
Screen-
ing 
 
Optimized Treatment and Titration 
Stable-
Dose 
Period 
DB Randomized-
Withdrawal Period 
Safety 
Follow-
up 
Period 
 
Events 
Study 
Entry 
Switch to 
or Start 
JZP-258 
Begin Titration 1 
End 
Titration 
Begin 
Stable-Dose 
End of 
Stable-Dose 
Begin DB 
Treatment 
End of DB 
Treatment or 
Early 
Termination 
Visits 2 
Phone contacts are shaded 
except for Wk 1 (see footnote) 
V1 
V2 
V3 
Clinic 
Visit 
Call 5 
V4 
V5 
Call 
V6 
V7 
V8 
V9 
Call 
V10 
V11 
Call 
V12 
Call 
V13 
Call 
V14 
V15 
V16 
V17 
End of Week (W) 
Day -30 
to -1 
Day 1 
(+ 3 days) 
(+ 3 days) 
(+ 3 days) 
(+ 3 days) 
(+ 3 days) 
W1 
W2, W3 W4 
W5, W6, W7 
W8 
W9 
W10 
W11 
W12 
W14 
W16 
W18 
Instruct subject on 
discontinuation of excluded 
medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cataplexy Frequency Diary 
 
X 
X 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review/discuss subject diaries 
for completeness  
 
 
X 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assess control of cataplexy, 
EDS and tolerability to current 
dose. 
 
 
X 5 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ESS 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
PGIc narcolepsy overall 6 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CGIs narcolepsy overall 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
CGIc narcolepsy overall 6 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
SF-36 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
EuroQoL 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
C-SSRS Screening/Baseline 
Version 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS Since Last Visit 
Version 
 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
PHQ-9 
X 
X 
 
X (W2 
only) 
X 
X (W6 only) 
X 
 
X 
 
X 
X 
X 
X 
AE Reporting 
 
X 
X 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Appendix 1.1 
Screening, Optimized Treatment and Titration, Stable-Dose, Double-Blind 
Randomized-Withdrawal, and Safety Follow-up Periods 
 
Screen-
ing 
 
Optimized Treatment and Titration 
Stable-
Dose 
Period 
DB Randomized-
Withdrawal Period 
Safety 
Follow-
up 
Period 
 
Events 
Study 
Entry 
Switch to 
or Start 
JZP-258 
Begin Titration 1 
End 
Titration 
Begin 
Stable-Dose 
End of 
Stable-Dose 
Begin DB 
Treatment 
End of DB 
Treatment or 
Early 
Termination 
Visits 2 
Phone contacts are shaded 
except for Wk 1 (see footnote) 
V1 
V2 
V3 
Clinic 
Visit 
Call 5 
V4 
V5 
Call 
V6 
V7 
V8 
V9 
Call 
V10 
V11 
Call 
V12 
Call 
V13 
Call 
V14 
V15 
V16 
V17 
End of Week (W) 
Day -30 
to -1 
Day 1 
(+ 3 days) 
(+ 3 days) 
(+ 3 days) 
(+ 3 days) 
(+ 3 days) 
W1 
W2, W3 W4 
W5, W6, W7 
W8 
W9 
W10 
W11 
W12 
W14 
W16 
W18 
Groups 1 and 2: Switch 
Xyrem to JZP-258 and 
maintain dose for 2 weeks 
 
X 
X 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Groups 3 and 4: Initiate 
JZP-258 and titrate over a 
minimum of 2 weeks 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Groups 2 and 3: Taper off 
anticataplectic over a minimum 
of 2 weeks 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Groups 2 and 3: Confirm taper 
completed and no 
anticataplectic use 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
All Groups: Further titration of 
JZP-258 as necessary 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All Groups: Maintain JZP-258 
at stable dose (Wks 10-12) 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomize subjects 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
All Groups: Dose with DB 
study drug (Wks 14-16) 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Dosing Diary; 
assess diary for completeness 
and compliance after start of 
dosing  
 
X 7 
X 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense Study Drug 
 
X 
 
 
X 
 
X 
 
 
 
X 
X8 
 
 
Collect study drug, measure 
compliance 
 
 
 
 
X 
 
X 
 
 
 
