A Multicenter Study of the Efficacy and Safety of Xyrem With an Open- Label Pharmacokinetic Evaluation and Safety Extension in Pediatric Subjects With Narcolepsy With Cataplexy
Phase: PHASE3
Conditions: Narcolepsy With Cataplexy
Sponsor: Jazz Pharmaceuticals

Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
 
Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
Xyrem® (sodium oxybate) oral solution 
 
Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
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Clinical Study Protocol: 13-005 
Study Title: 
A Double-Blind, Placebo-Controlled, Randomized-Withdrawal, 
Multicenter Study of the Efficacy and Safety of Xyrem with an Open-
Label Pharmacokinetic Evaluation and Safety Extension in Pediatric 
Subjects with Narcolepsy with Cataplexy 
Study Phase: 
Phase 2/3 
Product Name: 
Xyrem® (sodium oxybate) oral solution 
IND Number: 
49,641 
EUDRACT 
Number 
2014-001389-93 
Indication: 
Pediatric Cataplexy in Narcolepsy 
Investigators: 
Multicenter 
Sponsor: 
Jazz Pharmaceuticals  
3180 Porter Drive 
Palo Alto, CA 94304 
USA 
Tel: (650) 496-3777 
Medical Monitor: 
Contract 
Research 
Organization: 
Clinical 
Laboratory: 
 
 
Original Protocol: 
14 April 2014 
Amendment 1: 
29 August 2014 
Amendment 2: 
1 April 2015 
Amendment 3: 
05 August 2015 
Amendment 4: 
05 April 2016 
Amendment 5 
23 February 2017 
Confidentiality Statement 
The information in this document is Jazz Pharmaceuticals confidential information. This material may be used 
only for evaluating or conducting clinical investigations; any other proposed use requires written consent from 
Jazz Pharmaceuticals. Acceptance of this document constitutes an agreement by the recipient(s) that no 
unpublished information contained herein will be published or disclosed without first obtaining written approval 
from Jazz Pharmaceuticals. This document may be disclosed to appropriate Investigational Review 
Boards/Ethics Committees under the condition of confidentiality. 
This study will be conducted under Good Clinical Practice guidelines. 
 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
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SYNOPSIS 
SPONSOR 
Jazz Pharmaceuticals 
FINISHED PRODUCT Xyrem® (sodium oxybate) oral solution 
STUDY NUMBER 
13-005 
STUDY PHASE 
Phase 2/3 
TITLE 
A Double-Blind, Placebo-Controlled, Randomized-Withdrawal, 
Multicenter Study of the Efficacy and Safety of Xyrem with an Open-
Label Pharmacokinetic Evaluation and Safety Extension in Pediatric 
Subjects with Narcolepsy with Cataplexy 
LOCATIONS 
This study will be conducted globally at approximately 70 sites 
OBJECTIVES 
Primary objectives are: 
1) To evaluate the efficacy of Xyrem (sodium oxybate) oral 
solution in the treatment of cataplexy in pediatric subjects with 
narcolepsy 
2) To evaluate the safety of Xyrem in the treatment of cataplexy 
in pediatric subjects with narcolepsy for up to one year (and 
potentially more than one year in some subjects participating 
in a continuation of the open-label safety evaluation) 
Secondary objectives are:  
1) To evaluate the efficacy of Xyrem in the treatment of 
excessive daytime sleepiness (EDS) in pediatric subjects with 
narcolepsy with cataplexy 
2) To characterize the pharmacokinetics (PK) of Xyrem in 
pediatric subjects (ages 7-17 years) with narcolepsy with 
cataplexy   
3) To evaluate the safety of titrating Xyrem in pediatric subjects 
to an effective and tolerable dose  
DESIGN 
Under Amendment 5, this study is divided into two parts: Part 1 
includes one year of treatment, and Part 2, the Open-Label 
Continuation Period, provides the opportunity to continue treatment 
for up to an additional 2 years. 
Part 1 
Part 1 of this study was initially designed as a double-blind, placebo-
controlled, randomized-withdrawal, multicenter study of the efficacy 
and safety of Xyrem (sodium oxybate) oral solution. As a result of a 
preplanned interim analysis, which demonstrated positive efficacy 
results on the primary efficacy endpoint, the protocol was amended 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
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(Amendment 4) to replace placebo treatment in the Double-Blind 
Treatment Period with open-label Xyrem treatment. After 
Amendment 4 becoming effective, all subjects entering the Double-
Blind Treatment Period will receive open-label Xyrem treatment. For 
administrative reasons, the term “Double-Blind Treatment Period” 
will continue to be used throughout the protocol. Following the 
Double-Blind Treatment Period (2 weeks), this study also includes an 
open-label safety extension allowing subjects to continue Xyrem 
treatment for up to one year in Part 1.  
In addition, the PK of Xyrem will be evaluated in a subset of subjects.  
Children and adolescents, diagnosed with narcolepsy with cataplexy 
who are currently treated with Xyrem or are Xyrem naïve, with or 
without concomitant stable stimulant use, are eligible to enter the 
study. For this study, a Xyrem naïve subject is defined as a subject 
who has never been treated with Xyrem or who was previously treated 
with Xyrem and discontinued Xyrem for at least one month prior to 
the Part 1 Screening visit for reasons other than lack of efficacy and/or 
tolerability issues (e.g., lost insurance coverage, could not afford 
Xyrem, changed prescribers). 
All subjects will be evaluated for eligibility during the Part 1 
Screening Period (up to 30 days [if needed, additional time may be 
granted with permission of the Medical Monitor]). 
Following Part 1 screening, subjects who are Xyrem naïve will enter 
the Open-Label Titration Period of up to 10 weeks. Once the Xyrem 
dose has been optimized per the Investigator’s judgment, these 
subjects may enter the open-label Stable-Dose Period with that dose. 
Subjects who are on Xyrem at study entry will remain on their stable 
dose and regimen (i.e., two equally divided doses or two unequally 
divided doses) of Xyrem and enter the Stable-Dose Period following 
screening.  
Subjects are eligible to enter the Double-Blind Treatment Period if the 
dose and regimen of Xyrem 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 due to Xyrem treatment have occurred.  
Subjects entering the Double-Blind Treatment Period prior to 
Amendment 4 becoming effective, had been randomized 1:1 to 
receive one of the following two treatments during the 2-week 
Double-Blind Treatment Period (randomized-withdrawal): 
• Xyrem: Active Xyrem will be continued as a double-blind 
treatment at the stable dose taken and regimen used in the prior 
2 weeks 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
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• Xyrem placebo: Xyrem placebo will be initiated as a double-blind 
treatment at a volume and regimen equivalent to the Xyrem dose 
taken in the prior 2 weeks. 
Subjects entering the Double-Blind Treatment Period after 
Amendment 4 becoming effective will receive open-label Xyrem 
treatment in this period. 
Subjects who complete the entire Double-Blind Treatment Period will 
be eligible to continue in the Open-Label Safety Period. The Open-
Label Safety Period will allow subjects to continue Xyrem treatment 
for up to one year in Part 1. 
In addition, at certain study sites, a subset of subjects on a stable dose 
of Xyrem will participate in an open-label PK evaluation during 
Part 1. Subjects will be stratified to two age groups: 7-11 years of age 
and 12-17 years of age. Up to 18 subjects in each of the two age 
groups will be eligible to participate in the PK evaluation. Every effort 
will be made to ensure a minimum of 12 subjects in each age group 
complete the PK assessments. However, when sufficient data are 
obtained to characterize the PK profile with adequate precision during 
the study, as determined by the Data and Safety Monitoring Board 
(DSMB), or when enrollment of 100 subjects in the study has been 
reached, enrollment in the PK evaluation will stop and existing data 
will be analyzed and reported. These subjects will have a limited 
number of blood samples taken while on Xyrem at the clinic to 
measure sodium oxybate concentrations. Samples will be taken at the 
following times relative to the first Xyrem dose: 0 (pre-dose), 0.75, 
1.5, 2.5, and 4 hours (pre-2nd dose) to characterize the PK of the first 
Xyrem dose, and at 4.75 and 8 hours to characterize the peak and 
residual exposure associated with the second Xyrem dose (total blood 
volume for PK samples is 40 mL taken over a minimum of 2 days). 
Subjects evaluated for PK will also undergo all other study procedures 
specified in the protocol. 
Part 2 
Upon approval of Amendment 5, subjects who complete one year in 
the study (Part 1) will have the opportunity to continue open-label 
Xyrem treatment in Part 2 until the first occurrence of any of the 
following: 
• Up to an additional 2 years 
• Until the subject reaches 18 years of age  
• Until up to 3 months after the US FDA decision on the addition of 
pediatric data to the Xyrem US prescribing information (PI)  
Subjects who have already completed Part 1 may re-enroll in Part 2.  
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
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ESTIMATED 
DURATION OF 
STUDY 
It is anticipated that enrollment in Part 1 will be completed within 
2 years. The estimated duration of the study (Parts 1 and 2) will be 
approximately 4 years.  
STUDY POPULATION The study will enroll pediatric subjects who are diagnosed with 
narcolepsy with cataplexy, who have provided assent, and whose 
parent(s) or guardian(s) have signed the informed consent form in 
accordance with local IRB/IEC requirements. At least 100 subjects 
will be enrolled in the study. Every effort will be made to enroll 
approximately 30 subjects on Xyrem at study entry of the anticipated 
100 subjects enrolled. Other subjects enrolled will be Xyrem naïve at 
study entry.   
A subset of the subjects who are taking Xyrem at a stable dose for 
their narcolepsy symptoms will participate in the PK evaluation 
during Part 1.  
Subjects who have completed one year in the study (Part 1) may be 
eligible for up to an additional 2 years of treatment in Part 2.  
DIAGNOSIS AND 
MAIN CRITERIA FOR 
INCLUSION 
Children and adolescents who are diagnosed with narcolepsy with 
cataplexy and who are currently treated with Xyrem or are Xyrem 
naïve, with or without concomitant stable stimulant use, are eligible to 
enter the study. 
TEST PRODUCT 
Xyrem (sodium oxybate) oral solution  
Xyrem placebo (sodium citrate) oral solution (Placebo treatment only 
applicable to subjects who had already entered the Double-Blind 
Treatment prior to Amendment 4 becoming effective) 
Flavorant that can be added to the water that is used as diluent will be 
provided, if available, for study drug preparation if flavored diluent is 
requested by the subject/parent/guardian for palatability. 
REFERENCE 
PRODUCT 
None 
DURATION OF 
TREATMENT 
The treatment duration for each subject in Part 1 of the study will be 
approximately 52 weeks. Eligible subjects may participate in Part 2 
for up to an additional 2 years or until they reach 18 years of age or 
until up to 3 months after the US FDA decision on the addition of 
pediatric data to the Xyrem US PI, whichever occurs first. The total 
duration of a subject’s treatment during the study will be up to 
3 years. 
EFFICACY 
ASSESSMENTS 
For subjects who entered the Double-Blind Treatment Period prior to 
Amendment 4 becoming effective, all efficacy assessments will be 
comparisons of the measurement made during, or at the end of, the 
last 2 weeks of the Stable-Dose Period compared with the 2 weeks of 
Double-Blind Treatment Period. These assessments will continue to 
be collected during the Stable Dose and Double Blind Periods after 
CONFIDENTIAL
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
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Amendment 4 becoming effective. 
Primary endpoint:  
1. Change in weekly number of cataplexy attacks. 
Key secondary endpoints: 
2. Clinical Global Impression of Change (CGIc) for cataplexy severity 
3. Change in the Epworth Sleepiness Scale for Children and 
Adolescents (ESS [CHAD]) score  
Other secondary endpoints: 
4. CGIc for narcolepsy overall  
5. Change in Quality of Life (QoL) (SF-10)  
Exploratory endpoints: 
6. Change in weekly school attendance (if enrollment overlaps with 
school attendance period) 
7. Patient Global Impression of Change (PGIc) for narcolepsy overall  
SAFETY 
ASSESSMENTS 
Safety will be assessed at time points specified in the schedules of 
events, as well as throughout the study. Safety assessments will 
include the following:  
• Adverse event (AE) monitoring 
• Vital signs 
• Physical examinations (including weight and height) 
• 12-lead ECG 
• Polysomnography (PSG) parameters (including respiratory 
measures)  
• Clinical laboratory tests (chemistry, hematology, and 
urinalysis) 
• Assessments of growth and precocious puberty 
• C-SSRS for emergent suicidality 
• CDI 2:SR[S] for emergent or worsening depression 
• MASC-10 for emergent or worsening anxiety 
• Serum pregnancy tests (if applicable) 
Exploratory endpoint: 
• CO2 monitoring (end tidal CO2 [EtCO2] or transcutaneous CO2 
[TcCO2]) in sites where monitoring is routinely performed and 
performance will not negatively impact study participation or PSG 
data integrity 
A DSMB will review the safety data on a regular basis. 
PHARMACOKINETIC 
VARIABLES 
 
The PK parameters for plasma sodium oxybate concentrations 
include: the area under the plasma concentration time curve (AUC), 
maximum plasma drug concentration (Cmax), and time to maximum 
plasma drug concentration (Tmax), over the first 4-hour dosing interval. 
In addition, sodium oxybate concentrations at 4.75 hours (0.75 hours 
after the 2nd dose) and 8 hours (4 hours after 2nd dose) will be 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
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measured to estimate peak and residual exposure associated with the 
2nd nighttime dose. Dose proportionality will be based on the ratio of 
AUC values for each subject. Pharmacokinetics will be summarized 
for the 7-11 and 12-17 year age groups, and a comparison to historical 
PK data in adults will also be made. 
STATISTICAL 
ANALYSIS 
To address Primary Objective 1 and Secondary Objective 1: 
A tiered approach was planned to control the Type 1 family-wise error 
rate at the 0.05 significance level with all tests being two-sided for 
testing of the primary and secondary efficacy endpoints. 
 Due to the positive primary efficacy results from the pre-specified 
interim analyses, the DSMB recommended to stop the Double-Blind 
Randomized-Withdrawal Period.   Tiered testing on secondary 
endpoints, as defined below, will be conducted with a significance 
level of 0.05, with all tests being two-sided. 
Tier 1: Primary endpoint 
Change in weekly number of cataplexy attacks from the last 2 weeks 
of the Stable-Dose Period to the 2 weeks of the Double-Blind 
Treatment Period. 
The primary endpoint demonstrated efficacy at the interim analysis 
with a significance level <0.005.  Testing will continue with Tier 2. 
Tier 2: Key secondary endpoint #2 
CGIc for cataplexy severity from the end of the Stable-Dose Period to 
the end of the Double-Blind Treatment Period 
The testing of this endpoint will be conducted at the 0.05 significance 
level. If Xyrem is significantly better than placebo at this level, Tier 3 
tests will be conducted. 
Tier 3: Key secondary endpoint #3 
Change in the ESS (CHAD) score from the end of the Stable-Dose 
Period to the end of the Double-Blind Treatment Period 
The testing of this endpoint will be conducted at the 0.05 significance 
level. If Xyrem is significantly better than placebo at this level, Tier 4 
tests will be conducted. 
Tier 4: Other secondary endpoint #4 
CGIc for narcolepsy overall from the end of the Stable-Dose Period to 
the end of the Double-Blind Treatment Period 
The testing of this endpoint will be conducted at the 0.05 significance 
level. If Xyrem is significantly better than placebo at this level, Tier 5 
tests will be conducted. 
Tier 5: Other secondary endpoint #5 
Change in QoL (SF-10) from the end of the Stable-Dose Period to the 
end of the Double-Blind Treatment Period 
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The testing of this endpoint will be conducted at the 0.05 significance 
level. 
Exploratory efficacy endpoints will be tested without multiplicity 
adjustments.  For these parameters, nominal p-values will be reported.  
Non-categorical efficacy parameters will be analyzed by non-
parametric analysis of covariance (ANCOVA). Ordinal categorical 
parameters, including CGIc and PGIc, will be analyzed using 
Cochran–Mantel–Haenszel (CMH) tests for row mean score 
difference. 
Efficacy data in the open-label phase will be summarized by visit. 
To address Primary Objective 2 and Secondary Objective 3: 
Safety will be summarized using descriptive statistics and reported 
separately for Part 1 and Part 2 as well as across the entire study 
(Part 1 and Part 2) for select analyses. Adverse events will be assessed 
for subpopulations including Xyrem naïve, subjects on Xyrem at 
study entry, Ages 7-11, and Ages 12-17, as applicable. When 
summarizing data across the entire study by subpopulations, subjects 
are analyzed according to their initial enrollment status. For Part 1, 
adverse events will also be summarized by treatment group and by 
dose. Safety analyses will also include an analysis of the nadir oxygen 
saturation level at each dose, and number and duration of any 
confirmed desaturations below 90%, 80%, 70%, 60% and 50% on 
PSG nights excluding the screening PSG. For Part 2, safety data will 
be summarized by Ages 7-11, Ages 12-17, and overall.  
To address Secondary Objective 2: 
Concentration data for sodium oxybate will be summarized by 
sampling time point and by PK parameter using descriptive statistics 
for each age group and overall. Dose proportionality will be assessed 
from the ratio of AUC and Cmax values. The ratios and their 90% 
confidence intervals will be presented. If warranted, regression 
models will be used to explore the relationship between plasma 
concentration and dose on a mg/kg basis.  
An ongoing analysis of the PK data will also be conducted to 
characterize the PK of Xyrem in children and adolescents.   
DATE OF ORIGINAL 
PROTOCOL 
14 April 2014 
AMENDMENT 1 
29 August 2014 
AMENDMENT 2 
1 April 2015 
AMENDMENT 3 
05 August 2015 
AMENDMENT 4 
05 April 2016 
AMENDMENT 5 
23 February 2017 
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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
TABLE OF CONTENTS ...........................................................................................................9 
LIST OF IN-TEXT TABLES ..................................................................................................13 
LIST OF IN-TEXT FIGURES.................................................................................................13 
LIST OF APPENDIXES..........................................................................................................13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................16 
1 
INTRODUCTION ...........................................................................................................20 
1.1 
Background and Rationale .....................................................................................21 
1.1.1 
Clinical Experience ......................................................................................21 
1.1.2 
Postmarketing Safety Data: 2002 through September 30, 2012 ..................23 
1.1.3 
Drug-Drug Interaction .................................................................................24 
2 
STUDY OBJECTIVES ....................................................................................................24 
2.1 
Objectives ..............................................................................................................24 
3 
INVESTIGATIONAL PLAN ..........................................................................................25 
3.1 
Overall Study Design and Plan ..............................................................................25 
3.1.1 
Screening Period ..........................................................................................30 
3.1.2 
Open-Label Titration Period for Subjects who are Xyrem naïve (up to 
10 weeks) .....................................................................................................30 
3.1.3 
Open-Label Stable-Dose (Stable-Dose) Period (2-3 weeks) .......................31 
3.1.4 
Double-Blind Treatment Period (2 weeks) ..................................................31 
3.1.5 
Open-Label Safety Period (to allow up to 1 year Xyrem exposure) ............32 
3.1.6 
Safety Follow-up Visit (2 weeks post Part 1 termination) ...........................33 
3.1.7 
Open-Label PK Evaluation ..........................................................................33 
3.1.8 
Open-Label Continuation Period (Part 2) ....................................................35 
3.2 
Rationale for Study Design and Control Group .....................................................35 
3.3 
Study Duration .......................................................................................................36 
4 
STUDY POPULATION SELECTION ...........................................................................36 
4.1 
Study Population ....................................................................................................36 
4.2 
Inclusion Criteria ...................................................................................................37 
4.3 
Exclusion Criteria ..................................................................................................38 
4.4 
Screening Eligibility ..............................................................................................40 
5 
STUDY TREATMENT(S) ..............................................................................................41 
5.1 
Description of Treatment .......................................................................................41 
5.2 
Treatment Administered ........................................................................................41 
5.3 
Selection and Timing of Dose for Each Subject ....................................................42 
5.4 
Method of Assigning Subjects to Treatment Groups .............................................43 

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5.5 
Randomization .......................................................................................................43 
5.6 
Blinding..................................................................................................................44 
5.7 
Concomitant Therapy.............................................................................................44 
5.8 
Restrictions ............................................................................................................45 
5.8.1 
Prior Therapy ...............................................................................................45 
5.8.2 
Fluid and Food Intake ..................................................................................45 
5.8.3 
Subject Activity Restrictions .......................................................................46 
5.9 
Treatment Compliance ...........................................................................................46 
5.10 
Drug Discrepancies ................................................................................................46 
5.11 
Packaging and Labeling .........................................................................................46 
5.12 
Storage and Accountability ....................................................................................47 
5.13 
Investigational Product Retention at Study Site ....................................................47 
6 
STUDY PROCEDURES .................................................................................................47 
6.1 
Assent and Informed Consent ................................................................................47 
6.2 
Demographics ........................................................................................................48 
6.3 
Medical History .....................................................................................................48 
6.4 
Physical Examination.............................................................................................48 
6.5 
Vital Signs and Pulse Oximetry .............................................................................49 
6.6 
Other Assessments .................................................................................................49 
6.6.1 
Epworth Sleepiness Scale for Children and Adolescents (ESS [CHAD]) ...49 
6.6.2 
SF-10 Health Survey for Children ...............................................................50 
6.6.3 
Columbia-Suicide Severity Rating Scale (C-SSRS) ....................................50 
6.6.4 
Children’s Depression Inventory 2nd Edition Self-Report Short Version 
(CDI 2:SR[S]) ..............................................................................................50 
6.6.5 
Multidimensional Anxiety Scale for Children 10-item (MASC-10) ...........50 
6.6.6 
Cataplexy Frequency Diary .........................................................................51 
6.6.7 
Clinical Global Impression of Severity (CGIs) Questionnaires ..................51 
6.6.8 
Patient Global Impression of Change (PGIc) for Narcolepsy Overall ........51 
6.6.9 
Clinician Global Impression of Change (CGIc) for Narcolepsy Overall and 
for Cataplexy Severity .................................................................................52 
6.6.10 
Dosing Diaries .............................................................................................52 
6.6.11 
School Attendance Diary .............................................................................52 
6.6.12 
Plan of referral .............................................................................................52 
6.7 
12-Lead Electrocardiogram (ECG) ........................................................................53 
6.8 
Polysomnography (PSG) .......................................................................................53 
6.9 
Clinical Laboratory Tests .......................................................................................54 
6.9.1 
Laboratory Parameters .................................................................................54 
6.9.2 
Sample Collection, Storage, and Shipping ..................................................59 

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6.10 
Dispensing Study Drug ..........................................................................................60 
6.11 
Pharmacokinetic Assessments ...............................................................................61 
6.12 
Adverse Events Assessments .................................................................................61 
6.12.1 
Adverse Events (AEs) ..................................................................................61 
6.13 
Concomitant Medication Assessments ..................................................................66 
6.14 
Removal of Subjects from the Study or Study Drug .............................................66 
6.14.1 
Handling of Early Terminations ..................................................................67 
6.15 
Sponsor’s Termination of Study ............................................................................67 
6.16 
Appropriateness of Measurements .........................................................................68 
7 
STUDY ACTIVITIES .....................................................................................................68 
7.1 
Subjects on Xyrem at Study Entry–Safety, Efficacy, and PK Evaluation .............68 
7.1.1 
Part 1 Screening Visit (Days –30 to -1) Subjects on Xyrem at Study Entry 
(Visit 1) ........................................................................................................68 
7.1.2 
Start of Stable-Dose Period, Subjects on Xyrem at Study Entry (Visit 2, 
Day 1)...........................................................................................................70 
7.1.3 
PK Nights 1 and 2 - Subjects Included in the PK Evaluation ......................71 
7.1.4 
End of Stable-Dose Period/Beginning of the Double-Blind Treatment 
Period*, Subjects on Xyrem at Study Entry (Visit 3, Week 3 ±3 days) ......72 
7.1.5 
End Double-Blind Treatment Period, Subjects on Xyrem at Study Entry 
(Visit 4, Week 5 +3 days) ............................................................................73 
7.1.6 
Open-Label Safety Evaluation, Subjects on Xyrem at Study Entry (Visit 5, 
4 weeks after end of Double-Blind Period) .................................................74 
7.2 
Xyrem-naïve Subjects at Study Entry–Safety, Efficacy, and PK Evaluation ........74 
7.2.1 
Part 1 Screening Visit (Days –30 to –1), Xyrem-naïve Subjects (Visit 1) ..74 
7.2.2 
Part 1 Open-Label Titration Period, Xyrem-naïve Subjects ........................76 
7.2.3 
End Titration/Start of Stable-Dose Period, Xyrem–naïve Subjects at Study 
Entry (Visit 2, Week 10 ±3 days) ................................................................79 
7.2.4 
End of Stable-Dose Period/Beginning of the Double-Blind Treatment 
Period*, Xyrem–naïve Subjects (Visit 3, Week 12 +3 days) ......................80 
7.2.5 
End Double-Blind Treatment Period, Xyrem–naïve Subjects (Visit 4, 
Week 14 +3 days) ........................................................................................81 
7.2.6 
PK Nights 1 and 2, Xyrem–naïve Subjects ..................................................82 
7.2.7 
Open-Label Safety Evaluation, Xyrem–naïve Subjects ...............................82 
7.3 
PSG Night Procedures for All Subjects .................................................................82 
7.4 
Open-Label Safety Period for All Subjects ...........................................................86 
7.4.1 
Visit 5 (4 weeks after end of the Double-Blind Treatment Period) and Visits 
7, 9, 12 (Weeks 18, 26, 39 from Day 1) .......................................................86 
7.4.2 
Phone Call Visits 6, 8, 10, 11, 13, 14 (Weeks 16, 22, 30, 34, 43, and 48 
from Day 1) ..................................................................................................87 

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7.4.3 
Visit 15 Week 52 or Part 1 Early Termination ............................................87 
7.4.4 
Visit 16 Safety Follow-up Visit ...................................................................88 
7.5 
Part 2 Open-Label Continuation Period for Subjects Continuing Directly into Part 
2 after Completing Part 1 .......................................................................................88 
7.5.1 
Visit 15 for Subjects Continuing in Part 2 (Onsite) .....................................88 
7.5.2 
Visits 19, 20, 22, 23, 25, 26, 28, 29, 31, 32, 34, 35, 37, 38, 40, and 41 
(Phone Call) .................................................................................................89 
7.5.3 
Visits 21, 27, 33, and 39 (Onsite) ................................................................89 
7.5.4 
Visits 24, 30, and 36 (Onsite) ......................................................................90 
7.5.5 
Part 2 Study Termination/Part 2 Early Termination Visit 42 (Onsite) ........90 
7.6 
Part 2 Open-Label Continuation Period for Subjects Re-enrolling after 
Completing Part 1 ..................................................................................................91 
7.6.1 
Part 2 Screening Visit 17 (Onsite) for Subjects Re-enrolling after 
Completing Part 1 of the Study ....................................................................91 
7.6.2 
Part 2 Visits for Subjects Re-enrolling Who Do Not Require Titration ......92 
7.6.3 
Part 2 Visits for Subjects Re-enrolling Who Require Titration ...................92 
8 
QUALITY CONTROL AND ASSURANCE .................................................................93 
9 
PLANNED STATISTICAL METHODS ........................................................................93 
9.1 
General Considerations ..........................................................................................93 
9.2 
Determination of Sample Size ...............................................................................94 
9.3 
Analysis Populations ..............................................................................................94 
9.4 
Demographics and Baseline Characteristics ..........................................................95 
9.5 
Handling of Dropouts and Missing Data ...............................................................95 
9.6 
Efficacy Endpoints .................................................................................................96 
9.6.1 
Statistical Analysis .......................................................................................96 
9.7 
Statistical Analysis of Pharmacokinetic Variables ................................................97 
9.8 
Interim Analysis .....................................................................................................97 
9.9 
Safety Analysis ......................................................................................................98 
10 DATA QUALITY ASSURANCE ...................................................................................99 
10.1 
Data Management ..................................................................................................99 
10.2 
Case Report Forms ...............................................................................................100 
10.3 
Retention of Data .................................................................................................100 
10.4 
Data and Safety Monitoring Board (DSMB) .......................................................100 
10.5 
Panel of Narcolepsy Experts ................................................................................100 
11 ADMINISTRATIVE CONSIDERATIONS ..................................................................101 
11.1 
Investigators and Study Administrative Structure ...............................................101 
11.1.1 
Contract Research Organization ................................................................101 
11.1.2 
Sponsor’s Medical Monitor .......................................................................101 

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11.1.3 
EU Medical Monitor ..................................................................................101 
11.1.4 
Investigator ................................................................................................101 
11.1.5 
Clinical Laboratory ....................................................................................101 
11.1.6 
Bioanalytical Laboratory ...........................................................................101 
11.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ..............................................................................................................101 
11.3 
Form FDA 1572 ...................................................................................................102 
11.4 
Ethical Conduct of the Study ...............................................................................102 
11.5 
Subject Information Assent and Consent .............................................................103 
11.6 
Subject Confidentiality ........................................................................................103 
11.7 
Protocol Adherence – Amendments ....................................................................103 
11.8 
Required Documents ............................................................................................103 
11.9 
Study Monitoring .................................................................................................104 
11.10 Protocol Deviations ..............................................................................................104 
11.11 Retention of Data .................................................................................................104 
11.12 Publication and Disclosure Policy .......................................................................104 
12 REFERENCE LIST .......................................................................................................106 
 
LIST OF IN-TEXT TABLES 
Table 1 
Xyrem Dose Initiation and Titration for Xyrem-naïve Subjects .................31 
Table 2 
List of Laboratory Tests ...............................................................................55 
Table 3 
Estimated Blood Volumes for Assays in Part 1 – Non-PK Subjects ...........57 
Table 4 
Estimated Blood Volumes for Assays in Part 1 – PK Subjects ...................58 
Table 5 
Estimated Blood Volumes for Assays in Part 2 ...........................................58 
Table 6 
PSG Night Procedures .................................................................................84 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Part 1 Study Schema –for subjects entered in the Double-Blind Period prior 
to Amendment 4 becoming effective ..........................................................27 
Figure 2 
Part 1 Study Schema –for subjects entering the Double-Blind Period after 
Amendment 4 becoming effective ..............................................................28 
Figure 3 
Part 2 Study Schema* ..................................................................................29 
Figure 4 
Example Dosing Syringe and Gradations (lines) .........................................34 
 
LIST OF APPENDIXES 
APPENDIX 1 
SCHEDULE OF EVENTS–SUBJECTS ON XYREM AT STUDY  
ENTRY ......................................................................................................110 

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Appendix 1.1 
Part 1 Screening, Stable-Dose Period, Double-Blind Treatment 
Period, Open-Label Safety Period—Subjects on Xyrem at Study 
Entry ................................................................................................110 
Appendix 1.2 
PSG Night Procedures– Subjects on Xyrem at Study Entry............116 
APPENDIX 2 
SCHEDULE OF EVENTS–XYREM-NAÏVE SUBJECTS AT STUDY 
ENTRY ......................................................................................................117 
Appendix 2.1 
Part 1 Screening, Open-Label Titration Period, Stable-Dose Period, 
Double-Blind Treatment Period– Xyrem-Naïve Subjects at Study 
Entry .................................................................................................117 
Appendix 2.2 
Part 1 Open-Label Safety Period–Xyrem-Naïve Subjects at Study 
Entry .................................................................................................123 
Appendix 2.3 
PSG Night Procedures–Xyrem-Naïve Subjects at Study Entry .......125 
APPENDIX 3 
PK EVALUATION PROCEDURES–SUBJECTS PARTICIPATING IN 
THE PK EVALUATION ..........................................................................127 
APPENDIX 4 
SEATTLE CHILDREN’S HOSPITAL AND RESEARCH CENTER: 
MAXIMUM ALLOWABLE BLOOD DRAW VOLUMES ....................128 
APPENDIX 5 
TANNER STAGES ...................................................................................130 
APPENDIX 6 
EPWORTH SLEEPINESS SCALE FOR CHILDREN AND 
ADOLESCENTS – ESS (CHAD) (RESEARCH VERSION) ..................131 
APPENDIX 7 
SF-10™ HEALTH SURVEY FOR CHILDREN ......................................132 
APPENDIX 8 
COLUMBIA-SUICIDALITY SEVERITY RATING SCALES (C-SSRS)136 
APPENDIX 9 
CHILDREN’S DEPRESSION INVENTORY 2ND EDITION SELF-
REPORT SHORT VERSION (CDI 2:SR[S]) ...........................................149 
APPENDIX 10 MULTI-DIMENSIONAL ANXIETY SCALE FOR CHILDREN 
(MASC-10) ................................................................................................151 
APPENDIX 11 CATAPLEXY FREQUENCY DIARY .....................................................153 
APPENDIX 12 STUDY DRUG DOSING DIARY ............................................................155 
APPENDIX 13 STIMULANT DOSING DIARY ..............................................................156 
APPENDIX 14 SCHOOL ATTENDANCE DIARY .........................................................157 
APPENDIX 15 CLINICAL GLOBAL IMPRESSION OF SEVERITY (CGIS) FOR 
HISTORICAL NARCOLEPSY OVERALL SEVERITY PRIOR TO ANY 
NARCOLEPSY TREATMENT ................................................................158 
APPENDIX 16 CLINICAL GLOBAL IMPRESSION OF SEVERITY (CGIS) FOR 
HISTORICAL CATAPLEXY SEVERITY PRIOR TO ANY 
NARCOLEPSY TREATMENT ................................................................159 
APPENDIX 17 CLINICAL GLOBAL IMPRESSION OF SEVERITY (CGIS) FOR 
NARCOLEPSY OVERALL .....................................................................160 
APPENDIX 18 CLINICAL GLOBAL IMPRESSION OF SEVERITY (CGIS) FOR 
CATAPLEXY SEVERITY .......................................................................161 
APPENDIX 19 PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) FOR 
NARCOLEPSY OVERALL .....................................................................162 

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APPENDIX 20 CLINICAL GLOBAL IMPRESSION OF CHANGE (CGIC) FOR 
NARCOLEPSY OVERALL .....................................................................163 
APPENDIX 21 CLINICAL GLOBAL IMPRESSION OF CHANGE (CGIC) FOR 
CATAPLEXY SEVERITY .......................................................................164 
APPENDIX 22 PART 2–OPEN-LABEL CONTINUATION–SUBJECTS CONTINUING 
DIRECTLY INTO PART 2 FROM PART 1 ............................................165 
APPENDIX 23 PART 2–OPEN-LABEL CONTINUATION–SUBJECTS RE-
ENROLLING AFTER COMPLETING PART 1 AND DO NOT 
REQUIRE TITRATION ...........................................................................168 
APPENDIX 24 PART 2–OPEN-LABEL CONTINUATION–SUBJECTS RE-
ENROLLING AFTER COMPLETING PART 1 AND REQUIRE 
TITRATION ..............................................................................................171 
APPENDIX 25 SIGNATURES OF AGREEMENT FOR PROTOCOL ...........................176 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADI 
Acceptable daily intake 
AE 
Adverse event 
AHI 
Apnea hypopnea index 
AI 
Apnea index 
ALB 
Albumin 
ALT 
Alanine aminotransferase (SGPT) 
ANCOVA 
Analysis of covariance  
ANOVA 
Analysis of variance 
AP 
Alkaline phosphatase 
AR 
Adverse reaction 
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under the plasma concentration time curve 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
Cmax 
Maximum plasma drug concentration 
Ca 
Calcium 
CBC 
Complete blood count 
CDI 2:SR[S] 
Children’s Depression Inventory 2nd Edition Self-Report Short Version 
CFR 
Code of Federal Regulations 
CGIc 
Clinical Global Impression of change 
CGIs 
Clinical Global Impression of severity 
cGMP 
Current Good Manufacturing Practice 
CHQ 
Child Health Questionnaire 
Cl 
Chloride 
CMH 
Cochran–Mantel–Haenszel 
CNS 
Central nervous system 
CO2 
Carbon dioxide 
CRF 
Case report form 
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CRO 
Contract Research Organization 
CSF 
Cerebrospinal fluid 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
DEA 
Drug Enforcement Administration 
DMP 
Data management plan 
DNS 
Disrupted nighttime sleep 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDS 
Excessive daytime sleepiness 
EMA 
European Medicines Agency 
EMLA 
Eutectic mixture of local anesthetics 
ESS 
Epworth Sleepiness Scale 
ESS (CHAD) 
ESS for Children and Adolescents 
EtCO2 
End tidal CO2  
EU 
European Union 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
g 
gram 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GH 
Growth hormone 
GHB 
Gamma-hydroxybutyrate  
GVP 
Good Pharmacovigilance Practice 
hCG 
Human chorionic gonadotropin 
HLA 
Human Leukocyte Antigen 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
ICSD 
International Classification of Sleep Disorders 
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IEC 
Independent Ethics Committee 
IGF-1 
Insulin-like growth factor-1 
IND 
Investigational New Drug  
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
K 
Potassium 
LDH 
Lactic dehydrogenase 
LH 
Luteinizing hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
MASC-10 
Multidimensional Anxiety Scale for Children 10 Item 
MSLT 
Multiple Sleep Latency Test 
Na 
Sodium 
NDA 
New Drug Application 
OSA 
Obstructive Sleep Apnea 
OTC 
Over the counter 
PD 
Pharmacodynamics 
PGIc 
Patient Global Impression of change 
PI 
Prescribing information 
PK 
Pharmacokinetics 
PSG 
Polysomnography 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QoL 
Quality of life 
REM 
Rapid eye movement 
REMS 
Risk Evaluation and Mitigation Strategy 
RLS 
Restless leg syndrome 
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SAE 
Serious adverse event 
SF-10 
SF-10 for Children 
SmPC 
Summary of Product Characteristics 
SNRI 
Serotonin–norepinephrine reuptake inhibitor 
SOP 
Standard operating procedure 
SpO2 
Oxygen saturation 
SSADH 
Succinic semi-aldehyde dehydrogenase deficiency  
SSRI 
Selective serotonin reuptake inhibitor 
SUSAR 
Suspected unexpected serious adverse reactions 
Suspected AR 
An AE for which there is a lesser degree of certainty about causality than 
an adverse reaction  
SGOT 
Serum glutamic oxaloacetic transaminase (AST) 
SGPT 
Serum glutamic pyruvic transaminase (ALT) 
SOREMPs 
Sleep onset REM periods 
TcCO2 
Transcutaneous CO2  
TCA 
Tricyclic antidepressant 
Tmax 
Time to maximum plasma concentration 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
UK 
United Kingdom 
US 
United States 
WMA 
World Medical Association 
 
