Clinical trial NCT02221869
Conditions: Narcolepsy With Cataplexy
Sponsor: Jazz Pharmaceuticals
Start date: 2014-10-01; Completion date: 2019-01-25
Enrollment: 106 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this trial is to assess the efficacy and safety of Xyrem in pediatrics subjects with narcolepsy that includes cataplexy.

Detailed description:

Arms: arm 1: Active Xyrem at a dose ≤9 g/night arm 2: Xyrem placebo at a volume and regimen equivalent to the stable dose of Xyrem.
Interventions: intervention 1: Xyrem
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
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 1 of 158 
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unpublished information contained herein will be published or disclosed without first obtaining written approval 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. 
 
CONFIDENTIAL
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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 2 of 158 
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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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 3 of 158 
(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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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 4 of 158 
• 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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Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
 
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Xyrem® (sodium oxybate) oral solution 
 
Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
Page 5 of 158 
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 
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Signature Date: 20170309
JP: Protocol 13-005 Amendment 5.pdf
 
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Xyrem® (sodium oxybate) oral solution 
 
Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
Page 6 of 158 
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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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 7 of 158 
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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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 8 of 158 
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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Signature Date: 20170309
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Xyrem® (sodium oxybate) oral solution 
 
Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
Page 9 of 158 
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 


Signature Date: 20170309
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
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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. 
CONFIDENTIAL
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CONFIDENTIAL 
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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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CONFIDENTIAL 
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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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CONFIDENTIAL 
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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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Clinical Study Protocol: 13-005 Amendment 5 
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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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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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 
 
 
 
 
 
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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 
 
 
 
 
 
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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. 
Aran A, Einen M, Lin L, Plazzi G, Nishino S, Mignot E. Clinical and therapeutic aspects of 
childhood narcolepsy–cataplexy: a retrospective study of 51 children. SLEEP 2010; 
33(11):1457–1464. 
Broughton R, Ghanem Q, Hishikawa Y, Sugita Y, Nevsimalova S, Roth B. Life effects of 
narcolepsy in 180 patients from North America, Asia and Europe compared to matched 
controls. Le Journal Canadien des Sciences Neurologiques 1981; 8:299-304. 
Dauvilliers Y, Montplaisir J, Molinari N, Carlander B, Ondze B, Besset A, Billiard M. Age at 
onset of narcolepsy in two large populations of patients in France and Quebec. Neurol 2001; 
57:2029-2033. 
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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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.  
Provigil® (modafinil) Tablets, US prescribing information (October 2010) Cephalon, Inc., 
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 
 
 
 
 
 
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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. 
Tanner JM. Development of reproductive system. In: Growth at Adolescence, ed 2, Oxford, 
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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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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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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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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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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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 
 
CONFIDENTIAL
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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 
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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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 
 
 
 
 
 
CONFIDENTIAL 
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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
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) 
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
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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
 
 
 
 
 
 
 
 
 
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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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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Signature Date:
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Xyrem® (sodium oxybate) oral solution 
 
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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Signature Date: 20170309
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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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Jazz Pharmaceuticals 
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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Signature Date: 20170309
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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 
 
 
 
 
 
CONFIDENTIAL 
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Enter the total number of times you had 
cataplexy today: 
 
_________  time(s) 
 
 
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Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
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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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Signature Date: 20170309
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Signature Date:
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Xyrem® (sodium oxybate) oral solution 
 
Jazz Pharmaceuticals 
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” 
 
 
 
CONFIDENTIAL
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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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Signature Date: 20170309
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Signature Date:
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Xyrem® (sodium oxybate) oral solution 
 
Jazz Pharmaceuticals 
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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Signature Date:
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Xyrem® (sodium oxybate) oral solution 
 
Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
Page 141 of 158 
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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Signature Date: 20170309
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Jazz Pharmaceuticals 
Clinical Study Protocol: 13-005 Amendment 5 
 
 
 
 
 
CONFIDENTIAL 
Page 142 of 158 
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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Signature Date: 20170309
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Signature Date:
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Xyrem® (sodium oxybate) oral solution 
 
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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  
 
 
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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 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
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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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan 
 
03.007A.01     
  
 
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Sponsor Name: 
Jazz Pharmaceuticals 
Protocol Number and 
Title: 
 
13-005: 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 
Protocol Version and Date: Original Protocol: 14-April-2014 
Amendment 1: 29-August-2014 
Amendment 2: 01-April-2015 
Amendment 3: 05-August-2015 
Amendment 4: 05-April-2016 
Amendment 5: 23-February-2017 
SAP Version: 
 4.0 
SAP Version Date:  
19-Jan-2018 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Jazz Pharmaceuticals. 
Acceptance of this document constitutes agreement by the recipient that no information 
contained herein will be published or disclosed without prior written authorization from an 
official of Jazz Pharmaceuticals. However, this document may be disclosed to appropriate 
Institutional Review Board and Ethics Committees or duly authorized representatives of a 
national regulatory authority under the condition that they are requested to keep it confidential. 
In the event of an actual or suspected breach of this obligation, 
 should be notified 
promptly. 
 
 


 
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Version: 
4.0 
Version Date: 
19-Jan-2018 
 
I confirm that I have reviewed this document and agree with the content. 
 
APPROVALS 
 
 
  
  
 
  
 
 Date (dd-Mmm-yyyy) 
 
  
 
Date (dd-Mmm-yyyy) 
Jazz Pharmaceuticals  
 
  
 
 
  
 
 Date (dd-Mmm-yyyy) 
 
  
 
  
  
 
 Date (dd-Mmm-yyyy) 
 
  
 
  
  
 
 Date (dd-Mmm-yyyy) 
 


 
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TABLE OF CONTENTS 
1. 
GLOSSARY OF ABBREVIATIONS ................................................................ 8 
2. 
PURPOSE ..................................................................................................... 12 
2.1. 
Amendment Updates ......................................................................................................... 13 
2.2. 
Responsibilities ................................................................................................................. 16 
2.3. 
Timings of Analyses .......................................................................................................... 17 
3. 
STUDY OBJECTIVES ................................................................................... 18 
3.1. 
Primary Objectives ............................................................................................................ 18 
3.2. 
Secondary Objective(s) ..................................................................................................... 18 
3.3. 
Brief Description ................................................................................................................ 18 
3.4. 
Subject Selection ............................................................................................................... 22 
3.4.1. 
Inclusion Criteria .............................................................................................................. 22 
3.4.2. 
Exclusion Criteria ............................................................................................................. 22 
3.5. 
Determination of Sample Size .......................................................................................... 23 
3.6. 
Treatment Assignment & Blinding ................................................................................... 24 
3.7. 
Administration of Study Medication ................................................................................ 24 
3.8. 
Study Procedures and Flowchart ..................................................................................... 26 
4. 
ENDPOINTS .................................................................................................. 30 
4.1. 
Primary Efficacy Endpoint ................................................................................................ 30 
4.2. 
Secondary Efficacy Endpoints ......................................................................................... 30 
4.2.1. 
Key Secondary Efficacy Endpoints ................................................................................. 30 
4.2.2. 
Other Secondary Efficacy Endpoints ............................................................................... 30 
4.3. 
Exploratory Efficacy Endpoints ....................................................................................... 30 
4.4. 
Pharmacokinetic Endpoints ............................................................................................. 30 


 
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4.5. 
Safety Endpoints ................................................................................................................ 31 
4.6. 
Other Safety Exploratory Endpoints ................................................................................ 32 
5. 
STATISTICAL HYPOTHESES FOR TRIAL OBJECTIVES .......................... 33 
6. 
ANALYSIS POPULATIONS .......................................................................... 35 
6.1. 
Safety Population ............................................................................................................... 35 
6.2. 
Randomized Population .................................................................................................... 36 
6.3. 
PK Half-Dose Population .................................................................................................. 36 
6.4. 
PK Full-Dose Population ................................................................................................... 36 
6.5. 
PK Completer Population ................................................................................................. 36 
6.6. 
Efficacy Population ............................................................................................................ 36 
6.7. 
Per Protocol Population .................................................................................................... 36 
6.8. 
Continued Access Population .......................................................................................... 37 
6.9. 
Protocol Deviations ........................................................................................................... 37 
7. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ................................ 38 
7.1. 
General Methods ................................................................................................................ 38 
7.2. 
Key Definitions ................................................................................................................... 43 
7.3. 
Missing Data ....................................................................................................................... 49 
7.4. 
Visit Windows for Early Termination ............................................................................... 51 
7.5. 
Pooling of Centers ............................................................................................................. 52 
7.6. 
Subgroups .......................................................................................................................... 52 
8. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS, AND 
MEDICATION ....................................................................................................... 53 


 
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8.1. 
Subject Disposition and Withdrawals .............................................................................. 53 
8.2. 
Demographic and Other Baseline Disease Characteristics .......................................... 54 
8.3. 
Medical / Surgical History ................................................................................................. 55 
8.4. 
Medications ........................................................................................................................ 56 
8.5. 
Procedures ......................................................................................................................... 57 
9. 
EFFICACY ..................................................................................................... 58 
9.1. 
Primary Efficacy Endpoint and Analysis ......................................................................... 59 
9.1.1. 
Calculation of Weekly Number of Cataplexy Attacks ...................................................... 59 
9.1.2. 
Primary Efficacy Endpoint Analyses ................................................................................ 61 
9.2. 
Secondary Efficacy Endpoint(s) and Analyses .............................................................. 64 
9.2.1. 
Clinical Global Impression of Change (CGIc) for Cataplexy Severity ............................. 64 
9.2.2. 
Epworth Sleepiness Scale for Children and Adolescents (ESS [CHAD]) ....................... 65 
9.2.3. 
Clinical Global Impression of Change (CGIc) for Narcolepsy Overall ............................. 66 
9.2.4. 
Quality of Life (QoL) (SF-10) ........................................................................................... 66 
9.3. 
Exploratory Efficacy Endpoint(s) and Analyses ............................................................. 72 
9.3.1. 
Weekly School Attendance.............................................................................................. 72 
9.3.2. 
PGIc for Narcolepsy Overall ............................................................................................ 73 
10. 
ANALYSIS OF PHARMACOKINETICS .................................................... 74 
10.1. 
Sodium Oxybate Concentration Data .............................................................................. 74 
10.2. 
Area under the Plasma Time Concentration Curve 0-4 hours (AUC0-4) ........................ 75 
10.3. 
Maximum Plasma Drug Concentration (Cmax) ................................................................. 76 
10.4. 
Plasma Drug Concentration at 8 Hours (C8hours) ............................................................. 77 
10.5. 
Time to Maximum Plasma Concentration (Tmax) .......................................................... 77 
10.6. 
Area under the Plasma Time Concentration Curve (0-Infinity) and Half Life (T1/2) ..... 77 
11. 
SAFETY ..................................................................................................... 78 
11.1. 
Extent of Exposure ............................................................................................................ 78 


 
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11.2. 
Treatment Compliance ...................................................................................................... 80 
11.3. 
Adverse Events .................................................................................................................. 81 
11.3.1. 
Additional AE Analyses ............................................................................................... 84 
11.4. 
Laboratory Evaluations ..................................................................................................... 84 
11.5. 
Vital Signs / Oxygen Saturation, End Tidal CO2 / Transcutaneous CO2 ....................... 86 
11.6. 
Physical Stature ................................................................................................................. 87 
11.7. 
ECG ..................................................................................................................................... 88 
11.8. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ........................................................ 89 
11.9. 
Polysomnograpy (PSG) ..................................................................................................... 90 
11.10. 
MASC-10 ......................................................................................................................... 93 
11.11. 
CDI 2: SR[S] ................................................................................................................... 96 
11.12. 
Tanner Stage .................................................................................................................. 99 
11.13. 
Physical Examination .................................................................................................... 99 
12. 
INTERIM ANALYSES .............................................................................. 100 
13. 
DSMB ....................................................................................................... 101 
14. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ....................... 102 
15. 
REFERENCE LIST .................................................................................. 103 
16. 
PROGRAMMING CONSIDERATIONS .................................................... 104 
16.1. 
General Considerations .................................................................................................. 104 
16.2. 
Table, Listing, and Figure Format .................................................................................. 104 
16.2.1. 
General ...................................................................................................................... 104 
16.2.2. 
Headers and Footers ................................................................................................ 105 
16.2.3. 
Display Titles ............................................................................................................. 105 
16.2.4. 
Column Headers ....................................................................................................... 105 
16.2.5. 
Body of the Data Display ........................................................................................... 106 


 
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17. 
QUALITY CONTROL ............................................................................... 110 
18. 
INDEX OF TABLES ................................................................................. 111 
19. 
INDEX OF FIGURES ............................................................................... 112 
20. 
INDEX OF LISTINGS ............................................................................... 113 
21. 
MOCK-UPS .............................................................................................. 114 
21.1. 
Table Mock-Ups ............................................................................................................... 114 
21.2. 
Figure Mock-Ups .............................................................................................................. 114 
21.3. 
Listing Mock-Ups ............................................................................................................. 114 
22. 
APPENDICES .......................................................................................... 115 
 
 


 
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1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
A 
Number of Apnea with onset during Total Sleep Time 
ADaM 
Analysis Data Model 
AE 
Adverse Event  
AHI  
Apnea +  Hypopnea Index 
AI 
Apnea Index  
ALT 
Alanine aminotransferase (SGPT) 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate aminotransferase (SGOT) 
ATC 
Anatomical Therapeutic Chemical Classification System 
AUC 
Area under the plasma concentration time curve 
BLQ 
Below Limit of Quantification 
CA 
Number of Central Apnea with onset during Total Sleep Time  
CDI 2:SR[S]  
Children’s Depression Inventory 2nd Edition Self-Report Short 
Version 
CDISC 
Clinical Data Interchange Standards Consortium 
CGIc 
Clinical Global Impression of Change  
CHQ 
Child Health Questionnaire 
CI 
Central Apnea Index  
Cmax 
Maximum Plasma Drug Concentration  
CMH 
Cochran-Mantel-Haenszel 
CNS 
Central nervous system 
CO2 
Carbon Dioxide 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DB 
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Abbreviation 
Description 
DBP 
Diastolic Blood Pressure  
DSMB  
Data and Safety Monitoring Board  
DT 
Dose Titration 
ECG 
Electrocardiogram  
eCRF 
Electronic Case Report Form 
EDS 
Excessive Daytime Sleepiness 
ESS [CHAD]  
Epworth Sleepiness Scale for Children and Adolescents  
ET 
Early Termination 
EtCO2 
End tidal CO2 
FDA 
Food and Drug Administration 
g 
gram 
GHB 
Gamma-hydroxybutyrate 
H 
Number of Hypopnea with onset during Total Sleep Time 
IEC 
Institutional Ethics Committee 
IQR 
Interquartile Range  
IRB 
Institutional Review Board  
IWRS  
Interactive Web Response System 
kg 
Kilogram 
MASC-10 
Multidimensional Anxiety Scale for Children 10 item Anxiety 
Index 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
milliliter 
OA 
Obstructive Apnea 
OHI 
Obstructive Apnea + Hypopnea Index 
OI 
Obstructive Index  
OL 
Open-Label 


 
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Abbreviation 
Description 
PD 
Pharmacodynamics  
PGIc 
Patient Global Impression of Change  
PHS 
Physical Summary Score 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PR 
Interval from the beginning of the P wave to the beginning of 
the QRS complex on ECG 
PSG 
Polysomnography  
PSS  
Psychosocial Summary Score 
PT 
Preferred Term  
Q1 
1st Quartile 
Q3 
3rd Quartile 
QoL 
Quality of Life  
QT 
Interval between the start of the Q wave and the end of the T 
wave on ECG 
QTcB 
QT Interval corrected (Bazett's correction) 
REM 
Rapid Eye Movement  
REML 
REM latency 
RR 
Interval between an R wave and the next R wave on ECG 
S.I. 
Standardized International 
SAE 
Serious Adverse Event  
SaO2/Sp02 
Blood oxygen saturation 
SAP 
Statistical Analysis Plan  
SBP 
Systolic Blood Pressure 
SD 
Stable-Dose 
SDTM 
Study Data Tabulation Model 
SF-10 
SF-10 for Children 
SOC 
System Organ Class  


 
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Abbreviation 
Description 
SOL 
Sleep Onset latency 
SOP 
Standard Operating Procedure 
STDEVD 
Standard Deviation 
TcCO2 
Transcutaneous CO2 
TEAE 
Treatment-Emergent Adverse Events 
Tmax  
Time to Maximum Plasma Drug Concentration  
ULN 
Upper Limit of Normal 
USA 
United States of America  
WASO 
Wake after persistent sleep  
WHO 
World Health Organization 
 


 
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2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, 
summary tables and figures which will be produced, and the statistical methodologies 
that will be used, are complete and appropriate to allow valid conclusions regarding the 
study objectives. 
The purpose of this third amendment to the signed SAP, dated 19-Jan-2018, is to 
account for the planned analyses of the Part 2 data collected according to the 
Amendment 5 of the protocol document dated 23-Feb-2017.  The Amendment 5 added 
an Open-Label (OL) Continuation Period, where subjects could continue to receive open 
label Xyrem. This amendment also describes additional safety analyses that were 
performed post-hoc for the clinical study report (CSR), dated 31-Aug-2017, which 
included the primary analysis of efficacy, PK, and safety data through 10-Feb-2017.  
These post-hoc analyses will also be performed at the end of the study; therefore they 
are included in this SAP as pre-planned analyses for the final CSR.    
The purpose of this second amendment to the signed SAP, dated 05-Oct-2016, is to 
clarify that unblinding of the data will occur after the database snapshot for the 
primary analysis, which occurs after all randomized subjects discontinue or complete 
the Double-Blind (DB) period.   
The purpose of the first amendment to the original, signed SAP, dated 17-Nov-2015, was 
to account for the changes in the study design instituted with the implementation of 
Amendment 4 of the protocol. Additional efficacy analyses were added to assess the 
robustness of study results. Supplemental safety analyses were added to further assess 
the safety profile.   
The protocol was amended as a result of a pre-planned interim analysis which was 
conducted on the primary efficacy endpoint after 35 subjects completed or 
discontinued early from the study’s double-blind treatment period. Data were reviewed 
by the study’s independent Data and Safety Monitoring Board (DSMB), which 
recommended to “terminate the double-blind segment of the protocol as there are 
adequate data for deriving an inference of benefit in cataplexy” since a p-value <0.005 
was achieved, showing a benefit in the response of cataplexy with Xyrem compared to 
placebo in the 35-subject data set. Given the primary efficacy endpoint has been 
reached based on the interim analysis, the protocol was amended to follow the DSMB 
recommendation to terminate the placebo treatment during the double-blind segment 
of the protocol to minimize the exposure of pediatric subjects to placebo.  They also 
recommended to continue the Open-Label safety segment, and to continue enrollment 
of subjects in the Open-Label PK evaluation.  