X 
X 
X 
 
 
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Shaded columns indicate phone contacts 
1 All subjects will begin JZP-258 treatment at the beginning of this period and continue through Week 12. The subject must be maintained on a stable, tolerable and effective dose 
for at least 2 weeks, prior to entering the Stable-Dose Period. 
2 The Investigator may have the subject attend an unscheduled visit, at any time during the study, if deemed necessary. 
3 When necessary, a PSG may be performed, with the approval of the Jazz Pharmaceuticals Medical Monitor, to evaluate the subject for evidence of sleep disordered breathing, if 
the subject has not been adequately evaluated prior to study entry. A PSG and MSLT may also be performed, if necessary, with approval of the Jazz Pharmaceuticals’ Medical 
Monitor for diagnosis of narcolepsy. The PSG and MSLT will be performed according the study center’s standard procedures.  
4.  Electrolytes to include sodium (Na+), potassium (K+), magnesium (Mg+2), and calcium (Ca+2). 
5. At Week 1 subjects in Pre-randomization Groups 1 and 2 will have a phone contact for assessments unless the Investigator elects to assess the subject in the clinic. Only 
assessments labeled with this footnote will be conducted during the phone contact for Pre-randomization Groups 1 and 2. If these groups are seen in the clinic at Week 1 all 
assessments in the Week 1column should be completed. 
6. PGIc and CGIc questionnaires are not applicable for subjects who terminate the study early prior to the Double-Blind Treatment Period. 
7. The subject is expected to start Study Drug Dosing Diary completion on the morning after the subject is dispensed study drug at Visit 2. 
 
 
AE = adverse event; BP = blood pressure; CGIc = Clinical Global Impression of Change; CGIs = Clinical Global Impression of Severity; C-SSRS = Columbia-Suicide Severity 
Rating Scale; DB = double-blind; ECG = electrocardiogram; EDS = excessive daytime sleepiness; ESS = Epworth Sleepiness Scale; EuroQoL = European quality of life; HR = 
heart rate; MSLT = multiple sleep latency test; PGIc = Patient Global Impression of Change; PHQ-9 = Patient Health Questionnaire-9; PSG = polysomnogram; RR = respiratory 
rate; SF-36 = 36-Item Short Form Survey Questionnaire; TSH = thyroid stimulating hormone; UA = urinalysis; V = Visit; W, Wk = Week. 
 
 
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Appendix 1.2 
Open-Label Extension and Safety Follow-up Periods 
 
Rollover 
Subjects 1 
Re-entry 
Subjects 2 
OLE Period 3 
End of OLE 
Treatment 
or Early 
Termination 
Safety 
Follow-up 
Period 
Visits 4 
Phone contacts are shaded 
V16 
Additional 
procedures 
V18 
V19 
V20 
V21 
V22 
Call 
V23 
Call 5 
V24 
V25 
V26 
Call 
V27 
Call 5 
V28 
V29 
Call 
V30 
V31 
V32 
Call 5 
V33 
EOT 
V34 
End of Week (W) 
OLE Day 1 
OLE 
Day -30 
to -1 
OLE
Day 1 
(+ 3 days) 
(+ 3 days) 
(+ 3 days) 
W1, W2, W3 
W4 
W5, W6, W7 
W8 
W9. W10 
W12 
W16, W20 
W24 
W26 
Informed Consent OLE 
X 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
X 
 
 
 
 
 
 
 
 
 
Medical History 
 
X 
X 
 
 
 
 
 
 
 
 
 
Physical Examination 
 
X 
 
 
 
 
 
 
 
 
X 
 
Weight 
 
X 
X 
 
 
 
 
 
X 
 
X 
X 
Vital Signs (BP, HR, body 
temperature, RR) 
 
X 
X 
 
 
 
 
 
X 
 
X 
X 
Fasting chemistry, 
hematology, UA ;TSH 
(screening only) 
 
X 
 
 
 
 
 
 
 
 
X 
 
Electrolytes 6 
 
 
X 
 
 
 
 
 
X 
 
 
 
Urine Drug Screen  
 
X 
X 
 
 
 
 
 
X 
 
X 
 
Alcohol Screen 
 
X 
X 
 
 
 
 
 
X 
 
X 
 
Urine Pregnancy Test 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
Serum Pregnancy Test  
 
X 
 
 
 
 
 
 
 
 
 
 
12 Lead ECG 
 
X 
 
 
 
 
 
 
 
 
X 
 
Provide Light Breakfast 
(optional) 
 
X 
 
 
 
 
 
 
 
 
X 
 
Instruct Subject (on 
discontinuation of excluded 
medications) 
 
X 
 
 
 
 
 
 
X 
 
 
 
C-SSRS Since Last Visit 
Version 
 
X 
X 
 
 
 
 
 
X7 
 
X 
X 
PHQ-9 
 
X 
X 
 
 
 
 
 