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1 
INTRODUCTION 
Xyrem (sodium oxybate) oral solution (NDA 21-196) is approved in the United States (US) 
for the treatment of cataplexy in patients with narcolepsy (2002) and for the treatment of 
excessive daytime sleepiness (EDS) in patients with narcolepsy (2005). Xyrem is also 
approved in Canada for the treatment of cataplexy in patients with narcolepsy (2005) and in 
the European Union (EU) for the treatment of cataplexy in adult patients with narcolepsy 
(2005) and for use in the treatment of narcolepsy with cataplexy in adult patients with 
narcolepsy (2007).  Xyrem is currently marketed in the US, Canada, and 20 European 
countries. 
Xyrem has been on the US market for more than 14 years. It is a Schedule III controlled 
substance available only through a restricted distribution program managed by the Central 
Pharmacy under a Risk Evaluation and Mitigation Strategies (REMS). Xyrem is a CNS 
depressant and is taken at night in two equally divided doses. 
Narcolepsy is a life-long neurologic disease for which no cure has been identified. It affects 
an estimated 0.02% to 0.067% of the population worldwide and approximately 1 in 2000 
individuals in the United States (Ohayon 2007, Majid & Hirshkowitz 2010) and 4.7 of 
10,000 (0.047%) individuals in the general population of five European countries (United 
Kingdom (UK), Germany, Italy, Portugal, and Spain) (Ohayon et al. 2002). The 
symptomatology of this condition is well described in the literature, with consensus on the 
five core symptoms of narcolepsy: EDS, cataplexy, sleep paralysis, sleep-related 
(hypnagogic and hypnopompic) hallucinations, and disrupted nighttime sleep (DNS) 
(Morgenthaler et al. 2007), with EDS and cataplexy being the most common symptoms. 
Although the majority of adult patients with narcolepsy had symptoms develop before 
15 years of age—in rare cases before 5 years of age—there are no approved treatments for 
pediatric narcolepsy/cataplexy (Dauvilliers et al. 2001, Okun et al. 2002, Yoss & Daly 1960), 
although all treatments used for the treatment of adults are used to treat children with 
narcolepsy (Mignot 2012). Modafinil, a commonly used treatment for adult narcolepsy, is not 
approved in children because of safety concerns related to Stevens-Johnson syndrome and, 
per the US product label and the EU summary of product characteristics (SmPC), should not 
be used for any pediatric indication (Provigil US prescribing information (PI) 2010; Provigil 
SmPC 2012). Dextroamphetamine is the only medication that provides dosing information 
for pediatric narcolepsy (Dexedrine Spansules® US PI 2010); however, it is not approved for 
the treatment of narcolepsy for children or adolescents in Europe. Other stimulants, which 
are often used for the treatment of EDS, and antidepressants, which are often used for 
cataplexy, may provide insufficient benefit and are associated with known risks. Clearly a 
need exists for safe and effective treatments for pediatric patients with narcolepsy/cataplexy. 
The detrimental effects of narcolepsy on daily functioning and activities, psychosocial 
functioning, quality of life, and work performanceas well as effects on personal and public 
safety, given the increased risk of automotive and equipment accidentsare well described 
in the literature on adult patients (Broughton et al. 1981, Ingravallo et al. 2012). The effects 
of narcolepsy on the lives of pediatric patients (children and adolescents younger than 18 
years of age) are less commonly described but equally burdensome. Pediatric narcolepsy is 
associated with limitations on children’s activities due to EDS and cataplexy, poor 
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performance in school (after symptom onset) and difficulty with peers (Stores et al. 2006, 
Peraita-Adrados et al. 2011, Aran et al. 2010) and a variety of psychiatric and medical 
comorbidities including depression (Stores et al. 2006, Peraita-Adrados et al. 2011, Aran et 
al. 2010, Partinen et al. 2012), obesity (Peraita-Adrados et al. 2011, Poli et al. 2013), and 
precocious puberty (Peraita-Adrados et al. 2011, Poli et al. 2013).  
Xyrem has been used to treat narcolepsy symptoms in children and adolescents. Data from 
published studies in pediatric and adult patients indicate a similar safety profile and 
therapeutic response to Xyrem in the two age groups (<18 and ≥18 years). Post marketing 
data from nearly 1,500 pediatric patients treated with Xyrem also suggest a similar safety 
profile in the two age groups, although some non-serious events are reported more commonly 
in pediatric patients than in adults, and vice versa. 
Jazz Pharmaceuticals is conducting this clinical study with Xyrem in pediatric patients with 
narcolepsy with cataplexy to generate efficacy, safety, and pharmacokinetics (PK) 
information on Xyrem in the pediatric population.  
1.1 
Background and Rationale 
This study is being conducted under the US Food and Drug Administration’s (FDA) pediatric 
Written Request. 
On February 24, 2016, the Data and Safety Monitoring Board (DSMB) for this study 
reviewed the results from a pre-planned interim analysis of the primary efficacy results based 
on 35 subjects having completed or discontinued from the Double-blind Randomized 
Withdrawal Period of the protocol. The result of this analysis demonstrated positive efficacy 
on the primary endpoint, the change in weekly number of cataplexy attacks from the last 
2 weeks of the Stable-Dose Period to the 2 weeks of the Double-Blind Treatment Period at a 
significance level of p<0.005. Based on this analysis, the DSMB recommended that the 
placebo treatment in the Double-Blind Withdrawal Period of the trial be stopped and the 
open-label portion of the study be continued, so as not to expose further subjects to placebo 
treatment. Amendment 4 to this protocol was based on that recommendation. The current 
amendment (Amendment 5) provides subjects who have completed one year in the study 
(Part 1) the opportunity to continue treatment for up to an additional 2 years or until they 
reach 18 years of age or until up to 3 months after the US FDA decision on the addition of 
pediatric data to the Xyrem US PI, whichever occurs first. 
1.1.1 
Clinical Experience 
1.1.1.1 
Adult Studies 
The effectiveness of Xyrem in treating the two main symptoms of narcolepsy—EDS and 
cataplexy—in adult subjects was demonstrated in three controlled clinical trials with 611 
patients with narcolepsy (398 subjects treated with Xyrem). Adverse events seen with 
frequencies of ≥5% and twice the rate of placebo in Xyrem-treated patients were nausea 
(20.9%), dizziness (19.7%), vomiting (8.5%), enuresis (6.5%), and diarrhea (5%). Xyrem 
was also evaluated in one Phase 2 and two Phase 3 randomized, controlled clinical trials in 
patients with fibromyalgia; however, Xyrem is not approved for fibromyalgia. Results of 
those studies indicate a similar safety profile to that seen in clinical trials for narcolepsy 
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(Moldofsky et al. 2010, Russell et al. 2011, Spaeth et al. 2012, Spaeth et al. 2013). A study in 
patients with moderate to severe sleep apnea was conducted as a post marketing commitment 
(requirement).  Xyrem treatment was not associated with an increase in apnea hypopnea 
index (AHI) but some clinically significant desaturations were observed (George et al. 2010). 
The PK of Xyrem was extensively characterized in the clinical program that supported use of 
this drug for the indications of EDS and cataplexy in patients with narcolepsy. Xyrem is 
eliminated almost exclusively by metabolism through the Krebs cycle and does not inhibit 
CYP enzymes (Xyrem US PI 2016). Following oral administration, Xyrem is absorbed 
rapidly and consistently across the clinical dose range, with an absolute bioavailability of 
about 88%. The average peak concentrations (Cmax) following administration of each of two 
2.25 g doses given under fasting conditions 4 hours apart were similar. The average time to 
peak plasma concentration (Tmax) ranged from 0.5 to 1.25 hours. Following oral 
administration, the plasma concentrations of sodium oxybate increased more than dose-
proportionally, with blood levels increasing 3.7-fold as the total daily dose is doubled from 
4.5 to 9 g.  
1.1.1.2 
Pediatric Studies 
EFFICACY DATA IN THE LITERATURE 
The effectiveness of Xyrem in pediatric patients with narcolepsy/cataplexy has been 
described in five published studies: one controlled study and four published retrospective 
case analyses, with a combined total of 100 patients (Murali & Kotagal 2006, Aran et al. 
2010, Lecendreux et al. 2012, Mansukhani & Kotagal 2012, Huang & Guilleminault 2009). 
Overall, Xyrem was shown to be effective in treating the symptoms of cataplexy, EDS, and 
DNS in narcolepsy in the scientific literature reporting its effects in children and adolescents. 
SAFETY DATA IN THE LITERATURE 
Safety data from Xyrem in children and adolescents with narcolepsy/cataplexy were reported 
in six published studies: four retrospective case analyses and two prospective studies, with a 
combined total of 109 patients who took Xyrem for 2 to 90 months (Murali & Kotagal 2006, 
Aran et al. 2010, Lecendreux et al. 2012, Mansukhani & Kotagal 2012, Huang & 
Guilleminault 2009, Poli et al. 2012). The safety profile of Xyrem in children and 
adolescents as reported in the scientific literature is similar to the known safety profile of 
Xyrem in adults. 
Adverse events reported in these six studies were similar to those seen with adults. Adverse 
events reported by more than 10% of patients in any one study were as follows: weight loss, 
headache, nausea, DNS, irritability, parasomnias, dry mouth, increased awakenings, 
dizziness, terminal insomnia, groaning, and sleepiness. There were no reports of premature 
puberty in 11 pre-pubertal children taking Xyrem (Aran et al. 2010) or adverse effects on 
growth parameters including weight, height, and body mass index (BMI) in a study of 15 
children and adolescents (Mansukhani & Kotagal 2012). In these publications, the most 
serious AEs were increased nightmares and suicidal ideation and gesture in a 9-year-old 
patient (Murali & Kotagal 2006). 
Reasons for discontinuations across the six studies included increased nightmares and 
suicidal ideation, dissociative feelings, and problems receiving drug shipments (Murali & 
Kotagal 2006); AEs (not specified) in 18% of pre-pubertal patients, lack of efficacy in 15% 
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of peri- or post-pubertal patients, and cost of drug in 5% to 6% of all patients (Aran et al. 
2010); sleep loss and persistent nausea, each in 2 of 27 (7%) patients (Lecendreux et al. 
2012); nausea, constipation and dissociative feelings in 1 of 15 (7%) patients, and body aches 
and dizziness in 1 of 15 (7%) patients who later resumed use of the drug 
(Mansukhani & Kotagal 2012); and nausea in 1 of 9 (11%) patients (Poli et al. 2012). Huang 
& Guilleminault (2009) did not report discontinuations. These reasons for discontinuation are 
common in adult patients as well. 
PHARMACOKINETIC DATA  
There are no PK data on Xyrem in children under 18 years of age. Although there are no 
studies examining the PK of sodium oxybate in children, it is known that the gastrointestinal 
system, which may have direct consequences on absorption bioavailability, clearance, and 
biotransformation of drugs, is functionally mature by about 1 year of age (Walthall et al. 
2005). Intravenous GHB has been used and studied in children at doses of 25 to 50 mg/kg 
(Rousseau et al. 2012) and up to 90 mg/kg for sedation (Meyer et al. 2003); and at doses up 
to 100 mg/kg for anesthesia (Hunter et al. 1971). The central nervous system (CNS) effects 
were consistent with those obtained with intravenous GHB in adults (Kleinschmidt & 
Mertzlufft 1995, Solway & Sadove 1965), suggesting that post-absorption PK and 
pharmacodynamics are similar in children and adults. 
1.1.2 
Postmarketing Safety Data: 2002 through September 30, 2012  
A total of 43,306 US patients have received at least one shipment of Xyrem from product 
launch in 2002 through September 30, 2012. Of those, approximately 1,500 patients began 
Xyrem treatment when they were younger than 18 years old, totaling approximately 
1,150 patient-years of exposure in pediatric patients, with a duration of use up to 7.4 years. 
Overall, the safety profile for frequent AEs reported in pediatric patients on Xyrem is similar 
to that seen with adults, with nausea, vomiting, dizziness, headache, somnolence, insomnia, 
and fatigue among the most common AEs in both patient populations. Enuresis, 
somnambulism, drug dose omission, nasopharyngitis, drug ineffective, and cataplexy were 
among the most frequently reported AEs in pediatric patients but these AEs were not as 
commonly reported in adults. Most of these common pediatric AEs are typically not 
considered to be serious, and some are related to childhood development and/or the 
underlying disease. Enuresis, for example, is a typical childhood disorder, and Xyrem likely 
contributes to its re-emergence by promoting deep sleep. 
Three deaths were reported in children who had received Xyrem treatment: one case of 
aspiration pneumonia in a 3-year-old boy with substantial developmental issues, one 
unconfirmed cause of death in an 11-year-old girl with reported cancer pain, and one 
homicide victim who was a 16-year-old girl. There is no evidence that Xyrem was abused or 
misused by pediatric patients prescribed Xyrem, although medication errors, primarily from 
misunderstanding dosing instructions and abuse in one pediatric case associated with drug 
diversion from a patient, did occur. There is no signal that pediatric patients are more prone 
than adult patients taking Xyrem to depression, anxiety, convulsion, depressed level of 
consciousness, impaired respiratory drive, or psychiatric problems. No completed suicide 
was reported in pediatric patients. Suicidal ideation was coded in 5 pediatric patients, and 
suicide attempt was coded in 4 patients (all of whom were 16 or 17 years old); 3 of the 
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4 patients had a history of depression or bipolar disorder. Of these 4 patients, 2 used 
antiepileptic drugs, 2 used SSRIs, and one used an antidepressant (Xyrem IB). 
1.1.3 
Drug-Drug Interaction  
Several drug-drug interaction studies in healthy volunteers (Xyrem with zolpidem, 
protriptyline, modafinil, omeprazole, duloxetine, tramadol, lorazepam, ibuprofen, diclofenac, 
and divalproex sodium) were conducted to evaluate the effects of co-administration of 
medications likely to be used concomitantly with Xyrem. There were no significant PK or 
pharmacodynamic (PD) interactions between Xyrem and zolpidem, protriptyline, modafinil, 
omeprazole, duloxetine, tramadol, lorazepam, or ibuprofen. 
• Co-administration of Xyrem with diclofenac showed no significant differences in plasma 
PK or renal excretion of sodium oxybate, and it did not appear to affect the PK of 
diclofenac. However, PD interactions, including reduced impairments to attention, were 
observed in the co-administration of Xyrem with diclofenac.  
• Co-administration of Xyrem with divalproex sodium resulted in an increase in AUC and 
an increase in renal clearance of sodium oxybate; Cmax was unchanged. It did not appear 
to affect the PK of valproic acid. Pharmacodynamic interactions were also observed 
following co-administration; these included increased impairment to cognitive function 
and increased sleepiness.  
Among adverse events (AEs) occurring in at least 2 healthy subjects in any treatment group 
in these studies, the following AEs were seen more frequently with co-administration than 
with Xyrem alone: 
• Zolpidem: dizziness 
• Protriptyline: dizziness 
• Modafinil: headache, vomiting, emotional lability 
• Omeprazole: vomiting, stupor 
• Duloxetine: somnolence, depressed mood  
• Tramadol: somnolence, nausea, dizziness, abdominal pain, vomiting 
• Lorazepam: somnolence, nausea, dizziness, vomiting 
• Ibuprofen: dizziness, headache, euphoric mood 
• Diclofenac: dry mouth, feeling hot, somnolence, euphoric mood 
• Divalproex sodium: nausea, somnolence, euphoric mood. 
2 
STUDY OBJECTIVES 
2.1 
Objectives 
Primary objectives are: 
1. To evaluate the efficacy of Xyrem (sodium oxybate) oral solution in the treatment of 
cataplexy in pediatric subjects with narcolepsy 
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2. To evaluate the safety of Xyrem in the treatment of cataplexy in pediatric subjects 
with narcolepsy for up to one year (and potentially more than one year in some 
subjects participating in a continuation of the open-label safety evaluation) 
Secondary objectives are:  
1. To evaluate the efficacy of Xyrem in the treatment of excessive daytime sleepiness 
(EDS) in pediatric subjects with narcolepsy with cataplexy 
2. To characterize the pharmacokinetics (PK) of Xyrem in pediatric subjects (ages 7-17 
years) with narcolepsy with cataplexy    
3. To evaluate the safety of titrating Xyrem in pediatric subjects to an effective and 
tolerable dose 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
Under Amendment 5, this study is divided into two parts: Part 1 includes one year of 
treatment, and Part 2, the Open-Label Continuation Period, provides the opportunity to 
continue treatment for up to an additional 2 years. 
Part 1 of this study was initially designed as a double-blind, placebo-controlled, randomized-
withdrawal, multicenter study of the efficacy and safety of Xyrem (sodium oxybate) oral 
solution. As a result of a preplanned interim analysis, which demonstrated positive efficacy 
results on the primary efficacy endpoint, the protocol was amended (Amendment 4) to 
replace the placebo treatment in the Double-Blind Treatment Period with open-label Xyrem 
treatment. After Amendment 4 becoming effective, all subjects entering the Double-Blind 
Treatment Period will receive open-label Xyrem treatment. For administrative reasons, the 
term “Double-Blind Treatment Period” will continue to be used throughout the protocol. 
Following the Double-Blind Treatment Period (2 weeks), Part 1 includes an open-label safety 
extension allowing subjects to continue Xyrem treatment for up to one year. In addition, the 
PK of Xyrem will be evaluated in a subset of subjects in Part 1.  
Part 2 is an open-label continuation period, to provide continued access to Xyrem to subjects 
who have completed one year in the study and to monitor the long-term safety of Xyrem. 
Upon approval of Amendment 5, subjects who complete one year in the study (Part 1) may 
continue in Part 2, which will provide up to 2 years of additional treatment. Subjects who 
have already completed Part 1 prior to Amendment 5 may re-enroll in Part 2. Subjects will 
have the opportunity to continue open-label Xyrem treatment in Part 2 until the first 
occurrence of any of the following: 
• Up to an additional 2 years 
• Until the subject reaches 18 years of age 
• Until up to 3 months after the US FDA decision on the addition of pediatric data to the 
Xyrem US prescribing information (PI)  
Children and adolescents, diagnosed with narcolepsy with cataplexy who are currently 
treated with Xyrem or are Xyrem naïve, with or without concomitant stable stimulant use, are 
eligible to enter the study. For this study, a Xyrem-naïve subject is defined as a subject who 
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has never been treated with Xyrem or who was previously treated with Xyrem and 
discontinued Xyrem for at least one month prior to the Part 1 Screening visit for reasons 
other than lack of efficacy and/or tolerability issues (e.g., lost insurance coverage, could not 
afford Xyrem, changed prescribers). 
Figure 1 presents the study schema for subjects who entered the Double-Blind Period prior to 
Amendment 4 becoming effective and Figure 2 presents the study schema for subjects 
entering the Double-Blind Period after Amendment 4 becoming effective. Figure 3 presents 
the study schema for Part 2 of the study. Schedules of events for Part 1 are in Appendix 1 and 
Appendix 2 for subjects on Xyrem at study entry and Xyrem-naïve subjects, respectively. 
Schedules of events for Part 2 are in Appendix 22 for subjects continuing directly from 
Part 1, Appendix 23 for subjects re-enrolling who do not require titration, and Appendix 24 
for subjects re-enrolling who require titration. 
 
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Figure 1 
Part 1 Study Schema –for subjects entered in the Double-Blind Period prior to Amendment 4 becoming 
effective 
 
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Figure 2 Part 1 Study Schema –for subjects entering the Double-Blind Period after Amendment 4 becoming effective 
 
 
 
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Figure 3 
Part 2 Study Schema*  
 
 
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3.1.1 
Screening Period  
Part 1 Screening  
All subjects will be evaluated for eligibility during a Screening Period of up to 30 days. If 
needed, additional screening time may be granted with permission of the Medical Monitor. 
However, if it has been more than 45 days since the Screening safety labs pertinent to 
eligibility were drawn, these labs may need to be repeated as instructed by the Medical 
Monitor. Eligibility screening will be performed prior to the Xyrem Open-Label Titration for 
Xyrem-naïve subjects or prior to the open-label Stable-Dose Period for subjects already 
taking a stable dose of Xyrem and whose cataplexy symptoms are stable.  
All subjects who are eligible for Part 1 of the study must be evaluated by polysomnography 
(PSG) for sleep-disordered breathing during the Part 1 Screening Period.  
Blood volumes drawn during the study should not exceed the amounts recommended in the 
guidance from Seattle Children’s Hospital (Appendix 4), European Union (EU) Guidelines 
(2008), or other local regulations. Therefore, for those subjects on Xyrem at study entry who 
have low body weight and are participating in the PK evaluation during the Stable Dose 
Period, it is recommended that the screening blood draw be performed at the beginning of the 
Part 1 Screening Period and that the Part 1 Screening Period be as close as possible to 
30 days to minimize the amount of blood drawn over 30 days. 
Part 2 Screening  
All subjects who complete Part 1 of the study are eligible to participate in Part 2. Subjects 
who re-enroll after completing Part 1 of the study must complete the Part 2 Screening. Part 2 
Screening will occur within 2 weeks before the first drug-dispensing visit; however, 
additional screening time may be granted with permission of the Medical Monitor, if needed. 
Subjects re-enrolling in Part 2 within 2 weeks of Visit 15 will not require clinical laboratory 
tests, urine drug screening, an alcohol test, or a serum pregnancy test at the Part 2 Screening 
visit (Visit 17). For these subjects, Visit 17 and the first drug-dispensing visit (Visit 18) may 
occur on the same day. 
3.1.2 
Open-Label Titration Period for Subjects who are Xyrem naïve (up to 
10 weeks)  
For subjects who are Xyrem naïve or who re-enroll in Part 2 and require titration (i.e., have 
been off Xyrem for ≥1 month), Xyrem therapy will be initiated based on the subjects’ weight 
as specified in Table 1. Xyrem doses are administered in two equally divided doses (see 
Section 5.3).    
Subjects will be titrated on Xyrem to achieve a maximum clinical benefit in cataplexy and 
EDS while maintaining tolerability. Dose adjustment during the Part 1 Open-Label Titration 
Period and Part 2 Open-Label Titration will proceed based on the subject’s weight to a dose 
level no higher than the maximum dose described in Table 1 in 10 weeks. The study drug 
titration rate is ≤1 g/night/week for subjects <45 kg, and ≤1.5 g/night/week for subjects 
≥45 kg (Table 1). Each dose must match a printed line on the dosing syringe (Figure 4). Once 
the Xyrem dose has been optimized per the Investigator’s judgment, the subject may enter 
the open-label Stable-Dose Period (for Part 1) or continue in the Open-Label Continuation 
(for Part 2) with that dose.  
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Table 1 
Xyrem Dose Initiation and Titration for Xyrem-naïve Subjects 
Subject weight 
Initiation dose 
(taken in two equally 
divided doses)* 
Titration regimen 
Maximum total nightly dose 
<30 kg 
≤2 g/night 
≤1 g/night/week 
6 g/night 
≥30 kg – <45 kg 
≤3 g/night 
≤1 g/night/week 
7.5 g/night 
≥45 kg 
≤4.5 g/night 
≤1.5 g/night/week 
9 g/night 
*At bedtime and 2.5 to 4 hours later. For children who sleep more than 8 hours per night, Xyrem may be given 
after bedtime, while the child is in bed, in two equally divided doses 2.5 to 4 hours apart. 
Xyrem dose reduction is allowed for tolerability reasons at any time, at the Investigator’s 
discretion, in any decrement that is a multiple of 0.5 g/night. Stimulant taper and withdrawal 
may be attempted at the Investigator’s discretion during the Open-Label Titration Period. 
3.1.3 
Open-Label Stable-Dose (Stable-Dose) Period (2-3 weeks)  
3.1.3.1 
For Subjects on Xyrem at Study Entry  
Subjects who have been titrated to a stable dose of Xyrem prior to study entry will remain on 
the stable dose and regimen (i.e., two equally divided doses or two unequally divided doses) 
of Xyrem, and a stable stimulant dose if applicable, for 3 weeks with the exception of PK 
nights (if applicable) (see Section 3.1.7). During the first week of this 3-week period, 
subjects and/or parent(s)/guardian(s) will become familiar with methods of recording 
efficacy and safety data.  
3.1.3.2 
For Xyrem-naïve Subjects  
Xyrem-naïve subjects who have been titrated to an optimal Xyrem dose and a stimulant dose 
(if applicable), during the Open-Label Titration Period, will remain on the dose that is 
established at the end of the Open-Label Titration Period for 2 weeks during the Stable-Dose 
Period. Subjects and/or parent(s)/guardian(s) will become familiar with the methods of 
recording efficacy and safety data during the Open-Label Titration Period. 
On the last night of the Stable-Dose Period, Xyrem-naïve subjects will be assessed by PSG 
while taking Xyrem (End of Stable-Dose/Pre-Randomization PSG Night). [Note: Subjects 
entering the Double-Blind Treatment Period after Amendment 4 becoming effective will not 
be randomized, however, for administrative reasons the terminology for this PSG will retain 
the reference to “Pre-Randomization”.] 
3.1.4 
Double-Blind Treatment Period (2 weeks)  
3.1.4.1 
Subjects entering the Double-Blind Treatment (Randomized Withdrawal) Period 
prior to Amendment 4 becoming effective 
Subjects had been randomized 1:1 to one of the following two treatment groups at the end of 
the Stable-Dose Period (Visit 3). 
1. Xyrem: Active Xyrem will be continued as a double-blind treatment at the stable 
dose taken and regimen used in the prior 2 weeks 
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2. Placebo: Xyrem placebo will be initiated as a double-blind treatment at a volume and 
regimen equivalent to the Xyrem dose taken in the prior 2 weeks. 
During the Double-Blind Period, subjects will remain on the same dosing regimen they used 
during the Stable-Dose Period, with the exception of PK nights (if applicable) when all 
subjects have to take two equally divided doses 4 hours apart. For subjects on concomitant 
stimulant therapy, subjects will remain on the same stable stimulant dose as at the end of the 
Stable-Dose Period during the Double-Blind Treatment Period.  
Subjects who complete the entire 2-week Double-Blind Treatment Period will be eligible to 
continue in the open-label Xyrem safety evaluation.  
3.1.4.2 
Subjects entering the Double-Blind Treatment Period after Amendment 4 
becoming effective 
Subjects entering the Double-Blind Treatment Period after Amendment 4 becoming effective 
will receive open-label Xyrem treatment during this period. 
3.1.5 
Open-Label Safety Period (to allow up to 1 year Xyrem exposure) 
Subjects who are eligible to participate in the Open-Label Safety Period will participate in 
this period for 47 weeks if they entered the study on a stable dose of Xyrem or for a period of 
38-45 weeks if they entered as Xyrem naïve, depending on the duration of the titration period 
in which they participated (45 weeks assumes that the shortest titration period will be 
3 weeks for those subjects who reach an optimal response very quickly during titration).  
All study procedures and assessments will be carried out according to the planned schedule 
(changes in Xyrem dose will generally not affect the schedule).  
All subjects will be seen in the clinic 4 weeks after the Open-Label Safety Period begins 
(Visit 5) and then at Weeks 18, 26, 39, and 52 from study entry (Day 1). However, if in the 
case of subjects who are Xyrem naïve, Visit 5 is within 2 weeks of the Week 18 visit, the 
first clinic visit of the Open-Label Safety Period will be the Week 18 visit.  
Subjects/parent(s)/guardian(s) will be contacted in the interim by phone at Weeks 16, 22, 30, 
34, 43, and 48 from study entry (Day 1). A final PSG will be performed at Week 52 or the 
Part 1 early termination visit (if the subject who terminates early is willing to participate in 
another PSG night and if they are willing to take Xyrem the evening of the PSG). The Part 1 
early termination PSG does not apply for subjects who discontinue before entering the Open-
Label Safety Period. Clinicians may schedule clinic or phone visits between protocol-
specified clinic visits to ensure subject safety or to accommodate PK visits (if applicable). 
Additional drug dispensing visits may be added as required by local law or at the 
Investigator’s discretion based on safe drug storage requirements. Stimulants for EDS may 
be used as adjunctive therapy throughout the trial, and can be adjusted or discontinued as 
appropriate.   
For subjects who had entered the Double-Blind Treatment Period before Amendment 4 was 
effective, upon entering the Open-Label Safety Period, these subjects will be started at a dose 
no higher than half the Xyrem dose they received at the end of the Stable-Dose Period or the 
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initiation dose defined in Table 1, whichever is higher. Subjects will then be titrated up to 
their optimal dose as tolerated according to the Investigator’s judgment (the maximum dose 
should not exceed the doses defined in Table 1 or the stable dose prior to study entry, 
whichever is higher, and should not be greater than 9 g/night). Xyrem dose uptitration is 
allowed at no more than 1.5 g/night, and during dose up titration the Investigator must 
monitor tolerability, which includes AEs observed at night, such as confusion, respiratory 
depression, sleepwalking and other parasomnias; residual effect and AEs observed during 
daytime, such as confusion, somnolence, pronounced levels of depressed consciousness, 
depressed mood and suicidality, anxiety, abuse or misuse of Xyrem, and weight loss. 
Subjects may take two equally divided doses or two unequally divided doses with the 
exception of PK nights (if applicable) when all subjects have to take two equally divided 
doses 4 hours apart. Xyrem dose adjustment due to tolerability and efficacy is permitted. 
Only doses that match the printed gradations (lines) on the dosing syringe are permitted.  
3.1.6 
Safety Follow-up Visit (2 weeks post Part 1 termination)  
If a subject does not complete Part 1 of the study or does not immediately continue into Part 
2, a safety follow-up visit will be conducted 2 weeks following the Part 1 termination visit.   
After participation in Part 1 of the study, subjects will have received up to 12 months 
(52 weeks) active treatment. The duration of Part 1 is at most 54 weeks, including the 2-week 
post-study period before the safety follow-up visit. Subjects will not be given study drug 
during this 2-week period but are expected to be treated for their cataplexy and EDS with any 
commercially available medications as appropriate during this time by their treating 
physicians.  
See Appendix 1 and Appendix 2 for the Schedules of Events. 
3.1.7 
Open-Label PK Evaluation 
At certain study sites during Part 1, eligible subjects will additionally participate in the PK 
evaluation. Subjects will be stratified to two age groups: 7-11 years of age and 12-17 years of 
age. Up to 18 subjects in each of the two age groups will be eligible to participate in the PK 
evaluation. Every effort will be made to ensure a minimum of 12 subjects in each age group 
complete the PK assessments. If the variability of PK data in children and adolescents is 
comparable to that of adults, a sample size of 12 completers in each age group is expected to 
provide adequate precision to characterize the PK of sodium oxybate in each age group. 
However, when sufficient data are obtained to characterize the PK profile with adequate 
precision during the study, as determined by the Data and Safety Monitoring Board, or when 
enrollment of 100 subjects in the study has been reached, enrollment in the PK evaluation 
will stop and existing data will be analyzed and reported.   
Eligible subjects will spend two nights in the clinic for the PK evaluation (PK Nights 1 and 
2). PK evaluation will occur at any time while subjects are on a stable dose of Xyrem. 
On PK Night 1, subjects will receive one half of their usual and current total nightly Xyrem 
dose (administered as two equally divided doses, given while in bed at bedtime and 4 hours 
later).  Subjects will return to the clinic for PK Night 2 and will receive Xyrem at their stable, 
usual dose (administered as two equally divided doses, given while in bed at bedtime and 
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4 hours later). Each divided dose must match a printed gradation (line) on the dosing syringe; 
therefore, if a dose cannot be measured using the lines on the dosing syringe, the dose should 
be decreased to the next lower printed line on the dosing syringe. For example, if a subject is 
supposed to take a total dose of 4.25 g on a PK night, then the two equally divided doses 
would be 2.125 g each. There is no printed line for 2.125 g on the dosing syringe. The next 
lower line on the syringe would be 2 g (see Figure 4). The subject would then take the two 
equally divided doses of 2 g each, which would equal a total nightly dose of 4 g. The actual 
doses taken will be recorded on the CRF. 
Figure 4 
 
Example Dosing Syringe and Gradations (lines) 
 
 
 
  
 
 
 
 
A limited number of blood samples will be taken to measure sodium oxybate concentrations 
on each of these PK nights. Samples will be taken relative to the first nightly Xyrem dose at 
0 (pre-dose), 0.75, 1.5, 2.5, and 4 hours (pre-2nd dose), to characterize the PK of the first 
dose of Xyrem, and two samples will be taken to characterize the peak and residual exposure 
associated with the second dose, at 4.75 and 8 hours after the first dose of Xyrem (total blood 
volume required for PK samples is 40 mL taken over a minimum of 2 days). Following the 
PK nights, subjects will resume their usual Xyrem dose and regimen and their stimulant dose, 
if applicable.  
Subjects taking two unequally divided doses are eligible to participate in the PK evaluation if 
the subjects are willing to take two equally divided doses 4 hours apart on PK nights. The 
equally divided doses for these subjects must also match the printed lines on the dosing 
syringe (see above). 
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Subjects in the PK evaluation will also undergo all other Part 1 study procedures specified in 
the protocol.  
3.1.8 
Open-Label Continuation Period (Part 2) 
Upon approval of Amendment 5, subjects who have completed Part 1 in the study may 
participate in Part 2 of the study. Subjects ongoing in the study when Amendment 5 becomes 
effective may enter Part 2 after completing the Part 1 Open-Label Safety Period, bypassing 
the 2-week Safety Follow-up Period. These subjects will begin Part 2 at Visit 15. Subjects 
who have already completed Part 1 of the study may re-enroll in Part 2. Subjects who 
re-enroll must complete the Part 2 Screening Visit. Subjects must be on a stable dose of 
Xyrem, or if they have been off Xyrem for ≥1 month, must be titrated to an effective and 
tolerable Xyrem dose. For subjects who have been off Xyrem for less than 1 month, titration 
may also be required per the Investigator’s judgment. Subjects will be titrated to Xyrem as 
described in Section 3.1.2. In Part 2, subjects will have the opportunity to continue open-
label Xyrem treatment until the first occurrence of any of the following: 
• Up to an additional 2 years 
• Until the subject reaches 18 years of age  
• Until up to 3 months after the US FDA decision on the addition of pediatric data to the 
Xyrem US prescribing information (PI)  
Safety will be assessed at scheduled visits throughout Part 2. All subjects will be seen in the 
clinic at the beginning of Part 2 (Visit 15 for subjects continuing and Visits 17 and 18 for 
subjects re-enrolling) and every 3 months thereafter. Subjects/parent(s)/guardian(s) will be 
contacted in the interim months by phone. Clinicians may schedule clinic or phone visits 
between protocol-specified clinic visits to ensure subject safety. Additional drug dispensing 
visits may be added as required by local law or at the Investigator’s discretion based on safe 
drug storage requirements. For subjects turning 18 years of age, the Part 2 Study Termination 
visit must be scheduled prior to the subject’s 18th birthday. 
Subjects who re-enroll and require titration in Part 2 will be titrated on Xyrem to achieve 
clinical benefit in cataplexy and EDS while maintaining tolerability based on the 
Investigator’s assessment. Following Visit 18 (begin titration), the subject/parent(s)/ 
guardian(s) will be contacted by phone at titration weeks T2, T3, T4, T7, T8, and T10 to 
determine if additional titration is necessary or to follow up after the subject has reached a 
stable dose. 
3.2 
Rationale for Study Design and Control Group 
A double-blind placebo controlled randomized-withdrawal study of Xyrem in adult 
narcolepsy patients, OMC-SXB-21, was one of the pivotal studies that supported FDA 
approval of Xyrem for the treatment of cataplexy and EDS in patients with narcolepsy. This 
study design ensures that all subjects are able to receive Xyrem treatment and minimizes the 
duration of placebo exposure. This study is being conducted under FDA’s pediatric Written 
Request, in which the Agency requested a double-blind, placebo-controlled, randomized 
withdrawal, multicenter study of the efficacy and safety of sodium oxybate, combined with 
an open-label evaluation of the pharmacokinetics of sodium oxybate, and an open-label 
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safety evaluation with combined time of sodium oxybate treatment of up to one year (and 
potentially more than one year in some subjects participating in a continuation of the open-
label safety evaluation) in pediatric patients who have narcolepsy with cataplexy. Placebo is 
the only control group used in this study, there are no other medications approved for the 
treatment of cataplexy. In this study, the maximal time that any pediatric subject will be 
exposed to placebo is 2 weeks.   
As a result of a preplanned interim analysis, which demonstrated positive efficacy results on 
the primary efficacy endpoint, the protocol has been amended (Amendment 4) to replace 
placebo treatment in the Double-Blind Treatment Period with open-label Xyrem treatment. 
After Amendment 4 becoming effective, all subjects entering the Double-Blind Treatment 
Period will receive open-label Xyrem treatment during this period.  
Part 2 is an open-label continuation period, to provide continued access to Xyrem to subjects 
who have completed one year in the study and to monitor the long-term safety of Xyrem.  
3.3 
Study Duration 
It is anticipated that enrollment in Part 1 will be completed within 2 years. Following the Part 
1 Screening Period of up to 30 days (if needed, additional time may be granted with 
permission of the Medical Monitor), the expected duration of study participation for each 
subject in Part 1 will be approximately 54 weeks, including a 2-week safety follow-up 
period. Under Amendment 5, subjects may continue on in Part 2, the Open-Label 
Continuation Period, after 52 weeks in Part 1, bypassing the 2-week Safety Follow-up 
Period, or they may re-enroll in Part 2 after completing Part 1. Subjects may participate in 
Part 2 for up to an additional 2 years or until they reach 18 years of age or for up to 3 months 
after the US FDA decision on the addition of pediatric data to the Xyrem US PI, whichever 
occurs first. Therefore, a subject’s duration of participation in Part 2 will be up to 2 years. 
4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
The study will enroll pediatric subjects who are diagnosed with narcolepsy with cataplexy, 
who have provided assent, and whose parent(s) or guardian(s) have signed the informed 
consent form in accordance with local IRB/IEC requirements. At least 100 subjects will be 
enrolled in the study. Every effort will be made to enroll approximately 30 subjects on 
Xyrem at study entry of the anticipated 100 subjects enrolled. Other subjects enrolled will be 
Xyrem naïve at study entry. 
A subset of the subjects who are taking Xyrem at a stable dose for their narcolepsy symptoms 
will participate in the PK evaluation during Part 1. Up to 18 subjects in each of the two age 
groups (7-11 year olds and 12-17 year olds) will be enrolled. Every effort will be made to 
ensure a minimum of 12 subjects in each age group complete the PK assessments.  However, 
when sufficient data are obtained to characterize the PK profile with adequate precision 
during the study, as determined by the Data and Safety Monitoring Board, or when 
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enrollment of 100 subjects in the study has been reached, enrollment in the PK evaluation 
will stop and existing data will be analyzed and reported. 
4.2 
Inclusion Criteria  
Each subject must meet the following criteria to be enrolled in Part 1 of the study. 
1. Male or female subjects aged 7-16 years at Visit 2 for subjects on Xyrem at study 
entry and at Visit 1.1 for Xyrem-naïve subjects (to ensure subjects are <18 years of 
age at the end of Part 1) 
2. Have a primary diagnosis of narcolepsy with cataplexy that meets International 
Classification of Sleep Disorders (ICSD)-2 or ICSD-3 criteria, whichever was in 
effect at the time of the diagnosis or, with the permission of the Medical Monitor, 
completes a Multiple Sleep Latency Test (MSLT) during Screening to confirm the 
diagnosis of Type 1 narcolepsy by ICSD-3 criteria (i.e., the subject meets all other 
ICSD-3 criteria for Type 1 narcolepsy) 
3. Be positive for the Human Leukocyte Antigen (HLA) DQB1:0602 haplotype, 
determined prior to the study or as part of the study screening procedures, or have 
cerebrospinal fluid (CSF) hypocretin level ≤110 pg/mL determined prior to the study.  
In the absence of both, be evaluated by a panel of narcolepsy experts to confirm the 
diagnosis of narcolepsy with cataplexy in accordance with ICSD-3  
4. Have given documented assent per local IRB/IEC requirements indicating that he/she 
was aware of the investigational nature of the study and the required procedures and 
restrictions before participation in any protocol-related activities  
5. Have parent(s)/guardian(s) who have given informed consent for his/her/their child’s 
participation in the study 
6. 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 
7. Be willing to spend the required number of nights (2 to 3) in a sleep laboratory for 
PSG evaluations  
8. If currently treated with Xyrem, must have been taking unchanged doses (twice 
nightly dosing no higher than 9 g/night) of Xyrem, and stimulants, if applicable, for 
the treatment of narcolepsy symptoms for at least 2 months prior to screening   
9. If currently treated with Xyrem, must have demonstrated clinical improvement of 
cataplexy per Investigator’s clinical judgment 
10. Have agreed to abstain from caffeinated products during PSG and PK Nights 
11. Any female subject of child-bearing potential must be willing to use a method of 
contraception, deemed medically acceptable by the Investigator, or agree to abstain 
from sexual intercourse for the duration of the study and for 30 days after study 
termination 
12. Any male subject who is sexually active with a female partner must be willing to use 
a method of contraception, deemed medically acceptable by the Investigator, or agree 
to abstain from sexual intercourse for the duration of the study and for 30 days after 
study termination 
 