 
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2.1. 
AMENDMENT UPDATES  
To account for the Part 2 Open Label extension, the following sections in the SAP 
Version 4 (Amendment 3) were updated:  
• 
Timing of the final analyses  
• 
The statement of the primary objective was updated to match the protocol. 
• 
The brief description section was updated to summarize the Part 1 portion as 
past tense and the Part 2 as future tense.  All Part 1 analyses were pre-specified 
in the earlier amendment signed prior to the study unblinding.  
• 
The Administration of Study Medication and the Study Procedures and Flowchart 
The Continued Access Analysis Population, for summaries of Part 2, was added. 
• 
Summary of Deviations at the completion of Part 2 was added. 
• 
The rules for summarizations of OL Continuation Period were added. 
• 
The windowing rules for unscheduled visits in Part 2 were added. 
• 
Rules for categorization of adverse events, concomitant procedures, and 
concomitant medications were provided. 
• 
Key definition section has calculation of the change from the Start of Part 2 Visit 
included. 
• 
The mapping rules for ET Visits in Part 2 were added. 
• 
Summarizations of disposition, demographics, and baseline characteristics were 
added for Part 2. 
• 
Medical / Surgical History section was updated to discuss addition terms for Part 
2 subjects who were re-enrolled in Part 2 after completion of Part 1. 
• 
Concomitant medication summarization was added for Part 2. 
• 
Summaries and derivation of Xyrem Exposure for Part 2 and for combined Part 1 
and Part 2 were added. 
• 
Summaries and derivation of bottle weight compliance for Part 2 were added. 


 
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• 
Part 2 summaries of adverse events were added . Combined Part 1 and Part 2 
summaries of adverse events were added. 
• 
Modifications to the Laboratory evaluations section to provide a clarification in 
Part 1 and discuss collections during Part 2. 
• 
Modifications to the Vital Signs section to discuss summarizations in Part 2. 
• 
Modifications to the Physical Stature section to discuss summarizations in Part 2. 
• 
Safety figures including Part 2 data will include Part 1 Day 1 baseline, Part 2 Day 
1 baseline, and Part 2 visits. 
For further understanding the safety profile of Xyrem, post-hoc analyses were 
performed and included in the CSR dated, 31-Aug-2017. These analyses will also be 
performed for the final CSR and are considered pre-planned. To account for these 
analyses, the following sections were updated:  
• 
Summarization of Flavorant usage across the study 
• 
The extent of Xyrem exposure was summarized by exposure days across the 
study at the maximum total nightly dose based on weight per protocol dosing 
guideline. 
• 
Supplemental AE tables were created to concisely summarize results across 
part 1 and the study (Part 1 and Part 2). 
• 
Additional summaries of adverse event by most recent mg/kg categories 
(<96.49, 96.49-127.59, and >127.59) were added. 
• 
Safety figures (physical stature, CDI 2, and MASC-10) were updated to present  
the standard error  for the mean, the number of observations available per 
time point, and include subgroups in the same plot. 
The following are the key updates to the SAP Version 3 (Amendment 2) document. 
A potential interim analysis after all randomized subjects completed the double-blind 
portion of the study was specified in SAP Version 2.  This interim analysis is clarified as 
the primary analysis to be performed after all randomized subjects discontinue or 
complete the DB period of the study and after formal database snapshot.  As the study 
is ongoing, the database will not be locked prior to the primary analysis. This will be 
considered the final analysis for the DB period of the study. 
 


 
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For this analysis, the lead 
 biostatistician and blinded programming team as well as 
the Jazz study team will be unblinded after the database snapshot. 
 
As the DSMB members were unmasked during the efficacy interim analysis, the 
treatment groups were made available for the safety reviews. Thus language specifying 
masked treatment groups after the efficacy interim analysis was removed. 
 
All deviations relevant for deriving the per protocol population will be defined prior to 
the database snapshot.  This has been clarified as unblinding occurs after the database 
snapshot. Also, given that this is an ongoing study, the final list of protocol deviations 
will be available at database lock, which occurs at the end of the study. 
 
Clarification of the sample code for Cochran-Mantel-Haenszel (CMH) test for Row Mean 
Scores Difference was updated to specify the “Table” option. 
In the pharmacokinetic endpoint section, the collection times for the plasma sodium 
oxybate concentrations over an 8-hour period on two PK nights are clarified (on both 
nights, samples will be collected pre-dose, 0.75, 1.5, 2.5 and 4 (pre-2nd dose), 4.75, and 
8 hours post first Xyrem dose on the PK night. This update is consistent with the 
language in section 10.1. 
Summaries of the safety population by period are not performed for demographic, 
baseline characteristic and medical/surgical history results; therefore the analysis 
population section was clarified. 
Details of the Bottle Weight Compliance calculation were corrected. The numerator and 
denominator represent the quantity taken determined by bottle and the amount to be 
taken based on the dosing log, respectively. 
Graphical presentations of safety endpoints are updated to display the actual value 
across dosing periods. The interpretation of raw values is clearer compared to the 
change value over time. 
The following are the key updates to the SAP Amendment 1 document. 
• 
Clarifications were made to the Safety Populations to address updates from 
Protocol Amendment 4 
• 
P-value for presentation of analysis of the primary endpoint has been changed to 
a nominally reported p-value since the analysis of this endpoint at the time of 
the interim analysis showed a p-value <0.005. 
• 
A per protocol population is defined and will be used for sensitivity analysis of 
the primary efficacy endpoint and secondary efficacy endpoints. 


 
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• 
A sensitivity analysis assessing the Tier 3 endpoint of ESS will be performed, 
including baseline use of stimulants in the model. 
• 
Efficacy endpoint analyses in the DB period will be performed separately for 
subjects randomized prior to the implementation of Amendment 4 and subjects 
who entered the DB Period after implementation of Amendment 4 and received 
Open-Label Xyrem. 
• 
Safety endpoint analyses in the DB Period will be summarized by subjects who 
received Xyrem or placebo prior to Amendment 4, subjects who received Open-
Label Xyrem after the implementation of Amendment 4, and by all subjects who 
received Xyrem. 
• 
Additional by-week summaries of the weekly cataplexy attacks will be provided 
for the Stable-Dose (SD) Period and the DB Period. 
• 
An additional calculation of compliance has been added, calculated as the ratio 
of expected quantity of drug taken (in mL) to the amount taken based on the 
(quantity dispensed - quantity returned). 
• 
Additional figures summarizing endpoints over all periods of the study have been 
added. 
• 
An interim analysis may be performed after all randomized subjects have 
completed the DB period.   
2.2. 
RESPONSIBILITIES 
 will perform the statistical analyses and are responsible for 
the production and quality control of all tables, figures and listings. 
 will provide an independent unblinded biostatistician who will produce 
masked/unblinded summaries for a Data and Safety Monitoring Board (DSMB). Contents 
of the materials to be produced will be defined in a DSMB charter. The methodology to 
be used for DSMB summaries will be defined within this SAP. 
Calculation of non-compartmental pharmacokinetic (PK) parameters and statistical 
analysis of PK parameters will be completed by 
, and reviewed by Jazz’s 
Clinical Pharmacologist. PK parameters determination will be required to be completed 
prior to each DSMB meeting, as the DSMB is charged with determining if adequate 
numbers of subjects have been recruited to adequately describe the pharmacokinetics 
of Xyrem in children and adolescents. 


 
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2.3. 
TIMINGS OF ANALYSES 
The primary analysis of safety, efficacy and pharmacokinetics will be performed after 
all randomized subjects discontinue or complete the DB period. For these analyses, a 
formal database snapshot including data per a cut-off date is planned. These analyses 
were completed using a data cut-off date of 10-Feb-2017. The DSMB will review safety 
data on an ongoing basis, with the frequency of reviews defined in the DSMB charter. As 
well, an interim analysis was conducted after 35 randomized subjects completed or 
discontinued early from the DB Period as described in section 9.1.2.2. 
The DSMB is responsible for an ongoing review of the PK data to determine if a 
sufficient number of subjects have data to adequately characterize the PK of Xyrem in 
children and adolescents. 
A final analysis presenting the results of the Part 1 Open-Label Period and Part 2 Open-
Label Continuation Period as well as combined summaries will be completed after 
database lock at the completion of the study. 


 
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3. 
STUDY OBJECTIVES 
3.1. 
PRIMARY OBJECTIVES 
The 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) 
3.2. 
SECONDARY OBJECTIVE(S) 
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 
3.3. 
BRIEF DESCRIPTION 
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 became effective, all subjects 
entering the Double-Blind Treatment Period received open-label Xyrem treatment. For 
administrative reasons, the term “Double-Blind Treatment Period” was continued to be 
used throughout the protocol. Following the Double-Blind Treatment Period (2 weeks), 
subjects enter an open-label extension period and  continue to receive Xyrem treatment 
for up to one year in Part 1. 
In addition, the PK of Xyrem was evaluated during Part 1 in a subset of subjects. 
 


 
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Children and adolescents, diagnosed with narcolepsy with cataplexy who were currently 
treated with Xyrem or are Xyrem naïve, with or without concomitant stable stimulant 
use, were eligible to enter the study. For this study, a Xyrem-naïve subject was defined 
as a subject who had 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 were screened 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]).  
Eligibility screening was 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 were eligible for the study, were required to be evaluated by 
polysomnography (PSG) for sleep-disordered breathing during Screening Period. 
Following Part 1 Screening, subjects who were Xyrem-naïve entered an Open-Label 
Titration Period. Xyrem therapy was initiated based on the subject’s weight. These 
subjects were titrated on Xyrem to achieve a maximum clinical benefit in cataplexy and 
EDS while maintaining tolerability. Once the Investigator was satisfied that the Xyrem 
dose has been optimized, the subject could enter the Open-Label Stable-Dose Period. 
Subjects must have achieved a state of cataplexy stability (frequency and severity) with 
no further dose adjustment needed at the end of the Titration Period (up to 10 weeks). 
Prior to Amendment 4, any subject who showed no reduction in cataplexy compared 
with study entry was withdrawn from the study. 
During Part 1, all subjects  entered a Stable-Dose treatment period of 2 or 3 weeks 
length. The last 2 weeks of that period was the baseline data collection period for 
efficacy parameters. On the last night of the Stable-Dose Period, Xyrem-naïve subjects 
were assessed by PSG while taking Xyrem (End of Stable-Dose/Pre-Randomization PSG 
Night). 
During Part 1, subjects were eligible to enter the Double-Blind Treatment Period if the 
dose of Xyrem remained 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 had occurred during the 
Stable-Dose Period, and the subject continued to meet eligibility criteria (prior to 
Amendment 4). 


 
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Prior to Amendment 4 of the protocol being effective, subjects were 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 was continued as a double-blind treatment at the Stable-
Dose taken in the prior 2 weeks 
2. Placebo: Xyrem placebo was 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 was 
effective,  received Open-Label Xyrem treatment during this period. 
During the Double-Blind Period, subjects remained on the same dosing regimen they 
used during the Stable-Dose Period, with the exception of PK nights (if applicable) when 
all subjects had to take two equally divided doses 4 hours apart. 
Subjects who completed the entire 2-week Double-Blind Treatment Period were eligible 
to continue in the long-term, Open-Label Xyrem safety evaluation. The Open-Label 
Safety Period allowed subjects to continue Xyrem treatment for up to one year. 
Subjects who were eligible to participate in the Open-Label Safety Period during Part 1 
participated 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). 
Subjects, who entered the Double-Blind Treatment Period before Amendment 4 was 
effective, 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 was 
higher, upon entering the Open-Label Safety Period.  
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. 


 
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Subjects were then titrated up to their optimal dose as tolerated according to the 
Investigator’s judgment (the maximum dose should not have exceeded the doses 
defined in Table 1 or the stable dose prior to study entry, whichever was higher, and 
should not have been greater than 9 g/night). 
At certain study sites, eligible subjects additionally participated in the PK evaluation. 
Prior to Amendment 4, PK assessments on PK Night 1 and PK Night 2 could occur during 
the Stable-Dose Period or during the Open-Label Safety Period as follows: 
Eligible subjects spent two nights in the clinic for the PK evaluation (PK Nights 1 and 2). 
• 
For subjects on Xyrem at study entry, PK Nights 1 and 2 occurred at the 
beginning of the Stable-Dose Period or during the Open-Label Safety Period after 
the subject has been retitrated and is on a stable dose of Xyrem. If a subject is 
participating in the PK evaluation during the Stable-Dose Period, PK Night 1 will 
occur at the beginning of the Stable-Dose Period and PK Night 2 will occur the 
next night (or within 15 days after PK Night 1). 
• 
For Xyrem-naïve subjects, PK Nights 1 and 2 will occur during the Open-Label 
Safety Period when the subject has been retitrated and is on a stable dose of 
Xyrem. 
 
After the implementation of Amendment 4, the PK assessments on PK night 1 and PK 
Night 2 could occur at any point from the Stable-Dose Period and onward, after the 
subject has reached a stable dose of Xyrem. Those subjects who were Xyrem Naive at 
entry or who were on Xyrem at Entry are eligible to participate. 
 
For all subjects participating in the PK assessments, on PK Night 1, subjects received 
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 
returned to the clinic for PK Night 2 and received Xyrem at their stable, usual dose 
(administered as two equally divided doses, given while in bed at bedtime and 4 hours 
later). 
 
Upon approval of Amendment 5, subjects who completed one year in the study (Part 1) 
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). 
 


 
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Subjects continuing directly from Part 1 to Part 2 will initiate Part 2 at the Visit 15 of 
the Part 1 study. The site will initiate monthly phone contacts with these subjects 
starting with Visit 19 and every three month onsite contacts starting at Visit 21.  
 
Subjects who have already completed Part 1 may re-enroll in Part 2.  They initiate a 
screening period starting with Visit 17.  The screening visit will occur within 2 weeks of 
the start of treatment in Part 2. If needed, additional screening time may be granted 
with the permission of the Medical Monitor.  
 
For Part 2, subjects who had been off Xyrem for ≥ 1 month are required to do a 
Titration Period. The Titration Period in Part 2 may last up to 10 weeks. For subjects 
who have been off Xyrem for less than 1 month, titration may be required per the 
Investigator’s judgment. Subjects requiring a Titration Period in Part 2 will be dispensed 
study drug at Visit 18, then the site has telephone calls with the subject at Visit 18.1 
(Week T2 - occurs 10 days from Visit 18), Visit 18.2 (Week T3 - occurs 20 days from Visit 
18),  Visit 19 (Week T4/Mon 1 - occurs 30 days  from Visit 18), Visit 19.1 (Week T7 - 
occurs 45 days from visit 18), Visit 20 (Week T8/Mon 2 - occurs 60 days from visit 18), 
and  Visit 20.1 (Week T10 - occurs 75 days  from visit 18).  Then these subjects continue 
with Visits 21 – Visit 42, where onsite visits are held every three months. Visit 21 is the 
first scheduled onsite visit after the Titration Period.  
 
Subjects who are re-enrolling in Part 2 and do not require Titration are dispensed study 
drug at Visit 18. The sites initiate monthly phone contacts with these subjects starting 
with Visit 19  and an onsite visit every 3 months starting at Visit 21.  
 
3.4. 
SUBJECT SELECTION 
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. 
3.4.1. 
Inclusion Criteria 
The inclusion criteria for the study are described completely in section 4.2 of the 
protocol. 
3.4.2. 
Exclusion Criteria 
The exclusion criteria for the study are described completely in section 4.3 of the 
protocol. 


 
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3.5. 
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 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. 


 
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3.6. 
TREATMENT ASSIGNMENT & BLINDING 
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 biostatistician 
 
specified a dynamic 
randomization algorithm to assign treatments for the DB Period of the trial. The 
randomization balanced 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 (USA and ex-USA). The age entered by the site at the time of 
the randomization call is used for the treatment balancing. If emergency unblinding is 
required, the DB treatment assignment will be provided to the Investigator by the IWRS. 
 
The lead 
 biostatistician and the blinded programming team remained 
blinded throughout the study conduct until all randomized subjects discontinued or 
completed the double-blind period and the formal database snapshot was performed.  
As well, the Jazz study team, with the exception of the Jazz clinical trial material 
supply group, remained blinded until the formal database snapshot. 
 
The unblinded 
 
 SDTM programmer and unblinded 
 
 
biostatistician  received the randomization lists from the Bracket biostatistician for 
incorporation into the summaries presented to the DSMB, for their periodic safety 
reviews and interim analysis. Meetings are scheduled according to the DSMB charter. 
See SAP section 7.1 for details of display of treatment groups for the DSMB summaries.  
 
For DSMB meetings, the unblinded 
 SDTM programmer and unblinded 
 
 biostatistician will provide analyses with masked treatment groups for DSMB 
members. The DSMB requested and was unblinded to the 35 randomized subjects 
according to the DSMB charter for the interim review of the primary efficacy endpoint 
for superiority, and futility. 
 
3.7. 
ADMINISTRATION OF STUDY MEDICATION 
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 SD 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 of 
Section 3.1.2 of the protocol document. Once the Investigator is satisfied that the 


 
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Xyrem dose has been optimized, the subject may enter the 2-week SD Period if in Part 1 
of the study or continue the Open-Label Continuation Period if in Part 2. 
Prior to Amendment 4 becoming effective, at the end of the SD Period subjects were 
randomized 1:1 to receive either Xyrem or Xyrem placebo during the DB Period as 
follows: 
• 
Xyrem: Active Xyrem will be continued as a DB 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 becomes 
effective will receive Open-Label Xyrem treatment during this period. 
Prior to Amendment 4 becoming effective, upon entering the OL Period of Part 1, all 
subjects were started at a dose no higher than half the Xyrem dose they received at the 
end of the SD Period or the initiation dose defined in Table 1 of the protocol (in Section 
3.1.2), whichever is higher. Subjects were then 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 of the protocol (in Section 3.1.2) or the stable dose 
prior to study entry, whichever is higher, and should not be greater than 9 g/night). 
Subjects took two equally divided doses or two unequally divided doses with the 
exception of PK nights, if applicable. Xyrem dose titration was allowed at no more than 
1.5 g/night. Only doses that match the printed gradations (lines) on the dosing syringe 
were permitted.  
 
After the Protocol Amendment 4 became effective during the Open-Label Period of Part 
1 or 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. Subjects can continue the Open-Label Xyrem treatment at the 
appropriate dose as deemed by the investigator. 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. 
 
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 


 
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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. 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 (or of flavored diluent if requested and available; however, no flavored 
diluent will be provided on PSG and/or PK nights). 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. 
 
3.8. 
STUDY PROCEDURES AND FLOWCHART 
The study flowchart below is reproduced from the study schema contained in Figure 1 of 
the protocol. This applies to subjects who entered prior to Amendment 4 becoming 
effective.  


 
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The study flowchart below is reproduced from the study schema contained in Figure 2 of 
the protocol. This applies to subjects who enter after Amendment 4 became effective.  
 
The schedule of evaluations to be performed at each visit in Part 1 is contained in 
Appendices 1 and 2 of the protocol. 
• 
Appendix 1.1 Part 1 Screening, Stable-Dose Period, Double-Blind Treatment 
Period,  Open-Label Treatment Period – Subjects on Xyrem at Study Entry 
• 
Appendix 1.2 PSG Night Procedures – Subjects on Xyrem at Study Entry 
• 
Appendix 2.1 Part1 Screening, Open-Label Titration Period, Stable-Dose Period, 
Double-Blind treatment Period– Xyrem-Naïve Subjects at Study Entry  
• 
Appendix 2.2 Part1 Open-Label Safety Period–Xyrem-Naïve Subjects at Study 
Entry 
• 
Appendix 2.3 PSG Night Procedures–Xyrem-Naïve Subjects at Study Entry. 


 
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• 
Appendix 3 PK Evaluation  Procedures–Subjects Participating in the PK 
Evaluation 
• 
The study flowchart below is reproduced from the study schema contained in 
Figure 3 of the protocol. This applies to the Part 2 period.  
 