X 
 
X 
X 
AE Reporting 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rollover Subjects dosing 8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 1.2 
Open-Label Extension and Safety Follow-up Periods 
 
Rollover 
Subjects 1 
Re-entry 
Subjects 2 
OLE Period 3 
End of OLE 
Treatment 
or Early 
Termination 
Safety 
Follow-up 
Period 
Visits 4 
Phone contacts are shaded 
V16 
Additional 
procedures 
V18 
V19 
V20 
V21 
V22 
Call 
V23 
Call 5 
V24 
V25 
V26 
Call 
V27 
Call 5 
V28 
V29 
Call 
V30 
V31 
V32 
Call 5 
V33 
EOT 
V34 
End of Week (W) 
OLE Day 1 
OLE 
Day -30 
to -1 
OLE
Day 1 
(+ 3 days) 
(+ 3 days) 
(+ 3 days) 
W1, W2, W3 
W4 
W5, W6, W7 
W8 
W9. W10 
W12 
W16, W20 
W24 
W26 
Re-entry Subjects dosing 9, 10 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess Tolerability (to 
current dose) 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Dispense Study Drug 
X 
 
X 
 
 
 
 
 
X 3 
 
 
 
Collect Study Drug, Measure 
Compliance 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
Shaded columns indicate phone contacts 
1 Rollover Subjects are those who enter the Open-Label Extension at Visit 16 (rollover directly from the Main Study). Visit 16 for Rollover Subjects is the last day of the Main 
Study and Day 1 of the Open-Label Extension. 
2 Re-entry Subjects are those who complete the Main Study, undergo screening for the Open-Label Extension at Visit 18, and re-enter the study at Visit 19 (Day 1 of the Open-
Label Extension). 
3 All subjects will receive Open-Label JZP-258. 
4 The Investigator may have the subject attend an unscheduled visit, at any time during the study, if deemed necessary. 
5 Phone visit may be converted to a clinic visit if required due to logistical or regulatory constraints on IP management. If clinic visits needed dispensing may occur. 
6 Electrolytes to include sodium (Na+), potassium (K+), magnesium (Mg+2), and calcium (Ca+2).  
7 Subjects should taper anticataplectic agents by Visit 30 and return to Main Study treatment regimen as described in the Main Study. 
8 Rollover Subjects (enter directly from Main Study) will be started at Visit 16 at a dose no higher than the dose they received at the end of the Stable-Dose Period. A lower 
starting dose will be allowed at the discretion of the Investigator. If further titration is required, it will proceed at a rate of 1 or 1.5 g per night per week during this period, not to 
exceed a total dose of 9 g per night. The maximum dose should not be greater than 9 g/night. 
9 Re-entry Subjects (enter after completion of the Main Study) on Xyrem alone or with an additional anticataplectic will be switched from their current dose of Xyrem to JZP 258 
on a gram to gram straight conversion at the start of the Open-Label Extension. If further titration is needed, titration will proceed at a rate of 1 or 1.5 g per night per week 
during this period not to exceed a total dose of 9 g per night. 
10 Re-entry Subjects (enter after completion of the Main Study) on a non-Xyrem anticataplectic or not currently receiving treatment will receive an initial dose of JZP 258 of 4.5 g 
per night at the start of the Open-Label Extension. Dose adjustments will proceed at a rate of 1 or 1.5 g per night per week until a tolerable dose of JZP-258 is reached. If 
needed, the dose of JZP-258 may be further titrated to a stable, tolerable, and effective dose that does not exceed a total dose of 9 g per night.  
AE = adverse event; BP = blood pressure; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EOT = end of treatment; HR = heart rate, 
IP = investigational product; OLE = Open-Label Extension; PHQ-9 = patient health questionnaire-9; RR = respiratory rate; TSH = thyroid stimulating hormone; UA = urinalysis; 
V = Visit; W = Week. 
 
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JZP-258 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 15-006 Amendment 5 
Appendix 15 
Study Title: 
Signatures of Agreement for Protocol 
A Double-Blind, Placebo-Controlled, Randomized-Withdrawal, 
Multicenter Study of the Efficacy and Safety of JZP-258 in Subjects 
with Narcolepsy with Cataplexy 
Study Number: 
Original Protocol: 
Amendment 1: 
Amendment 2: 
Amendment 3: 
Amendment 4: 
Amendment 5: 
15-006 
25 February 2016 
05 August 20 16 
07 November 2016 
10 April2017 
15 December 2017 
15 May 2018 
This clinical study protocol was subject to critical review and has been approved by Jazz 
Pharmaceuticals. 
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