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In addition to the above inclusion criteria, prior to participating in the PK evaluation, 
subjects must meet the following inclusion criteria: 
13. Be willing to spend 2 additional nights in the clinic for PK evaluation 
14. This criterion was removed during Amendment 2 
15. Have given additional documented assent and consent by the parent(s) or guardian(s) 
indicating awareness of the investigational nature of the PK evaluation and the 
required procedures and restrictions before participation in any PK-related activities 
16. Have sufficient blood volume for PK sampling based on body weight in accordance 
with Seattle Children’s Hospital guideline (Appendix 4) or, for any particular 
investigational site, Institutional Review Board (IRB) eligibility guidelines for 
pediatric blood collection relevant to that site 
17. Demonstrate normal values on clinical laboratory coagulation tests (prothrombin time 
[PT]/international normalized ratio [INR], and activated partial thromboplastin time 
[PTT]) within 30 days prior to PK Night 1 
Subjects who have completed Part 1 of the study are eligible to re-enroll in Part 2 regardless 
of their current Xyrem treatment status if they meet Inclusion Criteria 4, 5, 11, and 12 and the 
following criteria at the Part 2 Screening visit (Visit 17) and the first drug-dispensing visit 
(Visit 18): 
18. Are less than 18 years of age 
19. If currently being treated with Xyrem, the subject is on a stable dose 
20. If currently being treated with Xyrem, the subject’s total twice nightly Xyrem dose 
must be no higher than 9 g/night 
4.3 
Exclusion Criteria 
Subjects who demonstrate any of the following will be excluded from Part 1 of the study. 
1. Inability to understand assent or follow study instructions for any reason, in the 
opinion of the Investigator 
2. Parent(s) or guardian(s) unable to comply with the requirements of the study for any 
reason, in the opinion of the Investigator 
3. Previously treated with Xyrem and discontinued Xyrem treatment because of lack of 
efficacy and/or tolerability issues 
4. Narcolepsy secondary to another medical condition, e.g., CNS injury or lesion 
5. Restless leg syndrome (RLS) requiring treatment other than iron supplements 
6. Succinic semi-aldehyde dehydrogenase deficiency (SSADH) 
7. Uncontrolled hypothyroidism 
8. History of seizure disorders  
9. History of head trauma associated with loss of consciousness 
10. Evidence of sleep-disordered breathing including: 
a. Presence of clinically significant obstructive or central sleep apnea as determined 
by the Investigator or documented previously; or 
b. Obstructive AHI >5 for subjects 7-11 years of age or obstructive AHI >10 for 
subjects 12-17 years of age; or 
c. Oxygen saturation nadir ≤85% at night; or 
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d. Clinically significant hypoventilation 
11. Oxygen saturation level <95% for at least 5 minutes on room air as measured by 
pulse oximetry while fully awake during daytime monitoring, or subjects with known 
or suspected respiratory difficulty, or any condition that may compromise a subject’s 
breathing. If oxygen saturation values lower than 95% are observed at study sites at 
high geographic elevations and are acceptable to the Investigator, enrollment of the 
subject requires permission from the Medical Monitor 
12. Past or current major thought disorder, e.g., schizophrenia, paranoia, mania, etc.  
13. Recent history of clinically significant parasomnia (e.g., sleep walking, REM 
behavior disorder, etc.) that would negatively affect the conduct of the study 
14. Current suicidal risk as determined from history or Columbia Suicide Severity Rating 
Scale (C-SSRS) or history of suicide attempt 
15. Clinically significant depression independent of narcolepsy symptoms  
o If the T-score is at or above 65 on the Children’s Depression Inventory 2nd 
Edition Self-Report Short Version (CDI 2:SR[S]), an evaluation of depression by 
the Investigator (if qualified as a mental health professional) or by the Investigator 
in consultation with a mental health professional must be performed to exclude a 
clinically significant depression 
16. This criterion was removed during Amendment 2  
17. Other documented clinically significant condition (including unstable medical and/or 
psychiatric conditions, chronic disease other than narcolepsy with cataplexy, 
porphyria, or history or presence of another neurological disorder) that might affect 
the subject’s safety and/or interfere with the conduct of the study in the opinion of the 
Investigator 
18. An electrocardiogram (ECG) with clinically significant deviation(s) from normal, or 
clinically significant physical examination findings, as determined by the Investigator 
19. Any clinically significant laboratory abnormality as determined by the Investigator 
20. A positive pregnancy test result at screening (pregnancy tests will be performed for 
any female subject who has reached menarche) 
21. 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) 
22. Treatment with benzodiazepines, non-benzodiazepine anxiolytics/ 
hypnotics/sedatives, neuroleptics, opioids, barbiturates, diclofenac, valproate, 
phenytoin, ethosuximide within 2 weeks prior to enrollment (discontinuation for the 
purpose of study enrollment is permitted only if considered safe by the Investigator 
and approved by the Medical Monitor) 
23. Treatment with any other medications that have anticataplectic effect (e.g., serotonin–
norepinephrine reuptake inhibitors [SNRIs], selective serotonin reuptake inhibitors 
[SSRIs], or tricyclic antidepressants [TCAs]) within 1 month before Part 1 Screening  
24. Current treatment with oral isotretinoin 
25. Inability to fast for 2 hours before the first dose through 4 hours after the last dose of 
Xyrem on PSG and PK nights 
26. Lack of parental (or legal guardian) commitment to ensuring home situation is safe 
for Xyrem use, in the opinion of Investigator 
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27. Received any investigational drug within 30 days or 5 half-lives (whichever is longer) 
before Screening 
28. Allergy to any components of topical, local anesthetics that might be used for blood 
collection (not applicable if numbing agents will not be used) 
29. Allergy or sensitivity to malic acid, sucralose, or ingredients in the study drug 
formulation and/or the flavorant, if used 
30. This criterion was removed during Amendment 4  
In addition to the above exclusion criteria, prior to participating in the PK evaluation, 
subjects must not demonstrate any of the following: 
31. Hemoglobin less than normal range for age and gender at Screening or at the end of 
the Double-Blind Period, whichever is closer to PK nights 
32. Use of tobacco products or products for smoking cessation within 90 days before PK 
Night 1, including nicotine-containing products, or history of significant use of 
tobacco (>10 cigarettes or equivalent per day) within 3 years prior to PK Night 1 
33. This criterion was removed during Amendment 2 
34. Noncompliance with prescribed Xyrem regimen in the 2 weeks prior to the first PK 
night 
Subjects will be excluded from re-enrolling in Part 2 if they meet Exclusion Criteria 1-10, 12, 
17, 19-22, 24, 26-29 or any of the following criteria at the Part 2 Screening visit (Visit 17) 
and the first drug-dispensing visit (Visit 18): 
35. Have not completed Part 1 
36. If they are ≥18 years of age 
37. If they have suicidal risk or clinically significant depression independent of 
narcolepsy symptoms as determined by the Investigator  
4.4 
Screening Eligibility 
Note: Title previously read “Screening and Randomization Eligibility”. The reference of 
randomization has been removed due to discontinuation of the placebo treatment in the 
Double-Blind Treatment Period. 
Subjects will be considered eligible for Part 1 screening if they meet the Part 1 inclusion 
criteria and do not meet any Part 1 exclusion criteria. Subjects who do not meet eligibility 
criteria at Part 1 Screening will be considered screen failures; however, subjects may be 
rescreened for Part 1 if they  
1) Failed to meet eligibility because of a T-score above 65 on the MASC-10 under 
Protocol Amendment 1 
2) Failed to meet eligibility because of being negative on HLA DQB1:0602 under 
Protocol Amendment 1 or 2 
3) Failed to meet eligibility because of a T-score at or above 65 on CDI 2:SR[S] under 
Protocol Amendment 1 or 2 (In this case, permission of the Medical Monitor is 
required before the subject is rescreened.)  
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In addition, rescreening following resolution of transient exclusionary conditions or 
stabilization of conditions that were exclusionary in the unstable state (e.g., unstable 
hypothyroidism) is permitted only with the permission of the Medical Monitor. 
Under Amendment 5, subjects who re-enroll in the study must complete the Part 2 Screening. 
Subjects who re-enroll within 2 weeks after completing Visit 15 in Part 1 of the study do not 
require clinical laboratory tests, a urine drug screen, an alcohol test, or a serum pregnancy 
test at the Part 2 Screening visit. For these subjects, the screening visit (Visit 17) and the first 
drug-dispensing visit (Visit 18) may occur on the same day. 
5 
STUDY TREATMENT(S) 
5.1 
Description of Treatment 
Xyrem® (sodium oxybate) oral solution, 500 mg/mL 
Xyrem Placebo: a sodium citrate solution prepared in equimolar concentration to sodium in 
the 500 mg/mL Xyrem (sodium oxybate) oral solution and pH adjusted with malic acid  
(Placebo treatment only applicable to subjects who had already entered the Double-Blind 
Treatment prior to Amendment 4 becoming effective). 
The bioequivalence of the study drug prepared in a flavored diluent versus prepared in water 
has been evaluated, and bioequivalence has been established. If available, a flavorant that can 
be added to the water that is used as diluent will be provided for study drug preparation if 
flavored diluent is requested by the subject/parent/guardian for palatability. Sucralose in the 
flavorant is equivalent to 28 mg sucralose in 60 mL, or 56 mg per daily intake of Xyrem 
prepared with flavored diluent. The FDA acceptable daily intake (ADI) for sucralose is 
5 mg/kg body weight/day (Federal Register, Vol. 63, No. 64, 1998) and the European Union 
ADI is 0 – 15 mg/kg body weight (SCF/CS/ADDS/EDUL/190 Final 12/9/2000). 
5.2 
Treatment Administered 
Subjects who have been titrated to a stable dose of Xyrem prior to study entry will remain on 
their stable dose and regimen of Xyrem for 3 weeks during the Stable-Dose Period. 
Xyrem-naïve subjects entering Part 1 and subjects re-enrolling in Part 2 who have been off 
Xyrem for ≥1 month will be titrated on Xyrem over a period of up to 10 weeks. Xyrem doses 
are administered in two equally divided doses 2.5 to 4 hours apart. Dose initiation and 
titration will be based on the subject’s weight as described in Table 1. Dose adjustment 
during the Part 1 and Part 2 titration periods will proceed at a rate of ≤1 g/night/week for 
subjects <45 kg, and ≤1.5 g/night/week for subjects ≥45 kg, to a dose level no higher than the 
maximum dose described in Table 1. Once the Investigator is satisfied that the Xyrem dose 
has been optimized, the subject may enter the 2-week Stable-Dose Period if in Part 1 of the 
study or continue the Open-Label Continuation Period if in Part 2.   
At the end of the Stable-Dose Period, subjects who had entered the Double-Blind Period 
prior to Amendment 4 becoming effective were randomized 1:1 to receive either Xyrem or 
Xyrem placebo during the Double-Blind Treatment Period as follows: 
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• Xyrem: Active Xyrem will be continued as a double-blind treatment at the stable dose 
taken and regimen used in the previous 2 weeks 
• Placebo: Xyrem placebo will be initiated as a double-blind treatment at a volume and 
regimen equivalent to that of the stable dose of Xyrem taken in the previous 2 weeks. 
During the Double-Blind Period, subjects will remain on the same dosing regimen they used 
during the Stable-Dose Period, with the exception of PK nights (if applicable) when all 
subjects have to take two equally divided doses 4 hours apart. 
Subjects entering the Double-Blind Treatment Period after Amendment 4 becoming effective 
will receive open-label Xyrem treatment during this period. 
During the Part 1 Open-Label Safety Period and following titration in the Part 2 Open-Label 
Continuation Period subjects may take two equally divided doses or two unequally divided 
doses with the exception of PK nights, if applicable. Xyrem dose adjustment due to 
tolerability and efficacy is permitted. Xyrem dose uptitration is allowed at no more than 
1.5 g/night. Only doses that match the printed gradations (lines) on the dosing syringe are 
permitted. 
Study Drug will be dispensed at clinic visits and, if applicable, at intervals specified by State 
or local regulations. Xyrem doses on PSG and PK nights will be administered by or under the 
supervision of qualified study site personnel. Each Xyrem dose will be diluted with 60 mL of 
water. On PK nights, Xyrem doses will be followed by 180 mL of water. Subjects will 
continue to take their usual nightly dose of Xyrem on non-PSG and non-PK nights.  
The actual time of dosing for each dose administered on PSG and PK nights will be recorded. 
5.3 
Selection and Timing of Dose for Each Subject 
In the studies reported in the literature, Xyrem doses used in children and adolescents were 
generally lower than the mean dose reported in adults (7.5 g/night). In one of these published 
studies, children with pre-pubertal onset of narcolepsy took a lower maximal Xyrem dose 
than those with peri- or post-pubertal onset (Aran et al. 2010).  
Data from the Central Pharmacy that dispenses Xyrem in the US also indicate that most 
children take lower doses than adults, as would be expected if there were no great differences 
in metabolism between children and adults and if effective doses were generally based on a 
mg/kg dose.  
Proposed starting doses and titration increments based on weight will be assessed in this 
study (Table 1).  
Sodium oxybate has a half-life 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.  
For this study, doses will be taken twice nightly. Each divided dose must match a printed line 
on the dosing syringe that is provided. Doses may be taken at the following times: 
• When the first dose can be taken at bedtime, the first dose should be taken at bedtime 
while in bed, and the second dose should be taken 2.5 to 4 hours later.  
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• When the first dose cannot be taken at bedtime, the first dose should be taken after 
bedtime while in bed, and the second dose should be taken 2.5 to 4 hours later.  
Investigators should caution subjects about operating hazardous machinery, including 
automobiles or airplanes, or going to school alone 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, for at least 6 hours after taking the second nightly dose of study drug. 
On PK Night 1, subjects in the PK evaluation will receive one half of their usual (stable) total 
nightly Xyrem dose (administered as two equally divided doses, given at bedtime and 
4 hours later while in bed). On PK Night 2, PK subjects will receive their usual nightly dose 
(administered as two equally divided doses, given at bedtime and 4 hours later while in bed). 
Subjects whose equally divided dose does not match a line on the dosing syringe will take the 
dose that matches the next lower printed line on the dosing syringe (see Section 3.1.7). Blood 
samples for PK assessment collected on these PK nights will allow assessment of dose 
proportionality within subjects.   
5.4 
Method of Assigning Subjects to Treatment Groups 
At the beginning of the Double-Blind Treatment Period, subjects who entered this period 
prior to Amendment 4 becoming effective had been randomized to either Xyrem at the stable 
dose established in the previous 2 weeks or to Xyrem placebo at a volume equivalent to the 
Xyrem dose that was established in the previous 2 weeks. During the Double-Blind Period, 
subjects will remain on the same dosing regimen they used during the Stable-Dose Period, 
with the exception of PK nights (if applicable) when all subjects have to take two equally 
divided doses 4 hours apart. 
Subjects who enter the Double-Blind Treatment Period after Amendment 4 becoming 
effective will receive open-label Xyrem treatment. 
5.5 
Randomization  
Randomization only applies to subjects who had entered the Double-Blind Randomized-
Withdrawal Period prior to Amendment 4 becoming effective. 
Prior to Amendment 4, a statistician selected by Jazz Pharmaceuticals specified a dynamic 
randomization algorithm to assign treatments for the double-blind portion of the trial. The 
randomization will balance treatment assignment for each age group (7 to 11 years and 12 to 
17 years), for prior Xyrem usage (subjects on Xyrem at study entry and Xyrem-naïve 
subjects), and for location (US and ex-US). 
If emergency unblinding is required, for subjects who entered the double-blind period prior 
to Amendment 4 becoming effective, the double-blind treatment assignment will be provided 
to the Investigator by an Interactive Voice Recognition System (IVRS) or Interactive Web 
Response System (IWRS). The treatment assignments for approximately 35 subjects were 
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available to the DSMB upon interim analysis. At other times, treatment assignments will be 
available to the DSMB upon request to address safety concerns. All treatment assignments 
will be generally available upon final unblinding of the double-blind portion of the study.   
5.6 
Blinding 
Blinding only applies to subjects who had entered the Double-Blind Randomized-
Withdrawal Period before Amendment 4 becoming effective.  A double-blind approach had 
been used during the Double-Blind Treatment Period for subjects entering this period before 
Amendment 4 becoming effective. Xyrem and Xyrem placebo oral solution were matched in 
volume, flavor, and appearance to ensure adequate blinding.  
5.7 
Concomitant Therapy 
In this study, the following medications are prohibited: 
• Benzodiazepines, non-benzodiazepine anxiolytics/hypnotics/sedatives, neuroleptics, 
opioids, barbiturates, diclofenac, valproate, phenytoin, and ethosuximide are 
prohibited during the study and must have been discontinued within 2 weeks prior to 
the beginning of the Stable-Dose Period for subjects on Xyrem at study entry and the 
beginning of the Open-Label Titration Period for Xyrem-naïve subjects. 
(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.  
• Other anticataplectic therapies (e.g., SNRI, SSRI, or TCA) are prohibited during Part 
1 and must have been discontinued within 1 month before Part 1 Screening. 
(Discontinuation for the purpose of study enrollment is only permitted if considered 
safe by the Investigator and approved by the Medical Monitor.) 
• Oral isotretinoin (Accutane) is prohibited during the study.  
• Investigational drugs other than study drug are prohibited during the study. 
The following concomitant medications are permitted during the study with the following 
stipulations: 
• Stimulant therapy may be continued, adjusted, or initiated during the study; however, 
prior to Amendment 4, stimulant use if any must be a stable dose throughout the 
Stable Dose and Double-Blind periods.  
• Other anticataplectic therapies may be allowed in Part 2 of the study  
• Vitamins in normal doses may be continued (herbal supplements are prohibited) 
• Acetaminophen (paracetamol) for fever, headache, or other pain in accordance with 
the allowable dose limits by age for each country and not to exceed the limits below: 
- 
Subjects 7 to 11 years of age: no more than 325 mg every 4 to 6 hours, not to 
exceed 1625 mg in 24 hours 
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- 
Subjects 12 years of age and older: no more than 650 mg every 4 to 6 hours, not 
to exceed 3250 mg in 24 hours 
• Ibuprofen for fever, headache, or other pain in accordance with the allowable dose 
limits by age for each country and not to exceed the limits below: 
- 
Subjects 7 to 11 years of age: no more than 100 mg every 6 to 8 hours, not to 
exceed 400 mg in 24 hours 
- 
Subjects 12 years of age and older: no more than 200 mg every 4 to 6 hours, not 
to exceed 1200 mg in 24 hours 
• Birth control pills, patches, injections, or implants (all hormonal contraceptives) may 
be continued 
• Local topical anesthetic agent for placement of indwelling catheter or before any 
blood draws 
• Non-sedating antihistamines 
• Anti-inflammatories for pain 
• Chronic topical or oral antibiotics for acne 
• Over-the-counter (OTC) decongestants. 
All concomitant medications taken during the study will be recorded on the Concomitant 
Medications case report form (CRF) with indication, total daily dose, and dates of drug 
administration. 
5.8 
Restrictions 
5.8.1 
Prior Therapy 
In addition to Xyrem and stimulant treatment at study entry, subjects may continue 
prescription and OTC medications with the exception of the prohibited medications listed in 
Section 5.7. Also, subjects who used any other investigational drug within 30 days or five 
half-lives (whichever is longer) before Part 1 or Part 2 Screening, or plan to use an 
investigational drug (other than the study drug) during the study will not be allowed to enter 
the study. 
5.8.2 
Fluid and Food Intake  
For all PSG and PK nights, with the exception of the Screening PSG for Xyrem-naïve 
subjects:  
During PSG and PK nights, all subjects will be required to eat a light dinner 2 hours before 
dosing and refrain from caffeinated products. A light dinner may be provided at home or at 
the study site, but must be eaten at least 2 hours before dosing. The light dinners on each 
PSG or PK night should be of the same or similar content. The Investigator will verify with 
the parent or guardian that a light dinner was consumed by the subject. Subjects will take 
Xyrem (diluted with 60 mL of water or flavored diluent if requested and available); subjects 
in the PK group will follow the diluted Xyrem with 180 mL of water. Following the light 
dinner, no food will be allowed until the following morning, approximately 8 hours after the 
first dose of Xyrem. Water is allowed at night, but may not be taken 1 hour before or after 
dosing during the PK nights. If the subject prefers to eat breakfast at the study center after the 
PSG or PK night, a breakfast will be provided.  
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Screening PSG for subjects who are Xyrem naïve:  
Xyrem-naïve subjects will not have meal restrictions but must refrain from caffeinated 
products prior to the Screening PSG. Following the subject’s dinner, no food will be allowed 
until the following morning; however, subjects may drink water during the night if desired. If 
the subject prefers to eat breakfast at the study center after the PSG night, a breakfast will be 
provided.  
5.8.3 
Subject Activity Restrictions 
Subjects should take study drug while in bed and lie down immediately after dosing as 
Xyrem may cause them to fall asleep abruptly without first feeling drowsy.  
On PSG and PK nights, all subjects who receive study drug should remain in bed after the 
first Xyrem dose for at least 8 hours. If it is necessary for subjects to move about during this 
time, they must be assisted.  
5.9 
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. In addition, 
subjects (if needed, with the help of caregiver) will complete an electronic Study Drug 
Dosing Diary (Appendix 12) every morning throughout Part 1 to document that doses of 
study drug were taken overnight and an electronic Stimulant Dosing Diary (Appendix 13) 
every evening through the Double-Blind Treatment Period to document that their regular 
stimulant dose was taken, if applicable, during the day). Compliance will be assessed 
throughout the trial based on a subject’s prescribed dose, data recorded in the subject’s 
Dosing Diaries (Part 1 only), and volume of solution returned. 
On PSG and PK nights, Xyrem will be administered by and taken in the presence of study 
personnel. Compliance with drug administration will be confirmed by watching the subjects 
swallowing the solution.  
5.10 Drug Discrepancies 
Study personnel will note if there is a significant difference in the actual volume and/or 
amount of study drug returned at each visit compared with the volume and/or amount 
expected to be returned. If such a difference is found, study personnel will take appropriate 
action, which may include checking the subject’s/parent(s)/guardian(s) dosing technique, re-
educating the subject/parent(s)/guardian(s) on proper dosing, and/or addressing potential 
abuse and/or diversion. 
5.11 Packaging and Labeling 
Jazz Pharmaceuticals will provide the clinical site with a supply of Xyrem (sodium oxybate) 
oral solution, 500 mg/mL, for use during all phases of the study. Xyrem placebo (sodium 
citrate oral solution) was supplied for use during the Double-Blind Treatment Period for 
subjects entering this period prior to Amendment 4 becoming effective. The flavorant will 
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also be provided, if available, to the clinical site. The flavored diluent will consist of a 
commercially available flavored unsweetened beverage mix sweetened with sucralose and 
added to water. 
All packaging and labeling operations of Xyrem and Xyrem placebo will be performed 
according to current Good Manufacturing Practices (cGMPs) and Good Clinical Practices 
(GCPs).   
5.12 Storage and Accountability 
All study medications will be stored, inventoried, reconciled, and retained or destroyed 
according to applicable state and federal regulations and instructions from Jazz 
Pharmaceuticals. Xyrem must be stored according to regulations for a Drug Enforcement 
Administration (DEA) Schedule III controlled substance in the US and according to any 
other regional regulations that apply. Jazz Pharmaceuticals will specify the conditions under 
which drug is stored. 
The Investigator or designated pharmacist will maintain accurate records of receipt of all 
study drugs, including dates of dispensing and receipt. At the study site, study drug supplies 
must be kept in a secure area and dispensed according to the protocol. Unused (or partially 
used) supplies must be accounted for on the drug inventory record. Receipt and dispensing of 
all study drugs must be documented throughout the study and reconciled at study completion. 
The Investigator must provide a written explanation for any missing study drug. After review 
of study drug accountability logs at study completion, one copy of the drug inventory record 
will be retained by the site and the other inventory record will be retained by the sponsor in 
the Study Master File.  
All labels, bottles, and unused Xyrem and Xyrem placebo must be destroyed or returned to 
Jazz Pharmaceuticals according to written instructions from Jazz Pharmaceuticals or its 
designee at the completion of the study for reconciliation and destruction. Used bottles of 
study drug will be destroyed upon Jazz Pharmaceuticals’ instruction following the review of 
study drug accountability. The Investigator must provide a written explanation for any 
missing study drug. 
5.13 Investigational Product Retention at Study Site 
Following study completion and notification by the Sponsor, investigational products 
(Xyrem and Xyrem placebo) do not need to be retained at the study site for FDA testing 
purposes. 
6 
STUDY PROCEDURES 
6.1 
Assent and Informed Consent 
All subjects will provide assent and their parent(s) or guardian(s) will give written informed 
consent in accordance with local IRB/IEC requirements before the performance of any study 
related procedures. 
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Each subject’s chart will have the subject’s assent documented and the informed consent 
form (ICF, most current version, if applicable) signed by the parent or guardian for study 
participation, and for PK evaluation if applicable, attached to it. When the study treatment is 
completed and the CRF has been monitored, the assent documentation and the ICF will be 
kept in the Investigator’s central study file. 
6.2 
Demographics 
Demographics will be collected at Part 1 Screening. The date of the subject’s assent and the 
date the parent or guardian signed the ICF will be collected. The date of the assent/consent 
for PK evaluation will also be collected; however, it may be after Part 1 Screening as long as 
the assent/consent is obtained before participation in the PK evaluation. 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, as required by regional or national regulations), sex, ethnicity, and race.   
Contact information of the parent or guardian will be obtained at Part 1 Screening and 
confirmed on admission to the sleep laboratory on the PSG nights and to the clinic on PK 
nights. Contact information will be updated at Part 2 Screening. This information will not be 
collected by the Sponsor. 
6.3 
Medical History 
The subject’s medical history will be taken at Part 1 Screening to ensure suitability of each 
subject for enrollment. Past (prior to any narcolepsy treatment) and current symptoms of 
narcolepsy including cataplexy, EDS, hallucinations, sleep paralysis, and DNS will be 
recorded. The subject’s usual Xyrem regimen, if applicable, including how Xyrem is 
prepared, usual times taken, and the usual bedtime and awakening time will also be recorded. 
The Investigator will assess the severity of the subject’s cataplexy and narcolepsy overall 
prior to any treatment by completing a clinical global impression of severity (CGIs) for 
historical narcolepsy overall and a CGIs for historical cataplexy severity (see Section 6.6.7). 
If a subject re-enrolls in Part 2, their previously recorded medical history will be reviewed 
and updated. In addition, any new medical history that occurs after the last Part 1 study visit 
(Visit 16) and prior to re-enrollment will be recorded. This would include any new clinically 
significant condition with onset after Visit 16 until assent/consent in Part 2. 
6.4 
Physical Examination 
A full review of body systems should be obtained on each subject. Physical examinations 
will be conducted at the Part 1 Screening Visit, the end of the Double-Blind Treatment 
Period, and at Visit 15 (Week 52 or Part 1 early termination) and will include a full 
examination of body systems (except a breast and genitourinary examination other than the 
observational evaluation needed for the Tanner Stage Assessment; Appendix 5), a brief 
neurological examination, and height and body weight measurements.   
An additional brief neurological exam will be performed prior to allowing the subject to be 
discharged the morning after PSG and PK nights (not applicable for the screening PSG for 
subjects who are naïve to Xyrem).  
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Tanner Stage assessments classifying sexual maturity will be conducted at Part 1 Screening 
and at Visit 15 (Week 52 or Part 1 early termination). 
A physical examination will also be conducted at the Part 2 Screening visit and will include a 
full examination of body systems (except a breast and genitourinary examination), a brief 
neurological examination, and height and body weight measurements. 
6.5 
Vital Signs and Pulse Oximetry 
Vital signs (systolic and diastolic blood pressure, pulse/heart and respiratory rate, and body 
temperature) will be monitored and recorded on the CRF after the subject has been resting 
for at least 5 minutes. Vital signs will be collected at each onsite visit in both Part 1 and 
Part 2 (Appendix 1, Appendix 2, Appendix 22, Appendix 23, and Appendix 24).  
On PSG nights, vital signs will be measured at the times specified in the schedules of events 
(Appendix 1.2 [subjects on Xyrem at study entry] and Appendix 2.3 [Xyrem-naïve 
subjects]). While the subject is being monitored with PSG, the respiratory and heart rate will 
be captured as part of the PSG parameters. At times when the subject is not undergoing PSG, 
the respiratory rate will be counted by visual inspection of thoracic movement and will be 
assessed over 30 seconds, and the pulse/heart rate will be taken.  
On PK nights, vital signs will be measured at the times specified in the schedule of events for 
PK nights (Appendix 3). 
Oxygen saturation by pulse oximetry will be measured while the subject is fully awake on 
room air and recorded at Part 1 Screening and on the mornings prior to discharge following 
PSG (excluding screening PSG for Xyrem-naïve subjects) and PK nights.  
On PSG nights, for subjects receiving study drug, oxygen saturation (SpO2) will be 
monitored continuously via PSG from the time immediately before the first dose through 
8 hours after the first dose and will be recorded pre-dose and at 1 h, 2 h, 4 h (pre-2nd dose), 
5 h, 6 h, and 8 h after the first dose (Appendix 1.2 and Appendix 2.3). During the screening 
PSG for subjects who are Xyrem naïve, SpO2 will be monitored as part of the PSG 
parameters to determine obstructive sleep apnea (OSA) status. End tidal CO2 (EtCO2) or 
transcutaneous CO2 (TcCO2) will be monitored and recorded at sites where monitoring is 
routinely performed and performance will not negatively impact study conduct. 
On PK nights, SpO2 will be monitored continuously by pulse oximetry from the time 
immediately before the first dose through 8 hours after the first dose and will be recorded at 
the times specified in the Schedule of Events for PK nights (Appendix 3). 
6.6 
Other Assessments 
6.6.1 
Epworth Sleepiness Scale for Children and Adolescents (ESS [CHAD])  
The ESS is a self-administered questionnaire with 8 questions. It provides a measure of a 
person’s general level of daytime sleepiness, or their average sleep propensity in daily life. It 
has been validated in narcolepsy and has demonstrated both a high specificity and sensitivity 
(Johns 1991, 2000). In the ESS (CHAD) for children and adolescents (Appendix 6), the third 
activity was modified to adapt to a school setting, the fourth activity was shortened from 
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1 hour to 30 minutes, the fifth activity omitted the phrase “when circumstances permit,” the 
seventh activity was modified to delete the mention of alcohol, and the eighth activity was 
replaced by the activity of sitting and eating a meal to avoid the redundancy to the fourth 
activity. 
6.6.2 
SF-10 Health Survey for Children 
The SF-10™ Health Survey for Children (Appendix 7) is a parent-completed survey that 
contains 10 questions adapted from the Child Health Questionnaire (CHQ). The SF-10 
provides coverage across a wide range of domains, and is scored to produce physical and 
psychosocial health summary measures. This survey is intended for children between the 
ages of 5 and 18, and is available with a standard 4-week recall period.  
6.6.3 
Columbia-Suicide Severity Rating Scale (C-SSRS)  
The C-SSRS is a widely used measure of suicidal ideation and behavior (Appendix 8). 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). The C-SSRS is available in versions 
for children and adolescents and for use in clinical trials. The C-SSRS Children’s 
Baseline/Screening and the C-SSRS Children’s Since Last Visit versions will be used in this 
study for subjects under 12 years of age. The Baseline/Screening and Since Last Visit 
versions will be used for subjects 12 years of age and older (Posner et al. 2011 and personal 
communication).  
6.6.4 
Children’s Depression Inventory 2nd Edition Self-Report Short Version 
(CDI 2:SR[S])  
The Children’s Depression Inventory (CDI) is a widely used pediatric self-report depressive 
symptoms assessment in clinical trials (Myers & Winters 2002). It is a comprehensive 
assessment of depressive symptoms in youth ages 7 to 17 years. The second edition of the 
CDI Self-Report (CDI 2:SR) contains 28 items to cover the age-appropriate depressive 
symptoms which cover affective, cognitive, motivational, neurovegetative, and secondary 
impairment domains. It covers the criterion symptoms of major depressive disorder and 
dysthymic disorder as operationalized in the DSM-IV. The CDI 2:SR[S] (Appendix 9) is the 
short form of CDI 2:SR. It contains 12 items and takes about half the time of the full-
length version to administer (5–10 minutes). The short report form covers primarily affective, 
cognitive, and neurovegetative aspects of depression. It has been shown that the Total Score 
of the CDI 2:SR[S] is highly correlated to a Total Score on the selected items of the full-
length version (Kovacs 2011). Due to its brevity, the CDI 2:SR[S] is a suitable screening 
assessment; however, this scale is not validated in pediatric patients with narcolepsy. Many 
narcolepsy symptoms overlap with items assessed in the CDI 2:SR[S], e.g., feeling tired, not 
having fun (in order to control cataplexy attacks); therefore, this scale is used only as a 
screening assessment for the risk of depression in this study. 
6.6.5 
Multidimensional Anxiety Scale for Children 10-item (MASC-10) 
The MASC-10, a short version of the MASC, is a multidimensional measure with ten items 
that combine the basic anxiety scales from the long version to produce one score that 
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indicates the severity of anxiety problems (Appendix 10). Satisfactory test-retest reliability 
was demonstrated for this instrument (March 1997, March & Sullivan 1999).  
6.6.6 
Cataplexy Frequency Diary 
The subject (if needed, with the help of caregiver) will complete a cataplexy frequency diary 
(Appendix 11) daily in the evening during Part 1 to record the daily frequency of the 
subject’s cataplexy attacks (Appendix 1 and Appendix 2).  
6.6.7 
Clinical Global Impression of Severity (CGIs) Questionnaires 
Clinical Global Impression of Severity (CGIs) is a 7-point Likert rating scale and is a widely 
used assessment in clinical psychopharmacology trials to assess severity of illness. The 
responses of this investigator-completed scale range from 1 = normal, no signs of illness, to 
7 = among the most extremely ill patients. Using the questionnaires described below, 
Investigators will rate their impression of the severity of the subject’s condition before the 
subject received any narcolepsy treatment (historical) and the severity of the subject’s current 
condition at specified times during Part 1 of the study. 
6.6.7.1 
CGIs for Historical Narcolepsy Overall Severity Prior to any Narcolepsy 
Treatment 
At Part 1 Screening (Visit 1), Investigators will rate their impression of the severity of the 
subject’s narcolepsy overall prior to any narcolepsy treatment (Appendix 15). 
6.6.7.2 
CGIs for Historical Cataplexy Severity Prior to any Narcolepsy Treatment 
At Part 1 Screening (Visit 1), Investigators will rate their impression of the severity of the 
subject’s cataplexy prior to any narcolepsy treatment (Appendix 16). 
6.6.7.3 
CGIs for Narcolepsy Overall (current condition) 
Investigators will rate their impression of the subject’s current severity of narcolepsy overall 
at the following time points: Part 1 Screening (Visit 1), the start of the Stable-Dose Period 
(Visit 2 [for subjects on Xyrem at study entry]) or beginning of titration (Visit 1.1 [for 
Xyrem-naïve subjects]) and the end of the Stable-Dose Period (Visit 3) (Appendix 17). 
6.6.7.4 
CGIs for Cataplexy Severity (current condition) 
Investigators will rate their impression of the subject’s current cataplexy severity at the 
following time points: Part 1 Screening (Visit 1), the start of the Stable-Dose Period (Visit 2 
[for subjects on Xyrem at study entry]) or beginning of Part 1 titration (Visit 1.1 [for Xyrem-
naïve subjects]) and the end of the Stable-Dose Period (Visit 3) (Appendix 18). 
6.6.8 
Patient Global Impression of Change (PGIc) for Narcolepsy Overall 
At the end of the Double-Blind Treatment Period (Visit 4), the subject (if needed, with the 
help of caregiver) will rate his/her narcolepsy overall since the last visit (Visit 3 [end of 
Stable-Dose Period]) on a 7-point scale ranging from “very much better” to “very much 
worse” (Appendix 19). If the subject discontinues during the Double-Blind Treatment Period, 
he/she will complete the PGIc at Part 1 early termination. 
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6.6.9 
Clinician Global Impression of Change (CGIc) for Narcolepsy Overall and 
for Cataplexy Severity 
At the end of the Double-Blind Treatment Period (Visit 4), Investigators will rate their 
impression of any change in the severity of the subject’s narcolepsy overall (Appendix 20) 
and their impression of any change in the severity of the subject’s cataplexy (Appendix 21) 
since the start of the Double-Blind Treatment Period on a 7-point scale ranging from “very 
much improved” to “very much worse.” If the subject discontinues during the Double-Blind 
Treatment Period, the Investigator will complete the CGIc for narcolepsy overall and for 
cataplexy severity at Part 1 early termination. 
6.6.10 
Dosing Diaries 
Electronic Dosing Diaries will be used to capture both study drug doses taken and, if 
applicable, stimulant doses taken during Part 1.  
6.6.10.1 
Study Drug Dosing Diary 
The subject (if needed, with the help of caregiver) will complete the Study Drug Dosing 
Diary (Appendix 12) each morning, from the Part 1 Screening Visit (Visit 1) for the subjects 
on Xyrem at study entry and from the start of the Part 1 Open-Label Titration Period 
(Visit 1.1) for Xyrem-naïve subjects through the end of Part 1 of the study. The diary is 
completed to capture if the first and second doses of study drug were taken the night before.  
6.6.10.2 
Stimulant Dosing Diary 
The subject (if needed, with the help of caregiver) will complete the Stimulant Dosing Diary 
(Appendix 13) each evening, from the Part 1 Screening Visit (Visit 1) for the subjects on 
Xyrem at study entry and from the start of the Part 1 Open-Label Titration Period (Visit 1.1) 
for Xyrem-naïve subjects through the end of the Double-Blind Treatment Period. The diary is 
completed to capture if the regular dose of stimulants was taken that day, if the subject is 
taking stimulants.  
6.6.11 
School Attendance Diary 
The School Attendance Diary will be completed if the subject has school during the last 
2 weeks of the Stable-Dose Period and during the Double-Blind Treatment Period. The 
subject (if needed, with the help of caregiver) will record daily in the diary if the subject had 
a scheduled school day and if the subject missed the school day because of narcolepsy 
(Appendix 14). 
6.6.12 
Plan of referral 
The Investigator should have a plan to refer for appropriate care or to provide appropriate 
care for subjects requiring emergent medical and/or psychiatric care during the course of 
study participation. 
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6.7 
12-Lead Electrocardiogram (ECG) 
A standard 12-lead ECG will be recorded with the subject resting supine for at least 
5 minutes at Part 1 Screening (Visit 1), the End of the Double-Blind Treatment Period 
(Visit 4), and the final Part 1 visit (Visit 15) or Part 1 early termination. 
6.8 
Polysomnography (PSG) 
A PSG will be performed on PSG nights according to a standard protocol, which will be 
provided in a manual to each site, at the times specified in the schedules of events. The 
manual will include all parameters to be recorded, methods, and a scoring appendix. Oxygen 
saturation will be monitored according to the study center’s standard procedures. Cardiac 
rhythm strips (over 30 seconds), closest to the specified time points with minimum artifact, 
will be extracted from the PSG data by the core lab. 
Standard PSG parameters will be recorded. The PSG parameters of interest include: 
• Apnea Index (AI) and Apnea Hypopnea Index (AHI) 
• SpO2 (mean and nadir) 
EtCO2 or TcCO2 will be recorded at sites where monitoring is routinely performed, provided 
it does not negatively impact participation or PSG data integrity. In addition, cardiac rhythm 
strips (30 seconds) will be obtained at 1 h, 4 h (pre-2nd dose), 5 h, and 8 h after the first 
Xyrem dose for subjects on Xyrem during the PSG.  
Study Personnel on PSG Nights: A physician, either the Investigator or a Sub-investigator, 
must be on call and be readily available during PSG nights. An experienced sleep 
technologist must be present to monitor the PSG during PSG nights.  
Multiple Sleep Latency Test (MSLT): If the subject has never been diagnosed with 
narcolepsy with cataplexy and meets all ICSD-3 Type 1 narcolepsy criteria A and B1 at 
Part 1 Screening other than the MSLT, an MSLT can be conducted during Part 1 Screening, 
with the permission of the Medical Monitor, to confirm the diagnosis of narcolepsy with 
cataplexy. 
The ICSD-3 diagnostic criteria for narcolepsy with cataplexy are as follows (Type 1, the 
International Classification of Sleep Disorders 3rd Revised Diagnostic and Coding Manual 
[ICSD-3]) (American Academy of Sleep Medicine 2014): 
• 
Type 1 (hypocretin deficiency syndrome, narcolepsy-cataplexy, narcolepsy with 
cataplexy): 
Criteria A and B must be met: 
A. Daily periods of irrepressible need to sleep or daytime lapses into sleep for 
≥3 months. 
B. The presence of one or both of the following: 
1. Cataplexy and a mean sleep latency of ≤8 minutes and two or more sleep 
onset REM periods (SOREMPs) on an MSLT performed according to 
standard techniques. A SOREMP (within 15 minutes of sleep onset) on the 
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preceding nocturnal polysomnogram may replace one of the SOREMPs on the 
MSLT. 
2. CSF hypocretin-1 concentration, measured by immunoreactivity, is either 
≤110 pg/mL or <1/3 of mean values obtained in normal subjects with the 
same standardized assay. 
6.9 
Clinical Laboratory Tests 
6.9.1 
Laboratory Parameters 
Blood and urine samples for laboratory tests will be collected at times indicated in the 
Schedules of Events (Appendix 1, Appendix 2, Appendix 22, Appendix 23, and Appendix 
24). 
Subjects will be in a seated or supine position during blood collection. Clinical laboratory 
tests will include the following: 
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Table 2 
List of Laboratory Tests 
Hematology: 
- 
Complete blood count (CBC) 
Urinalysis:  
- 
Protein 
- 
Glucose 
- 
Bilirubin 
- 
pH 
- 
Nitrite 
- 
Ketones 
- 
Urobilinogen 
- 
Occult blood 
- 
Leukocyte esterase 
Microscopic examination for blood, all types of 
cells and casts.  
 