The schedule of evaluations to be performed at each visit in Part 2 is contained in 
Appendices 22, 23, and 24 of the protocol. 
• 
Appendix 22 Part 2-Open-Label Continuation-Subjects Continuing Directly into 
Part2 from Part 1 
• 
Appendix 23 Part 2-Open-Label Continuation-Subjects Re-enrolling After 
Completing Part 1 and Do Not Require Titration  
• 
Appendix 24 Part 2-Open-Label Continuation-Subjects Re-enrolling After 
Completing Part 1 and Require Titration  
 


 
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4. 
ENDPOINTS 
4.1. 
PRIMARY EFFICACY ENDPOINT 
The primary efficacy endpoint is: 
• 
Change in the weekly number of cataplexy attacks  
4.2. 
SECONDARY EFFICACY ENDPOINTS 
4.2.1. 
Key Secondary Efficacy Endpoints  
The two key secondary efficacy endpoints are:  
• 
Clinical Global Impression of Change (CGIc) for cataplexy severity 
• 
Change in the Epworth Sleepiness Scale for Children and Adolescents (ESS 
[CHAD]) score 
4.2.2. 
Other Secondary Efficacy Endpoints  
The other two secondary efficacy endpoints are:  
• 
CGIc for narcolepsy overall 
• 
Change in Quality of Life (QoL) (SF-10) 
4.3. 
EXPLORATORY EFFICACY ENDPOINTS 
The two exploratory efficacy endpoints are:  
• 
Change in weekly school attendance (if enrollment overlaps with school 
attendance period) 
• 
PGIc for narcolepsy overall 
4.4. 
PHARMACOKINETIC ENDPOINTS 
Pharmacokinetic endpoints will include:  
• 
Plasma sodium oxybate concentrations over an 8-hour period on two PK nights 
(on both nights, samples will be collected pre-dose, 0.75, 1.5, 2.5 and 4 (pre-2nd 
dose), 4.75, and 8 hours post first Xyrem dose on the PK night) 


 
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• 
Area under the plasma concentration time curve over the first 4-hour post-dosing 
interval (AUC0-4) 
• 
Maximum plasma drug concentration (Cmax) over the first 4-hour post-dosing 
interval 
• 
AUC0-infinity using samples collected over the first 4-hour post dosing interval 
• 
T1/2  (Half-life) determined using samples over the first 4-hour post dosing 
interval 
• 
Time to maximum drug concentration (Tmax) over the first 4-hour post-dosing 
• 
Ratio of AUC0-4 on PK Night 2 to AUC0-4 on PK Night 1 
• 
Ratio of Cmax on PK Night 2 to Cmax on PK Night 1 
4.5. 
SAFETY ENDPOINTS  
Safety will be assessed at time points specified in the schedule of events, as well as 
throughout the study. Safety endpoints will evaluate the safety and tolerability as 
determined by the occurrence of and/or changes in: 
 
• 
Subject Incidence of Adverse events (AE)  
• 
Vital Signs  
• 
Physical examinations (including weight and height) 
• 
12-lead Electrocardiogram (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 


 
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• 
MASC-10 for emergent or worsening anxiety 
 
4.6. 
OTHER SAFETY EXPLORATORY ENDPOINTS 
Other endpoints will include: 
 
CO2 (EtCO2 or TcCO2)  
 


 
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5. 
STATISTICAL HYPOTHESES FOR TRIAL OBJECTIVES 
The primary hypothesis, corresponding to the primary efficacy variable (weekly number 
of cataplexy attacks), is the following: 
• 
Xyrem is superior to Placebo as measured by the change in the 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 statistical null hypothesis is that for the weekly number of cataplexy attacks 
endpoint, the rank based mean change is the same for the Xyrem treatment 
group and the Placebo treatment group. 
 
In addition to the primary hypothesis, the key secondary hypotheses are: 
 
• 
Xyrem is superior to Placebo as measured by CGIc for cataplexy severity at the 
end of the Double-Blind Treatment Period. 
 
The statistical null hypothesis is that for the CGIc cataplexy severity, the mean 
value for the Xyrem group is equal to the mean value for the Placebo treatment 
group.  
 
• 
Xyrem is superior to Placebo as measured by the change in the ESS (CHAD) from 
the end of the Stable-Dose Period to the end of the Double-Blind Treatment 
Period. 
 
The statistical null hypothesis is that for the ESS (CHAD), the rank based mean 
change is the same for the Xyrem treatment group and the Placebo treatment 
group.  
 
In addition to the key secondary hypotheses, the other secondary hypotheses are: 
 
• 
Xyrem is superior to Placebo as measured by CGIc for narcolepsy overall at the 
end of the Double-Blind Treatment Period. 
 
The statistical null hypothesis is that for the CGIc narcolepsy overall, the mean 
value for the Xyrem group is equal to the mean value for the Placebo treatment 
group.  
 
• 
Xyrem is superior to Placebo as measured by the change in the SF-10 Physical  
Health Score from the end of the Stable-Dose Period to the end of the Double-
Blind Treatment Period. 


 
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The statistical null hypothesis is that for the SF-10 Physical Score, the rank based 
mean change is the same for the Xyrem treatment group and the Placebo 
treatment group.  
 
• 
Xyrem is superior to Placebo as measured by the change in the SF-10 
Psychosocial Score from the end of the Stable-Dose Period to the end of the 
Double-Blind Treatment Period. 
 
The statistical null hypothesis is that the rank based mean change is the same 
for the Xyrem treatment group and the Placebo treatment group.  
 


 
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6. 
ANALYSIS POPULATIONS 
6.1. 
SAFETY POPULATION  
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. An overall Safety 
Population based on subjects who took study drug (regardless of period) is also used to 
summarize safety data across all periods. The Safety 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 within the different 
study periods. Analyses will include the Safety Populations as detailed below. 
 
The following subsets of the Safety Population will be used for disposition, concomitant 
medications, treatment compliance, and treatment exposure summaries in Part 1:  
 
• 
Safety Population who had Study Drug Dispensed in the DT Period 
• 
Safety Population who had Study Drug Dispensed in the SD Period 
• 
Safety Population who had Study Drug Dispensed in the DB Treatment Period 
• 
Safety Population who had Study Drug Dispensed in the OL Period 
 
The following subsets of the Safety Population will be used for descriptive summaries of 
efficacy parameters and all safety parameters including AEs, labs, vitals, ECGs, physical 
measures, CDI-2, MASC-10, and CSSR-S in Part 1:   
• 
Safety Population who took Study Drug in the DT Period 
• 
Safety Population who took Study Drug in the SD Period 
• 
Safety Population who took Study Drug in the DB Treatment Period 
• 
Safety Population who took Study Drug in the OL Period 
 
For subjects included in the Safety Population for the DB Treatment Period, summaries 
will be provided by the randomized treatment groups (subjects randomized to Placebo 
and Xyrem) and by Open-label Xyrem (subjects entering the DB period after Amendment 
4).   
 
For subjects on Xyrem at study entry who have their usual dosage of Xyrem dispensed 
on the PSG night at the screening assessment, administration of dose on the screening 
PSG night will not be considered for inclusion in the Safety Population nor be considered 
the first dose date.  
 


 
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6.2. 
RANDOMIZED POPULATION  
The Randomized Population will consist of all subjects who are randomized to either 
Xyrem or Xyrem Placebo for the Double-Blind Treatment Period. This population will be 
used to summarize demographics and baseline characteristics.  
 
6.3. 
PK HALF-DOSE POPULATION  
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. 
 
6.4. 
PK FULL-DOSE POPULATION 
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 if this population is different 
from the PK completer population.   
 
6.5. 
PK COMPLETER POPULATION 
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. 
 
6.6. 
EFFICACY POPULATION 
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. 
 
This population will include subjects who were randomized to either blinded Placebo or 
blinded Xyrem in the DB Period (prior to Amendment 4 being effective).  
 
6.7. 
PER PROTOCOL POPULATION  
The Per Protocol (PP) Population will consist of subjects from the Efficacy Population 
where subjects with major deviations will be assessed, flagged and excluded from this 
analysis population. All deviations will be reviewed and assessed prior to the data 
snapshot. The final list of protocol deviations will be determined and approved prior to 
data base lock at the end of the study.  


 
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This population will be used for sensitivity analyses of the primary and secondary 
efficacy endpoints during the DB period if it is found that the population is different 
from the efficacy population.  
 
6.8. 
CONTINUED ACCESS POPULATION  
The Continued Access Population will consist of all subjects who took drug in Part 2.  
This population will be used for tables and listings of Part 2 data. 
 
In this SAP and in the table shells and listings, the Continued Access Population is 
synonymous with the Safety Population who Took Study Drug in the Part 2 Open-Label 
Continuation Period. 
 
6.9. 
PROTOCOL DEVIATIONS 
Deviations from protocol will be maintained by the INC clinical team. Subjects with 
major deviations to be excluded from the PP population will be identified prior to 
database snapshot. Upon unblinding, deviations between randomized treatment 
assignment and actual treatment received during the DB Period will be documented and 
displayed in a listing. Subjects with deviations between randomized treatment 
assignment and actual treatment will be excluded from the PP population.  A listing of 
deviations will be summarized using the safety population and deviations that led to 
exclusion from the PP population will be flagged. 
 
For the final analysis of Part 2 data, a summary table of types of deviation and severity 
of the deviations (major vs. minor) will be completed using the Safety Population. The 
analysis will be done by Age Group, Xyrem Status at Entry, and overall.  


 
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7. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
7.1. 
GENERAL METHODS 
All statistical analyses detailed in this SAP will be conducted using SAS® Version 9.3 or 
higher. 
 
Unless otherwise specified, summarizations will be presented separately for each period 
(i.e. DT Period, SD Period, DB Period, OL Period, and Part 2 OL Continuation Period) as 
specified below.  
 
General Rules for Summarizations in the DT Period 
 
Unless otherwise specified, these are the general rules for summarizations in the DT 
Period.  
 
For Xyrem Naïve subjects at study entry, the visits Visit 1.1, Visit 1.2, Visit 1.3, Visit 
1.4, Visit 1.5, Visit 1.6, and Visit 1.7, Visit 2 (End of Titration/Begin Stable-Dose), and 
Early Termination (ET) visits that occurred in the DT Period will be included in the 
summaries for this period. 
 
Columns of presentation for this period will include the Age Group 7-11, Age Group 12-
17, and Total.  
 
General Rules for Summarizations in the SD Period 
 
Unless otherwise specified, these are the general rules for summarizations in the SD 
Period.  
 
Baseline values, Visit 3 (End of Stable Dose/Begin Double-Blind Period), and ET visits 
that occurred in the SD Period will be included in the summaries for this period.  
 
Summarizations of the SD Period will display columns for Age Group 7-11, Age Group 12-
17, Xyrem Naïve at Study Entry, On Xyrem at Study Entry, and Total. 
 
General Rules for Summarizations in the DB Period 
 
Efficacy analyses of DB Period data will be provided separately as follows: 
• 
For testing of the efficacy endpoints, subjects in the Efficacy population who 
were randomized (Placebo or Xyrem) prior to the implementation of Amendment 
4 will be assessed according to their randomized treatment group 


 
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o Columns for the randomized treatment assignment of Xyrem, Placebo and 
Total will be displayed 
o Analyses by subgroup will be provided separately for each subgroup 
• 
For all other applicable summaries using the Safety Population who took Study 
Drug in the DB Treatment Period  
o Columns for Randomized to Placebo, Randomized to Xyrem, Open-Label 
Xyrem, and All Xyrem will be displayed 
o Analyses by subgroup will be provided separately for each subgroup 
 
Unless otherwise specified, these are the general rules for summarizations in the DB 
Period. 
 
Visit 4 (End of Double-Blind Treatment/Begin Open-Label Safety), and ET visits that 
occurred in the DB Period will be included in the summaries for this period. Efficacy 
analyses will include the efficacy baseline value where applicable. For safety endpoints 
where a value is scheduled to be collected at Visit 3 (End of Stable Dose/Begin Double-
Blind Period), the Visit 3 results and changes from Visit 3 will also be summarized. 
 
The randomized treatment assignment will be used for all efficacy analyses as 
applicable.  Actual treatment received will be used for study drug exposure and safety 
analyses. 
 
Actual treatment received will be determined by comparing the dosing kit numbers 
assigned by the IWRS during the DB Period with the contents of those kits. Subjects who 
are given kits during the DB period, all containing Placebo, will be analysed as receiving 
Placebo. Subjects who are given at least one kit containing active Xyrem during the DB 
Period will be considered to have received Xyrem during the period. If any deviations 
between randomized treatment assignment and assigned treatment assignment occur, 
they will be presented in a listing. 
 
For the DSMB summaries, the treatment groups will be masked with columns labelled as 
Treatment A and Treatment B, OL Xyrem, All Xyrem, and Total. The unblinded 
 
 biostatistician decides the correspondence of Treatment A and Treatment B to 
Placebo and Xyrem prior to the first DSMB meeting. This correspondence will be used at 
all successive DSMB meetings throughout the study conduct. At the time of the interim 
analysis, the treatment correspondence was requested by the DSMB, and then revealed.  
 
General Rules for Summarizations in the OL Period 
 
Unless otherwise specified, these are the general rules for summarizations in the OL 
Period. 
 


 
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Baseline value, Visit 4 (End of Double-Blind Treatment Period/Beginning of Open-Label 
Safety Period), Visit 5 – Visit 15 values, and ET visits that occurred in the OL Period will 
be included in the summaries for this period. Changes from baseline and change from 
end of DB Period will also be summarized. 
 
Summarizations of measurements in the OL Period will be presented by the Age Group, 
Xyrem Status at Study Entry, and Total. 
 
For the efficacy endpoints Weekly Cataplexy Attacks, ESS(CHAD), SF-10 Physical 
Summary Score, and SF-10 Psychosocial Summary Score, summarizations for the OL 
Period will also be done by the treatment received during the DB Period (Xyrem vs. 
Placebo). 
 
General Rules for Summarizations for the Safety Follow-Up Assessment 
 
Assessments made at the Safety Follow-Up Assessment in Part 1 will be listed, but 
otherwise will not be used in any statistical summarization unless otherwise noted. 
 
General Rules for Summarizations in the Part 2 OL Continuation Period 
 
Unless specified, these are the rules for summarizations of the Part 2 OL Continuation 
Period. Summarizations based on the Safety Population who Took Study Drug in the Part 
2 Open-Label Continuation Period will be based on the Age Group at first dispense in 
Part 1. Columns will be presented as: Age 7-11, Age 12-17, and Total. 
 
Summarizations of combined Part 1 and Part 2 data for exposure and adverse events will 
be completed using the Safety Population who Took Study Drug.  These summaries will 
be provided by the Age Group at Entry into Part 1, Xyrem Status at Study Entry, and 
Total. 
 
Presentation of sample statistics 
 
Continuous variables will be summarized using descriptive statistics including number of 
observations (n), mean, standard deviation (STDEV) or standard error, median, 1st 
quartile (Q1), 3rd quartile (Q3),  minimum and maximum. Categorical variables will be 
summarized using the number of observations (n) and percentage of observations. 
 
Listings  
 
Except for PK listings and analysis population exclusion listings, all other listings will be 
provided using the safety population. PK listings will be presented using the PK Half-
Dose Population. In general, subject data listings will present data sorted in order of 
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randomized), country, subject identifier, period of collection, visit number, date and 
study day of collection. Some listings, where Part 2 data is shown, will indicate that a 
subject entered Part 2 and the type of Part 2 subject (entered directly, re-enrolled and 
required titration, re-enrolled and did not require titration).  
 
Summarization of Scheduled and Unscheduled Visits  
 
Scheduled visits will be analysed according to their nominal label. 
 
Unscheduled visits in Part 1 and Part 2 will be considered for analysis according to the 
visit number of the immediately preceding scheduled visit number within the study 
period. If an unscheduled visit occurs in a period where the subject has had no 
scheduled assessments, the unscheduled visit will be mapped according to the windows 
defined for the Early Termination (ET) visits. 
 
Summarization and Mapping of ET Visits 
 
Early termination visits will be analysed separately within the period that the 
termination occurred. 
 
Early termination visits will also be mapped into a scheduled visit for summarization, 
according to the period in which the termination occurred and according to the rules 
below.  An assessment at early termination can be mapped to a visit where the 
assessment was not scheduled to be collected.  In case assessments are not scheduled 
to be collected within a period, early termination results will be listed.  
 
Early termination assessments occurring in the DT Period will be mapped to a visit based 
on the calculated study day of the assessment. See Section 7.4 for the windows for the 
visits. 
 
Early termination assessments in the SD Period will be summarized as End of Stable 
Dose, as there is only one scheduled SD Period visit. 
 
Early termination assessments in the DB Period will be summarized as Double-Blind 
Treatment Period, as there is only one scheduled DB Period visit. 
 
Early termination assessments in the OL Period will be mapped to a visit based on the 
calculated study day of the assessment. See Section 7.4 for the windows for the visits. 
 
Early termination assessments in the Part 2 OL Continuation Period will be mapped to a 
visit based on the calculated study day of the assessment relative to the first dose date 
in Part 2. See section 7.4 for the windows for the visits. 
 


 
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Multiple Assessments within a Visit  
 
For Part 1, if multiple assessments have occurred within the same analysis visit, either 
due to unscheduled assessments or early termination mapping, then the first recorded 
value will be used for the by-visit summary, unless specified otherwise. 
 
For Part 2, if multiple assessments have occurred within the same analysis visit, then 
the first recorded value will be used in the by-visit summary. 
 
For shift tables where abnormal values are presented, the worst value (abnormal values 
are worse than normal) within the visit will be used in the summary. 
 
Categorization of AEs, Concomitant Procedures, and Concomitant Medications into 
Periods  
 
AEs, concomitant procedures, and concomitant medications will be categorized as 
occurring in periods if the AE Onset, Procedure Date, or period of use of the 
concomitant medication overlaps the periods defined below: 
 
Xyrem Status at 
Study Entry  
Period  
Starting Day  
(inclusive) 
Ending Day  
(inclusive) 
Xyrem Naïve 
Subjects and on 
Xyrem at Study 
Entry Subjects 
Screening 
No Lower Bound 
Day before Study 
Day 1  
Xyrem Naïve 
Subjects 
DT Period   
1st Day of Intake 
after Visit 1.1  
Day prior to first 
evening intake after 
Visit 2  
Xyrem Naïve 
Subjects and on 
Xyrem at Study 
Entry Subjects 
SD Period  
1st Day of Intake 
after Visit 2  
Day prior to first 
evening intake after 
Visit 3  
DB Period  
1st Day of Intake 
after Visit 3  
Day prior to first 
evening intake after 
Visit 4  


 
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Xyrem Status at 
Study Entry  
Period  
Starting Day  
(inclusive) 
Ending Day  
(inclusive) 
OL Period  
1st Day of Intake 
after Visit 4 
Last date in the 
Period for 
Concomitant 
Medications and 
Concomitant 
Procedures;  
30 days after last 
dose of study drug, 
inclusive, for 
Adverse Events. 
(See notes *, **). 
Part 2 Subjects  
OL Continuation 
Period 
1st Day of Intake in 
Part 2  
30 days after last 
dose of study drug 
in Part 2, inclusive, 
for Adverse Events. 
(See notes *, **). 
 
AEs, concomitant procedures, and concomitant medications that occur after the last 
period in which the subject had study drug dispensed, will be allocated to the subject’s 
final dispense period in which study medication was taken.   
 
* For subjects who did not continue into Part 2, Concomitant medications and 
Concomitant procedures with start date strictly after the last date in the study period 
will be allocated to the post-treatment follow-up period. They will be shown in listings 
only, and not included in the summary tables. For subjects who entered Part 2, 
concomitant medications eCRF with start date strictly after the last date in the OL 
study period, but strictly prior the first dose date in Part 2 will be summarized as Part 2 
prior medication. 
** For subjects who did not continue into Part 2, adverse events with onset more than 
30 days after the last dose of study drug in Part 1 will be allocated to the post-
treatment follow-up period.  They will be shown in listings only, and not included in the 
summary tables.  
 