Serum and urine human chorionic 
gonadotropin (hCG) (only for females who 
have reached menarche) 
 
HLA DQB1:0602 haplotype (at Part 1 
Screening only, for subjects with no previous 
documented results available) 
 
Tests of growth and precocious puberty: 
- 
Growth hormone (GH) 
- 
Insulin-like growth factor-1 (IGF-1, 
low sensitivity) 
- 
Prolactin 
- 
Luteinizing hormone (LH) 
- 
Follicle Stimulating Hormone (FSH) 
- 
Testosterone 
- 
Estradiol 
Serum Chemistry: 
- 
Albumin (ALB) 
- 
Alkaline phosphatase (AP) 
- 
Alanine aminotransferase (ALT; 
SGPT) 
- 
Aspartate aminotransferase (AST; 
SGOT) 
- 
Blood urea nitrogen (BUN) 
- 
Calcium (Ca) 
- 
Carbon dioxide (CO2) 
- 
Chloride (Cl) 
- 
Creatinine 
- 
Creatine kinase 
- 
Gamma-glutamyl transferase (GGT) 
- 
Globulin 
- 
Glucose 
- 
Lactate dehydrogenase (LDH) 
- 
Phosphorus 
- 
Potassium (K) 
- 
Sodium (Na) 
- 
Total bilirubin 
- 
Direct bilirubin 
- 
Total cholesterol 
- 
Total protein 
- 
Triglycerides 
- 
Uric acid 
 
Coagulation (within 30 days prior to PK 
Night 1 for PK subjects only): 
- 
Prothrombin time (PT)/International 
normalized ratio (INR) 
- 
Activated partial thromboplastin time 
(PTT) 
 
Thyroid Function 
- 
Thyroid stimulating hormone (TSH) 
(at Part 1 Screening only)  
 
The clinical laboratory tests will be performed at a central or local laboratory. An authorized 
back-up laboratory, as indicated on the Form FDA 1572 or equivalent, may be used if 
necessary as an emergency laboratory. The Investigator will supply Jazz Pharmaceuticals or 
its designee with the back-up laboratory’s current licensure and laboratory reference ranges. 
Please note exclusionary clinical laboratory parameters listed in the exclusion criteria. 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 
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Investigator will provide an explanation of all clinically significant observations. These 
findings will be reported as AEs. 
6.9.1.1 
Pregnancy Test 
Pregnancy tests will be performed for female subjects who have reached menarche. At Part 1 
Screening (Visit 1), the end of the Double-Blind Treatment Period (Visit 4), and Part 2 
Screening, a serum pregnancy test will be performed. A urine pregnancy test will be 
performed at the start of the Part 1 Open-Label Titration Period for Xyrem-naïve subjects 
(Visit 1.1), at the start of the Stable-Dose Period for subjects previously on Xyrem (Visit 2), 
and at the final Part 1 visit (Visit 15) or Part 1 early termination (Appendix 1 and Appendix 
2). During Part 2, a urine pregnancy test will be performed at Visit 18 (for re-enrollers only), 
at every 6-month visit (Visits 24, 30, and 36), and at Part 2 Study Termination/Part 2 Early 
Termination (Visit 42) (Appendix 22, Appendix 23, and Appendix 24). 
6.9.1.2 
Drug and Alcohol Screen 
At Part 1 Screening (Visit 1), the beginning of the Part 1 Open-Label Titration Period for 
Xyrem-naïve subjects (Visit 1.1), the start of the Stable-Dose Period for subjects previously 
on Xyrem (Visit 2), the end of the Double-Blind Treatment Period (Visit 4), and during the 
Open-Label Safety Period at Visits 5, 7, 9, 12, and 15 (Appendix 1 and Appendix 2), an 
alcohol test and a panel of urinary drug screens will be performed. During Part 2, an alcohol 
test and a panel of urinary drug screens will be performed at Part 2 Screening, at Visit 18 (for 
re-enrollers only), at every 6-month visit (Visits 24, 30, and 36), and at Part 2 Study 
Termination/Part 2 Early Termination (Visit 42) (Appendix 22, Appendix 23, and Appendix 
24). The panel of urinary drug screens will test for the following prohibited substances. (A 
positive amphetamine result will not exclude a subject who is taking prescribed 
amphetamines.) 
• Amphetamine (not prescribed) 
• Barbiturates  
• Benzodiazepines 
• Cannabinoids 
• Cocaine 
• Opiates 
6.9.1.3 
Estimated Total Blood Volume Required by Study 
Estimated blood volumes for subjects in Part 1 not participating in the PK evaluation are 
listed in Table 3. The approximate total blood volume to be collected for study assessments 
in these subjects is 45.5 mL over a period of one year.  
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Table 3 
Estimated Blood Volumes for Assays in Part 1 – Non-PK Subjects 
 
Screening 
(Day -30 to -1)a 
End of 
Stable-
Dose 
(Week 3 – 
Week 10) 
End of 
Double-
Blind 
(Week 5 – 
Week 12) 
Termination 
(Part 1 Early 
Termination 
or Week 52) 
Total 
Clinical chemistry  
7.5 mL 
-- 
7.5 mL 
7.5 mL 
22.5 mL 
TSH 
-- 
-- 
-- 
hCG 
-- 
Included in 
Chemistry 
-- 
Girls <8 years old: LH, FSH, 
estradiol 
Boys <9 years old: LH, FSH, 
testosterone 
-- 
-- 
Included in 
Chemistry 
Hematology  
2 mL 
-- 
2 mL 
2 mL 
6 mL 
HLA DBQ1 602 
3 mL 
-- 
-- 
-- 
3 mL 
GH, prolactin 
-- 
3.5 mL 
Included in 
Chemistry 
Included in 
Chemistry 
3.5 mL 
IGF-1 
-- 
3.5 mL 
3.5 mL  
3.5 mL 
10.5 mL 
Approximate total blood 
volume per subject  
12.5 mL 
7 mL 
13 mL 
13 mL 
45.5 mL 
a If needed, additional screening time may be granted with permission of the Medical Monitor. 
Estimated blood volumes for subjects who are participating in the PK evaluation are listed in 
Table 4. The approximate total blood volume to be collected for study assessments in these 
subjects is 88.2 mL over a period of one year. 
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Table 4 
Estimated Blood Volumes for Assays in Part 1 – PK Subjects 
 
Screening 
(Day -30 
to -1)a 
PK 
Night 1 
b 
PK 
Night 2 
b 
End of 
Stable-
Dose 
(Visit 3) 
End of 
Double-
Blind 
(Visit 4) 
Termination 
(Part 1 
Early 
Termination 
or Visit 15) 
Total 
Clinical chemistry  
7.5 mL 
-- 
-- 
-- 
7.5 mL 
7.5 mL 
22.5 mL 
TSH 
-- 
-- 
-- 
-- 
-- 
hCG 
-- 
-- 
-- 
Included in 
Chemistry 
-- 
Girls <8 years old: LH, 
FSH, estradiol 
Boys <9 years old: LH, 
FSH, testosterone 
-- 
-- 
-- 
-- 
Included in 
Chemistry 
Hematology  
2 mL 
-- 
-- 
-- 
2 mL 
2 mL 
6 mL 
HLA DBQ1 602 
3 mL 
-- 
-- 
-- 
-- 
-- 
3 mL 
GH, prolactin 
-- 
-- 
-- 
3.5 mL 
Included in 
Chemistry 
Included in 
Chemistry 
3.5 mL 
IGF-1 
-- 
-- 
-- 
3.5 mL 
3.5 mL 
3.5 mL 
10.5 mL 
Coagulation 
(Screening) 
2.7 mL 
-- 
-- 
-- 
-- 
-- 
2.7mL 
Pharmacokinetic 
samples 
-- 
7 × 2 mL 7 × 2 mL 
-- 
-- 
-- 
28 mL 
Volume for flushing 
indwelling catheter 
-- 
6 × 1 mL 6 × 1 mL 
-- 
-- 
-- 
12 mL 
Approximate total 
blood volume per 
subject  
15.2 mL 
20 mL 
20 mL 
7 mL 
13 mL 
13 mL 
88.2 mL 
a If needed, additional screening time may be granted with permission of the Medical Monitor. 
b PK Night 1 and PK Night 2 will occur while subjects are on a stable dose of Xyrem during the study. 
For subjects who continue directly into Part 2 from Part 1, no additional blood samples will 
be collected for clinical laboratory assays. Estimated blood volumes for subjects who re-
enroll in Part 2 are listed in Table 5. The approximate total blood volume to be collected for 
study assessments in these subjects will be 9.5 mL. 
Table 5 
Estimated Blood Volumes for Assays in Part 2  
 
Part 2 Screening 
Visit 17 
(within 2 weeks before Visit 18)a 
Clinical chemistry  
7.5 mL 
hCG 
Included in Chemistry 
Hematology  
2 mL 
Approximate total blood volume 
per subject  
9.5 mL 
a If needed, additional screening time may be granted with permission of the Medical Monitor. 
Per the World Health Organization, the existing guidelines for blood sample volume limits 
(ranging from 1–5% of total blood volume within 24 hours and up to 10% of total blood 
volume over 8 weeks) are consistent with the limited evidence available on “minimal risk” to 
children (Howie 2011). EU Guidelines (2008) for pediatric clinical trials state that, per 
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individual, the trial-related blood loss (including any losses in the maneuver) should not 
exceed 3% of the total blood volume during a period of 4 weeks and should not exceed 1% at 
any single time. Specific guidelines may vary, but a commonly used guidance from Seattle 
Children’s Hospital (Appendix 4) recommends no more than 2.5% of total blood volume in 
one blood draw and no more than 5% of the total blood volume in a 30-day period. To ensure 
that the total blood loss (including PK samples, samples for clinical labs, and any procedural 
losses) will not exceed the Seattle Children’s Hospital’s recommendation, EU Guidelines, or 
any particular investigational site IRB or Independent Ethics Committee (IEC) eligibility 
guidelines for pediatric blood draws relevant to that site, the following time periods should 
be maximized for subjects with low body weight participating in the PK evaluation to 
minimize the amount of blood drawn over 30 days: the Screening Period for subjects on 
Xyrem at study entry, and the time from Visit 4 to PK Night 1 and from PK Night 2 to 
Visit 15 for all subjects who participate in PK evaluations during the Open-Label Safety 
Period.  
6.9.2 
Sample Collection, Storage, and Shipping 
A local topical anesthetic agent such as lidocaine/tetracaine (Synera) topical patch, or 
lidocaine/prilocaine cream (EMLA) may be applied 20-30 minutes or 60-120 minutes, 
respectively, prior to venipuncture or placement of an indwelling catheter per the site’s usual 
procedures. If a numbing preparation will be used, the study staff will confirm that the 
subject is not allergic to the preparation prior to the application. Screening blood samples 
will be obtained by venipuncture. An indwelling catheter for obtaining blood samples for PK 
assessment will be placed in subjects participating in the PK evaluation on PK nights. If the 
catheter becomes non-functional (e.g., clogged or infiltrated), a second indwelling catheter 
may be placed; however, if the attempt to insert this second catheter fails, the PK blood 
sample collection for that night will be discontinued.   
6.9.2.1 
Clinical Laboratory Test Samples 
The laboratory will supply detailed instructions and all containers for blood and urine 
investigations. Blood and urine sample volumes will meet the laboratory’s specifications. 
The actual time of blood collection for all samples will be recorded. 
6.9.2.2 
Blood Samples for Pharmacokinetic Analyses 
For subjects participating in the PK evaluation, blood samples (2 mL) to measure plasma 
sodium oxybate concentrations will be collected on two PK nights (PK Night 1 and PK 
Night 2) at 0 (pre-dose), 0.75, 1.5, 2.5, 4 (pre-2nd dose), 4.75, and 8 hours after the first dose. 
PK samples will be taken within ±5 minutes of the specified time points. The actual time of 
blood collection for all samples will be recorded.  
Study Personnel on PK Nights: A physician, either the Investigator or a Sub-investigator, 
must be on call and be readily available during PK nights. An individual skilled in pediatric 
venous catheter placement must be present on PK nights when blood samples will be 
collected and processed for PK evaluation. 
To determine sodium oxybate concentrations, blood samples will be drawn according to the 
time points specified and dispensed into labeled sodium heparin tubes. 
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The blood samples will be collected and processed according to the PK lab manual provided 
to the sites, and the plasma samples will be shipped to the bioanalytical laboratory on dry ice 
as directed by the sponsor. 
The bioanalysis will be performed by a central bioanalytical laboratory 
.  
Plasma samples for sodium oxybate concentration determination will be shipped Monday 
through Wednesday via overnight carrier 
, on the appropriate 
amount of dry ice, to: 
On the day of shipment, please notify 
 by email 
 of the pending 
shipment, including sample shipment tracking information and sample information manifest 
in Excel format. 
6.10 Dispensing Study Drug 
Subjects on Xyrem at study entry will continue dosing with their own supply of drug during 
the Part 1 Screening Period; however, appropriate study drug will be provided on the 
screening PSG night and will be administered by or under the supervision of qualified study 
site personnel. Study drug will be dispensed to Xyrem-naïve subjects at the beginning of the 
Part 1 Open-Label Titration Period (Visit 1.1) and to subjects on Xyrem at study entry at the 
start of the Stable-Dose Period (Visit 2). For subject who re-enroll in Part 2, study drug will 
be dispensed at Visit 18. Study drug will be dispensed at study visits, excluding phone visits, 
according to the schedules of events (Appendix 1, Appendix 2, Appendix 22, Appendix 23, 
and Appendix 24).  
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/parent(s)/guardian(s) by 
the site personnel.  
Flavorant will be provided if available for study drug preparation if flavored diluent is 
requested by the subject and deemed appropriate by the Investigator (excluding PSG and PK 
nights). Instructions for preparation of study drug with flavored diluent will be supplied if 
flavored diluent is to be used. Additional drug dispensing visits will be made as required by 
State or local regulations.  
On all PSG and PK nights, study drug will be administered by or under the supervision of 
qualified study site personnel.  
The Investigator or designated pharmacist will maintain accurate records for all study drug 
administered or dispensed. 
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6.11 Pharmacokinetic Assessments 
The PK profile for two doses of Xyrem will be evaluated over an 8-hour period in a subset of 
subjects on two PK nights. The PK parameters for plasma sodium oxybate concentrations 
will include, but may not be limited to: the area under the plasma concentration time curve 
(AUC), maximum plasma drug concentration (Cmax), and time to maximum plasma drug 
concentration (Tmax), over the first 4-hour dosing interval. In addition, sodium oxybate 
concentrations at 4.75 hours (0.75 hours after the 2nd dose) and 8 hours (4 hours after the 
2nd dose) will be measured to estimate peak and residual exposure associated with the 
second nighttime dose. Dose proportionality will be based on the ratio of AUC values for 
each subject. Pharmacokinetics will be summarized for the 7-11 and 12-17 year age groups, 
and a comparison to historical PK data in adults will also be made. 
The blood sampling schedule and calculation of required number of patients needed to meet 
the objectives of this study were determined by Sponsor scientists with expertise in Clinical 
Pharmacology and Biostatistics. 
6.12 Adverse Events Assessments 
6.12.1 
Adverse Events (AEs) 
All AEs, whether observed by the Investigator, reported by the subject, determined from 
laboratory findings, or other means, will be recorded on the AE CRF.  
• For subjects who participate in Part 1 only, all AEs occurring after assent has been given 
or the ICF has been signed until the last study visit (through the Study Follow-up Visit or 
Part 1 early termination) will be recorded.  
• For subjects who continue directly into Part 2 from Part 1, all AEs occurring after assent 
has been given or the ICF has been signed until the last study visit (Part 2 Study 
Termination Visit/Part 2 Early Termination Visit) will be recorded.  
• For subjects who complete Part 1 and re-enroll in Part 2, all AEs occurring after assent 
has been given or the ICF has been signed in Part 1 until the last Part 1 study visit 
(through the Safety Follow-up Visit) and all AEs occurring after assent has been given or 
the ICF has been signed in Part 2 until the last study visit (Part 2 Study Termination 
Visit/Part 2 Early Termination Visit) will be recorded. 
Any new clinically significant condition with onset after the last Part 1 visit (Visit 16) until 
assent/consent is provided in Part 2 should be recorded as medical history. 
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. During the study, clinically 
significant adverse changes in clinical status, 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. Symptoms of narcolepsy are not considered as 
adverse events unless there is an exacerbation of the symptoms from baseline (Visit 1 for 
Part 1 and Visit 17 for subjects who re-enroll in Part 2). 
Adverse events include, but are not limited to: (1) a worsening or change in nature, severity, 
or frequency of conditions present at baseline (Visit 1 for Part 1 and Visit 17 for subjects 
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who re-enroll in Part 2); (2) subject deterioration due to primary illness; (3) intercurrent 
illness; (4) drug interaction; and/or (5) abnormal clinically significant laboratory values. 
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 should be 
documented as the AE and not the individual signs/symptoms. 
Following questioning and evaluation, all AEs, whether believed by the Investigator to be 
related or unrelated to the study drug or procedure, must be documented in the subject’s 
medical records, in accordance with the Investigator’s normal clinical practice, and on the 
AE CRF. Each AE is to be evaluated for duration, intensity, seriousness, and causal 
relationship to the study drug or procedure. An AE is deemed to be a suspected adverse drug 
reaction if there is a reasonable possibility that the AE may have been caused by the drug (or 
medicinal product) or study procedure as defined in Code of Federal Regulations Title 21 
CFR 312.32 [a] and ICH E2A II.A.2. 
6.12.1.1 
Severity 
Adverse events will be classified by the Investigator as mild, moderate, or severe as defined 
below. When the intensity of the AE changes over time, the change in intensity will be 
recorded on the AE CRF as a new AE. 
Mild 
Symptom(s) barely noticeable to subject or does not make subject 
uncomfortable; does not influence performance or functioning; prescription 
drug not ordinarily needed for relief of symptom(s) but may be given. 
Moderate 
Symptom(s) of a sufficient severity to make subject uncomfortable; 
performance of daily activities is influenced; treatment for symptom(s) may 
be needed. 
Severe 
Symptom(s) causes severe discomfort; symptom(s) incapacitate or 
significantly affect subject’s daily life; treatment for symptom(s) may be 
given and/or subject hospitalized.  
 
6.12.1.2 
Relationship to Study Drug or Procedure 
The Investigator’s assessment of an AE’s relationship to study drug or procedure is part of 
the documentation process, but it is not a factor in determining what is or is not reported in 
the study. If there is any doubt as to whether a clinical observation is an AE, the event should 
be reported. The relationship or association of the study drug or procedure in causing or 
contributing to the AE will be characterized using the following classification and criteria:  
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Related or 
Suspected to 
be Related 
to Study 
Drug or 
Procedure 
Some temporal relationship exists between the event and the 
administration of the study drug or procedure and the event is unlikely to 
be explained by the subject’s medical condition, other therapies or 
accident. 
The AE follows a reasonable temporal sequence from administration of 
the study drug or procedure and at least one of the following instances of 
clinical evidence: 
• Follows a known or suspected response pattern to the study drug or 
procedure. 
• Is confirmed by improvement upon stopping the study drug or 
procedure or decreasing the dose (dechallenge). 
• Reappears upon repeated exposure (rechallenge) if medically 
appropriate. 
There is a reasonable possibility that the study drug or procedure caused 
the event—i.e., there is evidence to suggest a causal relationship. In such 
case, the AE is considered an adverse reaction (AR). A suspected AR has 
a lesser degree of certainty about causality than an AR. 
Not Related 
to Study 
Drug or 
Procedure 
Event can be readily explained by other factors such as the subject’s 
underlying medical conditions, concomitant therapy, or accident; or there 
is no temporal relationship between study drug or procedure and the 
event. 
A reasonable possibility or clinical evidence that the study drug or 
procedure caused the event is lacking. 
 
6.12.1.3 
Immediately Reportable Experiences 
The following events may occur during participation in this clinical study and must be 
reported immediately: 
• Death or other serious AE (SAE) 
• Pregnancy of a subject or subject’s partner 
• 3-fold or greater elevation above the upper limit of normal (ULN) of alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) accompanied by an 
elevation of serum total bilirubin greater than two times the ULN 
• Liver enzyme (AST, ALT) value greater than or equal to 5 times the ULN 
The events listed above must be reported within 24 hours of first knowledge of the event by 
study personnel to the appropriate Jazz Pharmaceuticals contact or designee. For immediately 
reportable experiences, the appropriate form (e.g., SAE Report Form, Pregnancy Form) 
should be completed as thoroughly as possible and signed by the Investigator or his/her 
designee before transmittal to Jazz Pharmaceuticals Drug Safety and Pharmacovigilance.  
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For SAEs, it is important that the Investigator provide his/her assessment of causality to 
study drug or procedure at the time of the initial report. If the Investigator’s assessment of 
causality subsequently changes, then a follow-up SAE form must be submitted with a revised 
causality assessment. 
Jazz Pharmaceuticals Drug Safety is required to expedite to global regulatory authorities 
reports of Serious Adverse Events, including Suspected Unexpected Serious Adverse 
Reactions (SUSARs), as per the US FDA Code of Federal Regulations, European 
Commission Clinical Trials Directive (2001/20/EC), and other country-specific regulations.   
For the purposes of global expedited adverse event reporting for this clinical trial, the 
reference safety document for the determination of expectedness is the Investigator’s 
Brochure for Xyrem (sodium oxybate) oral solution for Pediatric Narcolepsy. 
SERIOUS ADVERSE EVENTS 
An SAE is an AE that fulfills the following criteria, as per Title 21 CFR 312.32 and ICH 
E2A.II.B. SAEs must be reported to Jazz Pharmaceuticals or its designee using the SAE 
Form. The following are defined as SAEs and must be reported within 24 hours of being 
notified of the event: 
• Is fatal (results in death) 
• Is life-threatening (Note: the term “life-threatening” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event that 
could hypothetically have caused death had it been more severe) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is medically significant or requires intervention to prevent one of the outcomes listed 
above 
• Suspected transmission of an infectious agent via a medicinal product [for EU sites 
only; EMA Guideline on Good Pharmacovigilance Practices (GVP) Module VI] 
Hospitalization is NOT considered an SAE if: 
• It is planned prior to subject entering 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 
• The subject is treated in the emergency room only AND no ‘other’ criteria of 
seriousness apply 
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Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based on appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed above in the definition of an SAE. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or 
at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, the 
development of drug dependency or drug abuse, and the occurrence of suicidal ideation. 
PREGNANCY 
If a subject [or male subject’s partner] becomes pregnant any time after the first dose of study 
drug until 30 days after the last dose of study drug, the Pregnancy Form should be used to 
report the pregnancy to Jazz Pharmaceuticals or its designee. Subject pregnancies must be 
followed until termination of pregnancy or for a minimum of 6 months following the birth of 
the child. If the pregnancy results in a child birth, the infant must be followed for a minimum 
of 6 months. The Infant Follow-Up Form should be used to report information regarding the 
status of the infant. 
6.12.1.4 
Adverse Event Recording and Reporting 
Each individual AE is to be listed as a separate entry on the AE CRF. The Investigator will 
provide information about dates of onset and resolution, seriousness, severity, frequency, 
action(s) taken, outcome, and relationship to study medication.  
Documentation of immediately reportable events will follow procedures described in 
Section 6.12.1.3, Immediately Reportable Experiences. 
The Investigator must report to Jazz Pharmaceuticals or its designee all AEs that occur 
during the study after the informed consent has been signed and assent has been given until 
the final study visit or early termination, regardless of their relationship to study drug. 
If an Investigator becomes aware of an SAE within 30 days after the last dose of study 
medication, the event must be documented and reported as described in Section 6.12.1.3. 
6.12.1.5 
Follow-up of Adverse Events and Serious Adverse Events 
Adverse events assessed as not related to study drug or procedure, including clinically 
significant laboratory tests, ECGs, or physical examination findings, must be followed until 
the event resolves, the condition stabilizes, the event is otherwise explained, or the final 
study visit occurs, whichever comes first. AEs and SAEs assessed as related to study drug or 
procedure will be followed for as long as necessary to adequately evaluate the subject’s 
safety, or until the event stabilizes, or the subject is lost to follow up. If resolved, a resolution 
date should be provided, and for SAEs, a follow-up SAE form must be submitted indicating 
the resolution date. The Investigator is responsible for ensuring that follow-up includes any 
supplemental investigations indicated to elucidate the nature and/or causality of the AE. This 
may include additional clinical laboratory testing or investigations, examinations, 
histopathological examinations, or consultation with other health care professionals as is 
practical. 
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6.13 Concomitant Medication Assessments 
Subjects will be asked to refrain from taking the prohibited medications specified in 
Section 5.7 from the time of Screening until completion of the study. If discontinuation of 
CNS depressants or any medication poses a safety risk to the subject, the subject should not 
be enrolled in the study. 
All concomitant medications taken during the study will be recorded on the Concomitant 
Medications CRF with indication, total daily dose, and dates of drug administration. 
6.14 Removal of Subjects from the Study or Study Drug  
All subjects are free to withdraw from participation in this study at any time, for any reason, 
and without prejudice. The Investigator must withdraw any subject from the study if the 
subject or subject’s parent(s)/guardian(s) requests 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 
• Clinically significant depression independent of narcolepsy symptoms 
o If the T-score is ≥65 on CDI 2SR[S], an evaluation of depression by the 
Investigator (if qualified as a mental health professional) or by the 
Investigator in consultation with a mental health professional must be 
performed to exclude clinically significant depression 
• Any PSG parameters that indicate, in the judgment of the Investigator, a risk to the 
subject’s safe continued participation 
• Subject becomes pregnant 
• A positive urine drug screen for benzodiazepines or drugs of abuse (if the subject 
takes prescribed amphetamines, a positive result for amphetamines will not exclude 
the subject) or any suspicion by the investigator of abuse or diversion of study drug 
• A positive alcohol test 
• 3-fold or greater elevation above the upper limit of normal (ULN) of alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) accompanied by an 
elevation of serum total bilirubin greater than two times the ULN  
• Liver enzyme (AST, ALT) value greater than or equal to 5 times the ULN 
• Experiences an intolerable AE that is related to the study drug and/or procedure 
• Develops any clinically significant worsening in narcolepsy symptoms during the 
Stable-Dose Period 
• Develops a clinically significant laboratory or ECG abnormality that is related to the 
study drug and/or procedure 
• Requires a medication that is prohibited by the protocol, with the exception of short-
term opioid or benzodiazepine use (see Section 5.7) 
• Does not follow guidelines or procedures specified in the protocol 
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•
Is lost to follow-up
•
Does not continue to meet certain entry criteria or meets certain exclusion criteria
during the course of the study
•
Subject reaches his/her 18th birthday. Subjects who terminate from Part 2 of the study
because they have reached 18 years of age will be considered to have completed the
study.
All subjects who prematurely discontinue from the study should have all early termination 
assessments performed (see Section 6.14.1, Handling of Early Terminations). 
The specific reason for the discontinuation should be carefully documented on the 
termination CRF. If assent or informed consent is withdrawn, the specific reason for 
withdrawing the assent or informed consent should be stated. 
Adverse events resulting in termination will be followed to the satisfactory resolution and 
determination of outcome as ascertained by the Investigator (and/or Jazz Pharmaceuticals or 
its designee). The data will be recorded on the appropriate CRF. 
6.14.1 
Handling of Early Terminations 
If a subject terminates early from the study, either at his or her request or the subject’s 
parent(s) or guardian(s), or at the Investigator’s discretion, the Investigator will record the 
reason(s) for early termination on the relevant CRF page and notify the Sponsor immediately. 
The specific reason for the withdrawal should be carefully documented on the CRF. For 
instance, rather than stating “withdrew informed consent,” the specific reason for 
withdrawing the informed consent should be stated. All subjects who terminate early from 
Part 1 should undergo all early termination assessments in Section 7.4.3. All subjects who 
terminate early from Part 2 should undergo all study termination assessments in 
Section 7.5.5. Subjects who terminate from Part 2 of the study because they have reached 
18 years of age will be considered to have completed the study. 
It is vital to obtain follow-up data on any subject who terminated because of an AE, 
abnormal laboratory test, or ECG finding.  In any case, every effort must be made to 
undertake safety follow-up procedures. 
6.15 Sponsor’s Termination of Study 
Jazz Pharmaceuticals reserves the right to discontinue the study at any time for any reason. 
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. 
In the situation of a serious issue/event causing study termination, the sudden stop of 
medication may be warranted. In the event the study is terminated for an administrative 
reason, Jazz Pharmaceuticals will provide a reasonable period to allow subjects either to be 
discontinued safely, or to obtain replacement medication. “A reasonable period” is defined as 
no less than 2 weeks from the time of site notification of impending termination. 
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6.16 Appropriateness of Measurements 
The primary efficacy endpoint (change in weekly number of cataplexy attacks) measure, the 
Cataplexy Frequency Diary, is similar to the measure used in a prior study to establish 
efficacy in adults. Cataplexy frequency data will be collected daily in a cataplexy frequency 
diary. Both the Cataplexy Frequency Diary and the ESS (CHAD) have been evaluated for 
their face and content validity in children with narcolepsy (Mapi Study JZ13770A). The 
CGIc has been used extensively in clinical trials.  
The PK parameters selected to characterize the PK profile of sodium oxybate are the 
standardized parameters used to characterize the PK profiles of all drugs. The blood 
collections for sodium oxybate concentrations will occur at specified time points up to 
8 hours after the first Xyrem dose.  
The parameters 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 Xyrem. The C-SSRS, CDI 2:SR[S], and MASC-10 have been validated for use in the 
pediatric population. 
7 
STUDY ACTIVITIES 
Study activities through the Double-Blind Treatment Period are presented by the following 
subject groups: subjects on Xyrem at study entry (Section 7.1) and Xyrem-naïve subjects 
(Section 7.2). PSG night activities are described in Section 7.3. Study activities for the Open-
Label Safety Period for all subjects are described in Section 7.4. Study activities for Part 2 
(Open-Label Continuation Period) are described in Section 7.5 for subjects continuing 
directly into Part 2 from Part 1 and in Section 7.6 for subjects re-enrolling in Part 2 after 
completing Part 1. Additional visits as required by local regulations may be conducted during 
the study. 
The medical monitor may give permission for visits outside any particular visit window to 
accommodate necessary changes to complete a particular visit (e.g., travel issues, parental or 
family illness, etc.).  
Subjects entering the Double-Blind Treatment Period after Amendment 4 becoming effective 
will receive open-label Xyrem treatment during this period. Subjects entering the Double-
Blind Treatment Period before Amendment 4 becoming effective will continue to receive 
double-blind treatment during this period. 
7.1 
Subjects on Xyrem at Study Entry–Safety, Efficacy, and PK 
Evaluation 
A Schedule of Events for subjects on Xyrem at study entry is in Appendix 1. 
7.1.1 
Part 1 Screening Visit (Days –30 to -1) Subjects on Xyrem at Study Entry 
(Visit 1) 
After the subject has provided assent and a parent(s) or guardian(s) has signed an ICF in 
accordance with local IRB/IEC requirements, the subject may be screened for enrollment 
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into the study. All subjects will provide their written informed consent prior to the 
performance of any study-related procedures. The Screening Visit (Visit 1) starts when a 
subject is assigned a subject number via IVRS/IWRS. Screening will occur within 30 days 
before dosing. (If needed, additional screening time may be granted with permission of the 
Medical Monitor. However, if it has been more than 45 days since the Screening safety labs 
pertinent to eligibility were drawn, these labs may need to be repeated as instructed by the 
Medical Monitor.)  
The following study evaluations will be performed: 
• Obtain subject assent and ICF signed by parent(s) or guardian(s). If the subject will 
be participating in the PK evaluation, obtain additional documented assent and 
consent for the PK evaluation. 
• Review the inclusion/exclusion criteria. 
• Interview parent(s)/guardian(s) to determine if the home situation is safe for Xyrem 
use and storage, and assess if there is a risk of use or abuse by family members or 
others living in the home. 
• Obtain demographic information and record contact information for the parent(s) or 
guardian(s). 
• Obtain a medical history, including past (prior to any narcolepsy treatment) and 
current symptoms of narcolepsy (Section 6.3).  
• Complete the Clinical Global Impression of severity (CGIs) for Historical Narcolepsy 
Overall Severity Prior to any Narcolepsy Treatment (Appendix 15) and CGIs for 
Historical Cataplexy Severity Prior to any Narcolepsy Treatment (Appendix 16). 
• Complete the CGIs for narcolepsy overall (current condition) (Appendix 17) and for 
cataplexy severity (current condition) (Appendix 18). 
• Record usual bedtime and awakening time. 
• Record all prior medications, including OTC and health and dietary supplements 
taken during the 30 days before Screening, and also record any concomitant 
medications. 
• Confirm the subject has been on a stable dose of Xyrem for the previous 2 months. 
Confirm the subject has been on a stable dose of stimulants, if applicable, for the 
previous 2 months. Record the subject’s prescribed usual dose and regimen of Xyrem 
and stimulants if applicable.  
• Perform a physical examination, including a brief neurological examination and a 
Tanner Stage Assessment (Appendix 5) but excluding a full genitourinary exam. 
• Record height and weight in ordinary indoor clothes (without shoes). 
• Administer the following and record results: 
◦ 
ESS (CHAD) (Appendix 6) 
◦ 
Columbia-Suicide Severity Rating Scale (C-SSRS) (Appendix 8; 
Baseline/Screening version for subjects ≥12 years of age and Children’s 
Baseline/Screening version for subjects <12 years of age) 
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◦ 
Children’s Depression Inventory 2nd Edition Self-Report Short Version 
(Appendix 9) 
◦ 
Multi-dimensional Anxiety Scale for Children (MASC-10) (Appendix 10) 
• Obtain vital signs (systolic and diastolic blood pressure, pulse/heart and respiratory 
rate, and body temperature) after the subject has been resting for at least 5 minutes. 
• Obtain pulse oximetry reading on room air while the subject is fully awake. 
• Obtain blood samples for the following: 
◦ 
Routine hematology, chemistry, and thyroid function (see Table 2) 
◦ 
Serum pregnancy test (only for female subjects who have reached menarche) 
◦ 
For PK subjects only: coagulation (PT/INR and PTT)  
◦ 
HLA DQB1:0602 (if the subject has no previous HLA DQB1:0602 result 
available and no documented CSF hypocretin level ≤110 pg/mL)  
◦ 
For girls <8 years of age: estradiol, FSH, and LH 
◦ 
For boys <9 years of age: testosterone, FSH, and LH  
• Obtain urine samples for urinalysis. 
• Perform alcohol test and urine drug screens.  
• Obtain a 12-lead ECG. 
• Schedule Screening PSG  
• Subjects will continue dosing with their own supply of Xyrem during the Screening 
Period, with the exception of the Screening PSG Night when Xyrem will be provided. 
• Instruct subjects or parent(s)/guardian(s) on how to complete the Dosing Diaries 
(Study Drug Dosing Diary in Appendix 12 and Stimulant Dosing Diary in Appendix 
13). 
• The Investigator must thoroughly review results of all screening procedures and 
confirm all eligibility criteria prior to enrolling the subject in the study. The PSG 
must be completed and reviewed before the subject is enrolled (For the PSG, follow 
the procedures in Column 2 of Table 6 for “Subjects on Xyrem at study entry.”) 
• Schedule next visit  
7.1.2 
Start of Stable-Dose Period, Subjects on Xyrem at Study Entry (Visit 2, 
Day 1) 
• Review inclusion/exclusion criteria to determine the subject’s eligibility to continue 
participating in the study. 
• Record height and weight in ordinary indoor clothes (without shoes). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse/heart and respiratory 
rate, and body temperature) after the subject has been resting for at least 5 minutes. 
• Perform alcohol test and urine drug screens.  
• Obtain urine sample for pregnancy test (only for female subjects who have reached 
menarche). 
• Complete the CGIs for narcolepsy overall (current condition) (Appendix 17) and for 
cataplexy severity (current condition) (Appendix 18). 
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•
Administer the following:
◦
ESS (CHAD) (Appendix 6)
◦
SF-10 (Appendix 7)
◦
C-SSRS (Appendix 8; Since Last Visit version for subjects ≥12 years of age and
Children’s Since Last Visit version for subjects<12 years of age)
◦
CDI 2:SR[S] (Appendix 9)
◦
MASC-10 (Appendix 10)
•
Instruct subject and parent(s)/guardian(s) on how to complete the School Attendance
Diary (Appendix 14) if the subject is currently attending school.
•
Instruct subjects or parent(s)/guardian(s) on how to complete the Cataplexy
Frequency Diary (Appendix 11).
•
Review the dosing diaries for compliance with dosing (Study Drug Dosing Diary in
Appendix 12 and Stimulant Dosing Diary in Appendix 13).
•
Record all AEs that occur after assent was given and the ICF was signed on the AE
CRF.
•
Record all concomitant medications that were taken after assent was given and the
ICF was signed on the concomitant medications CRF.
•
Dispense study drug at the subject’s current stable dose. (Access IVRS/IWRS.)
Provide instructions for dose administration and, if flavored diluent is requested and
available, the preparation of study drug with flavored diluent to
subjects/parent(s)/guardian(s). See Section 6.10.
•
Schedule Visit 3 in the morning, and inform subjects/parent(s)/guardian(s) that
subjects must be fasting for IGF-1, GH, and prolactin testing when they arrive at the
visit.
•
For subjects in the PK evaluation during the Stable-Dose Period, perform procedures 
for PK Night 1 and PK Night 2 in Section 7.1.3.
7.1.3 
PK Nights 1 and 2 - Subjects Included in the PK Evaluation 
Subjects on Xyrem who are willing to participate in the PK evaluation may participate while 
they are on a stable dose of Xyrem during the study: 
•
Ensure that coagulations test have been performed within 30 days prior to PK night 1
•
Ensure that a light dinner was taken >2 hours prior to dosing. The light dinner should
be the same or similar on both PK Nights. The light meal may be taken at the clinic or
at home.
•
Confirm parent(s)/guardian(s) contact information.
•
Administer study drug:
◦
PK Night 1: Administer ½ of the subject’s usual nightly dose, in two equally
divided doses 4 hours apart. (Access IVRS/IWRS.)
◦
PK Night 2: Administer the subject’s usual nightly dose, in two equally divided
doses 4 hours apart. (Access IVRS/IWRS.)
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Note: Subjects whose equally divided dose does not match a line on the dosing 
syringe will take the dose that matches the next lower printed line on the dosing 
syringe (see Section 3.1.7). 
• Obtain blood samples for sodium oxybate concentrations at the times specified in the 
schedule of PK Night procedures (Appendix 3). 
• Obtain vital signs at the times specified in the schedule of PK Night procedures 
(Appendix 3). 
• Monitor SpO2 continuously by pulse oximetry from immediately before the first dose 
through 8 hours after the first dose, and record at the times specified in the schedule 
of PK Night procedures (Appendix 3). Take an additional measurement while the 
subject is awake and before release from the clinic. 
• Perform a brief neurological exam before discharge on the morning after PK 
assessment. 
• Provide breakfast if the subject prefers to eat at the clinic. 
• Ensure that subjects of driving age who received study drug during the PK nights will 
not be driving themselves when leaving the clinic. 
7.1.4 
End of Stable-Dose Period/Beginning of the Double-Blind Treatment 
Period*, Subjects on Xyrem at Study Entry (Visit 3, Week 3 ±3 days) 
*Subjects entering the Double-Blind Treatment Period after Amendment 4 becoming 
effective will complete this visit and receive open-label Xyrem during this period. 
• Collect a fasting blood sample for GH, IGF-1, and prolactin. 
• Provide breakfast for the subject after the fasting blood sample is collected. 
• Record height and weight in ordinary indoor clothes (without shoes). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse/heart and respiratory 
rate, and body temperature) after the subject has been resting for at least 5 minutes. 
• Review Cataplexy Frequency Diary.  
• Review the Dosing Diaries for compliance with dosing.  
• Complete CGIs for narcolepsy overall (current condition) (Appendix 17) and for 
cataplexy severity (current condition) (Appendix 18). 
• Administer the following:  
◦ 
ESS (CHAD) (Appendix 6) 
◦ 
SF-10 (Appendix 7) 
◦ 
C-SSRS (Appendix 8; Since Last Visit version for subjects ≥12 years of age and 
Children’s Since Last Visit version for subjects <12 years of age) 
◦ 
CDI 2:SR[S] (Appendix 9) 
◦ 
MASC-10 (Appendix 10) 
• Collect information on school attendance (Appendix 14) if the subject is currently 
attending school and will be attending school during the Double-Blind Treatment 
Period. 
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• Record all AEs on the AE CRF.  
• Record all concomitant medications on the concomitant medications CRF. 
• Dispense study drug. (Access IVRS/IWRS.) Provide instructions for dose 
administration and, if flavored diluent is requested and available, the preparation of 
study drug with flavored diluent to subjects/parent(s)/guardian(s). See Section 6.10. 
• Collect study drug dispensed at Visit 2 and assess compliance. 
• Schedule next visit (Visit 4) in the morning, and inform subjects/parent(s)/guardian(s) 
that subjects must be fasting for IGF-1, GH, and prolactin testing when they arrive at 
the visit. 
7.1.5 
End Double-Blind Treatment Period, Subjects on Xyrem at Study Entry 
(Visit 4, Week 5 +3 days) 
• Obtain blood samples for the following: 
◦ 
Fasting blood sample for GH, IGF-1, and prolactin 
◦ 
Routine hematology and chemistry 
◦ 
Serum pregnancy test (only for female subjects who have reached menarche) 
• Provide breakfast for the subject after the fasting blood sample is collected. 
• Perform a physical examination and record height and weight in ordinary indoor 
clothes (without shoes). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse/heart and respiratory 
rate, and body temperature) after the subject has been resting for at least 5 minutes. 
• Obtain urine sample for urinalysis.  
• Perform alcohol test and urine drug screens for subjects who are continuing into the 
Open-Label Safety Period. 
• Obtain a 12-lead ECG. 
• Review Cataplexy Frequency Diary and review the Dosing Diaries for compliance 
with dosing. 
• Collect information from the School Attendance Diary (Appendix 14).  
• Have the subject complete the PGIc (Appendix 19). Instruct the subject to rate his/her 
impression of change since Visit 3 (the end of the Stable-Dose Period). 
• Complete CGIc for narcolepsy overall (Appendix 20) and for cataplexy severity 
(Appendix 21). 
• Administer the following:  
◦ 
ESS (CHAD) (Appendix 6) 
◦ 
SF-10 (Appendix 7) 
◦ 
C-SSRS (Appendix 8; Since Last Visit version for subjects ≥12 years of age and 
Children’s Since Last Visit version for subjects <12 years of age) 
◦ 
CDI 2:SR[S] (Appendix 9) 
◦ 
MASC-10 (Appendix 10) 
• Record all AEs on the AE CRF.  
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• Record all concomitant medications on the concomitant medications CRF. 
• Dispense study drug for the Open-Label Safety Period. (Access IVRS/IWRS.) 
◦ 
Subjects may take two equally divided doses or two unequally divided doses with 
the exception of PK nights (if applicable) when all subjects have to take two 
equally divided doses 4 hours apart. Only doses that match the printed gradations 
(lines) on the dosing syringe are permitted. 
◦ 
For subjects who had entered the Double-Blind Period prior to 
Amendment 4 becoming effective: 
Upon entering the Open-Label Safety Period, all subjects will be started at a dose 
no higher than half the Xyrem dose they received at the end of the Stable-Dose 
Period or the initiation dose defined in Table 1, whichever is higher. Subjects will 
then be titrated up to their optimal dose as tolerated according to the 
Investigator’s judgment (the maximum dose should not exceed the doses defined 
in Table 1 or the stable dose prior to study entry, whichever is higher, and should 
not be greater than 9 g/night). Xyrem dose uptitration is allowed at no more than 
1.5 g/night.  
◦ 
For subjects entering the Double-Blind Period after Amendment 4 becoming 
effective:  
Subjects will continue on in the Open-Label Safety Period at their appropriate 
dose. 
• Collect study drug dispensed at Visit 3 and assess compliance.  
• Schedule next visit. 
7.1.6 
Open-Label Safety Evaluation, Subjects on Xyrem at Study Entry (Visit 5, 
4 weeks after end of Double-Blind Period) 
• Follow procedures in Section 7.4 
7.2 
Xyrem-naïve Subjects at Study Entry–Safety, Efficacy, and PK 
Evaluation 
A Schedule of Events for subjects who are Xyrem naïve at study entry is in Appendix 2. 
7.2.1 
Part 1 Screening Visit (Days –30 to –1), Xyrem-naïve Subjects (Visit 1) 
After the subject has provided assent and a parent(s) or guardian(s) has signed an ICF in 
accordance with local IRB/IEC requirements, the subject may be screened for enrollment 
into the study. All subjects will provide their written informed consent prior to the 
performance of any study-related procedures. The Screening Visit (Visit 1) starts when a 
subject is assigned a subject number via IVRS/IWRS. Screening will occur within 30 days 
before dosing. (If needed, additional screening time may be granted with permission of the 
Medical Monitor. However, if it has been more than 45 days since the Screening safety labs 
pertinent to eligibility were drawn, these labs may need to be repeated as instructed by the 
Medical Monitor.)  
The following study evaluations will be performed: 
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CONFIDENTIAL 
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• Obtain subject assent and ICF signed by parent(s) or guardian(s). If the subject will 
be participating in the PK evaluation, obtain additional documented assent and 
consent for the PK evaluation. 
• Review the inclusion/exclusion criteria. 
• Interview parent(s)/guardian(s) to determine if the home situation is safe for Xyrem 
use and storage, and assess if there is a risk of use or abuse by family members or 
others living in the home. 
• Obtain demographic information and record contact information for the parent(s) or 
guardian(s). 
• Obtain a medical history, including past (prior to any narcolepsy treatment) and 
current symptoms of narcolepsy (Section 6.3).  
• Complete the CGIs for Historical Narcolepsy Overall Severity Prior to any 
Narcolepsy Treatment (Appendix 15) and the CGIs for Historical Cataplexy Severity 
Prior to any Narcolepsy Treatment (Appendix 16). 
• Complete CGIs for narcolepsy overall (current condition) (Appendix 17) and for 
cataplexy severity (current condition) (Appendix 18). 
• Record usual bedtime and awakening time. 
• Record all prior medications, including OTC and health and dietary supplements 
taken during the 30 days before Screening, and also record any concomitant 
medications. 
• Perform a physical examination, including a brief neurological examination and a 
Tanner Stage Assessment (Appendix 5) but excluding a full genitourinary exam. 
• Record height and weight in ordinary indoor clothes (without shoes). 
• Administer the following and record results: 
◦ 
ESS (CHAD) (Appendix 6) 
◦ 
C-SSRS (Appendix 8) – (Baseline/Screening version for subjects ≥12 years of age 
and Children’s Baseline/Screening version for subjects <12 years of age) 
◦ 
CDI 2:SR[S] (Appendix 9) 
◦ 
MASC-10 (Appendix 10) 
• Obtain vital signs (systolic and diastolic blood pressure, pulse/heart and respiratory 
rate, and body temperature) after the subject has been resting for at least 5 minutes. 
• Obtain pulse oximetry reading on room air while the subject is fully awake. 
• Obtain blood samples for the following: 
◦ 
Routine hematology, chemistry, and thyroid function (see Table 2) 
◦ 
Serum pregnancy test (only for female subjects who have reached menarche) 
◦ 
HLA DQB1:0602 (if the subject has no previous HLA DQB1:0602 result 
available and no documented CSF hypocretin level ≤110 pg/mL)  
◦ 
For girls <8 years of age: estradiol, FSH, and LH 
◦ 
For boys <9 years of age: testosterone, FSH, and LH   
• Obtain urine samples for urinalysis.  
• Perform alcohol test and urine drug screens.  
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• Obtain a 12-lead ECG. 
• Schedule Screening PSG.  
• The Investigator must thoroughly review results of all screening procedures and 
confirm all eligibility criteria prior to enrolling the subject in the study. The PSG 
must be completed and reviewed before the subject is enrolled (For the PSG, follow 
the procedures in Column 1 of Table 6 for Xyrem-naïve subjects.) 
• Schedule next visit (Visit 1.1) to begin the Open-Label Titration Period. 
7.2.2 
Part 1 Open-Label Titration Period, Xyrem-naïve Subjects 
Subjects who are naïve to Xyrem at study entry will be titrated to Xyrem as described in 
Section 3.1.2. The Open-Label Titration Period may last up to 10 weeks; however, once it is 
determined that the subject has achieved a maximum clinical benefit in cataplexy and EDS 
while maintaining tolerability, the subject may be advanced to the Stable-Dose Period. If it is 
determined that the subject is on a stable dose at a clinic visit (i.e., Visits 1.2, 1.5, or 1.7), the 
Investigator should perform the Visit 2 procedures to begin the Stable-Dose Period. If it is 
determined that the subject is on a stable dose at a phone visit (i.e., Visits 1.3, 1.4, or 1.6), the 
Investigator should schedule Visit 2 as soon as possible to start the Stable-Dose Period. A 
Schedule of Events for Xyrem-naïve subjects is in Appendix 2. 
7.2.2.1 
Visit 1.1 Begin Titration (Day 1) 
• Review inclusion/exclusion criteria to determine the subject’s eligibility to continue 
participating in the study. 
• Record height and weight in ordinary indoor clothes (without shoes). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse/heart and respiratory 
rate, and body temperature) after the subject has been resting for at least 5 minutes. 
• Perform alcohol test and urine drug screens.  
• Obtain urine sample for pregnancy test (only for female subjects who have reached 
menarche). 
• Complete CGIs for narcolepsy overall (current condition) (Appendix 17) and for 
cataplexy severity (current condition) (Appendix 18). 
• Administer the following:  
◦ 
ESS (CHAD) (Appendix 6) 
◦ 
SF-10 (Appendix 7) 
◦ 
C-SSRS (Appendix 8) (Since Last Visit version for subjects ≥12 years of age and 
Children’s Since Last Visit version for subjects <12 years of age) 
◦ 
CDI 2:SR[S] (Appendix 9) 
◦ 
MASC-10 (Appendix 10) 
• Instruct subjects or parent(s)/guardian(s) on how to complete the Cataplexy 
Frequency Diary (Appendix 11) and the Dosing Diaries (Study Drug Dosing Diary in 
Appendix 12 and Stimulant Dosing Diary in Appendix 13). 
• Record all AEs that occur after assent was given and the ICF was signed on the AE 
CRF.  
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•
Record all concomitant medications that were taken after assent was given and the
ICF was signed on the concomitant medications CRF.
•
Determine initial dose, and instruct subject and parent(s)/guardian(s) or
parent(s)/guardian(s) on Xyrem dosing.
•
Dispense study drug. (Access IVRS/IWRS.) Provide instructions for dose
administration and, if flavored diluent is requested and available, the preparation of
study drug with flavored diluent to subjects/parent(s)/guardian(s). See Section 6.10.
•
Schedule next visit.
7.2.2.2 
Visit 1.2 (Week 1 +3 days) 
•
Record height and weight in ordinary indoor clothes (without shoes).
•
Obtain vital signs (systolic and diastolic blood pressure, pulse/heart and respiratory
rate, and body temperature) after the subject has been resting for at least 5 minutes.
•
Review Cataplexy Frequency Diary and review the Dosing Diaries for compliance
with dosing.
•
Administer the following:
◦
C-SSRS (Appendix 8) (Since Last Visit version for subjects ≥12 years of age and 
Children’s Since Last Visit version for subjects <12 years of age)
◦
CDI 2:SR[S] (Appendix 9)
◦
MASC-10 (Appendix 10)
•
Record all AEs on the AE CRF.
•
Record all concomitant medications on the concomitant medications CRF.
•
Assess subject and determine if additional dose titration is necessary.
•
Dispense study drug. (Access IVRS/IWRS.) Provide instructions for dose
administration and, if flavored diluent is requested and available, the preparation of
study drug with flavored diluent to subjects/parent(s)/guardian(s). See Section 6.10.
•
Collect study drug dispensed at Visit 1.1 and assess compliance.
•
Schedule next visit.
7.2.2.3 
Phone Call Visit 1.3 (Week 2 +3 days) 
•
Review Cataplexy Frequency Diary, and review the Dosing Diaries for compliance
with dosing.
•
Administer the following:
◦
C-SSRS (Appendix 8) (Since Last Visit version for subjects ≥12 years of age and
Children’s Since Last Visit version for subjects <12 years of age)
◦
CDI 2:SR[S] (Appendix 9)
◦
MASC-10 (Appendix 10)
•
Record all AEs on the AE CRF.
•
Record all concomitant medications on the concomitant medications CRF.
•
Assess subject and determine if additional dose titration is necessary.
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CONFIDENTIAL 
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•
Schedule next visit.
7.2.2.4 
Phone Call Visit 1.4 (Week 3 +3 days) 
•
Review Cataplexy Frequency Diary and review the Dosing Diaries for compliance
with dosing.
•
Administer the following:
◦
C-SSRS (Appendix 8) (Since Last Visit version for subjects ≥12 years of age and 
Children’s Since Last Visit version for subjects <12 years of age)
◦
CDI 2:SR[S] (Appendix 9)
◦
MASC-10 (Appendix 10)
•
Record all AEs on the AE CRF.
•
Record all concomitant medications on the concomitant medications CRF.
•
Assess subject and determine if additional dose titration is necessary.
•
Schedule next visit.
7.2.2.5 
Visit 1.5 (Week 4 ±7 days) 
•
Record height and weight in ordinary indoor clothes (without shoes).
•
Obtain vital signs (systolic and diastolic blood pressure, pulse/heart and respiratory
rate, and body temperature) after the subject has been resting for at least 5 minutes.
•
Review Cataplexy Frequency Diary and review the Dosing Diaries for compliance
with dosing.
•
Administer the following:
◦
C-SSRS (Appendix 8) (Since Last Visit version for subjects ≥12 years of age and
Children’s Since Last Visit version for subjects <12 years of age)
◦
CDI 2:SR[S] (Appendix 9)
◦
MASC-10 (Appendix 10)
•
Record all AEs on the AE CRF.
•
Record all concomitant medications on the concomitant medications CRF.
•
Assess subject and determine if additional dose titration is necessary.
•
Dispense study drug. (Access IVRS/IWRS.) Provide instructions for dose
administration and, if flavored diluent is requested and available, the preparation of
study drug with flavored diluent to subjects/parent(s)/guardian(s). See Section 6.10.
•
Collect study drug dispensed at Visit 1.2 and assess compliance.
•
Schedule next visit.
7.2.2.6 
Phone Call Visit 1.6 (Week 6 +3 days) 
•
Review Cataplexy Frequency Diary and review the Dosing Diaries for compliance
with dosing.
•
Administer the following:
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◦ 
C-SSRS (Appendix 8) (Since Last Visit version for subjects ≥12 years of age and 
Children’s Since Last Visit version for subjects <12 years of age) 
◦ 
CDI 2:SR[S] (Appendix 9) 
◦ 
MASC-10 (Appendix 10) 
• Record all AEs on the AE CRF.  
• Record all concomitant medications on the concomitant medications CRF. 
• Assess subject and determine if additional dose titration is necessary. 
• Schedule next visit. 
7.2.2.7 
Visit 1.7 (Week 8 ±7 days) 
• Record height and weight in ordinary indoor clothes (without shoes). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse/heart and respiratory 
rate, and body temperature) after the subject has been resting for at least 5 minutes. 
• Review Cataplexy Frequency Diary and review the Dosing Diaries for compliance 
with dosing. 
• Administer the following:  
◦ 
C-SSRS (Appendix 8) (Since Last Visit version for subjects ≥12 years of age and 
Children’s Since Last Visit version for subjects <12 years of age) 
◦ 
CDI 2:SR[S] (Appendix 9) 
◦ 
MASC-10 (Appendix 10) 
• Record all AEs on the AE CRF.  
• Record all concomitant medications on the concomitant medications CRF. 
• Assess subject and determine if additional dose titration is necessary. 
• Dispense study drug. (Access IVRS/IWRS.) Provide instructions for dose 
administration and, if flavored diluent is requested and available, the preparation of 
study drug with flavored diluent to subjects/parent(s)/guardian(s). See Section 6.10. 
• Collect study drug dispensed at Visit 1.5 and assess compliance. 
• Schedule next visit. 
7.2.3 
End Titration/Start of Stable-Dose Period, Xyrem–naïve Subjects at Study 
Entry (Visit 2, Week 10 ±3 days) 
• Record height and weight in ordinary indoor clothes (without shoes). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse/heart and respiratory 
rate, and body temperature) after the subject has been resting for at least 5 minutes. 
• Review Cataplexy Frequency Diary and review the Dosing Diaries for compliance 
with dosing. 
• Administer the following:  
◦ 
C-SSRS (Appendix 8) (Since Last Visit version for subjects ≥12 years of age and 
Children’s Since Last Visit version for subjects <12 years of age) 
◦ 
CDI 2:SR[S] (Appendix 9) 
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◦
MASC-10 (Appendix 10)
•
Instruct subjects or parent(s)/guardian(s) on how to complete the School Attendance
Diary (Appendix 14) if the subject is currently attending school.
•
Record all AEs on the AE CRF.
•
Record all concomitant medications on the concomitant medications CRF.
•
Confirm that a stable dose has been reached (i.e., a dose that achieves a maximum
clinical benefit in cataplexy and EDS while maintaining tolerability).
•
Collect study drug dispensed at previous onsite visit and assess compliance.
•
Dispense study drug. (Access IVRS/IWRS.) Provide instructions for dose
administration and, if flavored diluent is requested and available, the preparation of
study drug with flavored diluent to subjects/parent(s)/guardian(s). See Section 6.10.
•
If the subject has been unable to be titrated to a stable dose of Xyrem in the last
10 weeks, conduct the termination visit and schedule the safety follow-up visit (see
procedures in Section 7.4.3 and 7.4.4).
•
Schedule the next visit in 14 (+3) days to begin the Double-Blind Treatment Period.
7.2.4 
End of Stable-Dose Period/Beginning of the Double-Blind Treatment 
Period*, Xyrem–naïve Subjects (Visit 3, Week 12 +3 days) 
*Subjects entering the Double-Blind Treatment Period after Amendment 4 becoming
effective will complete this visit and receive open-label Xyrem during this period. 
•
Record height and weight in ordinary indoor clothes (without shoes).
•
Obtain vital signs (systolic and diastolic blood pressure, pulse/heart and respiratory
rate, and body temperature) after the subject has been resting for at least 5 minutes.
•
Review Cataplexy Frequency Diary.
•
Review the Dosing Diaries for compliance with dosing.
•
Complete CGIs for narcolepsy overall (current condition) (Appendix 17) and for
cataplexy severity (current condition) (Appendix 18).
•
Administer the following:
◦
ESS (CHAD) (Appendix 6)
◦
SF-10 (Appendix 7)
◦
C-SSRS (Appendix 8) (Since Last Visit version for subjects ≥12 years of age and
Children’s Since Last Visit version for subjects <12 years of age)
◦
CDI 2:SR[S] (Appendix 9)
◦
MASC-10 (Appendix 10)
•
Collect information on school attendance (Appendix 14) if the subject is currently
attending school and will be attending school during the Double-Blind Treatment
Period.
•
Record all AEs on the AE CRF.
•
Record all concomitant medications on the concomitant medications CRF.
•
Collect study drug dispensed at Visit 2 and assess compliance.
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•
Perform an End of Stable-Dose/Pre-Randomization PSG according to procedures in
Column 3 of Table 6. (Note: For administrative reasons the terminology for this PSG
will retain the reference to “Pre-Randomization”).
•
Dispense study drug in the morning after the End of Stable-Dose/Pre-Randomization
PSG. (Access IVRS/IWRS.) Provide instructions for dose administration and, if
flavored diluent is requested and available, the preparation of study drug with
flavored diluent to subjects/parent(s)/guardian(s). See Section 6.10.
•
Schedule next visit in the morning, and inform subjects/parent(s)/guardian(s) that
subjects must be fasting when they arrive at the visit.
7.2.5 
End Double-Blind Treatment Period, Xyrem–naïve Subjects (Visit 4, 
Week 14 +3 days) 
•
Obtain blood samples for the following:
◦
Fasting blood sample for GH, IGF-1, and prolactin
◦
Routine hematology and chemistry (see Table 2)
◦
Serum pregnancy test (only for female subjects who have reached menarche)
•
Provide breakfast for the subject after the fasting blood sample is collected.
•
Perform a physical examination and record height and weight in ordinary indoor
clothes (without shoes).
•
Obtain vital signs (systolic and diastolic blood pressure, pulse/heart and respiratory
rate, and body temperature) after the subject has been resting for at least 5 minutes.
•
Obtain urine samples for urinalysis.
•
Perform alcohol test and urine drug screens for subjects who are continuing into the
Open-Label Safety Period.
•
Obtain a 12-lead ECG.
•
Review Cataplexy Frequency Diary and review the Dosing Diaries for compliance
with dosing.
•
Collect information from the School Attendance Diary (Appendix 14).
•
Have the subject complete the PGIc (Appendix 19). Instruct the subject to rate his/her
impression of change since Visit 3 (the end of the Stable-Dose Period).
•
Complete CGIc for narcolepsy overall (Appendix 20) and for cataplexy severity
(Appendix 21).
•
Administer the following:
◦
ESS (CHAD) (Appendix 6)
◦
SF-10 (Appendix 7)
◦
C-SSRS (Appendix 8) (Since Last Visit version for subjects ≥12 years of age and
Children’s Since Last Visit version for subjects <12 years of age)
◦
CDI 2:SR[S] (Appendix 9)
◦
MASC-10 (Appendix 10)
•
Record all AEs on the AE CRF.
•
Record all concomitant medications on the concomitant medications CRF.
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• Collect study drug dispensed at Visit 3 and assess compliance. 
• Dispense study drug for the Open-Label Safety Period. (Access IVRS/IWRS.) 
◦ 
Subjects may take two equally divided doses or two unequally divided doses, with 
the exception of PK nights (if applicable) when all subjects have to take two 
equally divided doses 4 hours apart. Only doses that match the printed gradations 
(lines) on the dosing syringe are permitted. 
◦ 
For subjects who had entered the Double-Blind Treatment Period prior to 
Amendment 4 becoming effective: 
◦ 
Upon entering the Open-Label Safety Period, all subjects will be started at a dose 
no higher than half the Xyrem dose they received at the end of the Stable-Dose 
Period or the initiation dose defined in Table 1, whichever is higher. Subjects will 
then be titrated up to their optimal dose as tolerated according to the 
Investigator’s judgment (the maximum dose should not exceed the doses defined 
in Table 1 or the stable dose prior to study entry, whichever is higher, and should 
not be greater than 9 g/night). Xyrem dose uptitration is allowed at no more than 
1.5 g/night. 
◦ 
For subjects entering the Double-Blind Period after Amendment 4 becoming 
effective:  
Subjects will continue on in the Open-Label Safety Period at the same dose that 
they have been taking. 
• Schedule next visit. 
7.2.6 
PK Nights 1 and 2, Xyrem–naïve Subjects  
Refer to Section 7.1.3 
7.2.7 
Open-Label Safety Evaluation, Xyrem–naïve Subjects  
• See procedures in Section 7.4 
7.3 
PSG Night Procedures for All Subjects 
Table 6 lists the procedures for the PSG nights by study period (Screening and End of Stable-
Dose/Pre-Randomization*) and subject population (subjects on Xyrem at study entry and 
Xyrem-naïve subjects). Note: *For administrative reasons the terminology for this PSG will 
retain the reference to “Pre-Randomization”. 
For all PSG nights when subjects receive study drug, a light dinner should be taken >2 hours 
prior dosing. The meal should be the same or similar on all PSG nights where dosing with 
study drug is required. The Investigator will confirm that the light dinner planned and 
consumed was acceptable. The meal may be taken at the Sleep Lab or at home. No dinner 
restriction is required for Xyrem-naïve subjects prior to the screening PSG night. 
The site will be supplied with appropriate study drug for use on Screening PSG nights. 
Subjects will bring the study drug dispensed to them for the End of Stable-Dose/Pre-
Randomization (Xyrem-naïve subjects only) and End of Study (Part 1) PSGs. 
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On PSG nights, when subjects have taken study drug, subjects should be allowed to sleep 
after the second dose until they wake.  
Ensure that subjects of driving age who received study drug during the PSG nights will not 
be driving themselves when leaving the sleep lab. 
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Table 6 
PSG Night Procedures 
1 
2 
3 
4 
Screening PSG 
 
End of Stable-
Dose/Pre-Randomization PSG* 
End of Study (Part 1) PSG or Part 1 
Early Terminationa 
Xyrem-naïve subjects 
Subjects on Xyrem at study 
entry 
Xyrem-naïve subjects 
All subjects 
Review inclusion/exclusion 
Review inclusion/exclusion 
No inclusion/exclusion review 
needed 
No inclusion/exclusion review needed 
No dinner restrictions 
Light dinner >2 hours before 
dosing 
Light dinner >2 h before dosing 
Light dinner >2 h before dosing 
Confirm parent/guardian contact 
information 
Confirm parent/guardian contact 
information 
Confirm parent/guardian contact 
information 
Confirm parent/guardian contact 
information 
No dosing 
Usual nightly dose of Xyrem 
divided into 2 doses, 4 h apart 
Nightly dose of Stable-dose Xyrem 
divided into 2 doses, 4 h apart 
Nightly Xyrem dose taken at end of Safety 
Period divided into 2 doses, 4 h apart 
Perform PSG 
Perform PSG 
Perform PSG 
Perform PSG 
EtCO2 or TcCO2
b 
EtCO2 or TcCO2
b 
EtCO2 or TcCO2
b 
EtCO2 or TcCO2
b 
Obtain vital signsc 
Obtain vital signsd 
Obtain vital signsd 
Obtain vital signsd 
Monitor SpO2
e  
Monitor and record SpO2
f 
Monitor and record SpO2
f 
Monitor and record SpO2
f 
Record AEs/Con Meds 
Record AEs/Con Meds 
Record AEs/Con Meds 
Record AEs/Con Meds 
--- 
Brief neuro examg 
Brief neuro examg 
Brief neuro examg 
No blood sample  
No blood sample 
The morning following the PSG, 
obtain fasting blood sample for GH, 
IGF-1, and prolactin 
The morning following the PSG, obtain 
blood samples for 
◦ Fasting blood sample for GH, IGF-1, 
and prolactin 
◦ Routine hematology and chemistry 
◦ For girls <8 years of age: estradiol, FSH, 
and LH 
For boys <9 years of age: testosterone, 
FSH, and LH 
Provide breakfast (if subject prefers to eat at the study center) in the morning after all PSG nights 
GH=growth hormone, IGF-1=insulin-like growth factor-1 (low sensitivity) 
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*For administrative reasons the terminology for this PSG will retain the reference to “Pre-Randomization”. 
 
a) 
If the subject withdraws early from Part 1 of the study during the Open-Label Safety Period, perform a PSG if the subject is willing to be dosed with 
study drug for this PSG night. Part 1 Early termination PSG does not apply for subjects who discontinue before entering the Open-Label Safety Period. 
b) 
At sites where EtCO2 or TcCO2 monitoring is routinely performed. 
c) 
Obtain vital signs after subject has been resting for at least 5 minutes before start of PSG and prior to release from study center.  
d) 
Obtain vital signs after subject has been resting for at least 5 minutes at pre-dose and prior to release from study center. At 1, 4 (pre-2nd dose), 5, and 
8 hours after the first Xyrem dose, heart and respiratory rates are recorded via PSG monitoring. 
e) 
Monitor SpO2 to determine obstructive sleep apnea status. 
f) 
Monitor SpO2 continuously from immediately before first dose through 8 hours after first dose, and record SpO2 pre-dose and at 1 h, 2 h, 4 h (pre-2nd 
dose), 5 h, 6 h, and 8 h after first dose and before release from study center while subject is awake. 
g) 
Brief neurological exam before discharge on the morning after the PSG. 
 
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7.4 
Open-Label Safety Period for All Subjects 
A Schedule of Events for subjects in the Open-Label Safety Period is in Appendix 1.1 for 
subjects on Xyrem at study entry and in Appendix 2.2 for subjects who are Xyrem-naïve at 
study entry.   
7.4.1 
Visit 5 (4 weeks after end of the Double-Blind Treatment Period) and Visits 
7, 9, 12 (Weeks 18, 26, 39 from Day 1) 
• Record height and weight in ordinary indoor clothes (without shoes).  
• Obtain vital signs (systolic and diastolic blood pressure, pulse/heart and respiratory 
rate, and body temperature) after the subject has been resting for at least 5 minutes. 
• Perform urine drug and alcohol test screens. 
• Review Cataplexy Frequency Diary. 
• Review Study Drug Dosing Diary.  
• Administer the following:  
◦ 
ESS (CHAD) (Appendix 6) 
◦ 
SF-10 (Appendix 7) 
◦ 
C-SSRS (Appendix 8; Since Last Visit version for subjects ≥12 years of age and 
Children’s Since Last Visit version for subjects <12 years of age) 
◦ 
CDI 2:SR[S] (Appendix 9) 
◦ 
MASC-10 (Appendix 10) 
• Record all AEs on the AE CRF.  
• Record all concomitant medications on the concomitant medications CRF. 
• Collect study drug dispensed at the previous visit and measure compliance. 
• Dispense study drug. (Access IVRS/IWRS.) Provide instructions for dose 
administration and, if flavored diluent is requested and available, the preparation of 
study drug with flavored diluent to subjects/parent(s)/guardian(s). See Section 6.10. 
• Schedule the next clinic or phone visit  
PK Evaluation  
Once the subject is on a stable dose of Xyrem, PK Nights 1 and 2 can be scheduled for a 
protocol-specified clinic visit or for an additional clinic visit.  
• If not done at a previous visit: 
- 
Obtain additional documented assent and consent for the PK evaluation. 
- 
Review the inclusion/exclusion criteria for subjects participating in the PK 
evaluation. 
- 
Obtain blood samples for coagulation (PT/INR and PTT) within 30 days of PK 
Night 1 
• Follow procedures for PK Nights 1 and 2 in Section 7.1.3. 
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7.4.2 
Phone Call Visits 6, 8, 10, 11, 13, 14 (Weeks 16, 22, 30, 34, 43, and 48 
from Day 1)  
• Record all AEs on the AE CRF.  
• Record all concomitant medications on the concomitant medications CRF. 
• Administer the following:  
◦ 
C-SSRS (Appendix 8) (Since Last Visit version for subjects ≥12 years of age and 
Children’s Since Last Visit version for subjects <12 years of age) 
◦ 
CDI 2:SR[S] (Appendix 9) 
◦ 
MASC-10 (Appendix 10) 
 
7.4.3 
Visit 15 Week 52 or Part 1 Early Termination 
If the subject will be continuing directly into Part 2, the Open-Label Continuation Period, see 
Section 7.5. 
• Perform a physical examination, including a brief neurological examination and a 
Tanner Stage Assessment (Appendix 5) but excluding a full genitourinary exam. 
• Record height and weight in ordinary indoor clothes (without shoes). 
• Review Cataplexy Frequency Diary. 
• Review Study Drug Dosing Diary. 
• Administer the following:  
◦ 
ESS (CHAD) (Appendix 6) 
◦ 
SF-10 (Appendix 7) 
◦ 
C-SSRS (Appendix 8) (Since Last Visit version for subjects ≥12 years of age and 
Children’s Since Last Visit version for subjects <12 years of age) 
◦ 
CDI 2:SR[S] (Appendix 9) 
◦ 
MASC-10 (Appendix 10) 
• Obtain vital signs (systolic and diastolic blood pressure, pulse/heart and respiratory 
rate, and body temperature) after the subject has been resting supine for at least 
5 minutes. 
• Obtain urine samples for urinalysis.  
• Perform alcohol test and urine drug screens. 
• Obtain urine sample for pregnancy test (only perform for female subjects who have 
reached menarche).  
• Obtain a 12-lead ECG. 
• Record all AEs on the AE CRF.  
• Record all concomitant medications on the concomitant medications CRF. 
• Collect study drug dispensed at the previous visit and measure compliance. 
• Perform End of Study (Part 1) PSG according to the procedures for all subjects in 
Column 4 of Table 6. If the subject withdraws early from the study during the Open-
Label Safety Period, perform the PSG if subject is willing to be dosed with study drug 
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on this PSG night. Part 1 early termination PSG does not apply for subjects who 
discontinue before entering the Open-Label Safety Period. 
• Obtain blood samples for the following the morning after the PSG night: 
◦ 
Fasting blood sample for GH, IGF-1, and prolactin 
◦ 
Routine hematology and chemistry 
◦ 
For girls <8 years of age: estradiol, FSH, and LH 
For boys <9 years of age: testosterone, FSH, and LH  
• If the subject will not be continuing into Part 2, record the reason why and schedule 
the Safety Follow-up visit.  
7.4.4 
Visit 16 Safety Follow-up Visit 
The Safety Follow-up Visit must be completed 14 days (+3 days) after the last dose of study 
drug for subjects who complete Part 1 of the study and are not continuing directly into Part 2 
or for subjects who terminate early from Part 1. 
• Record height and weight in ordinary indoor clothes (without shoes). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse/heart and respiratory 
rate, and body temperature) after the subject has been resting supine for at least 
5 minutes. 
• Administer the following: 
◦ 
C-SSRS (Appendix 8) (Since Last Visit version for subjects ≥12 years of age 
and Children’s Since Last Visit version for subjects <12 years of age) 
◦ 
CDI 2:SR[S] (Appendix 9) 
◦ 
MASC-10 (Appendix 10) 
• Record all AEs on the AE CRF.  
Subjects will not be given study drug during this 2-week follow-up period but are expected to 
be treated for their cataplexy and EDS with commercially available medications as 
appropriate during this time by their treating physicians. 
7.5 
Part 2 Open-Label Continuation Period for Subjects Continuing 
Directly into Part 2 after Completing Part 1 
7.5.1 
Visit 15 for Subjects Continuing in Part 2 (Onsite) 
• Confirm that subject provided assent and ICF signed by parent(s) or guardian(s) for 
Protocol Amendment 5. 
• Perform a physical examination, including a brief neurological examination and a 
Tanner Stage Assessment (Appendix 5) but excluding a full genitourinary exam. 
• Record height and weight in ordinary indoor clothes (without shoes). 
• Review Cataplexy Frequency Diary. 
• Review Study Drug Dosing Diary. 
• Administer the following:  
◦ 
ESS (CHAD) (Appendix 6) 
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◦ 
SF-10 (Appendix 7) 
◦ 
C-SSRS (Appendix 8) (Since Last Visit version for subjects ≥12 years of age and 
Children’s Since Last Visit version for subjects <12 years of age) 
◦ 
CDI 2:SR[S] (Appendix 9) 
◦ 
MASC-10 (Appendix 10) 
• Obtain vital signs (systolic and diastolic blood pressure, pulse/heart and respiratory 
rate, and body temperature) after the subject has been resting supine for at least 
5 minutes. 
• Obtain urine samples for urinalysis.  
• Perform alcohol test and urine drug screens. 
• Obtain urine sample for pregnancy test (only perform for female subjects who have 
reached menarche).  
• Obtain a 12-lead ECG. 
• Record all AEs on the AE CRF.  
• Record all concomitant medications on the concomitant medications CRF. 
• Collect study drug dispensed at the previous visit and measure compliance. 
• Perform End of Study (Part 1) PSG according to the procedures for all subjects in 
Column 4 of Table 6.  
• Obtain blood samples for the following the morning after the PSG night: 
◦ 
Fasting blood sample for GH, IGF-1, and prolactin 
◦ 
Routine hematology and chemistry 
◦ 
For girls <8 years of age: estradiol, FSH, and LH 
For boys <9 years of age: testosterone, FSH, and LH  
• Dispense study drug. (Access Interactive Response Technology [IRT].) Provide 
instructions for dose administration and, if flavored diluent is requested and available, 
the preparation of study drug with flavored diluent to subjects/parent(s)/guardian(s). 
See Section 6.10.  
• Determine when the subject will be 18 years of age. Schedule the Part 2 Study 
Termination Visit to occur prior to the subject’s 18th birthday. 
7.5.2 
Visits 19, 20, 22, 23, 25, 26, 28, 29, 31, 32, 34, 35, 37, 38, 40, and 41 
(Phone Call)  
• Record all AEs on the AE CRF.  
• Record all concomitant medications on the concomitant medications CRF.  
• Determine when the subject will be 18 years of age. Schedule the Part 2 Study 
Termination Visit to occur prior to the subject’s 18th birthday. 
7.5.3 
Visits 21, 27, 33, and 39 (Onsite)  
• Record height and weight in ordinary indoor clothes (without shoes). 
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• Obtain vital signs (systolic and diastolic blood pressure, pulse/heart and respiratory 
rate, and body temperature) after the subject has been resting for at least 5 minutes. 
• Record all AEs on the AE CRF.  
• Record all concomitant medications on the concomitant medications CRF.  
• Collect study drug dispensed at the previous visit and measure compliance. 
• Dispense study drug. (Access IRT.) Provide instructions for dose administration and, 
if flavored diluent is requested and available, the preparation of study drug with 
flavored diluent to subjects/parent(s)/guardian(s). See Section 6.10.  
• Determine when the subject will be 18 years of age. Schedule the Part 2 Study 
Termination Visit to occur prior to the subject’s 18th birthday. 
7.5.4 
Visits 24, 30, and 36 (Onsite)  
• Record height and weight in ordinary indoor clothes (without shoes). 
• Perform alcohol test and urine drug screens. 
• Obtain urine sample for pregnancy test (only perform for female subjects who have 
reached menarche).  
• Obtain vital signs (systolic and diastolic blood pressure, pulse/heart and respiratory 
rate, and body temperature) after the subject has been resting for at least 5 minutes. 
• Record all AEs on the AE CRF.  
• Record all concomitant medications on the concomitant medications CRF.  
• Collect study drug dispensed at the previous visit and measure compliance. 
• Dispense study drug. (Access IRT.) Provide instructions for dose administration and, 
if flavored diluent is requested and available, the preparation of study drug with 
flavored diluent to subjects/parent(s)/guardian(s). See Section 6.10.  
• Determine when the subject will be 18 years of age. Schedule the Part 2 Study 
Termination Visit to occur prior to the subject’s 18th birthday. 
7.5.5 
Part 2 Study Termination/Part 2 Early Termination Visit 42 (Onsite)  
• Record height and weight in ordinary indoor clothes (without shoes). 
• Perform alcohol test and urine drug screens. 
• Obtain urine sample for pregnancy test (only perform for female subjects who have 
reached menarche).  
• Obtain vital signs (systolic and diastolic blood pressure, pulse/heart and respiratory 
rate, and body temperature) after the subject has been resting for at least 5 minutes. 
• Record all AEs on the AE CRF.  
• Record all concomitant medications on the concomitant medications CRF.  
• Collect study drug dispensed at the previous visit and measure compliance. 
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7.6 
Part 2 Open-Label Continuation Period for Subjects Re-enrolling 
after Completing Part 1 
After the subject has provided assent and a parent(s) or guardian(s) has signed an ICF in 
accordance with local IRB/IEC requirements, the subject may be screened for re-enrollment 
in Part 2. All subjects will provide their written informed consent prior to the performance of 
any study-related procedures. The Part 2 Screening Visit (Visit 17) starts when a subject is 
registered for Part 2 in IRT. Screening will occur within 2 weeks before dosing. If needed, 
additional screening time may be granted with permission of the Medical Monitor. 
7.6.1 
Part 2 Screening Visit 17 (Onsite) for Subjects Re-enrolling after 
Completing Part 1 of the Study 
• Obtain subject assent and ICF signed by parent(s) or guardian(s).  
• Update the parent or guardian’s contact information 
• Review the inclusion/exclusion criteria for Part 2. 
• Interview parent(s)/guardian(s) to determine if the home situation is safe for Xyrem 
use and storage, and assess if there is a risk of use or abuse by family members or 
others living in the home. 
• Review the subject’s previously recorded medical history and update any new 
medical history information. Record any new medical history that occurs after 
Visit 16 and prior to re-enrollment. (Any new clinically significant condition with 
onset after the last Part 1 visit (Visit 16) until assent/consent is provided in Part 2 
should be recorded as medical history.) 
• Record all prior medications, including OTC and health and dietary supplements 
taken during the 2 weeks before Screening. Also record any concomitant medications. 
• Confirm the subject’s current Xyrem usage. If the subject is currently on Xyrem, 
record the subject’s prescribed usual dose and regimen of Xyrem. If currently on 
Xyrem, the subject should be on a stable dose. If the subject has been off Xyrem, 
record if the subject has been off Xyrem for ≥1 month. 
• Perform a physical examination, including a brief neurological examination. 
• Record height and weight in ordinary indoor clothes (without shoes). 
• Obtain blood samples for the following:* 
◦ 
Routine hematology and chemistry (see Table 2) 
◦ 
Serum pregnancy test (only for female subjects who have reached menarche) 
• Obtain urine samples for urinalysis.* 
• Perform alcohol test and urine drug screens.*  
• Obtain vital signs (systolic and diastolic blood pressure, pulse/heart and respiratory 
rate, and body temperature) after the subject has been resting for at least 5 minutes. 
* Subjects who re-enroll within 2 weeks of Visit 15 do not need clinical labs, drug screen, 
alcohol test, or serum pregnancy test at the Part 2 Screening. 
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7.6.2 
Part 2 Visits for Subjects Re-enrolling Who Do Not Require Titration 
Subjects who re-enroll after completing Part 1 do not require titration if they have continued 
to take Xyrem and are on a stable dose. 
7.6.2.1 
Visit 18 (Onsite) Subjects Re-enrolling Who Do Not Require Titration 
• 
Review the inclusion/exclusion criteria for Part 2 to determine the subject’s 
eligibility to continue participating in the study. 
• 
Record height and weight in ordinary indoor clothes (without shoes). 
• 
Perform alcohol test and urine drug screens.  
• 
Obtain urine sample for pregnancy test (only perform for female subjects 
who have reached menarche). 
• 
Obtain vital signs (systolic and diastolic blood pressure, pulse/heart and 
respiratory rate, and body temperature) after the subject has been resting for 
at least 5 minutes. 
• 
Record all AEs that occur after assent was given and the ICF was signed on 
the AE CRF. 
• 
Record all concomitant medications that were taken after assent was given 
and the ICF was signed on the concomitant medications CRF.  
• 
Dispense study drug. (Access IRT.) Provide instructions for dose 
administration and, if flavored diluent is requested and available, the 
preparation of study drug with flavored diluent to 
subjects/parent(s)/guardian(s). See Section 6.10.  
• 
Determine when the subject will be 18 years of age. Schedule the Part 2 
Study Termination Visit to occur prior to the subject’s 18th birthday. 
7.6.2.2 
Visits 19 through 42 for Subjects Who Do Not Require Titration 
Follow the activities in Sections 7.5.2 through 7.5.5. 
7.6.3 
Part 2 Visits for Subjects Re-enrolling Who Require Titration 
7.6.3.1 
Visit 18 (Onsite) Subjects Re-enrolling Who Require Titration − Begin Titration 
(Week T1) 
Titration is required for subjects who are re-enrolling after completing Part 1 of the study and 
have been off Xyrem for ≥1 month. For subjects who have been off Xyrem for less than 
1 month, titration may also be required per the Investigator’s judgment. Subjects will be 
titrated to Xyrem as described in Section 3.1.2. The Part 2 Titration may last up to 10 weeks. 
Once it is determined that the subject has achieved clinical benefit in cataplexy and EDS 
while maintaining tolerability, the subject may remain on that stable dose through the 
remainder of the titration period. However, Xyrem dose adjustment due to tolerability and 
efficacy is permitted per the Investigator’s judgment.  
Follow the activities in Section 7.6.2.1. 
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7.6.3.2 
Visits 18.1, 18.2, 19, 19.1, 20, 20.1 (Phone Calls) Subjects Re-enrolling Who 
Require Titration 
Study activities for Titration Phone Visits 18.1 (Week T2 +3 days), 18.2 (Week T3 +3 days), 
19 (Week T4 +3 days), 19.1 (Week T7 +3 days), 20 (Week T8 +3 days), 20.1 (Week T10 +3 
days) are as follows: 
• 
Record all AEs that occur after assent was given and the ICF was signed on 
the AE CRF.  
• 
Record all concomitant medications that were taken after assent was given 
and the ICF was signed on the concomitant medications CRF.  
• 
Determine if additional dose titration is necessary. 
• 
Determine when the subject will be 18 years of age. Schedule the Part 2 
Study Termination Visit to occur prior to the subject’s 18th birthday. 
7.6.3.3 
Visits 21 through 42 for Subjects Who Require Titration 
Follow activities in Sections 7.5.2 through 7.5.5. 
8 
QUALITY CONTROL AND ASSURANCE 
The study will be conducted according to GCP guidelines and according to local and national 
law. Quality audits may be performed at the discretion of Jazz Pharmaceuticals or its 
designee. 
9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
The primary objectives of this study are to evaluate the efficacy and safety of Xyrem in the 
treatment of cataplexy in narcolepsy in pediatric subjects. Secondary objectives are to 
evaluate the efficacy of Xyrem in the treatment of EDS in pediatric subjects with narcolepsy 
with cataplexy, to characterize the PK of Xyrem given as two doses to children and 
adolescents (ages 7-17 years) with narcolepsy with cataplexy, and to evaluate the safety of 
titrating Xyrem in children and adolescents to an effective and tolerable dose.  
Non-categorical efficacy parameters will be analyzed by non-parametric analysis of 
covariance (ANCOVA). Ordinal categorical parameters, including CGIc and PGIc, will be 
analyzed using Cochran–Mantel–Haenszel (CMH) tests for row mean score difference. PK 
parameters will be assessed by analysis of variance (ANOVA) models using natural log-
transformed data. Safety data will be summarized using descriptive statistics. When data are 
reported by age group, either ages 7-11 years or ages 12-17 years, subjects will be 
summarized by age at Visit 2 (start of the Stable-Dose Period) for subjects on Xyrem at study 
entry and at Visit 1.1 (start of the Titration Period) for Xyrem-naïve subjects.  
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9.2 
Determination of Sample Size 
The study will enroll pediatric subjects who are diagnosed with narcolepsy with cataplexy 
and who are between 7 and 16 years of age, inclusive, to ensure subjects are <18 years of age 
at the end of Part 1 of the study. At least 100 subjects will be enrolled in the study to assess 
the safety of Xyrem in this pediatric population.   
Prior to Amendment 4, a sample size of 70 subjects was planned to enter the randomized-
withdrawal (Double-Blind Treatment) period. This sample size was estimated based on 
repeated resampling of the data with replacement (bootstrapping) from previous narcolepsy 
trials in adults (GHB-2 and OMC-SXB-15). The analysis showed that a sample of 35 
subjects on Xyrem (sodium oxybate) treatment had at least 40% difference from endpoint to 
baseline in the mean weekly number of cataplexy attacks, as a percentage of endpoint, over 
95% of the time. The present study (13-005) differs from Studies GHB-2 and OMC-SXB-15 
in that pediatric subjects will be enrolled instead of adults, the study design is randomized-
withdrawal versus a standard randomized treatment study, and the length of the randomized 
period is 2 weeks for 13-005 versus 4 weeks for GHB-2 and 8 weeks for OMC-SXB-15. 
Discounting for these factors, a sample of 35 subjects in each arm was expected to have at 
least 80% power to detect a difference between the two treatment groups of 40% in the 
percentage change in the mean weekly number of cataplexy attacks during the 2-week 
Double-Blind Treatment Period of the study as compared with the mean weekly number of 
cataplexy attacks during the last 2 weeks of the immediately preceding stable-dose period, 
using a two-sided alpha of 0.05.  
Every effort will be made to enroll approximately 30 subjects on Xyrem at study entry of the 
anticipated 100 subjects enrolled. Other subjects enrolled will be Xyrem naïve at study entry. 
A subset of the subjects who are taking Xyrem at a stable dose for their narcolepsy symptoms 
will participate in the PK evaluation. Up to 18 subjects in each of the two age groups (7-11 
year olds and 12-17 year olds) will be enrolled to ensure a minimum of 12 completers in each 
age group. If the variability of PK data in children and adolescents is comparable to that of 
adults, a sample size of 12 completers in each age group is expected to provide adequate 
precision to characterize the PK of sodium oxybate in each age group. However, when 
sufficient data are obtained to characterize the PK profile with adequate precision during the 
study, as determined by the Data and Safety Monitoring Board (DSMB), or when enrollment 
of 100 subjects in the study has been reached, enrollment for the PK evaluation will stop and 
available data will be used for analysis.  
9.3 
Analysis Populations  
The Safety Population will consist of all subjects who are dispensed study drug. This 
population will be used for tables and listings of safety data. This population will also be 
used to summarize efficacy data as appropriate. The Safety Population will be additionally 
categorized by period and by whether the subject took study drug during the different study 
periods. 
 