Handling of incomplete dates for AEs and concomitant medications will be discussed 
specifically in the Section 7.3. 
 
7.2. 
KEY DEFINITIONS 
Dispensation of Study Drug  
 


 
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Dispensation of study drug in the periods will be based on the eCRF forms entitled 
“Study Drug Administration Titration Dosing”, “Study Drug Administration Stable Dosing” 
(which also contains the dispensation of DB Period data when the visit number is 3), 
“Study Drug Administration Open Label Safety Dosing”, and Study Drug Administration – 
Part 2. The earliest assignment date will be called the first study drug dispensation 
date. 
 
First Dose Intake in Part 1 
 
Dose intake will be determined using the two eCRF pages entitled “Study Drug First 
Taken” and “Study Drug Last Taken”, and the morning diary entries to the questions 
“Was the first nightly dose taken?” and “Was the second nightly dose taken?”  As these 
diary questions are answered in the morning and the dosing should occur in the evening 
prior to going to bed, if the response to either question is Yes, then the date of intake 
will be considered to be 1 calendar date prior to the diary date. The earliest date of 
intake from the “Study Drug First Taken” eCRF page and the morning diary entries will 
be the date of first dose intake. 
 
A subject will be considered to have taken a study dose in the study, if they have either 
the “Study Drug First Taken” in the DT Period (for Xyrem Naïve) or SD Period (for those 
on Xyrem at Study Entry) or if they have at least one morning diary entry where the 
answer to either dose taken question is Yes after the first dispense in the treatment 
period. 
 
First Dose Intake in Part 2 
 
The first dose intake in Part 2 will be based on the eCRF entry on the page titled “Study 
Drug First Taken” entered for Part 2 subjects. 
 
Study Day 1 in Part 1 
 
Study day 1 is the first study drug dispensation date. For Xyrem Naïve subjects, this is 
the first study drug assignment date record on the Study Drug Administration Titration 
Dosing page. For subjects on Xyrem at Study Entry, this is the dose assignment date on 
the Study Drug Administration Stable Dosing Page for Visit 2. 
 
Last Dose Date in Part 1 
 
If the investigator has completed the eCRF entitled “Study Drug Last Taken”, then the 
last dose date will be the date entered on this eCRF. 
Otherwise, the last dose date will be the calendar day of the last morning diary where 
at least one response to the dose taken questions is Yes. 
 


 
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Study Day  
 
For Part 1, study day will be calculated from the date of Study Day 1. If the assessment 
date is on or after Study Day 1 date, then Study Day = date of assessment – Study Day 1 
date + 1. If the assessment date is prior to Study Day 1, then Study Day = assessment 
date – Study Day 1 date. In this way, the day prior to Study Day 1 is noted as study day -
1. There will be no Study Day 0. 
 
For Part 2, a second study day will be calculated using the date of first dose in Part 2.  
If the assessment date is on or after the first dose in Part 2, then the second study day = 
date of assessment – first dose date + 1.  
 
Duration of Dosing in Periods 
 
Durations will be measured in days counting from the last date of dosing during the 
period minus the first date of dosing during the period + 1. Xyrem Naïve subjects at 
study entry will have durations for up to 4 treatment periods (DT, SD, DB, and OL) in 
Part 1. Subjects on Xyrem at study entry will have durations for up to 3 treatment 
periods (SD, DB, and OL) in Part 1. 
For the Part 2 OL Continuation period, the duration of dosing = date of last dose in Part 
2 – date of first dose in Part 2 + 1. 
 
Total Duration of Dosing 
 
The total duration of dosing in Part 1 will be calculated as Last Dose Date – First Dose 
Intake Date + 1. 
 
For combined Part 1 and Part 2 Duration of Dosing, the Total Duration of dosing will be 
the sum of the durations of dosing in Part 1 and Part 2.  If the last dose date in Part 1 is 
the same as the first dose date in Part 2, then the sum will have one day subtracted. 
 
Total Duration of Xyrem Usage  
 
For subjects who received Xyrem or OL Xyrem during the DB Period, the duration of 
Xyrem usage will be the same as the Total Duration of Dosing. For subjects who 
received Placebo during the DB Period, Total Duration of Xyrem Usage will equal the 
Total Duration of Dosing minus Duration of Treatment during the DB Period. A similar 
adjustment will be made for the combined Part 1 and Part 2 Duration of Xyrem Usage. 
 
Cumulative Dosage of Study Drug Used in a Period 
 
During each period in Part 1, the cumulative dosage of study drug (in g) will be 
determined utilizing the study medication dosage level assigned by the investigator on 


 
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the dosing log (in g/night) and the daily diary entries. On a morning diary where 
subjects indicated they did not take one of the previous night’s doses, the total dosage 
for that night will be determined using the relative typical 1st nightly dose amount and 
2nd nightly dosage amount. On a morning diary where the subjects indicated they took 
neither of the doses, the total dosage for that night will be 0. Missing diary entries will 
count as 0 toward the cumulative dosage used. For subjects who actually receive 
Placebo during the DB period, their cumulative Xyrem dosage during the DB period will 
be equal to 0. 
 
Because the daily diary entries are not collected in Part 2, an additional cumulative 
Xyrem dosage will be calculated based on dosing log only. This cumulative Xyrem 
dosage amount will be used only for the presentation of results in Part 2 and the 
combined Part 1 and Part 2 analyses. For each row on the dosing log, the dosage 
received will be calculated as the assigned dosage level (g/night) multiplied by the 
duration of time on that dosage, up to and including the last dose date in the period. 
The cumulative dose will be determined by adding each dosing log row’s dosage 
received value. For subjects who received Placebo during the DB period, their 
cumulative Xyrem dosage during the DB period will be set equal to 0.  
 
Average Dosage of Xyrem Used in a Period 
 
During the Part 1 OL period, the average dosage of Xyrem used during the period will be 
calculated as the cumulative dosage received (in g) (based on the diary entries and 
dosing log) and dividing by the duration of dosing in the period (in days). 
 
Calculation of Xyrem Dosage in mg/kg/night 
 
The dosage in mg/kg/night is calculated using the total nightly dosage assigned by the 
investigator (measured in g/night; called SDDOSE in the formula below) and the body 
weight (kg) (called WEIGHT in the formula below). 
 
DOSELEV = (SDDOSE x 1000) / WEIGHT. 
 
For the DT period, the weight collected closest up to the date of the Visit 1.1 will be 
used. For the SD and DB period, the weight collected closest to the date of the Visit 2 
will be used. For the OL period in Part 1, the dosage at last dose will be determined 
using the weight closest to the last dose. For PK nights and PSG nights, the weight 
collected closest to the collection night will be used. For visits in the Part 2 OL 
Continuation Period, the weight collected closest to the date of dose adjustment will be 
used. 
 
Xyrem dosage in mg/kg/night will be categorized as follows:  
 


 
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50-100 mg/kg/night 
>100 – 150 mg/kg/night 
> 150 – 200 mg/kg/night 
> 200 mg/kg/night 
 
Baseline Values  
For the cataplexy frequency endpoints and school attendance endpoints (i.e. endpoints 
calculated from daily diary entries), the baseline value will be calculated based on the 
diaries during the last 2 weeks of the SD Period. 
 
For the other efficacy endpoints: ESS (CHAD), and SF-10 scores, the baseline value will 
be the Visit 3 assessment (End of Stable Dose/Begin Double-Blind Period). 
 
For the safety endpoints, the baseline assessment will be the last non-missing value 
collected on or prior to Study Day 1. 
 
Change from Baseline and Percentage Change from Baseline Values  
 
Change from baseline will be calculated as Observed Value – Baseline Value. 
 
If the Baseline value is not-missing, and not 0, then percentage change will be 
calculated as: (Change from Baseline / Baseline Value) * 100%. 
 
Change from Visit 3 (End of Stable Dose/Begin Double-Blind Period), and Percentage 
Change from Visit 3  
 
For the following safety endpoints in the DB Period: Vital Signs, Physical Stature, CDI 
2:SR[S], and MASC-10, the change from Visit 3 will be calculated as Observed Value in 
DB – Visit 3 value, where the Visit 3 value will be the collected value at Visit 3 and prior 
to the first intake of study drug in the DB Period. 
 
If the Visit 3 value is not-missing, and not 0, then percentage change will be calculated 
as: (Change from Baseline / Visit 3 Value) * 100%. 
 
Change from End of Double-Blind Period and Percentage Change from End of Double-
Blind Period  
 
For all efficacy and safety endpoints in the Part 1 OL Period, the Change from the End 
of DB Treatment Period will be calculated as Observed Value in OL Period – End of DB 
Period Value, where the End of DB Period value will be: 1.) either the last collected 
value collected in the DB Period up to and including the date of the Visit 4, or 2.) for 
the Weekly Cataplexy Attacks endpoint, the Weekly Cataplexy Attack Count from the DB 
Period will be used.  


 
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If the end of DB Period value is not-missing, and not 0, then percentage change will be 
calculated as: (Change from Baseline / End of DB Period Value) * 100%. 
 
Change from the Start of  Part 2 Open Label Continuation and Percentage Change 
from Start of Part 2 Open Label Continuation  
 
For vital sign assessments and physical stature assessments in the open label 
continuation period in Part 2, the change from the start of the Part 2 OL period will be 
calculated as Observed Value in OL Continuation Period – Start of OL Continuation 
Period. For subjects who continued directly from Part 1 to Part 2, the value at Visit 15 
will be used as the start of OL Continuation.  For subjects who re-enrolled into Part 2, 
the last non-missing value collected on or prior to Visit 18 will be used as the start of OL 
Continuation.  
 
If the end of Start of OL Continuation value is not missing, and not 0, then percentage 
change will be calculated as: (Change from Baseline / Start of OL Continuation Period) * 
100%. 
 
Age at First Study Drug Dispensation 
 
Age will be calculated at the date of Study Day 1. 
 
For countries where regulations allow only the year of birth to be entered for birth 
date, July 1st of that year will be used for the calculation of age. In the event an age 
calculated using this imputed birth date results in an age of 6 years, then the age will 
be assigned as 7. 
 
The SAS function YRDIF will be utilized to calculate the age. 
 
AGE = FLOOR( YRDIF(DOB, STRTDT, ‘AGE’)), where DOB is the date of birth and STRTDT 
is the date of Study Day 1. 
 
Age at Start of Part 2 OL Continuation Period  
 
For subjects who enter Part 2 and take at least one dose in the OL Continuation Period, 
the age at first dose in Part 2 will be calculated.  The same formula for calculation of 
age at first study drug dispensation will be used. 
 
Age Group  
 
Age at first study drug dispensation will be categorized into age groups of 7-11 or 12-17. 
Deviations from protocol Inclusion Criterion #1, requiring subjects to be 7-16 years of 


 
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age at Visit 2, are unexpected. If a deviation does occur, then subjects aged less than 7 
will be categorized into the 7-11 age group and subjects aged older than 17 at entry will 
be categorized into the 12-17 age group. 
 
The age at start of OL Continuation (Part 2) will also be categorized as 7-11 and 12-17 
years.  
 
Years from Narcolepsy Diagnosis 
 
Years from Narcolepsy diagnosis will be calculated using the screening visit date. For 
subjects with partial dates for the narcolepsy diagnosis, the years since diagnosis will be 
calculated by assuming the earliest date implied by the portions of the date available, 
unless that implied date is prior to the date of birth. If that situation occurs, the date 
of birth will be used for determining the years since diagnosis. 
Years = (ScrDt – DXDT + 1) / 365.25, where ScrDt is the date of the screening visit and 
DXDT is the diagnosis date or imputed diagnosis date. Values will be rounded to one 
decimal. 
7.3. 
MISSING DATA 
Missing Efficacy Data for the DB Period  
 
Missing efficacy endpoints for the weekly number of cataplexy attacks or weekly school 
attendance during the whole DB period will be imputed. Methods for derivation for the 
parameters are described in Section 9. In the event that there are no cataplexy diary 
entries completed in the DB Period, the value computed for the SD Period will be 
carried forward as the DB Period value (i.e. baseline value carried forward).  
 
For the ESS (CHAD), SF-10 Physical Summary Score, and SF-10 Psychosocial Summary 
Score endpoints, a missing value in the DB Period will be imputed using the last 
available value from the SD Period (i.e. baseline value carried forward). 
 
Adverse Event Data 
 
Adverse event onset date, when a partial date has been provided, will be imputed using 
the following algorithm, defined to assign AEs to have occurred in a treatment period, if 
possible, and to assign the onset to the earliest applicable treatment period.  
 
If the year of onset only is provided and the year is the same as the year of first dose, 
then the date of first dose will be imputed as the onset date. If the year of onset is 
strictly greater than the year of first dose or strictly less than the year of first dose, 
then January 1st of the year provided will be imputed. 


 
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If the month and year of onset are provided, and the month and year are equal to the 
month / year of first dose, then the date of first dose will be imputed as the onset 
date. In all other cases, the 1st day of the provided month/year of onset will be imputed 
for the onset date.  
 
AEs with missing severity will be summarized separately. 
 
AEs with missing relationship to study treatment will be considered to be related to or 
suspected to be related to study treatment. 
 
In the situations where a partial onset date is provided, this imputed onset date will be 
utilized for determination of the period of onset for presentation of the summaries of 
the AEs. Partial onset dates will be presented as collected in the listings. Similarly, AEs 
with missing severity or relationship will be presented as missing in the listings. 
 
Concomitant Medications Data 
 
For concomitant medications with incomplete start dates, the start date will be 
imputed using the earliest possible date implied by the portions of the date provided. 
 
If the year of start only is provided, then January 1st of that year will be imputed for the 
start date, unless January 1st of that year is prior to the subject’s date of birth. In that 
case, the date of birth will be imputed as the start date. 
 
If the month and year of start are provided, the 1st day of the provided month/year of 
onset will imputed for the onset date, unless that imputed date is prior to the subject’s 
date of birth. In that case, the date of birth will be imputed as the start date. 
 
Incomplete concomitant medication end dates will be imputed using the latest possible 
date implied by the portions of the date provided. 
 
If the year of end only is provided, December 31st of that year will be imputed as the 
end date. If that date is after the subject’s termination from the study date, then the 
study termination date will be imputed for the medication end date. 
 
If the month and year of end are provided, then the last day of that month will be 
imputed as the end date. If that date is after the subject’s termination from the study 
date, then the study termination date will be imputed for the medication end date. 
 
An individual medication may be classified as having been used in multiple periods. 
 


 
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7.4. 
VISIT WINDOWS FOR EARLY TERMINATION 
Early termination visits that occur in the DT Period will be placed into analysis visits 
based on the following windows based on calculated study day and protocol defined 
windows. Windows for the early termination visits in the DT Period are defined as: 
 
 
 
Visit 
Scheduled Study Day 
(calculated from Study day 1)  
Start of 
Window 
End of 
 Window 
Visit 1.2 (Week 1) 
7 
1  
10 
Visit 1.3 (Week 2) 
14 
11 
17 
Visit 1.4 (Week 3) 
21 
18 
24 
Visit 1.5 (Week 4) 
28 
25 
31 
Visit 1.6 (Week 6) 
42 
32 
45 
Visit 1.7 (Week 8) 
56 
46 
63 
Visit 2 (Week 10) 
70 
64 
No upper bound  
 
 
Early termination visits that occur in the OL Period in Part 1 will be placed into analysis 
visits based on the following windows based on calculated study day. Windows for the 
early termination visits in the OL Period are defined as: 
 
Visit 
Scheduled Study Day 
(calculated from Study day 1)  
Start of 
Window 
End of 
 Window 
Visit 5 (4 Weeks 
after end of Double-
Blind Period) – for 
Xyrem Naïve 
subjects 
28 days after Visit 4, day 98 at 
latest  
Visit 4 Date + 1 
105 
Visit 5 (Week 9) for 
subjects on Xyrem 
at entry 
63 
Visit 4 Date +1 
70 
Visit 6 (Week 16) 
112 
106 (Xyrem 
Naïve)/71 (on 
Xyrem at entry) 
119 
Visit 7 (Week 18) 
126 
120 
133 
Visit 8 (Week 22) 
154 
134 
161 
Visit 9 (Week 26) 
182 
162 
189 
Visit 10 (Week 30) 
210 
190 
217 
Visit 11 (Week 34) 
238 
218 
245 
Visit 12 (Week 39) 
273 
246 
280 
Visit 13 (Week 43) 
301 
281 
308 
Visit 14 (Week 48) 
336 
309 
343 


 
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Visit 
Scheduled Study Day 
(calculated from Study day 1)  
Start of 
Window 
End of 
 Window 
Visit 15 (Week 52) 
364 
344 
No upper 
bound 
 
Early termination visits that occur in the OL Continuation Period (i.e. Part 2) will be 
placed into analysis visits based on the following windows based on calculated study day 
from first dose date in Part 2. Windows for the early termination visits in the OL 
Continuation Period are based on the every 3 month onsite visits.  They are defined as: 
 
Visit 
Scheduled Study Day 
(calculated from Study day 1)  
Start of 
Window 
End of 
 Window 
 
 
 
 
Visit 21 (Month 3) 
90 
1 
97 
Visit 24 (Month 6) 
180 
98 
187 
Visit 27 (Month 9) 
270 
188 
277 
Visit 30 (Month 12) 
360 
278 
367 
Visit 33 (Month 15) 
450 
368 
457 
Visit 36 (Month 18) 
540 
458 
547 
Visit 39 (Month 21) 
630 
548 
637 
Visit 42 (Month 24) 
720 
638 
no upper limit 
 
7.5. 
POOLING OF CENTERS 
Centers will be pooled into Country Groups (US, and Europe).  
Sites will be pooled into Site Groups (Site 112, Site 401, and Other Sites).   
7.6. 
SUBGROUPS 
For all efficacy endpoints except school attendance, subgroup analyses in the DB Period 
will be provided by Age Group, Xyrem Status at Study Entry, Country Group, and Site 
Group.  
For the following safety analyses, subgroup analyses in the DB Period will be provided 
by Age Group and Xyrem Status at Study Entry: 
• 
TEAEs by SOC/PT 
• 
Labs (eg., hematology, liver function, chemistry, growth hormones) 
• 
Vitals 
• 
Physical stature  
• 
ECG 


 
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8. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS, AND 
MEDICATION 
8.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
The number of subjects enrolled into the study and each of the periods along with 
disposition will be summarized using the subjects in the Safety Population or 
Randomized Population for each period as appropriate. 
For the DB Period, a comparison between treatments of the percentage of subjects who 
discontinued will be performed using a Pearson’s Chi-square test. This test will include 
only those subjects who were randomized prior to the implementation of Amendment 4. 
For the disposition tables for Part 1, the reasons for early termination include: Lack of 
Efficacy, Protocol Violation, Adverse Event, Death, Withdrawal of Consent/Assent, 
Cataplexy Instability during Stable-Dose Period, Dose Instability during Stable-Dose 
Period, Lost to Follow-Up, Treatment Non-Compliance, Diary Non-Compliance, Sponsor 
Decision, Investigator Decision, and Other. The reasons of Cataplexy Instability during 
the Stable-Dose Period and Dose Instability during Stable-Dose Period will only be 
presented for the terminations in the SD Period. 
For Part 1, the number of subjects by country, study site/investigator will be 
summarized for the Safety Population. The summarization will be done by Age Group, 
Xyrem Status at Study Entry, and Total.  
The number of subjects who entered the DB Period will be summarized by the 
treatment assigned during the period. The summarization will be done by Age Group, 
Xyrem Status at Study Entry and Total. This summarization will be done using the Safety 
Population who were dispensed Study Drug during the DB Period. 
The number of subjects in each of the study populations will be summarized by Age 
Group, Xyrem Status at Study Entry and Total. 
For subjects who completed Part 1 of the study after Amendment 5 was implemented, 
the number of subjects who did not enter Part 2 will be presented by Age Group.  
For the disposition table for Part 2, the reasons for completion of the study as well as 
reasons for early termination will be summarized. Reasons for completion of Part 2 
include: Subject turns 18 years, US FDA decision on the addition of pediatric data to the 
Xyrem US PI, and Subject completed additional 2 years. Reasons for early termination in 
Part 2 include: Lack of Efficacy, Protocol Violation, Adverse Event, Death, Withdrawal 
of Consent/Assent, Lost to Follow-up, Treatment Non-Compliance, Sponsor Decision, 
Investigator Decision, and Other. 