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The PK Half-Dose Population will consist of all subjects who have any PK data for PK 
Night 1 when subjects receive one half of their usual stable dose. This population will be 
used for listings and descriptive statistics of the half-dose PK data. 
The PK Full-Dose Population will consist of all subjects who have any PK data for PK 
Night 2 when subjects receive their usual stable dose. This population will be used for 
listings and descriptive statistics of the full-dose PK data. 
The PK Completer Population will consist of all subjects who have PK data for both PK 
nights. This population will be used for evaluating within subject dose proportionality.   
The Efficacy Population will consist of all subjects who are randomized to Xyrem or Xyrem 
placebo and who complete at least 5 days of dosing in the Double-Blind Treatment Period. 
This population will be used as the main analysis population for tables of the primary and 
secondary efficacy endpoints. 
The Randomized Population will consist of all subjects who are randomized to Xyrem or 
Xyrem placebo for the Double-Blind Treatment Period of the study. This population will be 
used to summarize exposure to double-blind treatment. This population may also be used for 
summaries of safety data specific to the Double-Blind Treatment Period. This population 
may also be used for an additional analysis of the primary and/or secondary efficacy 
endpoints. 
The Continued Access Population will consist of all subjects who took study drug in Part 2.  
This population will be used for tables and listings of Part 2 data.  
9.4 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for the safety population, the 
PK half-dose population, the PK completer population, the randomized population, the 
efficacy population, and the continued access population. The summaries of data will include 
numbers and percentages for categorical variables and mean, standard deviation, median, 
minimum, and maximum for continuous variables. Tables for the randomized population and 
the efficacy population will be by randomized treatment group (Xyrem or Xyrem placebo) 
and overall. The randomized population tables will include a comparison of the treatment 
groups, with categorical variables analyzed using a chi-square test and continuous variables 
analyzed using a one-way analysis of variance (ANOVA) model with treatment as the only 
factor. 
9.5 
Handling of Dropouts and Missing Data 
The following methods will be used to handle missing efficacy data and data from subjects 
who discontinue early in the Double-Blind Treatment Period. The weekly number of 
cataplexy attacks will be computed as the average from days with non-missing data, 
multiplied by 7. School attendance will be calculated as the number of missed days, 
multiplied by 100, divided by the actual number of school days (not including holidays) up to 
the point of Part 1 early termination or Double-Blind Treatment Period completion. The last 
post Stable-Dose Period assessment of all other measures will be used as the end of the 
Double-Blind Treatment Period assessment. 
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9.6 
Efficacy Endpoints  
All efficacy assessments will be comparisons of the measurement made during, or at the end 
of, the last 2 weeks of the Stable-Dose Period compared with the 2 weeks of Double-Blind 
Treatment Period. 
Primary endpoint:  
1. Change in weekly number of cataplexy attacks 
Key secondary endpoints: 
2. CGIc for cataplexy severity  
3. Change in the ESS (CHAD) score  
Other secondary endpoints: 
4. CGIc for narcolepsy overall  
5. Change in Quality of Life (QoL) (SF-10)  
Exploratory endpoints: 
6. Change in weekly school attendance (if enrollment overlaps with school attendance 
period) 
7. PGIc for narcolepsy overall  
9.6.1 
Statistical Analysis 
To address Primary Objective 1 and Secondary Objective 1: 
A tiered approach was planned to control the Type 1 family-wise error rate at the 0.05 
significance level with all tests being two-sided for testing of the primary and secondary 
efficacy endpoints. 
Due to the positive primary efficacy results from the pre-specified interim analyses 
(described in Section 9.8), the DSMB recommended to stop the Double-Blind Randomized-
Withdrawal Period.  Tiered testing on secondary endpoints, as defined below, will be 
conducted with a significance level of 0.05, with all tests being two-sided. 
Tier 1: Primary endpoint 
1. Change in weekly number of cataplexy attacks from the last 2 weeks of the Stable-
Dose Period to the 2 weeks of the Double-Blind Treatment Period. 
The primary endpoint demonstrated efficacy at the interim analysis with a significance level 
<0.005.  Testing will continue with Tier 2.  
Tier 2: Key secondary endpoint #2 
2. CGIc for cataplexy severity from the end of the Stable-Dose Period to the end of the 
Double-Blind Treatment Period 
The testing of this endpoint will be conducted at the 0.05 significance level. If Xyrem is 
significantly better than placebo at this level, Tier 3 tests will be conducted. 
Tier 3: Key secondary endpoint #3 
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3. Change in the ESS (CHAD) score from the end of the Stable-Dose Period to the end 
of Double-Blind Treatment Period 
The testing of this endpoint will be conducted at the 0.05 significance level. If Xyrem is 
significantly better than placebo at this level, Tier 4 tests will be conducted. 
Tier 4: Other secondary endpoints #4 
4. CGIc for narcolepsy overall from the end of the Stable-Dose Period to the end of the 
Double-Blind Treatment Period 
The testing of this endpoint will be conducted at the 0.05 significance level. If Xyrem is 
significantly better than placebo at this level, Tier 5 tests will be conducted. 
Tier 5: Other secondary endpoint #5 
5. Change in QoL (SF-10) from the end of the Stable-Dose Period to the end of the 
Double-Blind Treatment Period 
The testing of this endpoint will be conducted at the 0.05 significance level. 
Exploratory efficacy endpoints will be tested without multiplicity adjustments. For these 
parameters, nominal p-value will be reported.  
Non-categorical efficacy parameters will be analyzed by non-parametric analysis of 
covariance (ANCOVA). Ordinal categorical parameters, including CGIc and PGIc, will be 
analyzed using Cochran–Mantel–Haenszel (CMH) tests for row mean score difference. 
Efficacy data in the open-label phase will be summarized by visit. 
9.7 
Statistical Analysis of Pharmacokinetic Variables 
To address Secondary Objective 2: Concentration data for sodium oxybate will be 
summarized by sampling time point and by PK parameter using descriptive statistics for each 
age group and overall. Dose proportionality will be assessed from the ratio of AUC and Cmax 
values. The ratios and their 90% confidence intervals will be presented. If warranted, 
regression models will be used to explore the relationship between plasma concentration and 
dose on a mg/kg basis. 
9.8 
Interim Analysis  
A preplanned interim analysis was conducted after 35 subjects completed or discontinued 
early from the Double-Blind Treatment Period. The interim analysis was performed by a 
statistician not directly involved with the design and analysis of the study. The data were 
reviewed by a DSMB that recommended stopping placebo treatment in the Double-Blind 
Randomized-Withdrawal Period and continue the study as an open-label safety study because 
of positive efficacy results. 
Considerations for stopping the study early included the following as initially planned. Given 
now the placebo treatment is stopped after the interim analysis review by DSMB, the DSMB 
will continue to review safety and PK data as outlined below.  
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For stopping the study early because of treatment success, so that fewer subjects will be 
exposed to placebo: The O'Brien-Fleming approach will be used with the primary efficacy 
endpoint. This endpoint will be tested at a significance level of 0.005 at the interim analysis. 
If statistical significance is shown, the DSMB may recommend stopping the study 
considering the overall study objectives and subject’s safety. If the study is not stopped, to 
maintain an overall alpha of 0.05, the final analysis will be conducted at a significance level 
of 0.048, based on one prior look at the data. 
For stopping the study early because of treatment failure: In the interim analysis, if the 
null hypothesis for the primary efficacy endpoint is not rejected at the 0.005 significance 
level, then a futility analysis will be conducted. The conditional power approach will be used. 
Assuming the trend in the data observed up to the interim analysis will continue for the data 
collected between the interim analysis and the final analysis, the conditional power of 
rejecting the null hypothesis at the final analysis will be calculated. If the conditional power 
is less than 15%, it will be concluded that the study is unlikely to demonstrate efficacy and 
the DSMB may recommend stopping the study considering the overall study objectives and 
subject’s safety. The study may be discontinued early due to futility. 
For stopping the study early because of safety reasons: Safety data, including the 
incidence of adverse events, will be reviewed by the DSMB at regular intervals. Any serious 
adverse events or deaths will be given detailed attention. Taking all data reviewed into 
account, the DSMB will determine if the risk to subjects warrants study discontinuation.   
An ongoing analysis of the PK data will also be conducted to determine if a sufficient 
number of samples have been collected to adequately characterize the PK of Xyrem in 
children and adolescents.  
9.9 
Safety Analysis 
Safety will be assessed at time points specified in the schedules of events, as well as 
throughout the study. Safety assessments will include the following:  
• Adverse event (AE) monitoring 
• Vital signs 
• Physical examinations (including weight and height) 
• 12-lead ECG 
• PSG parameters (including respiratory measures)  
• Clinical laboratory tests (chemistry, hematology, and urinalysis) 
• Assessments of growth and precocious puberty 
• C-SSRS (Children’s Since Last Visit version for subjects under 12 years of age and 
the Since Last Visit version for subjects 12 years of age and older) for emergent 
suicidality 
• CDI 2:SR[S] for emergent or worsening depression 
• MASC-10 for emergent or worsening anxiety 
• Serum pregnancy tests (if applicable) 
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Exploratory endpoint: 
• CO2 monitoring (EtCO2 or TcCO2) in sites where monitoring is routinely performed 
and performance will not negatively impact study participation or PSG data integrity 
A DSMB will review the safety data on a regular basis, including monitoring for the 
following AEs: 
• Confusion 
• Somnolence and more pronounced levels of depressed consciousness 
• Respiratory depression 
• Depressed mood and suicidality 
• Anxiety 
• Sleepwalking and other parasomnias 
• Abuse and misuse of study drug 
• Weight loss 
Adverse events will be mapped to system organ classes and preferred terms using the 
Medical Dictionary for Regulatory Activities (MedDRA). 
To address Primary Objective 2 and Secondary Objective 3: Safety will be summarized 
using descriptive statistics and reported separately for Part 1 and Part 2 as well as across the 
entire study (Part 1 and Part 2) for select analyses. Adverse events will be assessed for 
subpopulations including Xyrem naïve, subjects on Xyrem at study entry, Ages 7-11, and 
Ages 12-17, as applicable. When summarizing data across the entire study by 
subpopulations, subjects are analyzed according to their initial enrollment status. For Part 1, 
adverse events will also be summarized by treatment group and by dose. Safety analyses will 
also include an analysis of the nadir oxygen saturation level at each dose, and number and 
duration of any confirmed desaturations below 90%, 80%, 70%, 60% and 50% on PSG 
nights excluding the screening PSG. For Part 2, safety data will be summarized by Ages 7-
11, Ages 12-17, and overall.   
10 DATA QUALITY ASSURANCE 
Steps to assure the accuracy and reliability of data include the selection of qualified 
Investigators and appropriate study sites, review of protocol procedures with the Investigator 
and associated personnel prior to the study, and periodic monitoring visits by Jazz 
Pharmaceuticals or its designee. Data will be reviewed for accuracy and completeness by 
Jazz Pharmaceuticals or its representatives during and after onsite monitoring visits, and any 
discrepancies will be resolved with the Investigator or designees as appropriate. 
10.1 Data Management 
The standard procedures for handling and processing records will be followed in compliance 
with 21 CFR 11, Good Clinical Practices, ICH Guidelines, and the Standard Operating 
Procedures (SOPs) of Jazz Pharmaceuticals or the Contract Research Organization (CRO). 
Data will be managed in accordance with the privacy regulations of the prevailing region. A 
comprehensive Data Management Plan (DMP) will be developed, including but not limited 
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to a Data Management Overview, Database Contents, annotated CRF, Pre-Entry Review 
List, Self-Evident Correction Conventions, Query Contacts, and Consistency Checks. 
10.2 Case Report Forms 
Jazz Pharmaceuticals or its designee will supply CRFs for the recording of all study data not 
recorded in subject diaries, ECG, or generated by laboratory report. All data recorded in the 
CRFs must be completed in the electronic case report forms (eCRFs). 
The Principal Investigator must review the CRFs 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 signs or 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 study documents as specified in Essential 
Documents for the Conduct of a Study (ICH E6 Good Clinical Practice) and as required by 
the applicable regulatory requirement(s). The Investigator/institution should take measures to 
prevent accidental or premature destruction of these documents.  
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period if required by the applicable regulatory requirements or 
by an agreement with Jazz Pharmaceuticals. It is the responsibility of Jazz Pharmaceuticals to 
inform the Investigator/institution when these documents no longer need to be retained. 
10.4 Data and Safety Monitoring Board (DSMB) 
The DSMB will review the safety data on a regular basis and data from the Interim Analysis 
(see Section 9.8).  
10.5 Panel of Narcolepsy Experts 
A panel of narcolepsy experts may be convened to confirm the diagnosis of narcolepsy with 
cataplexy in accordance with ICSD-3 if a subject is not positive for the Human Leukocyte 
Antigen (HLA) DQB1:0602 haplotype, determined prior to the study or as part of the study 
screening procedures, and does not have a CSF hypocretin level ≤110 pg/mL determined 
prior to the study. 
The membership and the primary responsibilities of the panel will be defined in a charter that 
will also provide procedures for case review, documentation, and communication of 
decisions. 
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11 ADMINISTRATIVE CONSIDERATIONS 
11.1 Investigators and Study Administrative Structure 
11.1.1 
Contract Research Organization  
 
 
 
 
11.1.2 
Sponsor’s Medical Monitor  
 
 
 
 
11.1.3 
EU Medical Monitor  
Contact information for the EU Medical Monitor will be provided separately. 
11.1.4 
Investigator 
Multicenter 
11.1.5 
Clinical Laboratory  
 
 
 
11.1.6 
Bioanalytical Laboratory 
 
 
 
 
 
11.2 Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval 
The final approved protocol and the informed consent form will be reviewed by the IRB/IEC. 
In addition, the IRB/IEC will review any other written information to be provided to the 
subject, advertisements for subject recruitment (if used), and subject compensation (if any). 
The committee’s decision concerning conduct of the study will be sent in writing to the 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
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Investigator and a copy will be forwarded to Jazz Pharmaceuticals. The Investigator agrees to 
make any required progress reports to the IRB/IEC, as well as reports of SAEs, 
life-threatening problems, death, or any significant protocol deviations. 
A list of the IRB/IEC members who actually participated in the review, their respective titles 
(occupational identification), and institutional affiliations or an IRB/IEC assurance number 
must be provided to Jazz Pharmaceuticals. The approval letter or notice must be provided on 
IRB/IEC letterhead and contain the date of the meeting and sufficient information to identify 
the version of the protocol unambiguously (by name and number) and state that the informed 
consent form was also reviewed. 
A clinical study may not be initiated before the proposed protocol and informed consent form 
have been reviewed and unconditionally approved by an IRB/IEC meeting federal 
regulations. The clinical study remains subject to continuing review by the IRB/IEC. Jazz 
Pharmaceuticals or its designee will supply all necessary data for the Investigator to submit 
to the IRB/IEC. Jazz Pharmaceuticals will not ship clinical supplies to an investigational site 
until written signed approval from the site’s IRB/IEC has been received by Jazz 
Pharmaceuticals. 
The Investigator is responsible for ensuring initial and continued review and approval of the 
clinical study by the IRB/IEC at his/her site. The Investigator must also ensure that he/she 
will promptly report to the IRB/IEC and Jazz Pharmaceuticals all changes in the research 
activity and all unanticipated problems involving risk to human subjects or others, and that 
he/she will not make any changes in the research without IRB/IEC approval, except where 
necessary to eliminate apparent hazards to human subjects. If the study 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 study completion or termination, a final 
report must be provided to the IRB/IEC by the clinical site. 
11.3 Form FDA 1572 
The investigator must sign a completed Form FDA 1572 before initiation of the study and 
provide the original hand-signed and hand-dated document along with the appropriate 
curriculum vitae to Jazz Pharmaceuticals or its designee.  
11.4 Ethical Conduct of the Study 
The study will be conducted in accordance with regulations relating to GCP and the standard 
operating procedures (SOPs) of the CRO and Jazz Pharmaceuticals. These standards respect 
the following guidelines: 
• Good Clinical Practice: Consolidated Guideline (International Conference on 
Harmonization of Technical Requirements for the Registration of Pharmaceuticals for 
Human Use, May 1996). 
• United States (US) Code of Federal Regulations (CFR) dealing with clinical studies (Title 
21 CFR Parts 11, 50, 54, 56, 312, and 314). 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
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• Current Declaration of Helsinki, concerning medical research in humans (“WMA 
Declaration of Helsinki - Ethical Principles for Medical Research Involving Human 
Subjects,” Fortaleza, Brazil 2013). 
11.5 Subject Information Assent and Consent 
All subjects will provide assent and their parent(s) or guardian(s) will give written informed 
consent in accordance with local IRB/IEC requirements before the performance of any study 
related procedures. 
Each subject’s chart will have the assent of the subject documented (written or verbal) and 
the ICF signed by the parent or guardian for study participation, and for PK evaluation if 
applicable, attached to it. When the study treatment is completed and the CRF has been 
monitored, the ICF will be kept in the investigator’s central study file. Regulatory authorities 
may check the existence of the signed ICF in this central study folder if not having done so 
during the performance of the study. 
11.6 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 or as required by regional or 
national regulations. These documents will be treated with strict adherence to professional 
standards of confidentiality and will be filed at the study site under adequate security and 
restricted access.  
Portions of the subject’s medical records pertinent to the study will be reviewed by Jazz 
Pharmaceuticals personnel or its designee and possibly by governmental agency personnel to 
ensure adequate source documentation, accuracy, and completeness of the CRFs. The IRB 
has the authority to review subject records. 
11.7 Protocol Adherence – Amendments 
The protocol must be read thoroughly and the instructions must be followed exactly. 
Any changes in the protocol will require a formal amendment. Such amendments will be 
agreed upon and approved in writing by the Investigator and the Jazz Pharmaceuticals 
designees. The IRB/IEC will be notified of all amendments to the protocol. Amendments to 
the protocol will not be implemented until written IRB/IEC approval has been received.  
If a country or region specific amendment is required based on local regulation, the 
amendment will be submitted to the IRB(s) and competent authority of that country or region 
only. 
11.8 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).  
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
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11.9 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 
CRFs 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 
study conduct.  
Upon completion of the study, the study monitor will arrange for a final review of the study 
files after which the files should be secured for the appropriate time period. The Investigator 
or appointed delegate will receive the study monitor during these onsite visits and will 
cooperate in providing the documents for inspection and respond to inquiries. In addition, the 
Investigator will permit inspection of the study files by authorized representatives of the 
regulatory agencies.  
11.10 Protocol Deviations 
All major protocol deviations must be reported to the IRB in an expedited fashion. It is the 
responsibility of the principal investigator to ensure proper reporting to the IRB. All protocol 
deviations (major and minor) must be reported to Jazz Pharmaceuticals or designee. 
11.11 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, however, 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 as to when these documents no longer 
need to be retained. 
11.12 Publication and Disclosure Policy 
All information concerning Xyrem, Jazz Pharmaceuticals’ operations, patent applications, 
formulas, manufacturing processes, basic scientific data, and formulation information 
supplied by Jazz Pharmaceuticals to the investigator and not previously published, are 
considered confidential and remain the sole property of Jazz Pharmaceuticals. CRFs also 
remain the property of Jazz Pharmaceuticals. The investigator agrees to use this information 
only to complete this study and will not use it for other purposes without the written consent 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
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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 study in connection with the study of Xyrem, 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 study 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 study may 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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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
Page 106 of 158 
12 REFERENCE LIST 
American Academy of Sleep Medicine (AASM). The International Classification of Sleep 
Disorders; Third Edition. American Academy of Sleep Medicine, Darien, Illinois; 2014. 
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Dexedrine® [dextroamphetamine sulfate] Spansule® sustained release capsules US 
prescribing information (December 2010) Amedra Pharmaceuticals, LLC., Middlesex, NJ. 
European Commission, Scientific Committee on Food. Opinion of the Scientific committee 
on Food on sucralose (SCF/CS/ADDS/EDUL/190 Final 12/9/2000) 
http://ec.europa.eu/food/fs/sc/scf/out68_en.pdf. 
European Union Guidelines on Ethical Considerations for Clinical Trials on Medicinal 
Products Conducted with the Paediatric Population.  2008 
ftp://ftp.cordis.europa.eu/pub/fp7/docs/ethical-considerations-paediatrics_en.pdf accessed on 
2 December 2013. 
Department of Health and Human Services, FDA 21 Code of Federal Regulations Pt. 172. 
Food Additives Permitted for Direct Addition to Food for Human Consumption; Sucralose. 
Federal Register, Vol. 63, No. 64, 1998, 
http://www.fda.gov/ohrms/dockets/98fr/040398a.pdf.  
George CFP, Feldman N, Inhaber N, Steininger TL, Grzeschik SM, Lai C, Zheng Y. A safety 
trial of sodium oxybate in patients with obstructive sleep apnea: Acute effects on sleep-
disordered breathing. Sleep Medicine 2010; 11:38-42.  
Howie S. Blood sample volumes in child health research: review of safe limits. Bulletin of 
the World Health Organization 2011;89:46-53. doi: 10.2471/BLT.10.080010 
http://www.who.int/bulletin/volumes/89/1/10-080010/en/index.html accessed on 2 December 
2013. 
Huang YS, Guilleminault C. Narcolepsy: action of two gamma-aminobutyric acid type B 
agonists, baclofen and sodium oxybate. Pediatr Neurol 2009; 41:9-16. 
Hunter A, Long W, Ryrie C. An evaluation of gamma-hydroxybutyric acid in paediatric 
practice. Brit J Anaesth 1971; 43:620-628. 
Ingravallo F, Gnucci V, Pizza F, Vignatelli L, Govi A, Dormi A, Pelotti S, et al. The burden 
of narcolepsy with cataplexy: How disease history and clinical features influence socio-
economic outcomes. Sleep Med 2012; 13:1293-1300. 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
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Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. 
Sleep 1991; 14 (6): 540–5.  
Johns, MW. Sensitivity and specificity of the multiple sleep latency test (MSLT), the 
maintenance of wakefulness test and the epworth sleepiness scale: failure of the MSLT as a 
gold standard J Sleep Res 2000; 9 (1): 5–11. 
Kleinschmidt S, Mertzlufft F. [Gammahydroxybutyric acid – What is its value in anesthesia 
and intensive care medicine?] Anasthesiol Intensivmed Notfallmed Schmerzther 1995; 30: 
393–402. [Note: English translation provided.] 
Kovacs M. and MHS Staff. Scores and scoring algorithms for the CDI 2 tools. In: Children’s 
depression Inventory 2nd Edition (CDI 2) Technical Manual. North Tonawanda, NY: Multi-
Health Systems Inc; 2011:60-63. 
Lecendreux M, Poli F, Oudiette D, Benazzouz F, Donjacour CE, Franceschini C, Finotti E, et 
al. Tolerance and efficacy of sodium oxybate in childhood narcolepsy with cataplexy: a 
retrospective study. SLEEP 2012; 35:709-711. 
Majid H, Hirshkowitz M. Therapeutics of narcolepsy. Sleep Med Clin 2010; 5:659-673. 
Mansukhani MP, Kotagal S. Sodium oxybate in the treatment of childhood narcolepsy-
cataplexy: A retrospective study. Sleep Med 2012; 13:606-610. 
March JS and MHS Staff. Normative and psychometric properties of the MASC. In: 
Multidimensional Anxiety Scale for Children, Technical Manual. North Tonawanda, NY: 
Multi-Health Systems Inc; 1997:40-51. 
March JS, Sullivan K. Test-retest of the multidimensional anxiety scale for children.  Journal 
of Anxiety Disorders 1999;13:349-358. 
Meyer S, Gottschling S, Georg T, Lothschutz D, Graf N, Sitzmann FC. Vergleich von 
Gamma-Hydroxybuttersäure und Clorprothixen/Phenobarbital zur Sedierung von Kindern für 
MRT-Untersuchungen [Gamma-hydroxybutyrate versus chlorprothixene/phenobarbital 
sedation in children undergoing MRI studies]. Klin Pädiatr 2003; 215:69-73 [English 
abstract]. 
Mignot EJ. A Practical Guide to the Therapy of Narcolepsy and Hypersomnia Syndromes. 
Neurother 2012; 9:739-752. 
Moldofsky H, Inhaber NH, Guinta DR, Alvarez-Horine SB. Effects of sodium oxybate on 
sleep physiology and sleep/wake-related symptoms in patients with fibromyalgia syndrome: 
a double-blind, randomized, placebo-controlled study. J Rheumatol. 2010;37(10):2156-2166. 
Morgenthaler TI, Kapur VK, Brown TM, Swick TJ, Alessi C, Aurora RN, Boehlecke B, et 
al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central 
origin. SLEEP 2007; 30:1705-1711. 
Murali H, Kotagal S. Off-label treatment of severe childhood narcolepsy–cataplexy with 
sodium oxybate. SLEEP 2006; 29(8):1025–1029.  
Myers K, Winters NC. Ten-year review of rating scales. II. Scales for internalizing disorders. 
J Am Acad Child Adolesc Psychiatry 2002; 41:634-659. 
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Xyrem® (sodium oxybate) oral solution 
 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
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Ohayon MM. Epidemiology of narcolepsy. In Narcolepsy and Hypersomnia 2007. C 
Bassetti, M Billiard, E Mignot, eds. New York: Informa Healthcare: pp 125-132. 
Ohayon MM, Priest RG, Zulley J, Smirne S, Paiva T. Prevalence of narcolepsy 
symptomatology and diagnosis in the European general population. Neurology 
2002;58:1826-1833. 
Okun ML, Lin L, Pelin Z, Hong S, Mignot E. Clinical aspects of narcolepsy-cataplexy across 
ethnic groups. Sleep 2002; 25:27-35. 
Partinen M, Saarenpaa-Heikkila O, Ilveskoski I, Hublin C, Linna M, Olsen P, Nokelainen P, 
et al. Increased incidence and clinical picture of childhood narcolepsy following the 2009 
H1N1 pandemic vaccination campaign in Finland. PLoS One 2012; 7:e33723. 
Peraita-Adrados R, Garcia-Penas JJ, Ruiz-Falco L, Gutierrez-Solana L, Lopez-Esteban P, 
Vicario JL, Miano S, et al. Clinical, polysomnographic and laboratory characteristics of 
narcolepsy-cataplexy in a sample of children and adolescents. Sleep Med 2011; 12:24-27. 
Poli F, Ricotta L, Vandi S, Franceschini C, Pizza F, Palaia V, Moghadam KK, et al. 
Catathrenia under sodium oxybate in narcolepsy with cataplexy. Sleep Breath 2012; 16:427-
434.  
Poli F, Pizza F, Mignot E, Ferri R, Pagotto U, Taheri S, Finotti E, et al. High prevalence of 
precocious puberty and obesity in childhood narcolepsy with cataplexy. Sleep 2013; 
36(2):175-181. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo M, Currier GW, Melvin 
GA, Greenhill L, Shen S, Mann JJ. The Columbia–Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry 2011;168:1266-1277.  
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Frazer, PA. 
Provigil, SmPC (21/09/2012) Cephalon (UK) Limited. Accessed 25 November 2013 at 
http://www.medicines.org.uk/EMC/medicine/11337/SPC/Provigil+100+mg+Tablets,+Provig
il+200+mg+Tablets/ 
Rousseau, A, Ledoux D, Sabourdin N, Richard P, Damas P, Constant I. Clinical sedation and 
bispectral index in burn children receiving gamma-hydroxybutyrate. Ped Anesth 2012; 
22:799-804. 
Russell IJ, Holman AJ, Swick TJ, Alvarez-Horine S, Wang YG, Guinta D. Sodium oxybate 
reduces pain, fatigue, and sleep disturbance and improves functionality in fibromyalgia: 
results from a 14-week, randomized, double-blind, placebo-controlled study. Pain 2011; 
152(5):1007-1017. 
Solway J, Sadove MS. 4-Hydroxybutyrate: a clinical study. Anesth Analg 1965; 44: 532–
539. 
Spaeth M, Bennett RM, Benson BA, Wang YG, Lai C, Choy EH. Sodium oxybate therapy 
provides multidimensional improvement in fibromyalgia: results of an international phase 3 
trial. Ann Rheum Dis; 2012;71(6):935-942.  
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
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Spaeth M, Alegre C, Perrot S, Wang YG, Guinta D, Alvarez-Horine S, Russell IJ, et al. 
Long-term tolerability and maintenance of therapeutic response to sodium oxybate in an 
open-label extension study in patients with fibromyalgia. Arthritis Res Ther 2013;15:R185. 
Stores G, Montgomery P, Wiggs L. The psychosocial problems of children with narcolepsy 
and those with excessive daytime sleepiness of uncertain origin. Pediatrics 2006; 118:e1116-
1123. 
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England: Blackwell Scientific; 1962:28-39. 
Walthall K, Cappon G, Hurtt M, Zoetis T. Postnatal development of the gastrointestinal 
system: A species comparison. Birth Defects Research Part B: Dev Reprod Tox 2005; 
74:132–156. 
Xyrem® (sodium oxybate) oral solution. US Prescribing Information, Jazz Pharmaceuticals, 
2016. 
Yoss RE, Daly DD. Narcolepsy in children. Pediatrics 1960; 25:1025-1033. 
 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
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Appendix 1 
Schedule of Events–Subjects on Xyrem at Study Entry 
Appendix 1.1 
Part 1 Screening, Stable-Dose Period, Double-Blind Treatment Period, Open-Label Safety 
Period—Subjects on Xyrem at Study Entry 
 
Screening 
Visit 
 
Start 
Stable-
Dose 
End Stable-
Dose/ 
Begin 
Double-
Blind 
Treatment* 
End 
Double-
Blind*/ 
Begin 
Open-
Label 
Safety  
Open-Label Safety Period with Xyrem 
Safety 
Follow-
up 
Visits 
V1  
Day -30 
to -1 a,b 
V2 
Day 1 
V3 
Week 3 
± 3 days 
V4 
Week 5 
+3 days 
V5  
Week 9  
±7 days  
V6 
W 16  
±7 
days 
Phone 
call  
V7 
W 18 
±7 
days 
V8 
W 22  
±7 
days 
Phone 
call 
V9 
W 26 
±7 
days 
 
V10 
W 30  
±7 
days 
Phone 
call 
V11 
W 34 
±7 
days 
Phone 
call 
V12 
W 39 
±7 
days 
 
V13 
W 43 
±7 
days 
Phone 
call 
V14 
W 48 
±7 
days 
Phone 
call 
Visit 15c 
W 52 
±7 days 
Or Part 1 
Early 
Termination 
V16d 
14 days 
after last 
treatment 
+3 days 
Informed 
Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
Contact 
Information  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
including 
narcolepsy history, 
usual bedtime and 
awakening time 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
including a brief 
neurological exam 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Tanner Stage 
Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Height 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
Weight 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
Vital Signse 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
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Appendix 1.1 
Part 1 Screening, Stable-Dose Period, Double-Blind Treatment Period, Open-Label Safety 
Period—Subjects on Xyrem at Study Entry 
 
Screening 
Visit 
 
Start 
Stable-
Dose 
End Stable-
Dose/ 
Begin 
Double-
Blind 
Treatment* 
End 
Double-
Blind*/ 
Begin 
Open-
Label 
Safety  
Open-Label Safety Period with Xyrem 
Safety 
Follow-
up 
Visits 
V1  
Day -30 
to -1 a,b 
V2 
Day 1 
V3 
Week 3 
± 3 days 
V4 
Week 5 
+3 days 
V5  
Week 9  
±7 days  
V6 
W 16  
±7 
days 
Phone 
call  
V7 
W 18 
±7 
days 
V8 
W 22  
±7 
days 
Phone 
call 
V9 
W 26 
±7 
days 
 
V10 
W 30  
±7 
days 
Phone 
call 
V11 
W 34 
±7 
days 
Phone 
call 
V12 
W 39 
±7 
days 
 
V13 
W 43 
±7 
days 
Phone 
call 
V14 
W 48 
±7 
days 
Phone 
call 
Visit 15c 
W 52 
±7 days 
Or Part 1 
Early 
Termination 
V16d 
14 days 
after last 
treatment 
+3 days 
Pulse Oximetry on 
room air while 
fully awake 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA DQB1:0602f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, 
Chemistryg  
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK subjects only:  
Coagulationh 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Only for Girls <8 
years: 
estradiol, LH, FSH 
Only for Boys <9 
years: 
testosterone, LH, 
FSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urine Drug Screen  
X 
X 
 
Xj 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
Alcohol Test 
X 
X 
 
Xj 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
Serum Pregnancy  
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-Lead ECG 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
Page 112 of 158 
Appendix 1.1 
Part 1 Screening, Stable-Dose Period, Double-Blind Treatment Period, Open-Label Safety 
Period—Subjects on Xyrem at Study Entry 
 
Screening 
Visit 
 
Start 
Stable-
Dose 
End Stable-
Dose/ 
Begin 
Double-
Blind 
Treatment* 
End 
Double-
Blind*/ 
Begin 
Open-
Label 
Safety  
Open-Label Safety Period with Xyrem 
Safety 
Follow-
up 
Visits 
V1  
Day -30 
to -1 a,b 
V2 
Day 1 
V3 
Week 3 
± 3 days 
V4 
Week 5 
+3 days 
V5  
Week 9  
±7 days  
V6 
W 16  
±7 
days 
Phone 
call  
V7 
W 18 
±7 
days 
V8 
W 22  
±7 
days 
Phone 
call 
V9 
W 26 
±7 
days 
 
V10 
W 30  
±7 
days 
Phone 
call 
V11 
W 34 
±7 
days 
Phone 
call 
V12 
W 39 
±7 
days 
 
V13 
W 43 
±7 
days 
Phone 
call 
V14 
W 48 
±7 
days 
Phone 
call 
Visit 15c 
W 52 
±7 days 
Or Part 1 
Early 
Termination 
V16d 
14 days 
after last 
treatment 
+3 days 
Cataplexy 
Frequency Diaryk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGIs for Historical 
Narcolepsy Overall 
Severity Prior to 
any Narcolepsy 
Treatment 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGIs for Historical 
Cataplexy Severity 
Prior to any 
Narcolepsy 
Treatment 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGIs (narcolepsy 
overall) 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGIs (cataplexy 
severity) 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGIc (narcolepsy 
overall) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CGIc (narcolepsy 
overall) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CGIc (cataplexy 
severity) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ESS (CHAD) 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
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Appendix 1.1 
Part 1 Screening, Stable-Dose Period, Double-Blind Treatment Period, Open-Label Safety 
Period—Subjects on Xyrem at Study Entry 
 
Screening 
Visit 
 
Start 
Stable-
Dose 
End Stable-
Dose/ 
Begin 
Double-
Blind 
Treatment* 
End 
Double-
Blind*/ 
Begin 
Open-
Label 
Safety  
Open-Label Safety Period with Xyrem 
Safety 
Follow-
up 
Visits 
V1  
Day -30 
to -1 a,b 
V2 
Day 1 
V3 
Week 3 
± 3 days 
V4 
Week 5 
+3 days 
V5  
Week 9  
±7 days  
V6 
W 16  
±7 
days 
Phone 
call  
V7 
W 18 
±7 
days 
V8 
W 22  
±7 
days 
Phone 
call 
V9 
W 26 
±7 
days 
 
V10 
W 30  
±7 
days 
Phone 
call 
V11 
W 34 
±7 
days 
Phone 
call 
V12 
W 39 
±7 
days 
 
V13 
W 43 
±7 
days 
Phone 
call 
V14 
W 48 
±7 
days 
Phone 
call 
Visit 15c 
W 52 
±7 days 
Or Part 1 
Early 
Termination 
V16d 
14 days 
after last 
treatment 
+3 days 
Study Drug Dosing 
Diaryk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stimulant Dosing 
Diaryk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review subject 
dosing diaries for 
compliance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review cataplexy 
frequency diary  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SF-10 
 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
C-SSRS for 
suicidalitym 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CDI2:SR[S] for 
depression 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MASC-10 for 
anxiety scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
School Attendance 
Diaryn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Reporting 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
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Appendix 1.1 
Part 1 Screening, Stable-Dose Period, Double-Blind Treatment Period, Open-Label Safety 
Period—Subjects on Xyrem at Study Entry 
 
Screening 
Visit 
 
Start 
Stable-
Dose 
End Stable-
Dose/ 
Begin 
Double-
Blind 
Treatment* 
End 
Double-
Blind*/ 
Begin 
Open-
Label 
Safety  
Open-Label Safety Period with Xyrem 
Safety 
Follow-
up 
Visits 
V1  
Day -30 
to -1 a,b 
V2 
Day 1 
V3 
Week 3 
± 3 days 
V4 
Week 5 
+3 days 
V5  
Week 9  
±7 days  
V6 
W 16  
±7 
days 
Phone 
call  
V7 
W 18 
±7 
days 
V8 
W 22  
±7 
days 
Phone 
call 
V9 
W 26 
±7 
days 
 
V10 
W 30  
±7 
days 
Phone 
call 
V11 
W 34 
±7 
days 
Phone 
call 
V12 
W 39 
±7 
days 
 
V13 
W 43 
±7 
days 
Phone 
call 
V14 
W 48 
±7 
days 
Phone 
call 
Visit 15c 
W 52 
±7 days 
Or Part 1 
Early 
Termination 
V16d 
14 days 
after last 
treatment 
+3 days 
Dispense Study 
Drugo 
 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
Collect study drug, 
measure 
compliance 
 
 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
Fasting morning 
blood sample: GH, 
IGF-1, prolactin 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
See 
Appendix 
1.2p 
 
Breakfast 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
See 
Appendix 
1.2p 
 
PSG 
See 
Appendix 
1.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
See 
Appendix 
1.2p 
 
PK subjects only:  
PK Nights 1 and 2  
 
 
When the subject is on a stable dose of Xyrem, PK Nights 1 and 2 can be scheduled for a protocol-specified clinic visit or for an 
additional clinic visit.  
See Appendix 3 
 
An arrow (               )   indicates that the assessment is continuous. 
* Subjects who enter the Double-Blind Period after Amendment 4 becoming effective will receive open-label Xyrem during the Double-Blind Period.  
 
a)  All subjects will provide their written informed consent prior to the performance of any study-related procedures. The Screening Visit (Visit 1) 
starts when a subject is assigned a subject number via IVRS/IWRS. If needed, additional screening time may be granted with permission of the 
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Medical Monitor. 
b)  The Screening Period for subjects with low body weight who are participating in the PK evaluation should be as close as possible to 30 days to 
minimize the amount of blood drawn over 30 days. 
c)  
If the subject is continuing directly into Part 2, see Appendix 22. 
d)  
Do not complete the Safety Follow-up visit for subjects who continue directly into Part 2 (see Appendix 22). 
e)  
Obtain vital signs (blood pressure, pulse/heart rate, body temperature, respiratory rate) after subject has been resting for ≥5 min.  
f) 
 
HLA DQB1:0602: Collect blood sample unless previous result available. 
g)  
See Table 2. 
h)  
Coagulation: prothrombin time (PT)/international normalized ratio (INR), and activated partial thromboplastin time (PTT). 
i) 
 
Collect coagulation samples within 30 days prior to PK Night 1.  PK evaluation will occur at any time while subjects are on a stable dose of 
Xyrem. 
j) 
 
Urine drug screen and alcohol test: only for subjects continuing to the Open-label Safety Period. 
k)  
Recorded daily in electronic diary.  
l) 
 
Impression of severity prior to any narcolepsy treatment. 
m)  
C-SSRS: Use Baseline/Screening Version at Visit 1 and Since Last Visit version at all other visits for subjects ≥12 years of age, and use 
Children’s versions for children <12 years of age. 
n)  
School attendance collected for subjects who attend school during Stable-Dose and Double-Blind Treatment Periods. 
o)  
Study drug quantities dispensed at study visits in accordance with protocol and as required by State or local regulation. 
p)  
If the subject withdraws early from the study during the Open-Label Safety Period, perform a PSG if subject is willing and if the subject is 
willing to be dosed with study drug for this PSG night. Part 1 early termination PSG does not apply for subjects who discontinue before 
entering the Open-Label Safety Period. 
 