 
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For Part 2, the number of subjects who entered the Part 2 OL Continuation Period by 
country, and study site/investigator will be summarized using the Safety Population who 
Took Study Drug in the Part 2 Open-Label Continuation Period.  
8.2. 
DEMOGRAPHIC AND OTHER BASELINE DISEASE 
CHARACTERISTICS 
For Part 1, demographic data, including age, sex, race, ethnicity, country, and country 
group will be summarized for the Safety Population, PK Half-Dose Population, PK Full 
Dose, PK Completer Population, Safety Population who had Drug Dispensed in the 
Double-Blind Treatment Period, and Efficacy Population. For categorical variables, 
missing values will be presented in a row labeled “Missing”. Percentages will be 
calculated using the number of subjects in the population.  
For the Safety Population who took Drug in the Part 2 Open Label Continuation Period, 
the demographic data at initial study entry age at first dose in Part 2, sex, race, 
ethnicity, country, and country group will be summarized. 
For Part 1, baseline disease characteristics, including: Xyrem status at entry (i.e. Xyrem 
Naive vs. On Xyrem at entry), years from narcolepsy diagnosis to study entry, narcolepsy 
symptoms experienced prior to any narcolepsy treatment, current narcolepsy 
symptoms, months of previous Xyrem exposure for subjects on Xyrem at study entry, 
subjects whose typical nighttime administration of 2 Xyrem doses was unevenly split, 
Tanner Stage at Screening, CGIs for Historical Narcolepsy Severity Prior to Any 
Narcolepsy Treatment, CGIs for Historical Cataplexy Severity Prior to Any Narcolepsy 
Treatment, CGIs for Narcolepsy overall at baseline, CGIs for Cataplexy Severity at 
baseline, typical bedtime, typical awaking time, usual hours of sleep per night, SF-10 
Physical Summary Score, SF-10 Psychosocial Summary Score, and Epworth Sleepiness 
Scale for Children and Adolescents (ESS [CHAD]) score, will be summarized for the same 
analysis populations noted for the demographic characteristics. The last non-missing 
assessment prior to or on Study Day 1 will be provided for SF-10 and ESS [CHAD]. The 
narcolepsy symptoms experienced prior to any narcolepsy treatment and currently 
summarized include: cataplexy, excessive daytime sleepiness, hypnagogic and/or 
hypnopompic hallucinations, sleep paralysis, and disrupted nighttime sleep. 
Usual hours of sleep will be determined using the data provided on the Xyrem regimen 
history eCRF for subjects on Xyrem at entry and the Usual Bed and Awakening Times 
eCRF for subjects who were Xyrem Naïve at entry. Bedtimes and awakening times are 
recorded with 24 hour clocks.  
The CGIs values are rated by the investigator. The CGIs for Historic Narcolepsy Severity 
and CGIs for Historic Cataplexy Severity rate the subject’s disease prior to any 
narcolepsy treatment. The CGIs for Cataplexy severity and Narcolepsy severity rate the 


 
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subject’s condition at the time of the current visit. Responses go from 0 = Normal; no 
signs of illness, 1 = Borderline ill, 2 = Slightly ill, 3 = Moderately ill, 4 = Markedly ill, 5 = 
Severely ill, to 6 = Among the most extremely ill. 
Details for calculation of the ESS [CHAD] score and SF-10 scores are contained in 
Sections 9.2.2 and Section 9.2.4, respectively. 
Baseline characteristics will be summarized using the Safety Population who had Study 
Drug Dispensed during the Double-Blind Treatment Period, PK Half-Dose Population, PK 
Full Dose, PK Completer Population, and Efficacy Population. For the Safety Population 
who had Study Drug Dispensed during the Double-Blind Treatment Period and Efficacy 
Population, differences in means between the two randomized treatments for 
continuous variables will be compared using a one-way ANOVA using treatment group as 
a factor. The comparison of the two randomized treatments for non-ordinal categorical 
endpoints will be done using a Pearson’s Chi-square test. The comparison of treatments 
for ordinal categorical variables will be compared using a Cochran-Mantel-Haenszel 
(CMH) test for Row Mean Scores Difference. Races with small frequencies may be 
collapsed for the Pearson’s Chi-Square test. Inferential comparisons of treatment groups 
will include only those subjects who were randomized into the DB Period prior to the 
implementation of Amendment 4. 
For the Safety Population who Took Drug in the Part 2 Open-label Continuation Period,  
the following baseline characteristics will be summarized: Xyrem status at entry, Part 2 
subject type, and the duration (days) between the last dose date in Part 1 and the first 
dose date in Part 2. The Part 2 Subject types include: Subject Continuing directly into 
Part 2, Re-enrolling and did not require titration, and Re-enrolling and required 
titration. 
8.3. 
MEDICAL / SURGICAL HISTORY 
During Part 1, Medical and surgical history, excluding narcolepsy and cataplexy, are 
recorded on the Medical/Surgical History eCRF. At the screening visit, the investigator 
indicates body system, diagnosis or condition or surgical procedure, onset date, end 
date, and indicates whether the condition is still ongoing. The medical history data are 
not being coded to any medical dictionary (e.g. Medical Dictionary for Regulatory 
Activities (MedDRA)).   
For Part 1, the Medical / Surgical History body systems will be summarized for the 
Safety Population and Safety Population who had Study Drug Dispensed in the Double-
Blind Treatment Period.  Summarization will be done by Age Group, Xyrem Status at 
Study Entry, and Total. Summarization for the Safety Population who had Study Drug 
Dispensed during the Double-Blind Treatment Period will be done by Randomized 
Treatment Group, OL Xyrem, and Total. 


 
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The Medical / Surgical History terms will be provided in a listing. For subjects who re-
enrolled into the study for Part 2, a column will be added to indicate terms that were 
entered into the Medical / Surgical History after completion of Part 1 and prior to 
enrollment in Part 2. Within subject number, the terms will be sorted by the Study Part 
(Part 1 vs. Part 2), investigator reported Body System, and investigator provided term.  
8.4. 
MEDICATIONS 
Medication usage (other than Xyrem) is collected on the Concomitant Medication eCRF. 
Medications will be coded using the WHO Drug dictionary (Version March 1, 2014). ATC 
classification of each medication will also be provided. The medication name, start 
date, start time (if available), stop date, stop time (if available), dosage, route of 
administration, and indication are collected. Medications will be classified as being used 
in one/or more study periods according to the rules described in Section 7.1. Time of 
start of usage/time of end of usage, if provided, will not be utilized in the 
determination of which period(s) the medication was used.  
Prior medications are defined as those medications started prior to Study Day 1, 
including medications continuing on or after Study Day 1.  
Prior medications will be summarized using the ATC Level 4 terms and the preferred 
names for the Safety Population.  
Concomitant medications used during each of the study periods (DT, SD, DB, OL, Period 
between end of OL and Start of OL Continuation Period, and OL Continuation Period) 
will be summarized using the ATC Level 4 terms and preferred names.  
For all medication tables, ATC Level 4 terms will be sorted alphabetically. Within ATC 
Level 4 terms, preferred names will be sorted in descending order of overall incidence.  
A listing of medications used will be provided, identifying the period(s) of usage.  
Stimulant Usage 
Usage of stimulants during the SD Period and DB Period will be assessed using the 
evening cataplexy frequency diaries and the responses to the questions “Did you take a 
stimulant today?” and “Reason stimulant was not taken”.  
A subject will be considered as “supposed to have taken stimulant” during the period if 
the response to the first stimulant question (i.e. did you take a stimulant today?) was 
yes, or the response to the reason stimulant was “I was supposed to take stimulant, but 
I didn’t” on any single day during the period.   


 
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The percentage of subjects who took all their stimulants during the period, the 
percentage of subjects who were supposed to take stimulants and only took stimulants 
part of the period, and the percentage of subjects who were supposed to take 
stimulants but didn’t take any will be determined.   
The summary for the SD Period will be determine using the diaries starting the day after 
Visit 2 and ending with the diary collected on the date of Visit 3. The summary for the 
DB period will be determined using the diary started the day after Visit 3 and ending 
with the diary collected on the date of Visit 4.  
Flavorant Usage  
Summaries of flavorant usage in Part 1 will be completed using the Safety Population 
who Took Study Drug. Dispensing of flavorant along with the study medication is 
reported by Bracket in their dispensing report. The intake of the flavorant is optional. 
For Part 1 visits during DT, SD, DB, and OL combined, the number of subjects who had 
flavorant dispensed at < 50% of their dispensing visits vs. ≥ 50% of their dispensing visits 
will be completed by Age Group, Xyrem status at Entry, and overall. Further, the 
number of visits where flavorant was dispensed to the subject will be done 
categorically. 
A similar analysis of flavorant usage in Part 2 will be completed using the Safety 
Population who Took Study Drug in the Part 2 Open-Label Continuation Period.  The 
summary will be done by Age Group at Entry into the study and overall.  
8.5. 
PROCEDURES 
Concomitant procedures are collected on the procedure eCRF. Procedures will be coded 
using the MedDRA dictionary version 17.0. The procedure name, start date, start time 
(if available), and indication are collected. Procedures will be classified as being in one 
of the study periods according to the rules described in Section 7.1. Procedure time, if 
provided, will not be utilized in the determination of which period the procedure 
occurred.  
A listing of procedures will be provided, identifying the period(s) of occurrence.  
No other summarization of concomitant procedures is planned. 


 
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9. 
EFFICACY 
Prior to Amendment 4, 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. 
The DSMB recommended stopping placebo treatment during Double-Blind Randomized-
Withdrawal Period due to the positive primary efficacy results from the pre-specified 
interim analyses. Since the primary efficacy endpoint was reached and the placebo 
treatment is discontinued, significance testing will be conducted starting at the Tier 2 
endpoint as defined below, using two-sided testing at each Tier.  
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 DB Treatment Period. 
The primary endpoint demonstrated efficacy at the interim analysis with a significance 
level <0.005, using methods described in Section 9.1.2.2. A nominal p-value will be 
provided.  Testing will continue with Tier 2.  
Tier 2: Key secondary endpoint #2 
2. CGIc for cataplexy severity from the end of the SD Period to the end of the DB 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 
3. Change in the ESS (CHAD) score from the end of the SD Period to the end of DB 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 SD Period to the end of the DB 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 


 
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5. Change in QoL (SF-10 Physical and Psychosocial Summary Score) from the end of the 
SD Period to the end of the DB Period 
The testing of the SF-10 endpoints will be conducted using the Hochberg procedure 
(1995), where the 2 p-values from the tests will be ordered from smallest to largest. 
The p-values (P(1), P(2)) will be compared to the Benjamini-Hochberg critical value. If 
the highest p-value is < 0.05, then both tests will be considered statistically significant. 
Otherwise, if the highest p-value ≥ 0.05 and the smallest p-value is < 0.025 then the 
hypothesis associated with the smallest p-value will be considered statistically 
significant.  
Inferential testing will only be performed for subjects who were randomized to double-
blind treatment and included in the efficacy population for the primary and secondary 
efficacy endpoints. All other efficacy analyses including sensitivity analyses of efficacy 
endpoints, exploratory efficacy endpoint analyses and subgroup analyses will be tested 
without multiplicity adjustments and nominal p-values will be provided.  
Unless otherwise specified, summaries will be provided as described in Section 7.1 using 
the populations as described in section 6.  Section 7.3 describes imputation for efficacy 
parameters. 
No efficacy data is collected during Part 2. No analyses of efficacy endpoints for Part 2 
will be completed. 
9.1. 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS 
The primary efficacy endpoint, change in the weekly number of cataplexy attacks, will 
be determined via the evening cataplexy frequency diary. For Xyrem-Naïve subjects, 
the diary is collected each evening from the start of the DT Period through the end of 
the OL Period. For subjects on Xyrem at study entry, the diary is collected each evening 
during the SD Period through the end of the OL Period. The primary efficacy endpoint is 
the Tier 1 endpoint. This endpoint is applicable only to Part 1 of the study. The 
cataplexy frequency diary is not collected during Part 2. 
9.1.1. 
Calculation of Weekly Number of Cataplexy Attacks  
Any diary day where the response is “No, I did not have cataplexy today” will count as a 
completed diary day and that day will count as a 0 in the attack frequency total. Diary 
days where a numeric frequency of cataplexy events is provided will be counted as a 
completed diary day and the number provided will contribute to the total number of 
attacks during the periods. 


 
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9.1.1.1. 
Calculation within the DT Period 
The DT Period will be separated into 7 day periods starting from the first dispense of 
study drug in the DT Period (i.e. Day 1-7, Day 8-14, etc.). For each 7 day period, the 
weekly number of cataplexy attacks will be determined by counting the total number of 
cataplexy attacks reported during the period and dividing this sum by the number of 
days during the period where a diary was completed, and then multiplying this ratio by 
7 in order to get a weekly number of attacks.  
Also, the weekly number of cataplexy attacks will be determined using the last 7 days 
of the DT period. The diary collected on the date of Visit 2 will be the last day of this 
period. If the subject does not have a Visit 2, then the last available collected diary 
during the DT period will be the last day of the period. The first day in this week would 
be determined by counting back 7 calendar days from the last diary collection during 
the period. The days utilized in the calculation of the weekly number in the last 7 days 
will not be mutually exclusive from the weekly frequency mentioned in the first 
paragraph of this section.  
9.1.1.2. 
Calculation within the SD Period 
The primary calculation of weekly number of cataplexy attacks during the SD Period will 
be determined using the last 14 days during the SD Period.  
The weekly number of cataplexy attacks in the period will be calculated by determining 
the total number of cataplexy attacks reported during the last 14 days of the SD Period, 
ending with the diary collected on the date of Visit 3 (End of Stable-Dose Period/Start 
of Double-Blind Treatment Period), dividing by the number of days during the period 
where a diary was completed. This ratio is then multiplied by 7 to determine the weekly 
number of attacks.  
As a supplemental analysis of the SD Period cataplexy attacks, the period will be 
separated into 7 day periods starting with the day after Visit 2 and ending with the diary 
collected on the date of Visit 3. The determination of weekly cataplexy attacks will be 
done similar to the calculation of attacks in the DT Period. As well, the weekly number 
of cataplexy attacks will be determined using the last 7 days of the SD Period.  
9.1.1.3. 
Calculation within the DB Period 
The primary analysis of weekly number of cataplexy attacks during the DB Period will be 
calculated using all diaries reported during the period starting from the day after the 
start of the DB Period through the date of Visit 4 (End of Double-Blind Treatment 
Period/Beginning of Open-Label Safety Period). The weekly number of cataplexy attacks 
during the DB Period will be calculated by counting the total number of cataplexy 


 
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attacks reported during the period starting from the day after the start of DB Period 
through the date of Visit 4 (End of Double-Blind Treatment Period/Beginning of Open-
Label Safety Period), dividing by the number of days during the period where a diary 
was completed. This ratio is then multiplied by 7 to determine the weekly number of 
attacks. The baseline value for the weekly number of cataplexy attacks for the DB 
Period is the value calculated for the last 14 days of the SD Period. Change from 
baseline will be calculated as weekly number of cataplexy attacks during the DB Period 
– weekly number of cataplexy attacks during the SD Period.  
As a supplemental analysis of the DB Period cataplexy attacks, the period will be 
separated into 7 day periods starting with the day after the start of the DB Period and 
ending with the diary collected on the date of Visit 3 through the date of Visit 4. The 
determination of weekly cataplexy attacks will be done similar to the calculation of 
attacks in the DT Period. As well, the weekly number of cataplexy attacks will be 
determined using the last 7 days of the DB Period.  Missing value imputation will not be 
used for this supplemental analysis. 
For the weekly summaries of attacks in the DB Period, the baseline value is the value 
calculated for the last 14 days of the SD Period. Change from baseline will be calculated 
as weekly number of cataplexy attacks during the DB Period – weekly number of 
cataplexy attacks during the SD Period. 
9.1.1.4. 
Calculation within the OL Period 
The weekly number of cataplexy attacks during the OL Period will be calculated in a 
similar method as the DT Period. The OL Period will be separated into 7 day periods, 
starting from the date after the first dispense of OL treatment. 
Similar to the DT Period calculation, a weekly number of cataplexy attacks will also be 
calculated for the last 7 days in the OL Period. The baseline value for the weekly 
number of cataplexy attacks for the OL Period is the value calculated for the SD Period. 
Change from baseline will be calculated as weekly number of cataplexy attacks during 
the OL Period – weekly number of cataplexy attacks during the SD Period. 
9.1.2. 
Primary Efficacy Endpoint Analyses 
9.1.2.1. 
Analysis of DB Period  
The observed weekly number of cataplexy attacks during the DB Period and change from 
baseline will be analyzed and summarized using the Efficacy Population (including 
subjects randomized prior to implementation of Amendment 4).  