 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
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Appendix 1.2 
PSG Night Procedures– Subjects on Xyrem at 
Study Entry 
 
Part 1 Screening Visit 
Open-Label Safety Period with 
Xyrem 
Visits 
V1  
Day -30 to -1a 
Visit 15 
Week 52 (±7 days) 
Or Part 1 Early Termination 
PSG Night Proceduresb 
Screening PSG 
 
End of Study (Part 1) PSG 
/Part 1 Early Termination 
Review inclusion/exclusion criteria 
X 
 
Light dinner >2 hours before dosing 
Xc 
Xc 
Confirm Parent(s)/ Guardian(s) 
Contact Information 
X 
X 
Administer or supervise the 
administration of Study Drugd 
X 
X 
PSG 
X 
Xe 
EtCO2 or TcCO2
f 
X 
X 
Vital Signsg 
X 
X 
Pulse Oximetryh 
X 
X 
Record AEs/Concomitant 
Medications 
X 
X 
Brief neurological exami 
X 
X 
Fasting morning blood sample: GH, 
IGF-1, prolactin 
 
X 
Breakfast (if subject prefers to eat at 
the study center) 
X 
X 
 
a) If needed, additional screening time may be granted with permission of the Medical Monitor. 
b) Perform all other procedures for the visit prior to the PSG night procedures.  
c) Light dinner taken >2 hours prior to dosing. The dinner should be the same or similar on all PSG nights 
and may be taken at the Sleep Lab or home. 
d) Administer the subject’s nightly dose of Xyrem divided in two doses, at bedtime and 4 hours later while 
in bed.  
e) Part 1 Early termination PSG does not apply for subjects who discontinue before entering the Open-Label 
Safety Period.  
f) CO2 monitoring on PSG nights only at sites where monitoring is routinely performed.  
g) Obtain vital signs (blood pressure, pulse/heart rate, body temperature, respiratory rate) after subject has 
been resting for ≥5 min. Obtain at pre-dose and before release from study center. At 1, 4 (pre-2nd dose), 
5, and 8 hours after the 1st Xyrem dose, heart and respiratory rates recorded via PSG. 
h) SpO2 monitored continuously from immediately before first dose through 8 hours post-first dose, and 
recorded pre-dose and at 1 h, 2 h, 4 h (pre-2nd dose), 5 h, 6 h, and 8 h after the first dose. Additional 
measurement is taken while the subject is awake and before release from the study center. 
i) Brief neurological exam before discharge on the morning after PSG. 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
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Appendix 2 
Schedule of Events–Xyrem-Naïve Subjects at Study Entry  
Appendix 2.1 
Part 1 Screening, Open-Label Titration Period, Stable-Dose Period, Double-Blind Treatment 
Period– Xyrem-Naïve Subjects at Study Entry 
 
Open-Label Titration Period (up to 10 weeks) 
Xyrem-naïve subjects only 
Stable-Dose Period 
Double-Blind 
Treatment 
Period* 
See 
Appendix 
2.2 for 
Schedule 
of Events 
for the 
Open-
Label 
Safety 
Period 
 
Events 
Screening 
 
Begin 
Titration 
 
 
 
 
 
 
End Titration 
Begin Stable-
Dose 
End of Stable-
Dose  
Begin Double-
Blind 
Treatment* 
End of Double-
Blind 
Treatment* 
Begin Open-
Label Safety  
Visits 
 
V1  
V1.1 
V1.2 
V1.3 
Phone 
Call 
V1.4 
Phone 
Call 
V1.5 
V1.6 
Phone 
Call 
V1.7 
V2 
 
V3 
V4 
Weeks (W) 
Day -30 
to -1a 
Day 1 
W1 
+3 days 
W2 
+3 days 
W3 
+3 days 
W4 
±7 days 
W6 
+3 days 
W8 
±7 days 
W10 
±3 days 
W12 
+3 day 
W14 
+3 day 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics and Contact 
Information  
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History including 
narcolepsy history, usual 
bedtime and awakening 
time 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
including a brief 
neurological exam 
X 
 
 
 
 
 
 
 
 
 
X 
 
Tanner Stage Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
Weight 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
Vital Signs (blood pressure, 
pulse/heart rate, body 
temperature, respiratory 
rate)b 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
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Appendix 2.1 
Part 1 Screening, Open-Label Titration Period, Stable-Dose Period, Double-Blind Treatment 
Period– Xyrem-Naïve Subjects at Study Entry 
 
Open-Label Titration Period (up to 10 weeks) 
Xyrem-naïve subjects only 
Stable-Dose Period 
Double-Blind 
Treatment 
Period* 
See 
Appendix 
2.2 for 
Schedule 
of Events 
for the 
Open-
Label 
Safety 
Period 
 
Events 
Screening 
 
Begin 
Titration 
 
 
 
 
 
 
End Titration 
Begin Stable-
Dose 
End of Stable-
Dose  
Begin Double-
Blind 
Treatment* 
End of Double-
Blind 
Treatment* 
Begin Open-
Label Safety  
Visits 
 
V1  
V1.1 
V1.2 
V1.3 
Phone 
Call 
V1.4 
Phone 
Call 
V1.5 
V1.6 
Phone 
Call 
V1.7 
V2 
 
V3 
V4 
Weeks (W) 
Day -30 
to -1a 
Day 1 
W1 
+3 days 
W2 
+3 days 
W3 
+3 days 
W4 
±7 days 
W6 
+3 days 
W8 
±7 days 
W10 
±3 days 
W12 
+3 day 
W14 
+3 day 
Pulse Oximetry on room air 
while fully awake 
X 
 
 
 
 
 
 
 
 
 
 
 
HLA DQB1:0602c 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistryd 
X 
 
 
 
 
 
 
 
 
 
X 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
Only for Girls <8 years:  
Estradiol, LH, FSH 
Only for Boys<9 years: 
Testosterone, LH, FSH  
X 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen  
X 
X 
 
 
 
 
 
 
 
 
Xe 
 
Alcohol Test 
X 
X 
 
 
 
 
 
 
 
 
Xe 
 
Serum Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
X 
 
Urine Pregnancy test 
 
X 
 
 
 
 
 
 
 
 
 
 
12 Lead ECG 
X 
 
 
 
 
 
 
 
 
 
X 
 
Cataplexy Frequency 
Diaryf 
 
 
 
 
 
 
 
 
 
 
 
 
CGIs for Historical 
Narcolepsy Overall 
Severity Prior to any 
Xg 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
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Appendix 2.1 
Part 1 Screening, Open-Label Titration Period, Stable-Dose Period, Double-Blind Treatment 
Period– Xyrem-Naïve Subjects at Study Entry 
 
Open-Label Titration Period (up to 10 weeks) 
Xyrem-naïve subjects only 
Stable-Dose Period 
Double-Blind 
Treatment 
Period* 
See 
Appendix 
2.2 for 
Schedule 
of Events 
for the 
Open-
Label 
Safety 
Period 
 
Events 
Screening 
 
Begin 
Titration 
 
 
 
 
 
 
End Titration 
Begin Stable-
Dose 
End of Stable-
Dose  
Begin Double-
Blind 
Treatment* 
End of Double-
Blind 
Treatment* 
Begin Open-
Label Safety  
Visits 
 
V1  
V1.1 
V1.2 
V1.3 
Phone 
Call 
V1.4 
Phone 
Call 
V1.5 
V1.6 
Phone 
Call 
V1.7 
V2 
 
V3 
V4 
Weeks (W) 
Day -30 
to -1a 
Day 1 
W1 
+3 days 
W2 
+3 days 
W3 
+3 days 
W4 
±7 days 
W6 
+3 days 
W8 
±7 days 
W10 
±3 days 
W12 
+3 day 
W14 
+3 day 
Narcolepsy Treatment 
CGIs for Historical 
Cataplexy Severity Prior to 
any Narcolepsy Treatment 
Xg 
 
 
 
 
 
 
 
 
 
 
 
CGIs (narcolepsy overall) 
X 
X 
 
 
 
 
 
 
 
X 
 
 
CGIs (cataplexy severity) 
X 
X 
 
 
 
 
 
 
 
X 
 
 
PGIc (narcolepsy overall) 
 
 
 
 
 
 
 
 
 
 
X 
 
CGIc (narcolepsy overall) 
 
 
 
 
 
 
 
 
 
 
X 
 
CGIc (cataplexy severity) 
 
 
 
 
 
 
 
 
 
 
X 
 
ESS (CHAD) 
X 
X 
 
 
 
 
 
 
 
X 
X 
 
Study Drug Dosing Diaryf  
 
 
 
 
 
 
 
 
 
 
 
 
Stimulant Dosing Diaryf 
 
 
 
 
 
 
 
 
 
 
 
 
Review subject dosing 
diaries for compliance and 
cataplexy frequency diary  
 
 
 
 
 
 
 
 
 
 
 
 
SF-10 
 
X 
 
 
 
 
 
 
 
X 
X 
 
C-SSRS for suicidalityh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CDI2:SR[S] for depression 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
MASC-10 for anxiety scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
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Appendix 2.1 
Part 1 Screening, Open-Label Titration Period, Stable-Dose Period, Double-Blind Treatment 
Period– Xyrem-Naïve Subjects at Study Entry 
 
Open-Label Titration Period (up to 10 weeks) 
Xyrem-naïve subjects only 
Stable-Dose Period 
Double-Blind 
Treatment 
Period* 
See 
Appendix 
2.2 for 
Schedule 
of Events 
for the 
Open-
Label 
Safety 
Period 
 
Events 
Screening 
 
Begin 
Titration 
 
 
 
 
 
 
End Titration 
Begin Stable-
Dose 
End of Stable-
Dose  
Begin Double-
Blind 
Treatment* 
End of Double-
Blind 
Treatment* 
Begin Open-
Label Safety  
Visits 
 
V1  
V1.1 
V1.2 
V1.3 
Phone 
Call 
V1.4 
Phone 
Call 
V1.5 
V1.6 
Phone 
Call 
V1.7 
V2 
 
V3 
V4 
Weeks (W) 
Day -30 
to -1a 
Day 1 
W1 
+3 days 
W2 
+3 days 
W3 
+3 days 
W4 
±7 days 
W6 
+3 days 
W8 
±7 days 
W10 
±3 days 
W12 
+3 day 
W14 
+3 day 
School Attendance Diary i 
 
 
 
 
 
 
 
 
 
 
 
 
Assess subject and 
determine if additional dose 
titration is necessary 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
AE Reporting 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK subjects only:  
Coagulation 
 
 
 
 
 
 
 
 
Xj 
 
 
 
Dispense Study Drugk 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
Collect study drug, measure 
compliance 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
 
Fasting morning blood 
sample: GH, IGF-1, 
prolactinl 
 
 
 
 
 
 
 
 
 
See 
Appendix 
2.3 
X 
 
Breakfast 
 
 
 
 
 
 
 
 
 
See 
Appendix 
2.3 
X 
 
PSG 
See 
Appendix 
2.3 
 
 
 
 
 
 
 
 
See 
Appendix 
2.3 
 
 
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CONFIDENTIAL 
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Appendix 2.1 
Part 1 Screening, Open-Label Titration Period, Stable-Dose Period, Double-Blind Treatment 
Period– Xyrem-Naïve Subjects at Study Entry 
 
Open-Label Titration Period (up to 10 weeks) 
Xyrem-naïve subjects only 
Stable-Dose Period 
Double-Blind 
Treatment 
Period* 
See 
Appendix 
2.2 for 
Schedule 
of Events 
for the 
Open-
Label 
Safety 
Period 
 
Events 
Screening 
 
Begin 
Titration 
 
 
 
 
 
 
End Titration 
Begin Stable-
Dose 
End of Stable-
Dose  
Begin Double-
Blind 
Treatment* 
End of Double-
Blind 
Treatment* 
Begin Open-
Label Safety  
Visits 
 
V1  
V1.1 
V1.2 
V1.3 
Phone 
Call 
V1.4 
Phone 
Call 
V1.5 
V1.6 
Phone 
Call 
V1.7 
V2 
 
V3 
V4 
Weeks (W) 
Day -30 
to -1a 
Day 1 
W1 
+3 days 
W2 
+3 days 
W3 
+3 days 
W4 
±7 days 
W6 
+3 days 
W8 
±7 days 
W10 
±3 days 
W12 
+3 day 
W14 
+3 day 
PK Evaluation 
 
 
 
 
 
 
 
 
When the subject is on a stable dose of 
Xyrem, PK Nights 1 and 2 can be scheduled 
for a protocol-specified clinic visit or for an 
additional clinic visit. See Appendix 3. 
 
An arrow (               )   indicates that the assessment is continuous. 
Note: A Xyrem naïve subject is defined as a subject who has never been treated with Xyrem or who was previously treated with Xyrem and discontinued Xyrem 
for at least one month prior to the Screening visit for reasons other than lack of efficacy and/or tolerability issues (e.g., lost insurance coverage, could not afford 
Xyrem, changed prescribers). 
* Subjects who enter the Double-Blind Period after Amendment 4 becoming effective will receive open-label Xyrem during the Double-Blind Period.  
 
a) 
 
All subjects will provide their written informed consent prior to the performance of any study-related procedures. The Screening Visit (Visit 1) 
starts when a subject is assigned a subject number via IVRS/IWRS. If needed, additional screening time may be granted with permission of the 
Medical Monitor. 
b) 
 
Obtain vital signs after subject has been resting for ≥5 min. 
c) 
 
HLA DQB1:0602: Collect blood sample unless previous result available. 
d) 
 
See Table 2. 
e) 
 
Urine drug screen and alcohol test: only for subjects continuing into the Open-Label Safety Period. 
f) 
 
Recorded daily in electronic diary. 
g) 
 
Impression of severity prior to any narcolepsy treatment. 
h) 
 
C-SSRS: Use Baseline/Screening Version at Visit 1 and Since Last Visit version at all other visits for subjects ≥12 years of age and use 
Children’s versions for children <12 years of age.  
i) 
 
School attendance collected for subjects who attend school during Stable-Dose and Double-Blind Treatment Periods. 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
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j) 
 
Coagulation: prothrombin time (PT)/international normalized ratio (INR), and activated partial thromboplastin time (PTT). Collect coagulation 
samples within 30 days prior to PK Night 1. PK evaluation will occur at any time while subjects are on a stable dose of Xyrem. 
k) 
 
Study drug dispensed at study visits in accordance with protocol and as required by State or local regulation.  
l) 
 
See Table 6. 
 
 
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Appendix 2.2 
Part 1 Open-Label Safety Period–Xyrem-Naïve Subjects at Study Entry 
Events 
 
Open-Label Safety Period with Xyrem 
Safety 
Follow-up  
Visits (V) 
Weeks (W) 
V5 a 
(4 weeks after 
end of Double-
Blind 
Treatment 
Period) 
±7 days 
V6 
W 16 
Phone 
Call 
±7 days 
V7 
W18 
±7 days 
V8 
W22  
±7 days 
Phone call 
V9 
Week 26 
±7 days 
 
V10 
W30  
±7 days 
Phone call 
V11 
Week 34 
±7 days 
Phone call 
V12 
Week 39 
±7 days 
 
V13 
Week 43 
 ±7 days 
Phone call 
V14 
Week 48 
±7 days 
Phone call 
Visit 15b 
Week 52 
±7 days 
Or Part 1 
Early 
Termination  
V16c 
14 days after 
last 
treatment 
+3 days 
Physical Examination 
including brief 
neurological exam 
 
 
 
 
 
 
 
 
 
 
X 
 
Tanner Stage Assessment 
 
 
 
 
 
 
 
 
 
 
X 
 
Height 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
Weight 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
Chemistry, Hematology 
 
 
 
 
 
 
 
 
 
 
X 
 
Urinalysis  
 
 
 
 
 
 
 
 
 
 
X 
 
Only for Girls <8 years:  
Estradiol, LH, FSH 
Only for Boys<9 years: 
Testosterone, LH, FSH 
 
 
 
 
 
 
 
 
 
 
X 
 
Urine Drug Screen  
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
Alcohol Test 
X 
 
X 
 
X 
 
 
X 
 
 
X 
Urine Pregnancy test 
 
 
 
 
 
 
 
 
 
 
X 
 
Study Drug Dosing 
Diaryd 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs (blood 
pressure, pulse/heart rate, 
body temperature, 
respiratory rate)e 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
Cataplexy frequency 
diaryd 
 
 
 
 
 
 
 
 
 
 
 
 
ESS (CHAD) 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
C-SSRSf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Appendix 2.2 
Part 1 Open-Label Safety Period–Xyrem-Naïve Subjects at Study Entry 
Events 
 
Open-Label Safety Period with Xyrem 
Safety 
Follow-up  
Visits (V) 
Weeks (W) 
V5 a 
(4 weeks after 
end of Double-
Blind 
Treatment 
Period) 
±7 days 
V6 
W 16 
Phone 
Call 
±7 days 
V7 
W18 
±7 days 
V8 
W22  
±7 days 
Phone call 
V9 
Week 26 
±7 days 
 
V10 
W30  
±7 days 
Phone call 
V11 
Week 34 
±7 days 
Phone call 
V12 
Week 39 
±7 days 
 
V13 
Week 43 
 ±7 days 
Phone call 
V14 
Week 48 
±7 days 
Phone call 
Visit 15b 
Week 52 
±7 days 
Or Part 1 
Early 
Termination  
V16c 
14 days after 
last 
treatment 
+3 days 
Depression scale 
(CDI2:SR[S]) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anxiety scale (MASC-10) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life (SF-10) 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
PSG 
 
 
 
 
 
 
 
 
 
 
See Appendix 
2.3g 
 
AE Reporting 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense Study Drugh 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
Collect trial medicine, 
measure and review 
compliance 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
PK evaluation  
When the subject is on a stable dose of Xyrem, PK Nights 1 and 2 can be scheduled for a protocol-specified clinic visit or for an additional clinic visit. See 
Appendix 3. 
An arrow (               )   indicates that the assessment is continuous. 
Note: A Xyrem naïve subject is defined as a subject who has never been treated with Xyrem or who was previously treated with Xyrem and discontinued Xyrem 
for at least one month prior to the Screening visit for reasons other than lack of efficacy and/or tolerability issues (e.g., lost insurance coverage, could not afford 
Xyrem, changed prescribers).  
a)  Visit 5 will be conducted 4 weeks after the end of the Double-Blind Treatment Period unless Visit 5 is within 2 weeks of the Week 18 visit. Visits 6-16 
will be conducted at Weeks 16, 18, 22, 26, 30, 34, 39, 43, 48, 52, and 54 after Day 1. 
b)  If the subject is continuing directly into Part 2, see Appendix 22. 
c)  Do not complete the Safety Follow-up visit for subjects who continue directly into Part 2 (see Appendix 22). 
d)  Recorded daily in electronic diary. 
e)  Obtain vital signs after the subject has been resting for ≥5 minutes. 
f) 
 C-SSRS: Use Since Last Visit version for subjects ≥12 years of age and use Children’s versions for children <12 years of age. 
g)  Part 1 Early termination PSG does not apply for subjects who discontinue before entering the Open-Label Safety Period. 
h)  Study drug dispensed at study visits in accordance with protocol and as required by State or local regulation. 
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Appendix 2.3 
PSG Night Procedures–Xyrem-Naïve Subjects at 
Study Entry 
 
Part 1 Screening 
Visit 
End Stable-Dose Period 
Begin Double-Blind 
Treatment Period* 
Open-Label Safety Period 
with Xyrem 
Visits 
V1  
Day -30 to -1a 
V3 
Week 3 (± 3 days) 
Visit 15 
Week 52 (±7 days) 
Or Part 1 Early 
Termination 
PSG Night Proceduresb 
Screening PSG 
 
End of Stable-Dose/Pre-
Randomization PSG** 
End of Study (Part 1) PSG 
/Part 1 Early Termination 
Review inclusion/exclusion 
criteria 
X 
 
 
Light dinner >2 hours before 
dosing 
Xc 
Xd 
Xd 
Confirm Parent(s)/ Guardian(s) 
Contact Information 
X 
X 
X 
Administer or supervise the 
administration of Study Druge 
 
X 
X 
PSG 
X 
X 
Xf 
EtCO2 or TcCO2
g 
X 
X 
X 
Vital Signsh 
Xi 
Xj 
Xj 
Pulse Oximetry 
Xk 
Xl 
Xl 
Record AEs/Concomitant 
Medications 
X 
X 
X 
Brief neurological examm 
 
X 
X 
Fasting morning blood sample: 
GH, IGF-1, prolactin 
 
X 
X 
Breakfast (if subject prefers to 
eat at the study center) 
X 
X 
X 
Note: A Xyrem naïve subject is defined as a subject who has never been treated with Xyrem or who was 
previously treated with Xyrem and discontinued Xyrem for at least one month prior to the Screening visit for 
reasons other than lack of efficacy and/or tolerability issues (e.g., lost insurance coverage, could not afford 
Xyrem, changed prescribers). 
Note: 
*Subjects who enter the Double-Blind Period after Amendment 4 becoming effective will receive open-label 
Xyrem treatment during the Double-Blind Period. 
**For administrative reasons the terminology for this PSG will retain the reference to “Pre-Randomization”). 
 
a) If needed, additional screening time may be granted with permission of the Medical Monitor. 
b) Perform all other procedures for the visit prior to the PSG night procedures.  
c) No food restrictions. 
d) Light dinner taken >2 hours prior to dosing. The dinner should be the same or similar on all PSG nights 
and may be taken at the Sleep Lab or at home. 
e) Administer the subject’s nightly dose of Xyrem divided in two doses, at bedtime and 4 hours later while 
in bed.  
f) Part 1 Early termination PSG does not apply for subjects who discontinue before entering the Open-
Label Safety Period.  
g) CO2 monitoring on PSG nights only at sites where monitoring is routinely performed.  
h) Obtain vital signs (blood pressure, pulse/heart rate, body temperature, respiratory rate) after subject has 
been resting for ≥5 min.  
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i) Vital signs obtained prior to the start of the PSG and prior to release from study center.  
j) Vital signs obtained at pre-dose and before release from the study center. At 1, 4 (pre-2nd dose), 5, and 8 
hours after the first Xyrem dose, heart and respiratory rates recorded via PSG. 
k) Monitor SpO2 to determine obstructive sleep apnea status. 
l) SpO2 monitored continuously from immediately before first dose through 8 hours post-first dose, and 
recorded pre-dose and at 1 h, 2 h, 4 h (pre-2nd dose), 5 h, 6 h, and 8 h after the first dose. Additional 
measurement is taken while the subject is awake and before release from the study center. 
m) Brief neurological exam before discharge on the morning after PSG. 
 
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Appendix 3 
PK Evaluation Procedures–Subjects Participating in the 
PK Evaluation  
Events/Visits 
Prior to PK 
Night 1 
PK Night 1 
 
PK Night 2 
 
Informed Consent/Assent for PK 
evaluation 
X 
 
 
Coagulation within 30 days prior to PK 
Night 1a 
X 
 
 
Light dinner >2 hours before dosingb 
 
X 
X 
Confirm Parent(s)/Guardian(s) Contact 
Information 
 
X 
X 
Blood samples for PK Assessmentc  
 
X 
X 
Vital Signs (blood pressure, pulse/heart 
rate, body temperature, respiratory rate)d 
 
X 
X 
Pulse Oximetrye 
 
X 
X 
Administer or supervise the 
administration of Study Drug from 
subject’s study drug supply on PK nights 
 
Xf 
Xg 
Brief neurological examh 
 
X 
X 
Breakfast (if subject prefers to eat at the 
study center) 
 
X 
X 
 
a)  Coagulation: prothrombin time (PT)/international normalized ratio (INR), and activated partial 
thromboplastin time (PTT). 
b)  Light dinner taken >2 hours prior to dosing should be the same or similar on both PK Nights. Light meal 
may be taken at the clinic or at home. 
c)  Blood samples for sodium oxybate concentrations will be collected at 0 (pre-dose) and 0.75, 1.5, 2.5, 4 
(pre-2nd dose), 4.75, and 8 hours after the first dose. Samples taken within ±5 minutes of the protocol 
specified time points. 
d)  Obtain vital signs after subject has been resting for ≥5 min. Obtain vital signs at pre-dose. At 1, 4 (pre-2nd 
dose), 5, and 8 hours after the first Xyrem dose, obtain pulse/heart and respiratory rates. 
e)  SpO2 is monitored continuously from immediately before first dose through 8 hours after the first dose, 
and recorded pre-dose and at 1 h, 2 h, 4 h (pre-2nd dose), 5 h, 6 h, and 8 h after the first dose. An 
additional measurement will be taken while the subject is awake and before release from the study center. 
f) 
 Administer ½ of the subject’s usual nightly dose in two equally divided doses, at bedtime and 4 hours 
later while in bed. Subjects whose equally divided dose does not match a line on the dosing syringe will 
take the dose that matches the next lower printed line on the dosing syringe (see Section 3.1.7). 
g)  Administer the subject’s nightly dose of Xyrem in two equally divided doses, at bedtime and 4 hours later 
while in bed. Subjects whose equally divided dose does not match a line on the dosing syringe will take 
the dose that matches the next lower printed line on the dosing syringe (see Section 3.1.7). 
h)  Brief neurological exam before discharge on the morning after pharmacokinetic assessment. 
 
 
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Appendix 4 
Seattle Children’s Hospital and Research Center: 
Maximum allowable blood draw volumes 
 
 
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TOTAL VOLUME
MAXIMUM mL IN    
ONE BLOOD DRAW
MAXIMUM mL IN     
A 30-DAY PERIOD
Kg
lbs
mL
2.5% of total blood vol
5% of total blood vol 
1
2.2
100
2.5
5
2
4.4
200
5
10
3
3.3
240
6
12
4
8.8
320
8
16
5
11
400
10
20
6
13.2
480
12
24
7
15.4
560
14
28
8
17.6
640
16
32
9
19.8
720
18
36
10
22
800
20
40
11 thru 15
24 thru 33
880-1200
22-30
44-60
16 thru 20
35 thru 44
1280-1600
32-40
64-80
21 thru 25
46 thru 55
1680-2000
42-50
64-100
26 thru 30
57 thru 66
2080-2400
52-60
104-120
31 thru 35
68 thru 77
2480-2800
62-70
124-140
36 thru 40
79 thru 88
2880-3200
72-80
144-160
41 thru 45
90 thru 99
3280-3600
82-90
164-180
46 thru 50
101 thru 110
3680-4000
92-100
184-200
51 thru 55
112 thru 121
4080-4400
102-110
204-220
56 thru 60
123 thru 132
4480-4800
112-120
224-240
61 thru 65
134 thru 143
4880-5200
122-130
244-260
66 thru 70
145 thru 154
5280-5600
132-140
264-280
71 thru 75
156 thru 165
5680-6000
142-150
284-300
76 thru 80
167 thru 176
6080-6400
152-160
304-360
81 thru 85
178 thru 187
6480-6800
162-170
324-340
86 thru 90
189 thru 198
6880-7200
172-180
344-360
91 thru 95
200 thru 209
7280-7600
182-190
364-380
96 thru 100
211 thru 220
7680-8000
192-200
384-400
Based on blood volume of:
1 to 2 kg
100 mL/kg
(pre-term infant)
>2 kg
80 mL/kg
(term infant - adult)
This information is similar to that used by the Committee on Clinical Investigations at
Children's Hospital in Los Angeles, and at Baylor College of Medicine in Dallas, TX.
Adapted by Rhona Jack, Ph.D. August 2001
Children's Hospital and Regional Medical Center Laboratory
Seattle, WA
Maximum allowable blood draw volumes:
PATIENT'S WEIGHT
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Appendix 5 
Tanner Stages  
CLASSIFICATION OF SEXUAL MATURITY STATES IN GIRLS 
SMR* 
STAGE 
PUBIC HAIR 
BREASTS 
1 
Preadolescent 
Preadolescent 
2 
Sparse, lightly pigmented, straight, medial 
border of labia 
Breast and papilla elevated as small mound; diameter of 
areola increased 
3 
Darker, beginning to curl, increased amount 
Breast and areola enlarged, no contour separation 
4 
Coarse, curly, abundant, but less than in 
adult 
Areola and papilla form secondary mound 
5 
Adult feminine triangle, spread to medial 
surface of thighs 
Mature, nipple projects, areola part of general breast 
contour 
 
CLASSIFICATION OF SEX MATURITY STATES IN BOYS 
SMR* 
STAGE 
PUBIC HAIR 
PENIS 
TESTES 
1 
None 
Preadolescent 
Preadolescent 
2 
Scanty, long, slightly pigmented 
Minimal change/enlargement 
Enlarged scrotum, pink, 
texture altered 
3 
Darker, starting to curl, small amount Lengthens 
Larger 
4 
Resembles adult type, but less 
quantity; coarse, curly 
Larger; glans and breadth 
increase in size 
Larger, scrotum dark 
5 
Adult distribution, spread to medial 
surface of thighs 
Adult size 
Adult size 
From Tanner JM: Growth at adolescence, ed 2, Oxford, England, 1962, Blackwell Scientific. 
* SMR = sexual maturity rating. 
 
 
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Appendix 6 
Epworth Sleepiness Scale for Children and Adolescents – 
ESS (CHAD) (Research Version) 
In the last week, how likely have you been to fall asleep while doing the things that are described 
below (activities)? Please check the box that describes you best in the last week. 
Even if you haven’t done some of these things in the last week, try to imagine how they would 
have affected you.  
It is important that you answer every question as best you can.  
1. Sitting and reading  
☐   Would never fall asleep 
☐   Slight chance of falling asleep 
☐   Moderate chance of falling asleep 
☐   High chance of falling asleep 
2. Sitting and watching TV or a video 
☐   Would never fall asleep 
☐   Slight chance of falling asleep 
☐   Moderate chance of falling asleep 
☐   High chance of falling asleep 
3. Sitting quietly in a classroom at school 
during the morning                                   
☐   Would never fall asleep 
☐   Slight chance of falling asleep 
☐   Moderate chance of falling asleep 
☐   High chance of falling asleep 
4. Sitting and riding in a car or a bus for 
about half an hour  
☐   Would never fall asleep 
☐   Slight chance of falling asleep 
☐   Moderate chance of falling asleep 
☐   High chance of falling asleep 
 
5. Lying down to rest or nap in the afternoon 
☐   Would never fall asleep 
☐   Slight chance of falling asleep 
☐   Moderate chance of falling asleep 
☐   High chance of falling asleep 
6. Sitting and talking to someone 
☐   Would never fall asleep 
☐   Slight chance of falling asleep 
☐   Moderate chance of falling asleep 
☐   High chance of falling asleep 
7. Sitting quietly by yourself after lunch  
☐   Would never fall asleep 
☐   Slight chance of falling asleep 
☐   Moderate chance of falling asleep 
☐   High chance of falling asleep 
 
8. Sitting and eating a meal 
☐   Would never fall asleep 
☐   Slight chance of falling asleep 
☐   Moderate chance of falling asleep 
☐   High chance of falling asleep 
 
 
 
 
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Appendix 7 
SF-10™ Health Survey for Children 
 
 
 
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SF-10™ Health Survey for Children ƕ 2001, 2005 QualityMetric Incorporated. All rights reserved. 
SF-10™ is a trademark of QualityMetric Incorporated. 
United States (English) Version 
 
 
 
 
 
SF-10TM Health Survey for Children 
 
 
 
 
 
 
 
 
 
 
 
 
INSTRUCTIONS 
 
 
1. This survey asks about your child’s health and well-being. 
 
 
2. There are no right or wrong answers. 
 
 
3. If you are unsure how to answer an item, please give the best response 
you can. 
 
 
4. For each item, please select the response that best describes your 
answer by marking the appropriate box ✔ . 
 
 
5. Please answer all items. 
 
 
 
 
 
Thank you for completing this survey. 
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SF-10™ Health Survey for Children ƕ 2001, 2005 QualityMetric Incorporated. All rights reserved. 
SF-10™ is a trademark of QualityMetric Incorporated. 
United States (English) Version 
  
SF-10TM  Health Survey for Children  
 
 
 
 
 
 
 
 
 
1.  In general, would you say your child’s health is: 
 
Excellent 
Very good 
Good 
Fair 
Poor 
 
 
1 
2 
3 
4 
5 
 
 
 
2.  During the past 4 weeks, has your child been limited in any of the following activities due to 
HEALTH problems? 
 
Yes, limited 
 
Yes, limited Yes, limited 
 
No, not 
a lot 
some 
a little 
limited 
 
 
a. Doing things that take some energy such as riding 
a bike or skating? 
1 
2 
3 
4 
 
b. Bending, lifting or stooping? 
1 
2 
3 
4 
 
 
 
3.  During the past 4 weeks, has your child been limited in the KIND of schoolwork or activities with 
friends he/she could do because of PHYSICAL health problems? 
 
Yes, limited a lot 
Yes, limited some 
Yes, limited a little 
No, not limited 
 
 
1 
2 
3 
4 
 
 
 
4.  During the past 4 weeks, has your child been limited in the KIND of schoolwork or activities with 
friends he/she could do because of EMOTIONAL or BEHAVIORAL problems? 
 
 
Yes, limited a lot 
Yes, limited some 
Yes, limited a little 
No, not limited 
 
 
1 
2 
3 
4 
 
 
 
 
5.  During the past 4 weeks, how much bodily pain or discomfort has your child had? 
 
None 
Very mild 
Mild 
Moderate 
Severe 
Very severe 
 
 
1 
2 
3 
4 
5 
6 
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SF-10TM  Health Survey for Children  
 
SF-10™ Health Survey for Children ƕ 2001, 2005 QualityMetric Incorporated. All rights reserved. 
SF-10™ is a trademark of QualityMetric Incorporated. 
United States (English) Version 
 
 
 
 
 
 
 
 
 
6.  During the past 4 weeks, how satisfied do you think your child has felt about his/her 
friendships? 
 
Very 
satisfied 
 
Somewhat 
satisfied 
 
Neither satisfied 
nor dissatisfied 
 
Somewhat 
dissatisfied 
 
Very 
dissatisfied 
 
 
1 
2 
3 
4 
5 
 
 
 
 
7.  During the past 4 weeks, how satisfied do you think your child has felt about his/her life overall? 
 
Very 
satisfied 
 
Somewhat 
satisfied 
 
Neither satisfied 
nor dissatisfied 
 
Somewhat 
dissatisfied 
 
Very 
dissatisfied 
 
 
1 
2 
3 
4 
5 
 
 
 
 
8. During the past 4 weeks, how much of the time do you think your child acted bothered or upset? 
 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
 
 
1 
2 
3 
4 
5 
 
 
 
 
9. Compared to other children your child’s age, in general would you say his/her behavior is: 
 
Excellent 
Very good 
Good 
Fair 
Poor 
 
 
1 
2 
3 
4 
5 
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Appendix 8 
Columbia-Suicidality Severity Rating Scales (C-SSRS) 
• 
Children’s Baseline/Screening for ages under 12 years 
• 
Children’s Since Last Visit for ages under 12 years 
• 
Baseline/Screening for ages 12 years and older 
• 
Since Last Visit for ages 12 years and older 
 
 
 
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COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Children’s Baseline/Screening 
Version 6/23/10 
 
 Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained 
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale. 
 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside 
Drive, New York, New York, 10032; inquiries and training requirements contact posnerk@childpsych.columbia.edu  
© 2008 The Research Foundation for Mental Hygiene, Inc. 
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SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is 
“yes”, ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” 
section below. 
 
Lifetime 
Past 6 
Months  
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you thought about being dead or what it would be like to be dead? 
Have you wished you were dead or wished you could go to sleep and never wake up? 
Do you ever wish you weren’t alive anymore?  
 
If yes, describe: 
 
 
Yes       No 
 □    □
 
Yes       No 
 □    □
2.  Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways 
to kill oneself/associated methods, intent, or plan during the assessment period. 
Have you thought about doing something to make yourself not alive anymore? 
Have you had any thoughts about killing yourself? 
 
If yes, describe: 
 
 
 Yes      No 
 □    □ 
 
 Yes      No 
 □    □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan 
with time, place or method details worked out (e.g., thought of method to kill self but not a specific plan).  Includes person who would say, “I 
thought about taking an overdose but I never made a specific plan as to when, where or how I would actually do it…and I would never go 
through with it.” 
Have you thought about how you would do that or how you would make yourself not alive anymore (kill yourself)? What did you think 
about? 
 
If yes, describe: 
 
 
 Yes      No 
 □    □ 
 
 Yes      No 
 □    □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts 
but I definitely will not do anything about them.” 
When you thought about making yourself not alive anymore (or killing yourself), did you think that this was something you might actually 
do? 
This is different from (as opposed to) having the thoughts but knowing you wouldn’t do anything about it. 
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
 
Yes       No 
 □    □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you ever decided how or when you would make yourself not alive anymore/kill yourself? Have you ever planned out (worked out the 
details of) how you would do it?  
What was your plan?  
When you made this plan (or worked out these details), was any part of you thinking about actually doing it? 
   
If yes, describe: 
 
 
 Yes      No 
 □    □ 
 
 Yes      No 
 □    □ 
INTENSITY OF IDEATION 
 
The following feature should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the 
least severe and 5 being the most severe).  
                                             
Most Severe Ideation:         
                                               ___________              _________________________________________________ 
                                                                                                           Type # (1-5)                                         Description of  Ideation 
Most 
Severe 
Most 
Severe 
Frequency 
How many times have you had these thoughts?                Write response________________________________ 
 (1) Only one time    (2) A few times    (3)  A lot    (4) All the time    (0) Don’t know/Not applicable 
 
____ 
 
____ 
 
 
 
 
 
 
 
 
 
 
Version 6/23/10 
CONFIDENTIAL
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Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
 
Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
 
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
 
Lifetime  
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, 
this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly lethal 
act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). Also, if 
someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Did you ever do anything to try to kill yourself or make yourself not alive anymore? What did you do? 
Did you ever hurt yourself on purpose? Why did you do that? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to make yourself not alive anymore when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons, not at all to end your life or kill yourself (like to make yourself feel better, or get 
something else to happen)? (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Has subject engaged in Self-Injurious Behavior, intent unknown? 
 
Yes      No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
Yes    No 
□   □ 
Yes    No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around 
neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to make yourself not alive anymore (end your life or kill yourself) but 
someone or something stopped you before you actually did anything? What did you do? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to make yourself not alive anymore (end your life or kill yourself) but 
you changed your mind (stopped yourself) before you actually did anything? What did you do? 
If yes, describe: 
 
 
Yes      No 
□   □ 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a specific 
method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a suicide note).  
Have you done anything to get ready to make yourself not alive anymore (to end your life or kill yourself)- like giving things 
away, writing a goodbye note, getting things you need to kill yourself? 
If yes, describe: 
 
 
Yes      No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Answer for Actual Attempts Only 
Most Recent  
Attempt 
Date: 
Most Lethal         
Attempt 
Date: 
Initial/First  
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with 
reflexes intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-
degree burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
Enter Code
 
 
 
______ 
 
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had 
potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying 
on train tracks with oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 
Enter Code
 
 
 
______ 
 
 
CONFIDENTIAL
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Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
 
Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
 
 
 
 
 
 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Children’s Since Last Visit 
Version 6/23/10 
 
 Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained 
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale. 
 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside 
Drive, New York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
CONFIDENTIAL
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CONFIDENTIAL
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Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
 
Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 6/23/10 
SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes”, 
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below. 
 
Since Last 
Visit 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you thought about being dead or what it would be like to be dead? 
Have you wished you were dead or wished you could go to sleep and never wake up? 
Do you wish you weren’t alive anymore?  
 
If yes, describe: 
 
 
Yes       No 
□    □ 
2.  Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan during the assessment period. 
Have you thought about doing something to make yourself not alive anymore? 
Have you had any thoughts about killing yourself? 
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g., thought of method to kill self but not a specific plan).  Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it…and I would never go through with it.” 
Have you thought about how you would do that or how you would make yourself not alive anymore (kill yourself)? What did you think about? 
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them.” 
When you thought about making yourself not alive anymore (or killing yourself), did you think that this was something you might actually do? 
This is different from (as opposed to) having the thoughts but knowing you wouldn’t do anything about it. 
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you decided how or when you would make yourself not alive anymore/kill yourself? Have you planned out (worked out the details of) how you 
would do it?  
What was your plan?  
When you made this plan (or worked out these details), was any part of you thinking about actually doing it? 
   
If yes, describe: 
 
 
Yes       No 
 □    □ 
INTENSITY OF IDEATION 
The following feature should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the least severe 
and 5 being the most severe).  
                                             
Most Severe Ideation:         ___________              _________________________________________________ 
                                               
                                                                                                           Type # (1-5)                                         Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts?                      Write response___________________________________ 
 (1) Only one time    (2) A few times   (3)  A lot    (4) All the time    (0) Don’t know/Not applicable 
 
____ 
CONFIDENTIAL
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CONFIDENTIAL
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Signature Date: 20170309
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Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
 
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last 
Visit 
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, 
this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly lethal 
act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). Also, if 
someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Did you do anything to try to kill yourself or make yourself not alive anymore? What did you do? 
Did you hurt yourself on purpose? Why did you do that? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to make yourself not alive anymore when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons, not at all to end your life or kill yourself (like to make yourself feel better, or get 
something else to happen)? (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Has subject engaged in Self-Injurious Behavior, intent unknown? 
 