 
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Statistical testing for a difference between Xyrem and Placebo will be completed using 
a non-parametric analysis of covariance (ANCOVA) with a two-sided test (Conover, Iman 
1981). This is completed by ranking both the baseline covariate and the change from 
baseline value without regard to assigned treatment group. In the event of ties in the 
baseline or change from baseline, average ranks are used. The ranks are used in the 
ANCOVA with the rank for the change from baseline as the dependent variable, 
treatment as a factor, and the rank for the baseline value as the covariate. 
Example SAS code for the modeling is shown below. 
PROC RANK DATA=ANAL OUT=RANKED TIES=MEAN; 
  VAR BASE CHG; 
  RANKS RBASE RCHG; 
RUN; 
 
PROC GLM DATA=RANKED; 
  CLASS TRT01PN; 
  MODEL RCHG = TRT01PN RBASE / SS3; 
RUN; 
 
A histogram augmented with a kernel distribution of the change from baseline in weekly 
number of cataplexy attacks during the DB Period will be presented.   
Sensitivity analysis of the primary endpoint will include:  
• 
Including the stratification factor of Age Group to the PROC GLM model noted 
above.  
• 
Analysis using the per protocol analysis set  
Subgroup analyses of the primary endpoint will be completed, including the non-
parametric ANCOVA and histograms. Any p-values presented for the subgroup analysis 
will be considered exploratory. 
9.1.2.2. 
Interim Analysis of the DB Period 
The interim analysis was completed after 35 randomized subjects completed or 
discontinued early from the DB Period.  
The interim analysis was performed by an 
 biostatistician not directly 
involved with the design and analysis of the study. The data were reviewed by the 
DSMB. The possible recommendations that the DSMB considered were whether to 


 
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continue the study or to stop it early considering the objectives of the study and 
subjects’ safety. Considerations for stopping the study early included the following: 
For stopping the study early because of treatment success, so that fewer subjects 
will be exposed to placebo: The O'Brien-Fleming approach was used with the primary 
efficacy endpoint. This endpoint was tested at a two-sided significance level of 0.005 at 
the interim analysis. 
If statistical significance was shown, the DSMB could recommend stopping the study 
considering the overall study objectives and subject’s safety. If the study was not 
stopped, to maintain an overall alpha of 0.05, the final analysis was to 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 had not been rejected at the 0.005 
significance level, then a futility analysis was to be conducted. The conditional power 
approach was to be used.  
Assuming the trend in the data observed up to the interim analysis would 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 was to be calculated. If the 
conditional power was less than 15%, it was to be concluded that the study was unlikely 
to demonstrate efficacy and the DSMB may recommend stopping the study considering 
the overall study objectives and subjects’ safety. The study could have been 
discontinued early due to futility. 
Conditional power at the time of the interim analysis was calculated using the B-value 
method (Lan and Wittes, 1988).  
Let f be the information fraction (i.e. the proportion of planned subjects at the time of 
the interim analysis) = n / 70. “n” will be the total number of subjects in the efficacy 
population among both randomized treatment groups at the time of the interim 
analysis.  
An LS Means statement for the difference between treatment groups from the ANCOVA 
model on ranks will be used to provide the Z statistic at the time of the interim analysis 
for the conditional power, Zn. Let the B value be 
𝐵𝐵(𝑓𝑓) = 𝑍𝑍𝑛𝑛∗ඥ𝑓𝑓 
The conditional power, at the current trend, will be calculated as: 


 
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1 − 𝛷𝛷[
൬𝑍𝑍𝛼𝛼/2 −(𝐵𝐵(𝑓𝑓)
𝑓𝑓)൰
ඥ1 −𝑓𝑓
] 
where Φ is the cumulative normal distribution, Zα/2 is the Z value from a normal 
distribution for rejection at the final analysis, in this case Z(0.048/2).  
9.1.2.3. 
Additional Analyses of Cataplexy 
Summaries of the number of cataplexy attacks will be completed for the DT, SD, and OL 
Periods. Summaries in the DT and OL periods will be done by 1 week periods and for the 
last 7 days of the period. Supplemental summaries of the SD and DB periods will be 
done by 1 week periods and for the last 7 days of the period. 
Supplemental summaries of the number of cataplexy attacks will be completed for the 
SD and DB period using the 7 day period summaries. 
A separate summary of the number of cataplexy attacks during the DB period using 
subjects who received Open-Label Xyrem in the DB Period. 
Graphical presentations of weekly cataplexy frequency along with bars representing the 
median and interquartile range (IQR) will be created over all dosing periods. This 
presentation will be done using the Safety Population who took Study Drug during the 
study. For the DB Period, the presentation will be separated for those randomized to 
Placebo, those randomized to Xyrem and those assigned OL Xyrem in the DB Period. 
Similar presentations by Age Subgroup and Xyrem Status Subgroup will be presented. 
9.2. 
SECONDARY EFFICACY ENDPOINT(S) AND ANALYSES 
9.2.1. 
Clinical Global Impression of Change (CGIc) for Cataplexy Severity  
CGIc for cataplexy severity is the Tier 2 endpoint.  
The CGIc for cataplexy severity is collected at the end of the DB Period of Part 1. The 
CGIc for cataplexy severity is not collected during Part 2. The investigator rates their 
impression of any change in severity of a subject’s cataplexy severity using the rating 
scale (score) of:  
• 
Very Much Improved (3) 
• 
Much Improved (2) 
• 
Minimally Improved (1) 
• 
No Change (0) 
• 
Minimally Worse (-1) 


 
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• 
Much Worse (-2) 
• 
Very Much Worse (-3) 
 
The summarization will include a frequency analysis showing percentage by category 
within treatment group. Percentages will be based on those subjects with an observed 
value for the assessment. Subjects with missing values are not included in the 
inferential testing but will be identified in a row labeled “Missing”. Percentages will be 
calculated using the number of subjects with a value for the CGIc. 
A CMH test for Row Mean Scores Difference will be used to test the CGIc endpoint. 
There will be no stratification factors used in the analysis. 
Example SAS code for the modeling is shown below. 
PROC FREQ DATA=ANAL; 
  TABLE TRT03PN * AVAL / CMH2 SCORES=TABLE;  
RUN; 
 
Descriptive statistics of the ordinal scores (-3 to 3), including mean and standard 
deviation) will also be provided as an aid for interpretation. 
The number and percent of subjects of CGI-C responders defined as “much improved” 
or “very much improved” will be summarized.  A chi-square test will be performed.  
The p-value will be considered exploratory.  
9.2.2. 
Epworth Sleepiness Scale for Children and Adolescents (ESS 
[CHAD])  
The ESS [CHAD] is the Tier 3 endpoint.  
The ESS [CHAD] 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. The responses to each of the 8 questions have the following 
possibilities: Would never fall asleep, slight chance of falling asleep, moderate chance 
of falling asleep, and high chance of falling asleep. These responses are scored as 0, 1, 
2, and 3 respectively. The ESS [CHAD] score is calculated as the sum of the response 
scores for the 8 questions resulting in a total score from 0 to 24 (Johns, 1991). If a 
subject does not complete all 8 questions during an assessment, the ESS [CHAD] score at 
the assessment will be set to missing.  
ESS [CHAD] scores will be categorized as follows:  


 
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• 
0-10 = Normal  
• 
11-12 = Mildly Increased  
• 
13-15 = Moderately increased 
• 
≥ 16 Greatly Increased  
 
Summarizations of ESS [CHAD] will be completed for the DB and OL Periods of Part 1. 
The ESS [CHAD] is not collected during Part 2. 
 
For the DB Period, the non-parametric ANCOVA model, used for the primary endpoint, 
will be used. The p-value from the ANCOVA will be used as the Tier 3 endpoint testing.   
 
A sensitivity analysis will be used adjusting for use of stimulants in the SD period.  This 
will be included as a Yes/No variable based on whether the subject was supposed to 
take stimulants during the last 14 days of the SD period according to the dosing diary.    
 
9.2.3. 
Clinical Global Impression of Change (CGIc) for Narcolepsy Overall  
CGIc for narcolepsy overall is the Tier 4 endpoint.  
The CGIc for narcolepsy overall is collected at the end of the DB Period of Part 1. The 
CGIc for narcolepsy overall is not collected during Part 2. The investigator rates their 
impression of any change in severity of a subject’s overall condition of narcolepsy using 
the CGIc rating scale (score) of:  
• 
Very Much Improved (3) 
• 
Much Improved (2) 
• 
Minimally improved (1)  
• 
No Change (0) 
• 
Minimally Worse (-1) 
• 
Much Worse (-2) 
• 
Very Much Worse (-3)  
 
The analyses described for the CGIc for Cataplexy Severity will be used for this CGIc 
endpoint. 
9.2.4. 
Quality of Life (QoL) (SF-10) 
The SF-10 Physical Summary Score (PHS-10) and Psychosocial Summary Score (PSS-10) 
final are the Tier 5 endpoints. 
The SF-10™ Health Survey for Children is a parent-completed survey that contains 10 
questions adapted from the Child Health Questionnaire (CHQ). The SF-10 provides 


 
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coverage across a wide range of domains, and is scored to produce physical and 
psychosocial health summary measures (QualityMetric, 2007).  
For subjects on Xyrem at entry, the SF-10 is collected at Visits 2, 3, 4, 5, 7, 9, 12, 15, or 
Early Termination (if applicable) of Part 1. For Xyrem Naïve subjects at entry, the SF-10 
is collected at Visits 1.1, 3, 4, 5, 7, 9, 12, 15 or ET of Part 1. The SF-10 is not collected 
during Part 2. 
9.2.4.1. 
Scoring the SF-10 
Each of the 10 questions responses is scored with a point value from 1 to 6, so that 1 is 
the worst possible condition and 6 is the best possible condition. Mapping of the 
question responses to point values is as follows:  
Question 1: In general, would you say your child’s health is: 
Response Choices 
Code 
Point Value  
Excellent 
1 
6 
Very Good 
2 
4.75 
Good 
3 
3.5 
Fair 
4 
2.25 
Poor 
5 
1 
 
Question 2a: During the past 4 weeks, has your child been limited in any of the 
following activities due to HEALTH problems?  
a. Doing things that take some energy such as riding a bike or skating? 
Response Choices 
Code 
Point Value  
Yes, limited a lot  
1 
1 
Yes, limited some  
2 
2.67 
Yes, limited a little 
3 
4.33 


 
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Question 2a: During the past 4 weeks, has your child been limited in any of the 
following activities due to HEALTH problems?  
a. Doing things that take some energy such as riding a bike or skating? 
Response Choices 
Code 
Point Value  
No, not limited  
4 
6 
 
Question 2b: During the past 4 weeks, has your child been limited in any of the 
following activities due to HEALTH problems?  
b. Bending, lifting, or stooping? 
Response Choices 
Code 
Point Value  
Yes, limited a lot  
1 
1 
Yes, limited some  
2 
2.67 
Yes, limited a little 
3 
4.33 
No, not limited  
4 
6 
 
Question 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?  
Response Choices 
Code 
Point Value  
Yes, limited a lot  
1 
1 
Yes, limited some  
2 
2.67 
Yes, limited a little 
3 
4.33 
No, not limited  
4 
6 
 


 
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Question 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?  
Response Choices 
Code 
Point Value  
Yes, limited a lot  
1 
1 
Yes, limited some  
2 
2.67 
Yes, limited a little 
3 
4.33 
No, not limited  
4 
6 
 
Question 5: During the past 4 weeks, how much bodily pain or discomfort has your 
child had? 
Response Choices 
Code 
Point Value  
None  
1 
6 
Very mild 
2 
5 
Mild  
3 
4 
Moderate  
4 
3 
Severe 
5 
2 
Very severe 
6 
1 
 
Question 6: During the past 4 weeks, how satisfied do you think your child has felt 
about his/her friendships? 
Response Choices 
Code 
Point Value  
Very satisfied 
1 
6 


 
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Question 6: During the past 4 weeks, how satisfied do you think your child has felt 
about his/her friendships? 
Response Choices 
Code 
Point Value  
Somewhat satisfied 
2 
4.75 
Neither satisfied nor 
dissatisfied 
3 
3.5 
Somewhat dissatisfied  
4 
2.25 
Very dissatisfied 
5 
1 
 
Question 7: During the past 4 weeks, how satisfied do you think your child has felt 
about his/her life overall? 
Response Choices 
Code 
Point Value  
Very satisfied 
1 
6 
Somewhat satisfied 
2 
4.75 
Neither satisfied nor 
dissatisfied 
3 
3.5 
Somewhat dissatisfied  
4 
2.25 
Very dissatisfied 
5 
1 
 
Question 8: During the past 4 weeks, how much of the time do you think your child 
acted bothered or upset?  
Response Choices 
Code 
Point Value  
All of the time  
1 
1 
Most of the time  
2 
2.25 


 
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Question 8: During the past 4 weeks, how much of the time do you think your child 
acted bothered or upset?  
Response Choices 
Code 
Point Value  
Some of the time  
3 
3.5 
A little of the time  
4 
4.75 
None of the time  
5 
6 
 
Question 9: Compared to other children your child's age, in general would you say 
his/her behavior is: 
Response Choices 
Code 
Point Value  
Excellent 
1 
6 
Very Good 
2 
4.75 
Good 
3 
3.5 
Fair 
4 
2.25 
Poor 
5 
1 
 
The questions and associated point values are separated into the PHS-10 domain (5 
questions; questions 1, 2a, 2b, 3, and 5) and PSS-10 domain (5 questions; questions 4, 6, 
7, 8, 9). The sum of the scores in the domain (PHS-10 agg and PSS-10 agg) will be 
standardized using the mean and standard deviation from a normal population (2006 
sample).  
PHS-10 standard = (PHS-10 agg – 27.3525139) / 3.6706635.  
PSS-10 standard = (PSS-10 agg - 24.2583251) / 4 .6749490. 
The final scores will be calculated by transforming the standardized scores to the norm-
based scoring (NBS) metric.  


 
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PHS-10 final = (PHS-10 standard x 10) + 50 
PSS-10 final = (PSS-10 standard x 10) + 50 
For the statistical analysis, the final scores will be rounded to one decimal of accuracy.  
Summary aggregate scores, standard scores, and final scores at an assessment will be 
calculated only if all questions within the domain are answered.  
The summary of results in the DB Period will be conducted using the same methodology 
as used for the primary endpoint. A summary of the OL Period results will also be 
completed.  
Descriptive, frequency summaries of the 10 individual questions will be performed. 
The inferential analysis will be performed using the Efficacy population for the summary 
aggregate scores.    
9.3. 
EXPLORATORY EFFICACY ENDPOINT(S) AND ANALYSES 
Exploratory efficacy endpoints will be tested without multiplicity adjustments. For 
these parameters, nominal p-values will be reported. 
9.3.1. 
Weekly School Attendance   
9.3.1.1. 
Calculation of Endpoint  
In Part 1, the school attendance diary is collected from subjects who attend school 
during the last two weeks of the SD Period and during the DB Period. The school 
attendance diary is not collected during Part 2. The diary collects whether the child was 
scheduled to attend school on the day and whether the child missed school that day due 
to narcolepsy.  
For the SD Period and DB Period of Part 1, the percentage of school days missed due to 
narcolepsy will be calculated as: (the count of days missed / the count of days where 
the child was scheduled to attend) x 100%. This value will be calculated only if a 
subject has submitted a diary indicating that they were scheduled to attend school on 
at least one day during the period. 
The % of days missed will be calculated only if the total number of days the subject was 
scheduled to attend during the period (using available, collected diary days) is at least 
7. The change in percentage missed will be calculated as the percentage of days missed 
in the DB Period minus the percentage of days missed in the SD Period.  


 
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The analysis of school attendance will be presented only for subjects in the Efficacy 
Population who have school diaries in both the SD Period and DB Period. A separate, 
descriptive summarization will be performed using those subjects who received Open-
Label Xyrem during the DB Period, and have school diaries in the SD Period and DB 
Period.  
Observed values and change from baseline in the percentage of days missed will be 
summarized using the same methodology as the primary endpoint.  
9.3.2. 
PGIc for Narcolepsy Overall   
During Part 1, the PGIc for narcolepsy overall is collected at the end of the DB Period or 
ET visit, if the subject discontinues in the DB Period. The PGIc for narcolepsy overall is 
not collected during Part 2. 
The subject is asked to respond to the question “How would you rate your narcolepsy 
since Visit 3 (the end of the Stable-Dose Period)?” Responses are from a 7 point scale 
(score) of:  
• 
Very much better (3) 
• 
Much better (2) 
• 
A little better (1) 
• 
No change (0) 
• 
A little worse (-1) 
• 
Much Worse (-2) 
• 
Very Much Worse (-3)  
 
Summarization of the DB Period will be done using the same method as used for CGIc 
for Cataplexy Severity.  
This analysis will be performed using the Efficacy population. A separate, descriptive 
summarization will be performed using those subjects who received Open-Label Xyrem 
during the DB Period.  


 
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10. 
ANALYSIS OF PHARMACOKINETICS 
The analysis of PK data will address the Secondary Objective #2.  
The collection of PK data is only done during Part 1 of the study. 
Summaries by Xyrem dosage will include: by-subject plots of sodium oxybate 
concentrations and log transformed sodium oxybate concentrations, summaries of 
sodium oxybate concentrations by collection time, summaries of calculated PK 
parameters, and analyses of dose proportionality using the Area under the Plasma Time 
Concentration Curve through 4 hours (AUC0-4),  AUC0-infinity and Maximum Plasma Drug 
Concentration (Cmax).  
10.1. 
SODIUM OXYBATE CONCENTRATION DATA  
Plasma samples for the characterization of sodium oxybate pharmacokinetic profiles are 
collected during the SD Period or during the OL Period. Samples for the collection of 
sodium oxybate concentrations are collected on two separate PK nights.  
For subjects on Xyrem at study entry participating in the PK assessments in the SD 
Period, PK Night 1 will occur on the first night of the SD Period and PK Night 2 will occur 
the next night or within 15 days of PK Night 1.  
Prior to Amendment 4, subjects on Xyrem at study entry or Xyrem Naïve subjects at 
study entry participating in the PK assessments in the OL Period, the PK Night 1  
occurred after retitration to a stable dose and there is no restriction on timing of PK 
Night 2. 
After Amendment 4, subject PK assessments could occur at any point in time where the 
subject was on a stable does of Xyrem. 
On the PK night 1, the subject will receive ½ of their usual and current nighttime Xyrem 
dosage (separated into two equally divided dosages delivered at bedtime and 4 hours 
later). On the PK Night 2, the subject will receive their usual current nighttime Xyrem 
dosage (separated into two equally divided dosages delivered at bedtime and 4 hours 
later).  
On both nights, samples will be collected pre-dose, 0.75, 1.5, 2.5 and 4 (pre-2nd dose), 
4.75, and 8 hours post first Xyrem dose on the PK night. The allowable windows for the 
sample collections are +/- 5 minutes. Concentration data from first dose on each PK 
night will be used to calculate sodium oxybate PK parameters (see SAP sections 10.2-
10.6). Sodium oxybate concentrations at 4.75 hours (0.75 hours after the 2nd dose) and 8 


 
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hours (4 hours after the 2nd dose) will be presented as peak and residual exposure 
associated with the second nighttime dose. 
Samples will be summarized by scheduled time point. Elapsed time from dose will be 
used for the calculation of PK parameters.  
All sodium oxybate concentrations recorded below limit of quantification (BLQ) will be 
imputed with a concentration of 0.  
Using the PK Half-Dose Population, concentration data will be presented in listings. 
Xyrem dosage in (g/night), subject’s weight (kg) and BMI (kg/m2) collected closest to 
the PK night, actual date/ time of dosing, scheduled collection time, actual date/time 
of sample collection, elapsed time from first dosing on that PK night, and concentration  
will be provided. The concentration data and log transformed concentration data will 
also be presented in by-subject plots with the results of PK night 1 and PK night 2 shown 
on the same page.  A natural logarithmic transformation will be used (i.e. loge). 
Summaries of the concentrations on PK Night 1 will be presented using the PK Half-Dose 
Population as well as for the PK Full-Dose Population and PK Completer Population. A 
summary of concentrations by time point on PK Night 1 and PK Night 2 will be presented 
for the PK Full-Dose Population and PK Completer Population. 
By time point summaries will be provided by Age Group, available Xyrem dosage levels 
(g/night), and overall using scheduled time point. Summary statistics for number of 
observations, mean, standard deviation, coefficient of variation (CV(%)), median, Q1, 
Q3, minimum, and maximum values will be presented.  
10.2. 
AREA UNDER THE PLASMA TIME CONCENTRATION CURVE 0-4 
HOURS (AUC0-4)   
The AUC0-4 on PK Night 1 and PK Night 2 will be calculated using the samples collected 
up to and including the scheduled 4 hour (pre-2nd dose) sample, as long as these samples 
were collected prior to the 2nd nightly dose. The linear trapezoidal rule will be used for 
the calculation.  
𝐴𝐴𝐴𝐴𝐴𝐴= ∑
ቀ
1
2ቁ∗(𝐶𝐶𝑘𝑘+ 𝐶𝐶𝑘𝑘+1) ∗(𝑡𝑡𝑘𝑘+1 −𝑡𝑡𝑘𝑘)
𝑘𝑘−1
1
 , where k=1, 2, .., n are the collection 
numbers, Ck are the concentration values and tk are the elapsed time in hours from the 
first dose of Xyrem on the PK night. Scheduled pre-dose samples will have 0 used for the 
elapsed time from dosing for calculation of AUC values.  
If the subject does not have a sample collected at the 4 hour time point, the AUC0-4 will 
not be calculated. 


 
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AUC0-4 Summaries 
Summaries of the AUC0-4 on PK Night 1 will be completed, using the PK Half-Dose 
Population, PK Full-Dose Population and PK Completers Population, by Age Group, 
available Xyrem dosage levels (g/night),  and overall. A summary of AUC0-4 on PK Night 1 
and PK Night 2 will be completed using the PK Full-Dose Population and PK Completer 
Population. Summary statistics presented will include the number of observations (n; 
number of AUC0-4 values), Mean, Standard Deviation, CV (%), Geometric Mean, 
Geometric Standard Deviation, Median, Minimum and Maximum. 
Dose Proportionality  
For subjects in the PK Completer population, analyses for dose proportionality will be 
performed for AUC0-4. The analyses will be done utilizing those subjects with AUC0-4 
parameters available on both PK night 1 and 2.  
For each parameter, the log transformed value on PK night 2 minus the log transformed 
value on PK night 1 will be the response variable. The natural log function will be used. 
The estimated mean difference and 90% confidence interval will be back-transformed to 
ratio scale by exponentiation in order to interpret the results in ratio scale. If the value 
2 is contained within the 90% confidence interval, it will indicate proportionality. For 
the PK Completer population, the subject’s AUC0-4 on PK night 2 will be plotted against 
the AUC0-4 on PK night 1 as a visual aid for dose proportionality.  
Regression Modeling  
Regression models will explore the relationship between AUC0-4 vs. Xyrem dosage. A 
repeated measures model will be fit using the AUC0-4 parameter as the dependent 
variable with the first nightly Xyrem dosage in mg/kg, Age Group, and PK night as the 
fixed effects.  A log transformation may be used for the dependent variable. Visit will 
be considered a repeated effect and compound symmetry specified as the covariance 
structure.  If compound symmetry fails to converge, autoregressive (1) will be used.  
Regression coefficients will be provided. 
AUC0-4 values will also be presented with a scatterplot plotting the AUC vs. the first 
nightly Xyrem dosage in mg/kg. The regression model and scatterplot will be done for 
the PK Half-Dose Population.  
10.3. 
MAXIMUM PLASMA DRUG CONCENTRATION (CMAX) 
On each PK night, Cmax will be determined from post dosing concentrations up to and 
including the 4 hour post dose, as long as the 4 hour sample was collected prior to or at 
the same time as the 2nd evening dosing. Cmax is the defined as the highest concentration 


 
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through 4 hours post dose for the subject on the night. The summarization will utilize 
the same populations and methodology used for the AUC including analyses for dose 
proportionality and multivariate regression modeling as appropriate. 
10.4. 
PLASMA DRUG CONCENTRATION AT 8 HOURS (C8HOURS) 
On each PK night, C8Hours will be determined from the post dosing concentration at 8 
hours post first dose. The summarization will utilize the same populations and 
methodology used for the AUC including analyses for multivariate regression modeling 
as appropriate; however, total nightly dose will be used for analysis purposes. 
10.5. 
TIME TO MAXIMUM PLASMA CONCENTRATION (TMAX)  
On each PK night, Tmax will be determined from post dosing concentrations up to and 
including the 4 hour post dose. It is defined as the elapsed time from the first dose on 
the PK night associated with the highest sodium oxybate concentration, measured in 
hours. Values will be summarized descriptively. 
10.6. 
AREA UNDER THE PLASMA TIME CONCENTRATION CURVE (0-
INFINITY) AND HALF LIFE (T1/2) 
The AUC0-infinity on PK Night 1 and PK Night 2 will be calculated using the samples 
collected up to and including the scheduled 4 hour (pre-2nd dose) sample, as long as the 
samples are prior to the 2nd nightly dose. The linear trapezoidal rule will be used for the 
calculation of AUC through the last measurable concentration above limit of 
quantification. Samples after the Cmax time point through the 4 hour sample, which are 
above limit of quantification, will be used for the terminal phase. If there are at least 3 
samples in the terminal phase, a linear regression of log transformed concentration vs. 
time will be completed. AUC0-infinity will be calculated as AUC0-Last + Last Concentration / 
(-1* slope of the regression line). 
The summarization will utilize the same populations and methodology used for the   
AUC0-4 including analyses for dose proportionality, if appropriate. 
The half-life on PK Night 1 and PK Night 2 will be calculated using the slope from the log 
transformed concentrations vs. time used to determine the AUC0-infinity. T1/2 will be 
calculated as log 2 / slope. The natural logarithmic function will be used. 


 
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11. 
SAFETY 
Subject safety will be assessed via incidence of AEs, vital signs, physical examinations 
(including weight and height), 12-lead ECG, PSG parameters, clinical laboratory results, 
assessments of growth and precocious puberty, C-SSRS, CDI 2: SR[S], and MASC-10 
assessments.  
Unless otherwise specified, summaries will be provided as described in Section 7.1 using 
the populations as described in Section 6. 
Subgroup analyses for key safety endpoints are provided in Section 7.6. 
Analyses of extent of exposure, adverse events, vital signs, physical examinations 
(including height and weight) will be collected during Part 2. They will be summarized 
for Part 2 using the Safety Population who Took Study Drug in the Part 2 Open-Label 
Continuation Period.  
11.1. 
EXTENT OF EXPOSURE 
Exposure to study drug will be summarized separately for the DT Period, SD Period, DB 
Period, and OL Period.  
For the DT Period, the following variables will be summarized: 
• 
starting Xyrem dosage (in g/night and mg/kg/night), 
• 
number of adjustments (upward titrations and reductions), 
• 
cumulative Xyrem dosage (in grams), 
• 
total duration of exposure (in days) 
The summarization will be done by Age Group, subject weight at the start of titration 
(categorized as < 30 kg, ≥ 30 kg - < 45 kg, and ≥ 45 kg) and overall. 
For the SD Period, the following variables will be summarized: 
• 
Xyrem dosage level (in g/night and mg/kg/night), 
• 
cumulative dosage received (in grams), 
• 
total duration of treatment in days 


 
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For the DB Period, the following variables will be summarized using the actual 
treatment received:  
• 
starting dosage level dispensed (in g/night and mg/kg/night),  noting that the 
subjects randomized to receive placebo will be receiving a matching placebo,  
• 
cumulative dosage received (in grams), 
• 
total duration of treatment in days 
For the OL Period the following variables will be summarized:  
• 
final dosage level used in the period (in g/night and mg/kg/night), 
• 
cumulative dosage received (in grams), 
• 
average nightly dosage during the OL Period (calculated as cumulative dosage 
and dividing by the duration of treatment), 
• 
total duration of treatment in days 
Calculation of dosage in mg/kg/night for DT, SD, and DB period will be completed using 
the latest weight collected prior to or on the start of each Period. For the OL period, 
the latest weight collected prior to or on the last dose will be used. 
For Part 2, an overall summarization of Xyrem exposure will be completed. The total 
days of exposure to Xyrem and cumulative total Xyrem exposure (in g) will be 
summarized using the Safety Population who Took Study Drug in the Part 2 Open-Label 
Continuation Period. The duration is defined as last dose date in Part 2 – first dose date 
in Part 2 + 1 day. 
A cumulative exposure summary to Xyrem over Part 1 and Part 2 periods will be 
completed using the Safety Population who Took Study Drug. The total days of exposure 
to Xyrem, cumulative Xyrem exposure (in g) will be summarized. A categorical 
summarization of exposure to Xyrem will be completed, categorizing exposure at the 
cut points: at least 6 months, at least 1 year, at least 18 months, at least 2 years, and 
at least 3 years will be provided. 
For the total exposure period across Part 1 and the entire study (Part 1 and Part 2), the 
number of subjects who were treated at the maximum proposed dosage for use in the 
study will be summarized by age group. The maximum dosage allowable per protocol is 
shown in Table 1 of the protocol document (in Section 3.1.2) and is determined based 
on the subject’s baseline weight in Part 1. Subjects entering on Xyrem will be assessed 


 
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using the same dosing table.  The duration in days treated at this maximum dosage will 
be calculated and summarized. For subjects treated with Placebo during the DB period, 
the number of days treated in the DB period will not be included in the total exposure 
days at the maximum assigned nightly dose. 
11.2. 
TREATMENT COMPLIANCE  
For Part 1, compliance will be assessed using the parent/subject completed morning 
dosing diary entries. Percentage compliance will be computed separately for each 
subject in each period. In Part 2, morning dosing diaries are not collected. Compliances 
based on dosing diaries will not be calculated for Part 2. 
Percent compliance will be calculated as the percentage of doses taken out of the 
expected number of doses. The number of doses taken will be determined using the 
morning diary entries completed during the period. It will be assumed that any morning 
where a dosing diary was not submitted indicates that the doses on that night were not 
taken. The number of doses expected to have been taken will be calculated as 2 times 
the number of days in the dosing period. 
A second compliance calculation will be completed based on the duration of treatment 
in the each period, the dosage in g/night that the subject was expected to take based 
on the exposure log records, and the quantity of study drug (measured in mL) returned 
at each visit. This will be referred to as Bottle Weight Compliance on the tables and 
listings. The Bottle Weight Compliance will be determined for each period of Part 1. 
The Bottle Weight Compliance will be determined in Part 2 for the Subjects in Safety 
Population who Took Study Drug in the Part 2 Open-Label Continuation Period.  
Details of calculation of Bottle Weight Compliance are as follows. 
The initial quantity of drug in a dispensed bottle is 180 mL. The concentration of Xyrem 
in a bottle is 500 mg/mL. The returned quantity (in mL) is recorded on the CRF. The 
difference is the actual quantity of drug taken, in mL.  
For both Part 1 and Part 2, each night’s expected quantity of drug to be taken, based 
on the assigned dosage level calculated as D * 1000 / 500, where D is the dosage level in 
g per administration, 1000 is the number of mg per g, and 500 is the concentration of 
Xyrem in the solution (in mg/mL).  
As an example, if a subject was on a dose of 5 g/night, evenly split into 2.5 g per each 
nightly administration, the quantity of drug in mL expected to be given at that 
administration is:  
(2.5 g x 1000 mg/g) / (500 mg/mL) = 5 mL. 


 
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100 times the ratio of [the quantity taken determined by bottle divided by the 
calculated amount to be taken based on dosing log] will be the Bottle Weight 
Compliance. 
Compliance and Bottle Weight Compliance will be categorized as < 75%, 75-90%, or > 
90%. 
For each study period in Part 1, the percent compliance, percent bottle weight 
compliance, categorized compliance, and categorized bottle weight compliance will be 
summarized. 
For Part 2, the percent bottle weight compliance and categorized bottle weight 
compliance will be summarized for the following periods:  
• 
Part 2 Day 1 – Visit 21 Month 3 
• 
Visit 21 Month 3 – Visit 24 Month 6  
• 
Visit 24 Month 6 – Visit 27 Month 9 
• 
Visit 27 Month 9 – Visit 30 Month 12 
• 
Visit 30 Month 12 – Visit 33 Month 15 
• 
Visit 33 Month 15 – Visit 36 Month 18 
• 
Visit 36 Month 18 – Visit 39 Month 21 
• 
Visit 39 Month 21 – Visit 42 Month 24 
• 
Overall Part 2 Compliance 
Early termination visits in Part 2 will be mapped according to the rules in Section 7.4 
and summarized accordingly. For each of these periods, the expected weight to be 
taken will be determined starting one day after the bottle dispense at the start of the 
period and ending at the day of the bottle return.   
11.3. 
ADVERSE EVENTS 
For Part 1, AEs occurring after patient assent or informed consent and until the last 
study visit (through the Study Follow-up Visit or early termination) will be recorded on 
the eCRF. For Part 2, AEs occurring after reconsent or assent for Amendment 5 through 
completion of the Part 2 visit will be recorded on the eCRF. Terms will be coded to the 


 
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MedDRA dictionary version 17.0. Events will be assessed as occurring in treatment 
periods based on the onset date and the date of first dosing in each of the treatment 
periods. Treatment emergent AE (TEAE) will be defined for a period. As times of dosing 
are not reported at the start of each of the treatment periods, onset times will not be 
considered for determination of the period in which the event occurred. In instances 
where the subject has reported multiple events with the same preferred term (PT) and 
the onset date indicates that the events had onsets in different dosing periods, the 
event will be counted as occurring in each of the periods. Terms will be summarized 
using the system organ class (SOC) and preferred term (PT). 
 
Events that occurred after consent or assent that have onset dates prior to the first 
dose in the DT Period (for Xyrem Naïve subjects) or SD Period (for subjects on Xyrem at 
entry) will be shown in listings but will not be included in any AE summary. 
 
For Part 1, AEs with onset date that are on or after the last dose date and up to and 
including 30 days after the last dose date will be included in the AE summaries. These 
events will be allocated to the last treatment period in which the subject took study 
medication. AEs with onset date more than 30 days after the last dose date in Part 1, 
but not after the date of first dosing in Part 2, will not be included in the AE summaries 
but will be displayed in listings. AEs with onset date more than 30 days after the last 
dose date in Part 2 will not be included in the AE summaries for Part 2 but will be 
displayed in listings. 
 
Events with completely missing onset dates are unexpected. However, if they occur, 
they will be classified as having onset in the earliest dosing period implied by the 
portion of the onset date provided (see SAP Section 7.3).  
 
Drug-related or procedure-related adverse events will be defined based on the 
investigator’s assessment. Events with missing values for relationship to study drug or 
procedure will be classified as being related to study drug or procedure, respectively.  
 
AEs of special interest will be defined with agreement from the Jazz clinical team and 
DSMB. The PTs included in this list will be kept in a separate document from this SAP 
and may be amended by the DSMB or the Jazz clinical team. The list of terms will be 
finalized prior to the data base snapshot or data base lock for the final analysis, and 
will include, at least the PTs related to the terms noted in Section 9.9 of the protocol. 
• 
Confusion 
• 
Somnolence and more pronounced levels of depressed consciousness 
• 
Respiratory depression 
• 
Depressed mood and suicidality 
• 
Anxiety 
• 
Sleepwalking and other parasomnias 


 
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• 
Abuse and misuse of study drug 
• 
Weight loss 
 
Results across the study are presented by Age Group and Xyrem status at initial study 
entry for the Safety Population who took study drug. All summarizations of AEs will 
provide the number and percentage (i.e., subject incidence) of subjects who 
experienced the event. Subjects who experienced multiple events within the same SOC 
during a period will be counted once in the SOC summary. Subjects who experienced 
multiple occurrences of events with the same PT during a period will be counted once in 
the PT summary. Percentages will be calculated using the total number of subjects in 
the population.  
 
Separate summaries by the Safety Population who took study drug in the period will be 
provided for:  
• 
Overall summary of TEAE incidence 
• 
TEAEs with onset in each period by SOC and PT (sorted in descending order of 
subject incidence) 
• 
TEAEs with onset in each period by PT (sorted in descending order of incidence) 
• 
TEAEs with onset in each period by Maximum Severity (sorted in descending 
order of incidence) 
• 
Treatment-Related TEAEs with onset in each period (sorted in descending order 
of incidence) 
• 
TEAEs of Special Interest with onset in each period (sorted in descending order 
of incidence)Serious TEAEs (sorted in descending order of incidence) 
• 
TEAEs leading to Permanent Withdrawal of Study Drug (sorted in descending 
order of incidence) 
 
Due to the small number of Serious TEAEs and TEAEs leading to Permanent 
Withdrawal of Study, these summaries may be presented only in listings.  
 
TEAE summaries across Part 1 will include the following: 
• 
Overall summary of TEAE incidence 
• 
TEAEs by PT while receiving Xyrem (excluding DB Period events for those treated 
with Placebo during the DB Period) 
 
Combined adverse event summaries across the study (Part 1 and Part 2) will be provided 
for: 
• 
Overall summary of TEAE incidence 
• 
TEAE by PT, regardless of treatment during the DB period 
• 
TEAE by PT while receiving Xyrem  


 
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• 
TEAEs of Special Interest while receiving Xyrem  
 
11.3.1. 
Additional AE Analyses 
For each period and across the study, the subject incidence of TEAEs will be 
summarized for each nightly dose level by SOC and PT. The nightly dose will be based 
on the dose taken the night prior to the start date of the adverse event. For adverse 
events occurring on Study Day 1, the dose taken the night of the AE will be used. 
Additionally, the incidence of TEAEs by SOC, PT, and most recently assigned dosage of 
Xyrem in mg/kg/night will be provided for the DT period and combining all periods from 
the SD period onwards. The most recently assigned dosage of Xyrem in mg/kg will be 
categorized based on the tertiles of Xyrem mg/kg dosage in the SD period for subjects 
treated in the SD period. The subject incidence and exposure adjusted event rate of 
TEAEs using SOC/PT (as well as the subset of TEAEs of Special Interest) while on Xyrem 
will be summarized across the study. The exposure adjusted event rate will be defined 
as the number of events experienced divided by the number of days of Xyrem exposure. 
Recurrent AEs are included in the event rates. Results are provided per 100 days of 
exposure, as it is expected to be easier to interpret given the low rates with patient-
days of exposure alone. Therefore, event rates are multiplied by a factor of 100. Events 
recorded during the DB Period for subjects who received Placebo will not be included. 
Similarly, the days of exposure during the DB period will not be included in the duration 
of Xyrem exposure during the DB period for subjects who received Placebo during the 
period. 
11.4. 
LABORATORY EVALUATIONS 
For Part 1, routine blood and urine samples for the assessment of hematology, 
chemistry and urinalysis parameters are collected at the screening visit, at the end of 
the DB Period (or early termination), and at the end of the OL Period (or early 
termination). Abnormal laboratory parameters deemed clinically significant (by the 
investigator) must be re-evaluated. For Part 2, blood and urine samples for the 
assessment of hematology, chemistry and urinalysis are only scheduled to be collected 
at Screening Visit 17 for subjects who re-enrolled in Part 2 after completion of Part 1. 
Otherwise for Part 2, only available local laboratories results (urine pregnancy test, 
urine drug screen, and alcohol test) will be provide. These will not be included in any 
analyses, but will be shown in listings.  
For Part 1, assessments of growth and precocious puberty are collected at the Screening 
visit, End of Stable Dose PSG for Xyrem Naive subjects, Visit 4, and at the end of the OL 
Period (or early termination). These assessments include: growth hormone, insulin-like 
growth factor, and prolactin. Sex hormones are collected only for females under 8 years 


 
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and for males under 9 years at screening and at the end of the study conduct.  Tests for 
growth and precocious puberty are not scheduled for collection in Part 2. 
Samples for coagulation will be collected within 30 days prior to PK Night 1 for those 
subjects participating in the PK evaluations. Coagulation test samples are not collected 
in Part 2. 
During Part 1, thyroid stimulating hormone (TSH) will be collected at screening for all 
subjects. TSH is not scheduled for collection in Part 2. 
Pregnancy tests will be done for female subjects who reached menarche. During Part 1, 
these are done at screening, at the start of the DT Period, at the start of the SD Period 
(for Xyrem experienced subjects), at the end of the DB Period, and at the end of the OL 
Period. During Part 2, for subjects who re-enrolled in Part 2 after completion of Part 1, 
pregnancy tests are collected at Visit 17 and Visit 18. For all female subjects in Part 2 
who have reached menarche, pregnancy tests are collected every six months and at 
study completion or early termination. Pregnancy test results will be listed only. 
During Part 1, drug and alcohol screening assessments will be collected at screening, at 
the beginning of the DT Period (for Xyrem Naïve subjects), at the start of the SD Period 
(for subjects previously on Xyrem), at the end of the DB Period, and during the OL 
Period. During Part 2, drug and alcohol screenings are collected at Visit 17 and Visit 18, 
for subjects who re-enrolled in Part 2 after completion of Part 1.  For all subjects in 
Part 2, drug and alcohol screening will be collected every six months. Drug and alcohol 
screening will be listed only. 
Scheduled collections will be assessed by a central laboratory. Follow-up of clinically 
significant abnormal values may be done by a local laboratory or the central laboratory. 
For by-visit summaries, only the central laboratory results will be included. 
Summarizations for hematology, chemistry, and assessments of growth and precocious 
puberty, will be done using the results reported in standardized international (S.I.) 
units. 
For Part 1, by visit summarizations of hematology, chemistry, urine pH, and growth 
hormones will be done using descriptive statistics. Observed values and changes from 
baseline will be summarized. 
For Part 1, summarizations of baseline values will be done using the Safety Population. 
Additional summaries will be completed for the DB and OL Periods. 