Yes      No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
Yes    No 
□   □ 
 
Yes    No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around neck 
but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to make yourself not alive anymore (end your life or kill yourself) but 
someone or something stopped you before you actually did anything? What did you do? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
 
Aborted Attempt or Self-Interrupted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to make yourself not alive anymore (end your life or kill yourself) but you 
changed your mind (stopped yourself) before you actually did anything? What did you do? 
If yes, describe: 
 
 
Yes      No 
□   □ 
Total # of 
aborted  
or self-
interrupted  
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a specific 
method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a suicide note).  
Have you done anything to get ready to make yourself not alive anymore (to end your life or kill yourself)- like giving things away, 
writing a goodbye note, getting things you need to kill yourself? 
If yes, describe: 
 
 
Yes      No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Suicide: 
Yes    No 
□   □ 
Answer for Actual Attempts Only 
Most Lethal 
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes intact; third-degree burns less 
than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree burns over 20% of body; 
extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
 
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for very serious 
lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away before 
run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
Enter Code 
 
 
 
______ 
 
 
CONFIDENTIAL
Page 121 of 144
CONFIDENTIAL
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Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
 
Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
 
 
 
 
 
 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS)  
Baseline/Screening Version 
Version 1/14/09 
 
  
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained in 
the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of suicidal 
ideation or behavior depends on the judgment of the individual administering the scale. 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History Form, 
developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@childpsych.columbia.edu  
© 2008 The Research Foundation for Mental Hygiene, Inc. 
CONFIDENTIAL
Page 122 of 144
CONFIDENTIAL
Page 143 of 176

Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
 
Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to 
question 2 is “yes”, ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete 
“Intensity of Ideation” section below. 
Lifetime: Time 
He/She Felt 
Most Suicidal 
Past __ 
Months 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
If yes, describe: 
 
Yes       No 
□    □ 
 
Yes     No 
□   □ 
2.  Non-Specific Active Suicidal Thoughts 
General non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts 
of ways to kill oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
    Yes       No 
   □    □ 
 
Yes     No 
□   □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a 
specific plan with time, place or method details worked out (e.g.  thought of method to kill self but not a specific plan).  Includes person 
who would say, “I thought about taking an overdose but I never made a specific plan as to when, where or how I would actually do 
it…and I would never go through with it.” 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 
    Yes      No 
 □    □ 
 
Yes     No 
□   □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the 
thoughts but I definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
 
If yes, describe: 
 
 
   Yes      No 
□    □ 
 
Yes     No 
□   □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
   
If yes, describe: 
 
 
   Yes       No 
 □    □ 
 
Yes     No 
□   □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being 
the least severe and 5 being the most severe).  Ask about time he/she was feeling the most suicidal.  
                                   
Lifetime -           Most Severe Ideation:  _______                  ________________________________________ 
                                                                       Type # (1-5)                                                 Description of  Ideation 
 
Past X Months - Most Severe Ideation:  _______                   ________________________________________ 
                                                                      Type # (1-5)                                                 Description of  Ideation 
Most  
Severe 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
 
 
____ 
 
 
____ 
Duration 
When you have the thoughts how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time 
____ 
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts  with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to 
die or acting on thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
____ 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain 
or stop the way you were feeling (in other words you couldn’t go on living with this pain or how you were 
feeling) or was it to get attention, revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain                                                                         living with the pain or  how you were feeling) 
                                                                                                                 (0)  Does not apply 
 
 
 
 
____ 
 
 
____ 
 
Version 1/14/09 
CONFIDENTIAL
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CONFIDENTIAL
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Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
 
Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Lifetime 
Past __ 
Years 
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill 
oneself. Intent does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide 
attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in 
mouth but gun is broken so no injury results, this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a 
highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a 
high floor/story). Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or Did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better,  
get sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes     No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
□   □ 
Yes     No 
□   □ 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would 
have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted 
attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once 
they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. 
Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before 
you actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
 
Total # of 
interrupted 
 
______ 
 
Yes     No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-
destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by 
something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
aborted 
 
______ 
Yes     No 
□   □ 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as 
assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a 
suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, 
getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
 
Yes      No 
□   □ 
 
 
Yes     No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Yes     No 
□   □ 
Answer for Actual Attempts Only 
Most Recent 
Attempt 
Date: 
Most Lethal        
Attempt 
Date: 
Initial/First 
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes 
intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree 
burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had 
potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying 
on train tracks with oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
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COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit 
Version 1/14/09 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained 
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale. 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
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SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes”, 
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below. 
 
Since Last 
Visit 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
2.  Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
 Yes      No 
 □    □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g., thought of method to kill self but not a specific plan).  Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it…and I would never go through with it.” 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 
 Yes      No 
 □    □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
   
If yes, describe: 
 
 
 Yes      No 
 □    □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the least severe 
and 5 being the most severe).  
                                             
Most Severe Ideation:             _____                      _________________________________________________ 
                                               
                                                                                                           Type # (1-5)                                         Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time                                                                    
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting on 
thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop the way 
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention, 
revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain                                                                         living with the pain or  how you were feeling) 
                                                                                                                 (0)  Does not apply 
 
 
 
 
____ 
Version 1/14/09 
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SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last 
Visit 
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, 
this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly 
lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). 
Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get 
sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Yes      No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around 
neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
 
 
Yes      No 
□   □ 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a 
specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, 
giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
Yes      No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Suicide: 
   Yes    No 
□   □ 
Answer for Actual Attempts Only 
Most Lethal 
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes intact; third-degree burns 
less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree burns over 20% of body; 
extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for very serious 
lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away 
before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
Enter Code 
 
 
 
______ 
 
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Signature Date: 20170309
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Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
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Appendix 9 
Children’s Depression Inventory 2nd Edition Self-
Report Short Version (CDI 2:SR[S])  
 
 
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By Maria Kovacs, Ph.D.
Name/ID:_________________________________________________
Date of Birth:_ ______ /_______/_______
Age:_______	
Grade:_______ 	
Sex:	
Male	
Female
Today’s Date:_______ /_______/_______
Year	
Month	
Day
Year	
Month	
Copyright © 2011 Maria Kovacs, Ph.D. and Multi-Health Systems Inc. All rights reserved.  
In the United States, P.O. Box 950, North Tonawanda, NY 14120-0950, 1-800-456-3003. In Canada, 3770 Victoria Park Avenue, Toronto, ON  M2H 3M6, 
1-800-268-6011, 1-416-492-2627, Fax 1-416-492-3343. Internationally, +1-416-492-2627. Fax, +1-416-492-3343 or (888) 540-4484.
Remember, for each group, pick out the sentence that describes you best in the past two weeks.
Item 1
 I am sad once in a while.
 I am sad many times.
 I am sad all the time.
Item 7
 I feel cranky all the time.
 I feel cranky many times.
 I am almost never cranky.
Item 2
 Nothing will ever work out for me.
 I am not sure if things will work out for me.
 Things will work out for me O.K.
Item 8
 I cannot make up my mind about things.
 It is hard to make up my mind about things.
 I make up my mind about things easily.
Item 3
 I do most things O.K.
 I do many things wrong.
 I do everything wrong.
Item 9
 I have to push myself all the time to do my schoolwork.
 I have to push myself many times to do my schoolwork.
 Doing schoolwork is not a big problem.
Item 4
 I have fun in many things.
 I have fun in some things.
 Nothing is fun at all.
Item 10
 I am tired once in a while.
 I am tired many days.
 I am tired all the time.
Item 5
 I am important to my family.
 I am not sure if I am important to my family.
 My family is better off without me.
Item 11
 Most days I do not feel like eating.
 Many days I do not feel like eating.
 I eat pretty well.
Item 6
 I hate myself.
 I do not like myself.
 I like myself.
Item 12
 I do not feel alone.
 I feel alone many times.
 I feel alone all the time.
Kids sometimes have different feelings and ideas.
This form lists the feelings and ideas in groups. From each 
group of three sentences, pick one sentence that describes 
you best for the past two weeks. After you pick a sentence 
from the first group, go on to the next group.
There is no right or wrong answer. Just pick the sentence 
that best describes the way you have been recently. Put a 
mark like this  next to your answer. Put the mark in the 
box next to the sentence that you pick.

Here is an example of how this form works.  
Try it. Put a mark next to the sentence that  
describes you best.
Example:
 I read books all the time.
 I read books once in a while.
 I never read books.
Self-Report 
Short
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
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Appendix 10 
Multi-dimensional Anxiety Scale for Children 
(MASC-10) 
 
 
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MASC-10: Multidimensional Anxiety Scale for Children-10 Item 
by John March, M.D., M.P.H. 
Age: ____ _ 
Sex: 
Male 
Female 
(Circle one) 
Date: 
I 
I 
School Grade: ----
Month 
Day 
Year 
This questionnaire asks you how you have been thinking, feeling, or acting recently. For each item, please circle the 
number that shows how often the statement is true for you. If a sentence is true about you a lot of the time, circle 3. If it 
is true about you some of the time, circle 2. If it is true about you once in a while, circle I. If a sentence is not ever true 
about you, circle 0. Remember, there are no right or wrong answers, just answer how you have been feeling recently. 
Here are two examples to show you how to complete the questionnaire. In Example A, if you were hardly ever scared of 
dogs, you would circle I, meaning that the statement is rarely true about you. In Example B, if thunderstorms sometimes 
upset you, you would circle 2, meaning that the statement is sometimes true about you. 
never 
rarely 
true 
true 
about me about me 
Example A I'm scared of dogs ............................................................................. .. 
0 
Q) 
Example B Thunderstorms upset me ..................................................................... . 
0 
1 
Now try these items yourself. 
I. 
The idea of going away to camp scares me .......................................................... O 
1 
2. 
I'm afraid that other kids will make fun of me ..................................................... O 
1 
3. 
I try to stay near my mom or dad ......................................................................... O 
1 
4. 
I get dizzy or faint feelings ................................................................................... 0 
1 
5. 
I feel restless and on edge ..................................................................................... O 
6. 
I feel sick to my stomach ...................................................................................... O 
1 
7. 
I get nervous ifl have to perform in public .......................................................... 0 
1 
8. 
Bad weather, the dark, heights, animals, or bugs scare me .................................. O 
9. 
I check to make sure things are safe ..................................................................... O 
10. I feel shy ............................................................................................................... O 
1 
~ MHS Copyright© 1997, 1999, Multi-Health Systems Inc. All rights reserved. In the U.S.A., P.O. Box 950, North Tonawanda, NY 14120-0950, (800) 456-3003. 
515 
In Canada, 3770 Victoria Park Avenue, Toronto, ON M2H 3M6, (800) 268-6011. Internationally, +1-416-492-2627. Fax, +1-416-492-3343 or (888) 540-4484. 
sometimes 
often 
true 
true 
about 
about 
me 
me 
2 
3 
0 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
Printed in Canada 
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Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
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Appendix 11 
Cataplexy Frequency Diary 
 
To be completed in the evening 
Subject Number:  
 
 
Date:  
 
 
Please check who is completing the diary:  Parent/Guardian      Subject 
 
 
Cataplexy is a sudden feeling of weakness in your 
legs, arms, head, or face. 
 
It can be different for each person.  
 
These are some examples  of cataplexy: 
 
• Falling down or feeling weak in my legs  
• Feeling weak in my arms or like I couldn’t 
move my arms 
• My face doing weird things (for example: my 
tongue sticking out, mouth opening, eyes 
closing or eyes rolling) 
• My head dropping or feeling like I couldn't 
hold my head up 
☐ Yes, I had cataplexy today  
 
☐ No, I did not have cataplexy today 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If yes, next 
screen  
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
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Enter the total number of times you had 
cataplexy today: 
 
_________  time(s) 
 
 
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Appendix 12 
Study Drug Dosing Diary 
To be completed in the morning 
Subject Number:  
 
 
Date:  
 
 
Please check who is completing the diary:  Parent/Guardian      Subject 
 
Was the first nightly dose taken?   Yes  No 
 
Was the second nightly dose taken?   Yes  No 
 
 
 
 
 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
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Appendix 13 
Stimulant Dosing Diary  
 
To be completed in the evening 
Subject Number:  
 
 
Date:  
 
 
Please check who is completing the diary:  Parent/Guardian      Subject 
 
Did you take a stimulant today?   Yes 
 No 
 
If the answer is “No”, the following item will be displayed: 
Select the reason the stimulant was not taken today.  
“I was supposed to take stimulant today, but I didn’t”  
 
“I was not supposed to take stimulant today” 
 
 
 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
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Appendix 14 
School Attendance Diary 
 
Subjects or the parent(s)/guardian(s) will record the following during the last 2 weeks of the 
Stable-Dose Period and during the Double-Blind Period. 
 
Date:  
 
Parent/guardian completed:  
Was your child scheduled to attend school today?    Yes    No 
If yes, then did your child miss school today because of narcolepsy?  Yes   No 
 
 
Date:  
 
Subject completed:  
Were you scheduled to attend school today?    Yes    No 
If yes, then did you miss school today because of narcolepsy?  Yes   No 
 
 
 
 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
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Appendix 15 
Clinical Global Impression of Severity (CGIs) for 
Historical Narcolepsy Overall Severity Prior to any 
Narcolepsy Treatment 
Investigators will rate their impression of the severity of the subject’s narcolepsy overall 
prior to any narcolepsy treatment as follows: 
Considering your total clinical experience with narcolepsy subjects, how ill was the subject 
before he/she received any narcolepsy treatment? 
 Normal; no signs of illness 
 Borderline ill 
 Slightly ill 
 Moderately ill 
 Markedly ill 
 Severely ill 
 Among the most extremely ill 
 
 
 
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Signature Date: 20170309
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
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Appendix 16 
Clinical Global Impression of Severity (CGIs) for 
Historical Cataplexy Severity Prior to any Narcolepsy 
Treatment 
Investigators will rate their impression of the severity of the subject’s cataplexy prior to any 
narcolepsy treatment as follows: 
Considering your total clinical experience with narcolepsy subjects, how ill was the subject 
before he/she received any narcolepsy treatment? 
 Normal; no signs of illness 
 Borderline ill 
 Slightly ill 
 Moderately ill 
 Markedly ill 
 Severely ill 
 Among the most extremely ill 
 
 
 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
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Appendix 17 
Clinical Global Impression of Severity (CGIs) for 
Narcolepsy Overall  
Investigators will rate their impression of the severity of the subject’s narcolepsy overall as 
follows: 
Considering your total clinical experience with narcolepsy subjects, how ill is the subject at 
this time? 
 Normal; no signs of illness 
 Borderline ill 
 Slightly ill 
 Moderately ill 
 Markedly ill 
 Severely ill 
 Among the most extremely ill  
 
 
CONFIDENTIAL
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
Page 143 of 158 
Appendix 18 
Clinical Global Impression of Severity (CGIs) for 
Cataplexy Severity  
Investigators will rate their impression of the severity of the subject’s cataplexy as follows: 
Considering your total clinical experience with narcolepsy subjects, how ill is the subject at 
this time? 
 Normal; no signs of illness 
 Borderline ill 
 Slightly ill 
 Moderately ill 
 Markedly ill 
 Severely ill 
 Among the most extremely ill  
 
 
CONFIDENTIAL
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
Page 144 of 158 
Appendix 19 
Patient Global Impression of Change (PGIc) for 
Narcolepsy Overall 
The PGIc is a 7-point scale. Subjects will be asked “How would you rate your narcolepsy 
since Visit 3 (the end of the Stable-Dose Period)?” 
 Very much better 
 Much better 
 A little better 
 No change  
 A little worse 
 Much worse 
 Very much worse 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
Page 162 of 176

Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
 
Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
Xyrem® (sodium oxybate) oral solution 
 
Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
Page 145 of 158 
Appendix 20 
Clinical Global Impression of Change (CGIc) for 
Narcolepsy Overall 
Investigators will rate their impression of any change in the severity of a subject’s overall 
condition of narcolepsy since the start of the Double-Blind Treatment Period using the CGIc 
rating scale (whether or not, in the Investigator’s judgment, the improvement is entirely due 
to treatment) as follows: 
 Very much improved 
 Much improved 
 Minimally improved 
 No change  
 Minimally worse 
 Much worse 
 Very much worse 
 
 
 
CONFIDENTIAL
Page 163 of 176

Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
 
Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
Xyrem® (sodium oxybate) oral solution 
 
Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
Page 146 of 158 
Appendix 21 
Clinical Global Impression of Change (CGIc) for 
Cataplexy Severity 
Investigators will rate their impression of any change in the severity of a subject’s cataplexy 
since the start of the Double-Blind Treatment Period using the CGIc rating scale (whether or 
not, in the Investigator’s judgment, the improvement is entirely due to treatment) as follows: 
 Very much improved 
 Much improved 
 Minimally improved 
 No change  
 Minimally worse 
 Much worse 
 Very much worse 
 
 
 
 
CONFIDENTIAL
Page 164 of 176

Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
Xyrem® (sodium oxybate) oral solution 
Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
CONFIDENTIAL 
Page 147 of 158 
Appendix 22 
Part 2–Open-Label Continuation–Subjects Continuing Directly into Part 2 from Part 1 
Open-Label Continuationa Visits
Events 
Part 1 
Visit 15 
(±7 days) 
Onsite 
Month 1 
Visit 19 
Month 2 
Visit 20 
Month 3 
Visit 21 
Month 4 
Visit 22 
Month 5 
Visit 23 
Month 6 
Visit 24 
Part 2 Study 
Termination/
Part 2 Early 
Termination 
Visit 42 
(±7 days) 
Onsite 
Month 7 
Visit 25 
Month 8 
Visit 26 
Month 9 
Visit 27 
Month 10 
Visit 28 
Month 11 
Visit 29 
Month 12 
Visit 30 
Month 13 
Visit 31 
Month 14 
Visit 32 
Month 15 
Visit 33 
Month 16 
Visit 34 
Month 17 
Visit 35 
Month 18 
Visit 36 
Month 19 
Visit 37 
Month 20 
Visit 38 
Month 21 
Visit 39 
Month 22 
Visit 40 
Month 23 
Visit 41 
(±7 days) 
Onsite 
(±7 days) 
Phone call 
(±7 days) 
Phone call 
(±7 days) 
Onsite 
(±7 days) 
Phone call 
(±7 days) 
Phone call 
Confirm informed 
Consent/Assent for 
Amendment 5 
X 
Maintain 
monthly 
schedule for 
Months 1 
through 23 
until the 
subject 
reaches age 
18 yearsb or
within 
3 months 
after the US 
FDA 
decision on 
the addition 
of pediatric 
data to the 
Xyrem US 
PI, 
whichever 
occurs first. 
Physical Examination 
including brief 
neurological exam 
X 
Tanner Stage 
Assessment 
X 
Height 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
Chemistry, Hematology 
X 
Urinalysis 
X 
Only for Girls <8 years: 
Estradiol, LH, FSH 
Only for Boys<9 years: 
Testosterone, LH, FSH 
X 
Urine Drug Screen 
X 
X 
X 
Alcohol Test 
X 
X 
X 
Urine Pregnancy test 
X 
X 
X 
CONFIDENTIAL
Page 165 of 176

Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
Xyrem® (sodium oxybate) oral solution 
Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
CONFIDENTIAL 
Page 148 of 158 
Appendix 22 
Part 2–Open-Label Continuation–Subjects Continuing Directly into Part 2 from Part 1 
Open-Label Continuationa Visits
Events 
Part 1 
Visit 15 
(±7 days) 
Onsite 
Month 1 
Visit 19 
Month 2 
Visit 20 
Month 3 
Visit 21 
Month 4 
Visit 22 
Month 5 
Visit 23 
Month 6 
Visit 24 
Part 2 Study 
Termination/
Part 2 Early 
Termination 
Visit 42 
(±7 days) 
Onsite 
Month 7 
Visit 25 
Month 8 
Visit 26 
Month 9 
Visit 27 
Month 10 
Visit 28 
Month 11 
Visit 29 
Month 12 
Visit 30 
Month 13 
Visit 31 
Month 14 
Visit 32 
Month 15 
Visit 33 
Month 16 
Visit 34 
Month 17 
Visit 35 
Month 18 
Visit 36 
Month 19 
Visit 37 
Month 20 
Visit 38 
Month 21 
Visit 39 
Month 22 
Visit 40 
Month 23 
Visit 41 
(±7 days) 
Onsite 
(±7 days) 
Phone call 
(±7 days) 
Phone call 
(±7 days) 
Onsite 
(±7 days) 
Phone call 
(±7 days) 
Phone call 
Review Study Drug 
Dosing Diary 
X 
12-Lead ECG 
X 
Vital Signsc
X 
X 
X 
X 
Review Cataplexy 
frequency diary 
X 
ESS (CHAD) 
X 
C-SSRSd
X 
Depression scale 
(CDI2:SR[S]) 
X 
Anxiety scale (MASC-
10) 
X 
Quality of Life (SF-10) 
X 
PSG 
Xe
Fasting morning blood 
sample: GH, IGF-1, 
prolactin 
Xe
AE Reporting 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Study Drugf
X 
X 
X 
CONFIDENTIAL
Page 166 of 176

Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
Xyrem® (sodium oxybate) oral solution 
Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
CONFIDENTIAL 
Page 149 of 158 
Appendix 22 
Part 2–Open-Label Continuation–Subjects Continuing Directly into Part 2 from Part 1 
Open-Label Continuationa Visits
Events 
Part 1 
Visit 15 
(±7 days) 
Onsite 
Month 1 
Visit 19 
Month 2 
Visit 20 
Month 3 
Visit 21 
Month 4 
Visit 22 
Month 5 
Visit 23 
Month 6 
Visit 24 
Part 2 Study 
Termination/
Part 2 Early 
Termination 
Visit 42 
(±7 days) 
Onsite 
Month 7 
Visit 25 
Month 8 
Visit 26 
Month 9 
Visit 27 
Month 10 
Visit 28 
Month 11 
Visit 29 
Month 12 
Visit 30 
Month 13 
Visit 31 
Month 14 
Visit 32 
Month 15 
Visit 33 
Month 16 
Visit 34 
Month 17 
Visit 35 
Month 18 
Visit 36 
Month 19 
Visit 37 
Month 20 
Visit 38 
Month 21 
Visit 39 
Month 22 
Visit 40 
Month 23 
Visit 41 
(±7 days) 
Onsite 
(±7 days) 
Phone call 
(±7 days) 
Phone call 
(±7 days) 
Onsite 
(±7 days) 
Phone call 
(±7 days) 
Phone call 
Collect trial medicine, 
measure and review 
compliance 
X 
X 
X 
X 
An arrow (               )   indicates that the assessment is continuous. 
a  Following Part 1, subjects may receive Xyrem treatment in Part 2 for up to an additional 2 years or until they reach 18 years of age or until up to 3 months after 
the US FDA decision on the addition of pediatric data to the Xyrem US prescribing information (PI), whichever occurs first. 
b  For subjects turning 18 years of age, the Part 2 Study Termination visit must be scheduled prior to the subject’s 18th birthday. 
c Obtain vital signs (blood pressure, pulse/heart rate, body temperature, respiratory rate) after the subject has been resting for ≥5 minutes. 
d  Use Since Last Visit version for subjects ≥12 years of age and Children’s versions for children <12 years of age. 
e  See Appendix 1.2 for subjects on Xyrem at study entry and Appendix 2.3 for Xyrem-Naïve Subjects at Study Entry. 
f  Study drug dispensed at study visits in accordance with protocol and as required by State or local regulation. 
CONFIDENTIAL
Page 167 of 176

Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
Xyrem® (sodium oxybate) oral solution 
Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
CONFIDENTIAL 
Page 150 of 158 
Appendix 23 
Part 2–Open-Label Continuation–Subjects Re-enrolling After Completing Part 1 and Do 
Not Require Titration 
Open-Label Continuationa Visits
Events 
Part 2 
Screening 
Visit 17b,c
Onsite 
Visit 18c,d
Onsite 
Month 1 
Visit 19 
Month 2 
Visit 20 
Month 3 
Visit 21 
Month 4 
Visit 22 
Month 5 
Visit 23 
Month 6 
Visit 24 
Part 2 Study 
Termination/ 
Part 2 Early 
Termination 
Visit 42 
(±7 days) 
Onsite 
Month 7 
Visit 25 
Month 8 
Visit 26 
Month 9 
Visit 27 
Month 10 
Visit 28 
Month 11 
Visit 29 
Month 12 
Visit 30 
Month 13 
Visit 31 
Month 14 
Visit 32 
Month 15 
Visit 33 
Month 16 
Visit 34 
Month 17 
Visit 35 
Month 18 
Visit 36 
Month 19 
Visit 37 
Month 20 
Visit 38 
Month 21 
Visit 39 
Month 22 
Visit 40 
Month 23 
Visit 41 
(±7 days) 
Onsite 
(±7 days) 
Phone call 
(±7 days) 
Phone call 
(±7 days) 
Onsite 
(±7 days) 
Phone call 
(±7 days) 
Phone call 
Informed 
Consent/Assent 
X 
Maintain 
monthly 
schedule for 
Months 1 
through 23 
until the 
subject 
reaches age 
18 yearsg or
within 
3 months 
after the US 
FDA 
decision on 
the addition 
of pediatric 
data to the 
Xyrem US 
PI, 
whichever 
occurs first. 
Inclusion/ 
Exclusion 
Criteriae
X 
X 
Update parent/ 
guardian contact 
information 
X 
Medical Historyf
X 
Physical 
Examination 
including a brief 
neurological 
exam 
X 
Height 
X 
Xh
X 
X 
X 
Weight 
X 
Xh
X 
X 
X 
Chemistry, 
Hematology 
Xc
Urinalysis 
Xc
Urine Drug 
Screen 
Xc
X 
X 
X 
CONFIDENTIAL
Page 168 of 176

Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
Xyrem® (sodium oxybate) oral solution 
 
Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
 
CONFIDENTIAL 
Page 151 of 158 
Appendix 23 
Part 2–Open-Label Continuation–Subjects Re-enrolling After Completing Part 1 and Do 
Not Require Titration 
 
Open-Label Continuationa Visits 
 
 
Events 
Part 2 
Screening 
Visit 17b,c 
Onsite 
Visit 18c,d 
Onsite 
Month 1 
Visit 19 
Month 2 
Visit 20 
Month 3 
Visit 21 
Month 4 
Visit 22 
Month 5 
Visit 23 
Month 6 
Visit 24 
 
Part 2 Study 
Termination/ 
Part 2 Early 
Termination 
Visit 42 
(±7 days) 
Onsite 
Month 7 
Visit 25 
Month 8 
Visit 26 
Month 9 
Visit 27 
Month 10 
Visit 28 
Month 11 
Visit 29 
Month 12 
Visit 30 
Month 13 
Visit 31 
Month 14 
Visit 32 
Month 15 
Visit 33 
Month 16 
Visit 34 
Month 17 
Visit 35 
Month 18 
Visit 36 
Month 19 
Visit 37 
Month 20 
Visit 38 
Month 21 
Visit 39 
Month 22 
Visit 40 
Month 23 
Visit 41 
(±7 days) 
Onsite 
(±7 days) 
Phone call 
(±7 days) 
Phone call 
(±7 days) 
Onsite 
(±7 days) 
Phone call 
(±7 days) 
Phone call 
Alcohol Test 
Xc 
X 
 
 
 
 
 
X 
X 
Serum Pregnancy 
test 
Xc 
 
 
 
 
 
 
 
 
Urine Pregnancy 
test 
 
X 
 
 
 
 
 
X 
X 
Vital Signsi 
X 
Xh 
 
 
X 
 
 
X 
X 
AE reporting 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
Xh 
X 
X 
X 
X 
X 
X 
X 
Dispense Study 
Drugj 
 
X 
 
 
X 
 
 
X 
 
Collect study 
drug and assess 
compliance 
 
 
 
 
X 
 
 
X 
X 
An arrow (               )   indicates that the assessment is continuous. 
a  Following Part 1, subjects may receive Xyrem treatment in Part 2 for up to an additional 2 years or until they reach 18 years of age or until up to 3 months after 
the US FDA decision on the addition of pediatric data to the Xyrem US prescribing information (PI), whichever occurs first. 
b  All subjects will provide their written informed consent prior to the performance of any study-related procedures. The Part 2 Screening Visit (Visit 17) starts 
when a subject is registered for Part 2 in IRT. 
c  Subjects who re-enroll within 2 weeks after completing Visit 15 in Part 1 of the study do not require clinical labs, urine drug screen, alcohol test, or serum 
pregnancy test at the Part 2 Screening visit. For these subjects, Visit 18 may occur on the same day as Visit 17. 
d  Visit 18 is within 2 weeks after Visit 17. If needed, additional screening time may be granted with permission of the Medical Monitor.  
CONFIDENTIAL
Page 169 of 176

Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
Xyrem® (sodium oxybate) oral solution 
 
Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
 
CONFIDENTIAL 
Page 152 of 158 
e  Subjects must meet the inclusion and exclusion criteria for re-enrollment in Part 2 specified in Sections 4.2 and 4.3 of the protocol. 
f  Review the subject’s previously recorded medical history and update any new medical history information. Record any new medical history that occurs after 
Visit 16 and prior to re-enrollment. Any new clinically significant condition with onset after the last Part 1 visit (Visit 16) until assent/consent is provided in 
Part 2 should be recorded as medical history. 
g  For subjects turning 18 years of age, the Part 2 Study Termination visit must be scheduled prior to the subject’s 18th birthday. 
h Assessment only completed for Visit 17 if Visit 17 and Visit 18 are conducted on the same day. 
i Obtain vital signs (blood pressure, pulse/heart rate, body temperature, respiratory rate) after the subject has been resting for ≥5 minutes. 
j Study drug dispensed at study visits in accordance with protocol and as required by State or local regulation 
 
 
 
 
 
 
CONFIDENTIAL
Page 170 of 176

Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
Xyrem® (sodium oxybate) oral solution 
 
Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
 
CONFIDENTIAL 
Page 153 of 158 
 
Appendix 24 
Part 2–Open-Label Continuation–Subjects Re-enrolling After Completing Part 1 and Require 
Titration 
 
 
Open-Label Continuationa Visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
Events 
Part 2 
Screening 
Visit 17b,c 
Onsite 
 
Part 2 
 
Open-Label Titration 
Weeks T1-T10 
-- 
-- 
Month 3 
Visit 21 
Month 4 
Visit 22 
Month 5 
Visit 23 
Month 6 
Visit 24 
 
Part 2 
Study 
Term 
Part 2 
Early 
Term 
Visit 42 
(±7 days) 
Onsite 
Month 7 
Visit 25 
Month 8 
Visit 26 
Month 9 
Visit 27 
Month 
10 Visit 
28 
Month 
11 Visit 
29 
Month 
12 Visit 
30 
Month 
13 
Visit 31 
Month 
14 
Visit 32 
Month 
15 
Visit 33 
Month 
16 
Visit 34 
Month 
17 
Visit 35 
Month 
18 
Visit 36 
Month 
19 
Visit 37 
Month 
20 
Visit 38 
Month 
21 
Visit 39 
Month 
22 
Visit 40 
Month 
23 
Visit 41 (±7 days) 
Onsite 
Onsite 
Phone Call 
+3 days 
(±7 days) 
Phone 
call 
(±7 days) 
Phone 
call 
(±7 days) 
Onsite 
(±7 days) 
Phone 
call 
(±7 days) 
Phone 
call 
 
 
W T1c,d 
Visit 18 
Begin 
titration 
W T2 
Visit 
18.1 
W T3 
Visit 
18.2 
Mon 1/
W T4 
Visit 
19 
W T7 
Visit 
19.1 
Mon 2/
W T8 
Visit 
20 
W T10 
Visit 
20.1 
 
 
 
 
 
 
 
Informed 
Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maintain 
monthly 
schedule 
for Months 
1 through 
23 until the 
subject 
reaches age 
18 yearsg 
or within 
3 months 
 
Inclusion/ 
Exclusion 
Criteriae 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Update parent/ 
guardian 
contact 
information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
Historyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
Page 171 of 176

Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
Xyrem® (sodium oxybate) oral solution 
 
Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
 
CONFIDENTIAL 
Page 154 of 158 
Appendix 24 
Part 2–Open-Label Continuation–Subjects Re-enrolling After Completing Part 1 and Require 
Titration 
 
 
Open-Label Continuationa Visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
Events 
Part 2 
Screening 
Visit 17b,c 
Onsite 
 
Part 2 
 
Open-Label Titration 
Weeks T1-T10 
-- 
-- 
Month 3 
Visit 21 
Month 4 
Visit 22 
Month 5 
Visit 23 
Month 6 
Visit 24 
 
Part 2 
Study 
Term 
Part 2 
Early 
Term 
Visit 42 
(±7 days) 
Onsite 
Month 7 
Visit 25 
Month 8 
Visit 26 
Month 9 
Visit 27 
Month 
10 Visit 
28 
Month 
11 Visit 
29 
Month 
12 Visit 
30 
Month 
13 
Visit 31 
Month 
14 
Visit 32 
Month 
15 
Visit 33 
Month 
16 
Visit 34 
Month 
17 
Visit 35 
Month 
18 
Visit 36 
Month 
19 
Visit 37 
Month 
20 
Visit 38 
Month 
21 
Visit 39 
Month 
22 
Visit 40 
Month 
23 
Visit 41 (±7 days) 
Onsite 
Onsite 
Phone Call 
+3 days 
(±7 days) 
Phone 
call 
(±7 days) 
Phone 
call 
(±7 days) 
Onsite 
(±7 days) 
Phone 
call 
(±7 days) 
Phone 
call 
 
 
W T1c,d 
Visit 18 
Begin 
titration 
W T2 
Visit 
18.1 
W T3 
Visit 
18.2 
Mon 1/
W T4 
Visit 
19 
W T7 
Visit 
19.1 
Mon 2/
W T8 
Visit 
20 
W T10 
Visit 
20.1 
 
 
 
 
 
 
 
Physical 
Examination 
including a 
brief 
neurological 
exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
after the 
US FDA 
decision on 
the 
addition of 
pediatric 
data to the 
Xyrem US 
PI, 
whichever 
occurs 
first. 
 
Height 
X 
Xh 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Weight 
X 
Xh 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Chemistry, 
Hematology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug 
Screen  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
CONFIDENTIAL
Page 172 of 176

Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
Xyrem® (sodium oxybate) oral solution 
 
Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
 
CONFIDENTIAL 
Page 155 of 158 
Appendix 24 
Part 2–Open-Label Continuation–Subjects Re-enrolling After Completing Part 1 and Require 
Titration 
 
 
Open-Label Continuationa Visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
Events 
Part 2 
Screening 
Visit 17b,c 
Onsite 
 
Part 2 
 
Open-Label Titration 
Weeks T1-T10 
-- 
-- 
Month 3 
Visit 21 
Month 4 
Visit 22 
Month 5 
Visit 23 
Month 6 
Visit 24 
 
Part 2 
Study 
Term 
Part 2 
Early 
Term 
Visit 42 
(±7 days) 
Onsite 
Month 7 
Visit 25 
Month 8 
Visit 26 
Month 9 
Visit 27 
Month 
10 Visit 
28 
Month 
11 Visit 
29 
Month 
12 Visit 
30 
Month 
13 
Visit 31 
Month 
14 
Visit 32 
Month 
15 
Visit 33 
Month 
16 
Visit 34 
Month 
17 
Visit 35 
Month 
18 
Visit 36 
Month 
19 
Visit 37 
Month 
20 
Visit 38 
Month 
21 
Visit 39 
Month 
22 
Visit 40 
Month 
23 
Visit 41 (±7 days) 
Onsite 
Onsite 
Phone Call 
+3 days 
(±7 days) 
Phone 
call 
(±7 days) 
Phone 
call 
(±7 days) 
Onsite 
(±7 days) 
Phone 
call 
(±7 days) 
Phone 
call 
 
 
W T1c,d 
Visit 18 
Begin 
titration 
W T2 
Visit 
18.1 
W T3 
Visit 
18.2 
Mon 1/
W T4 
Visit 
19 
W T7 
Visit 
19.1 
Mon 2/
W T8 
Visit 
20 
W T10 
Visit 
20.1 
 
 
 
 
 
 
 
Alcohol Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Serum 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine 
Pregnancy test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Vital Signsi 
X 
Xh 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Determine if 
additional dose 
titration is 
necessary 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
AE reporting 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
Page 173 of 176

Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
Xyrem® (sodium oxybate) oral solution 
 
Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
 
CONFIDENTIAL 
Page 156 of 158 
Appendix 24 
Part 2–Open-Label Continuation–Subjects Re-enrolling After Completing Part 1 and Require 
Titration 
 
 
Open-Label Continuationa Visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
Events 
Part 2 
Screening 
Visit 17b,c 
Onsite 
 
Part 2 
 
Open-Label Titration 
Weeks T1-T10 
-- 
-- 
Month 3 
Visit 21 
Month 4 
Visit 22 
Month 5 
Visit 23 
Month 6 
Visit 24 
 
Part 2 
Study 
Term 
Part 2 
Early 
Term 
Visit 42 
(±7 days) 
Onsite 
Month 7 
Visit 25 
Month 8 
Visit 26 
Month 9 
Visit 27 
Month 
10 Visit 
28 
Month 
11 Visit 
29 
Month 
12 Visit 
30 
Month 
13 
Visit 31 
Month 
14 
Visit 32 
Month 
15 
Visit 33 
Month 
16 
Visit 34 
Month 
17 
Visit 35 
Month 
18 
Visit 36 
Month 
19 
Visit 37 
Month 
20 
Visit 38 
Month 
21 
Visit 39 
Month 
22 
Visit 40 
Month 
23 
Visit 41 (±7 days) 
Onsite 
Onsite 
Phone Call 
+3 days 
(±7 days) 
Phone 
call 
(±7 days) 
Phone 
call 
(±7 days) 
Onsite 
(±7 days) 
Phone 
call 
(±7 days) 
Phone 
call 
 
 
W T1c,d 
Visit 18 
Begin 
titration 
W T2 
Visit 
18.1 
W T3 
Visit 
18.2 
Mon 1/
W T4 
Visit 
19 
W T7 
Visit 
19.1 
Mon 2/
W T8 
Visit 
20 
W T10 
Visit 
20.1 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Study 
Drugj 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Collect study 
drug and assess 
compliance 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
An arrow (               )   indicates that the assessment is continuous. 
a  Following Part 1, subjects may receive Xyrem treatment in Part 2 for up to an additional 2 years or until they reach 18 years of age or until up to 3 months after 
the US FDA decision on the addition of pediatric data to the Xyrem US prescribing information (PI), whichever occurs first. 
b  All subjects will provide their written informed consent prior to the performance of any study-related procedures. The Part 2 Screening Visit (Visit 17) starts 
when a subject is registered for Part 2 in IRT. 
c  Subjects who re-enroll within 2 weeks after completing Visit 15 in Part 1 of the study do not require clinical labs, urine drug screen, alcohol test, or serum 
pregnancy test at the Part 2 Screening visit. For these subjects, Visit 18 may occur on the same day as Visit 17. 
CONFIDENTIAL
Page 174 of 176

Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
Xyrem® (sodium oxybate) oral solution 
 
Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
 
CONFIDENTIAL 
Page 157 of 158 
d  Week T1 (Visit 18) Begin Titration is within 2 weeks after Visit 17. If needed, additional screening time may be granted with permission of the Medical 
Monitor. 
e  Subjects must meet the inclusion and exclusion criteria for re-enrollment specified in Sections 4.2 and 4.3 of the protocol. 
f  Review the subject’s previously recorded medical history and update any new medical history information. Record any new medical history that occurs after 
Visit 16 and prior to re-enrollment. Any new clinically significant condition with onset after the last Part 1 visit (Visit 16) until assent/consent is provided in 
Part 2 should be recorded as medical history. 
g  For subjects turning 18 years of age, the Part 2 Study Termination visit must be scheduled prior to the subject’s 18th birthday. 
h  Assessment only completed for Visit 17 if Visit 17 and Visit 18 are conducted on the same day. 
i  Obtain vital signs (blood pressure, pulse/heart rate, body temperature, respiratory rate) after the subject has been resting for ≥5 minutes. 
j  Study drug dispensed at study visits in accordance with protocol and as required by State or local regulation. 
 
 
 
 
 
 
CONFIDENTIAL
Page 175 of 176

Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
 
Signature Date:
JP: Protocol 13-005 Amendment 5.pdf
Xyrem® (sodium oxybate) oral solution 
 
Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
Page 158 of 158 
 
Appendix 25 
Signatures of Agreement for Protocol 
Study Title: 
A Double-Blind, Placebo-Controlled, Randomized-Withdrawal, 
Multicenter Study of the Efficacy and Safety of Xyrem with an 
Open-Label Pharmacokinetic Evaluation and Safety Extension in 
Pediatric Subjects with Narcolepsy with Cataplexy 
Study Number: 
13-005 
Original Protocol: 
14 April 2014 
Amendment 1: 
29 August 2014 
Amendment 2: 
1 April 2015 
Amendment 3: 
05 August 2015 
Amendment 4 
05 April 2016 
Amendment 5 
23 February 2017 
This clinical study protocol was subject to critical review and has been approved by Jazz 
Pharmaceuticals. The following personnel contributed to writing and/or approving this 
protocol: 
Signed:  {Please see appended electronic signature page}  
Date: 
  
 
Signed:  {Please see appended electronic signature page}  
Date: 
  
 
 
Signed:  {Please see appended electronic signature page}  
Date: 
  
 
  
 
 
CONFIDENTIAL
Page 176 of 176

Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
 
 
 
 
Signature Manifestation