 
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For Part 1, summarizations of maximum ratio to upper limit of normal for AST 
(Aspartate aminotransferase (SGOT)), ALT (Alanine aminotransferase (SGPT)), and Total 
Bilirubin within the DB Period and OL Period will be conducted. 
AST and ALT values will be categorized as: 
• 
≤ 1 x ULN,  
• 
> 1 - < 3 x ULN,  
• 
≥ 3 - < 5 x ULN,  
• 
≥ 5 x ULN 
 
Total Bilirubin values will be categorized as: 
• 
≤ 1 x ULN,  
• 
> 1 - ≤ 1.5 x ULN,  
• 
> 1.5 - < 2 x ULN,  
• 
≥ 2 x ULN 
 
For Part 1, occurrences of ≥ 3 x ULN elevations in either AST or ALT accompanied by a ≥ 
2 x ULN elevation in total bilirubin (i.e. on the same collection date) will also be 
summarized.  
All laboratory data will be provided in listings. Separate listings will be produced for 
subjects with at least one abnormal laboratory recording that the investigator has 
deemed clinically relevant. On these listings, all records that the subject has for the 
particular test with one (or more) clinically relevant value will be shown and will 
identify the date/time of collection, visit, period of collection and the indication of 
clinical relevance. Liver function tests for subjects with at least one of: AST > 3 x ULN, 
ALT > 3 x ULN, or Bilirubin ≥ 2 x ULN will be displayed on the clinically relevant 
laboratory result listing. Indications for abnormality and the noted elevations will be 
made. 
11.5. 
VITAL SIGNS / OXYGEN SATURATION, END TIDAL CO2 / 
TRANSCUTANEOUS CO2 
For Part 1, vital signs, including systolic blood pressure (SBP), diastolic blood pressure 
(DBP), pulse rate (in beats per minute), respiratory rate (breaths per minute), and body 
temperature, measured in degrees Celsius, are collected at each clinic visit.  During 
Part 2, the SBP, DPB, pulse rate, respiratory rate, and body temperature are collected 
at Visit 17 and Visit 18 (for subjects who re-enrolled after completion of Part 1), and at 
the quarterly onsite clinic visits Visit 21 Month 3, Visit 24 Month 6, Visit 27 Month 9, 


 
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Visit 30 Month 12, Visit 33 Month 15, Visit 36 Month 18, Visit 39 Month 21, and Visit 42 
Month 24 or Early Termination. 
For Part 1 and Part 2, summaries of observed values, changes from Part 1 Day 1 
baseline, and change from Part 2 Day 1 baseline will be provided for all treatment 
periods as applicable. 
During PSG nights in Part 1, SBP, DBP, pulse rate, respiratory rate, oxygen saturation 
(SpO2), End Tidal CO2 (EtCO2), and Transcutaneous CO2 are collected prior to the first 
Xyrem dosage, 1 hour post dose, 4 hours post dose (prior to second Xyrem dosage for 
the night), 5 hours post first dose, 8 hours post first dose and prior to release from the 
study center. 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.  PSG sessions are not scheduled for collection in Part 
2. 
On each PSG night, changes will be calculated from the pre-dose value collected on that 
night. Summaries of vital signs for PSG nights will be completed using the Safety 
Population. Observed values and changes from pre-dose will be done by Age Group and 
overall. 
For subjects participating in the PK evaluations, SBP, DBP, pulse rate, respiration rate, 
body temperature and SpO2 are obtained prior to dosing on both PK nights. At 1 hour 
post dose, 4 hours post dose (prior to second nightly Xyrem dosage), 5 hours post dose, 
and 8 hours post dose, the BP, pulse rate, and respiration rates are collected. SpO2 is 
recorded pre-dose and at 1 hour post dose, 2 hours post dose, 4 hours post dose (pre-
2nd dose), 5 hours post dose, 6 hours post dose, 8 hours post dose, and while the 
subject is awake and before release from the study center. 
On each PK night, changes will be calculated from the pre-dose value collected on that 
night. A summary of vital signs on PK night 1 will be completed using the PK Half-Dose 
Population. A summary of vital signs on PK night 1 and 2 will be completed using the PK 
Full-Dose Population.  
11.6. 
PHYSICAL STATURE  
For Part 1, measurements of physical stature, height (cm) and weight (kg), are 
completed at each clinic visit during the study. For Part 2, the measurements of 
physical stature are collected at Visit 17 and Visit 18 (for subjects who re-enrolled after 
completion of Part 1), and at the quarterly on-site clinic visits. 
Body mass index (BMI) will be calculated at each visit as: 
BMI = Weight (kg) / (Height (m)2). 


 
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Age and sex based percentiles for height, weight, and BMI at each assessment will be 
determined using the 2000 CDC growth charts published by the Centers for Disease 
Control (CDC) (Kuczmarski et al, 2002). The CDC has published a SAS program, including 
reference datasets for determination of these percentiles. The website containing the 
information with this information is at:  
http://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm 
Percentiles will be based on age in months at the date of the assessment. 
Percent change from baseline in weight will be categorized as:  
• 
≥ 15% decrease  
• 
10 - < 15% decrease  
• 
7 - < 10% decrease 
• 
< 7% weight change 
• 
7 - < 10% increase 
• 
10  -< 15% increase 
• 
≥ 15% increase 
 
For Part 1 and Part 2, summaries of observed values, change from Part 1 Day 1 baseline, 
change from Part 2 Day 1 baseline, and categorized percent changes (Part 1 only) in 
weight, height, and BMI values and percentiles will be provided for all treatment 
periods.  
Graphical summaries of height, weight, and BMI percentiles will be created separately 
for Part 1 and Part 2. The graph of the mean values, with bars for +/- 1 SD (or Standard 
Error as appropriate), will be presented covering all dosing periods, using the Safety 
Population who Took Study Drug in any period. For the DB Period, means and error bars 
will be presented separately for those who received Placebo in the DB Period vs. those 
who received Xyrem in the DB Period.  Similar presentations by Age Subgroup and Xyrem 
Status Subgroup will be presented.  
11.7. 
ECG  
During Part 1, ECGs are collected at Visit 1 (Screening), Visit 4 (End of Double-Blind 
Treatment Period/Beginning of Open-Label Safety Period), and at Visit 15 (Week 52) or 
ET. The interval measurements and interpretations are being provided by a central 
reader, Clinilabs. ECGs are not scheduled for collection in Part 2. The reader will 
provide for each assessment the following assessments: 
• 
Heart Rate (HR) in beats/minute  
• 
RR Interval in msec  


 
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• 
PR Interval in msec 
• 
QRS Interval in msec 
• 
QT Interval in msec  
• 
QTc Bazett’s correction (QTcB) in msec  
• 
Overall Interpretation of ECG  
 
Threshold values for the QT and QTcB will be defined as follows:  
 
• 
QT > 440 msec  
• 
QT > 450 msec 
• 
QT > 480 msec 
• 
QT > 500 msec 
• 
QTcB > 440 msec  
• 
QTcB > 450 msec  
• 
QTcB > 480 msec  
• 
QTcB > 500 msec  
• 
Change from baseline in QT > 30 msec 
• 
Change from baseline in QT > 60 msec 
• 
Change from baseline in QTcB > 30 msec 
• 
Change from baseline in QTcB > 60 msec 
 
In the event of multiple assessments during a period, the worst evaluation will be 
selected for analysis and highest interval values will be selected for analysis. 
 
Summarizations of Overall Interpretation, QT and QTcB values exceeding the defined 
thresholds, observed values and change from baseline in ECG intervals will be provided 
for the Screening, DB, and OL treatment periods. 
 
A shift table comparing Overall Evaluation at Screening vs. the Overall Evaluation at the 
end of DB Period will be completed. A similar shift table comparing Overall evaluation 
at Screening vs. Overall Evaluation at the final visit will be completed. 
 
11.8. 
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS)  
The Columbia-Suicide Severity Rating Scale (C-SSRS) is used to measure suicide ideation 
and behavior. 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. During Part 1, assessments of the C-SSRS are made at each contact with the 
subject, including phone contacts. The C-SSRS is not scheduled for collection in Part 2. 
The instruments are presented in full in the protocol document Appendix 8. 


 
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The following C-SSRS questions on the scale have binary responses (yes/no). 
 
• 
Suicidal Ideation (Categories 1 – 5) 
1. Wish to be dead 
2. Non-specific active suicidal thoughts 
3. Active suicidal ideation with any methods (not plan) without intent to act 
4. Active suicidal ideation with some intent to act, without specific plan 
5. Active suicidal ideation with specific plan and intent 
• 
Suicidal Behavior (Categories 6 – 10) 
6. Preparatory acts or behavior 
7. Aborted attempt 
8. Interrupted attempt 
9. Non-fatal suicide attempt 
10. Completed suicide (only collected on “Since Last Visit” version) 
• 
Any Suicidal Ideation or Behavior (1-10) 
• 
Self-injurious Behavior without Suicidal Intent 
 
For each period, the observed Suicidal Ideation, Suicidal Behavior, any Suicidal Ideation 
or Behavior, and any Self-injurious behavior without suicidal intent will be summarized 
by visit. 
 
A listing of subjects with any Suicidal Ideation, Suicidal Behavior, or Self-Injurious 
Behavior without Suicidal Intent will be provided.  
 
11.9. 
POLYSOMNOGRAPY (PSG)  
During Part 1, polysomnography assessments are done during the Screening Period, Visit 
3 (End of Stable Dose Period) (for Xyrem Naïve subjects at study entry), and Visit 15 
(Week 52) or ET. PSG assessments are not scheduled for collection in Part 2. The data 
for these assessments will be provided by Clinilabs. The following list of parameters, 
provided by the vendor Clinilabs, will be summarized. For subjects on Xyrem at entry, 
the parameters are recorded for the first half of the night, second half of the night, and 
full night. For Xyrem Naïve subjects, the parameters are provided for the full night at 
screening and by first half of the night, second half of the night, and full night at 
subsequent visits.  
PSGNAME  
(Parameter Name) 
PSGLABEL  
(Description) 
PSGRESU 
(Unit) 
SOL 
Sleep Onset latency 
MIN 


 
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PSGNAME  
(Parameter Name) 
PSGLABEL  
(Description) 
PSGRESU 
(Unit) 
REML 
REM latency 
MIN 
TNRM 
Total NREM 
MIN 
WASO 
Wake after persistent sleep 
MIN 
REM 
Stage R in minutes 
MIN 
STN1 
Stage N1 Sleep in minutes 
MIN 
STN2 
Stage N2 Sleep in minutes 
MIN 
STN3 
Stage N3 Sleep in minutes 
MIN 
P_REM 
Stage R in percentage 
% 
P_STN1 
Stage N1 Sleep in percentage 
% 
P_STN2 
Stage N2 Sleep in percentage 
% 
P_STN3 
Stage N3 Sleep in percentage 
% 
SaO2_L90 
Total time in minutes that SaO2 is less than 
90% during TST 
MIN 
SaO2_L85 
Total time in minutes that SaO2 is less than or 
= to 85% during TST 
MIN 
SaO2_L80 
Total time in minutes that SaO2 is less than 
80% during TST 
MIN 
SaO2_L70 
Total time in minutes that SaO2 is less than 
70% during TST 
MIN 
SaO2_L60 
Total time in minutes that SaO2 is less than 
60% during TST 
MIN 


 
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PSGNAME  
(Parameter Name) 
PSGLABEL  
(Description) 
PSGRESU 
(Unit) 
SaO2_L50 
Total time in minutes that SaO2 is less than 
50% during TST 
MIN 
SaO2_MN 
Mean SaO2 during TST 
% 
SaO2_MIN 
Minimum oxygen saturation (nadir) during 
Total Sleep Time 
% 
SaO2_1hr 
Average SaO21 hr after 1st dose = IPAP 1 
% 
SaO2_2hr 
Average SaO2 2 hrs after 1st dose = IPAP 2 
% 
SaO2_4hr 
Average SaO2 4 hrs after 1st dose = IPAP 3 
% 
SaO2_6hr 
Average SaO2 6 hrs after 1st dose = IPAP 4 
% 
SaO2_8hr 
Average SaO2 8 hrs after 1st dose = IPAP 5 
% 
EtCo2MX 
Highest EtCO2 (study time) 
TORR 
CA 
Number of Central Apnea with onset during 
Total Sleep Time 
NUM  
OA 
Number of Obstructive Apnea with onset 
during Total Sleep Time 
NUM  
A 
Number of Apnea with onset during Total 
Sleep Time 
NUM  
H 
Number of Hypopnea with onset during Total 
Sleep Time 
NUM  
CI 
Central Apnea Index 
NUM/H  
OI 
Obstructive Index 
NUM/H  
AI 
Apnea Index 
NUM/H  


 
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PSGNAME  
(Parameter Name) 
PSGLABEL  
(Description) 
PSGRESU 
(Unit) 
OHI 
Obstructive Apnea + Hypopnea Index 
NUM/H  
AHI 
Apnea + Hypopnea Index  
NUM/H  
 
The percentage of sleep time where the SaO2 was below 90%, less than or equal to 85%, 
below 80%, below 70%, below 60%, and below 50% will be derived by dividing the 
parameters named SaO2_L90, SaO2_L85, SaO2_L80, SaO2_L70, SaO2_L60, and SaO2_L50 
by the Total Sleep Time and multiplying by 100%.  
A summary of values during the screening period will be completed using the Safety 
Population.  
For Xyrem Naïve subjects, observed values and changes from baseline in the parameters 
at the end of the SD Period will be completed using the Safety Population who Took 
Study Drug during the SD Period.  
End of study assessments will be summarized for the Safety Population. The 
summarization of observed values and change from baseline will be done by Xyrem 
Status at Study Entry, Age Group, and Total for subjects who have an end of study PSG 
performed at the end of the OL Period. The minimum oxygen saturation (nadir) during 
the test (PSGNAME = SaO2_MIN) will be summarized by Xyrem dosage level in g/night at 
the time of each PSG night.  
11.10. 
MASC-10  
The Multidimensional Anxiety Scale for Children-10 Item (MASC-10) is a short version of 
the MASC and produces a score that indicates the severity of anxiety problems. During 
Part 1, the instrument is completed at each clinic visit, as well as at each phone 
contact that the site makes with the subject during the study for Xyrem Naïve subjects. 
The MASC-10 is not being collected during Part 2. A response to each of the 10 questions 
is provided and scored as follows:  
 
• 
0 = never true about me 
• 
1 = rarely true about me 
• 
2 = sometimes true about me 
• 
3 = often true about me 
 
The sum of the 10 scores yields a total raw score, which ranges from 0 to 30. A higher 


 
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score is indicative of more risks of anxiety in the subject. The total raw score is then 
converted to an age-based T-score ranging from 29 to 90 using the chart on the next 
page. If a response is not provided to one or more of the prompts then, the total raw 
score and T-score will be missing at the visit. T-scores will be determined using the age 
in years at each assessment. Subjects who are younger than age 8 will be assigned a 
T-score using the 8-11 age category. 
 
T-scores will be categorized as:  
• 
< 40 = Below Average 
• 
40-55 = Average 
• 
56-60 = Slightly Above Average 
• 
61-65 = Above Average 
• 
66-70 = Much Above Average 
• 
> 70 = Very Much Above Average 
 


 
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In the event of multiple recordings of MASC-10 at an analysis visit, the highest reported 
T-score at the visit will be utilized in the analysis.  
Summaries of observed values and changes from baseline, and categorized T-Scores will 
be completed for all treatment periods. 
A graphical presentation of the mean MASC-10 T-Score, with error bars for +/- 1 SD (or 
Standard Error), will be presented covering all dosing periods, using the Safety 
Population who Took Study Drug in any period. For the DB Period and the OL Period, 
means and error bars will be separated, for those who received Placebo in the DB 
Period vs. those who took Xyrem. The graphical presentation will be also provided by 
Age Group and Xyrem status at study entry. 
11.11. 
CDI 2: SR[S]  
The Children’s Depression Inventory 2nd Edition Self-Report Short Version (CDI 2: SR[S]) 
is a comprehensive assessment of depression symptoms in youth ages 7 to 17 years. It is 
designed to assess symptoms in the 2 weeks prior to the assessment. During Part 1, this 
assessment is done at each contact with the subject, including phone contacts 
throughout the study conduct during the Dose Titration Period for Xyrem Naïve subjects. 
The CDI 2 is not scheduled for collection in Part 2. 
 
There are 12 items, each with 3 possible responses. The responses to each item are 
scored from 0 to 2 so that 0 is the best condition and 2 is the worst condition for the 
test. The items are scored as follows: 
 
 
CDI 2: SR[S] Response Score 
Item 0 
1 
2 
1 
I am sad once in a while 
I am sad many times 
I am sad all the time 
2 
Things will work out for 
me O.K 
I am not sure if things 
will work out for me 
Nothing will ever work 
out for me 
3 
I do most things O.K 
I do many things wrong 
I do everything wrong 
4 
I have fun in many things 
I have fun in many things 
Nothing is fun at all 
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 
6 
I like myself 
I do not like myself 
I hate myself 
7 
I am almost never cranky I feel cranky many times 
I feel cranky all the time 
8 
I make up my mind about 
things easily 
It is hard to make up my 
minds about things 
I cannot make up my 
minds about things 
9 
Doing schoolwork is not a 
big problem 
I have to push myself 
many times to do my 
schoolwork 
I have to push myself all 
the 
time 
to 
do 
my 
schoolwork 


 
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CDI 2: SR[S] Response Score 
Item 0 
1 
2 
10 
I am tired once in a 
while 
I am tired many days 
I am tired all the time 
11 
I eat pretty well 
Many days I do not feel 
like eating 
Most days I do not feel 
like eating 
12 
I do not feel alone 
I feel alone many times 
I feel alone all the time 
 
The sum of the responses to the scores for the 12 items ranges from 0-36 will be the 
total score. This total score is converted to a sex and age-based T-score using the chart 
below. T-scores will be determined using the age in years at each assessment. 


 
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The T-score will be used in all analyses. The T-score will have a value from “<= 40” to 
“90+”. In the event of a subject having a T-score of “<= 40”, 40 will be used for the 
numeric summaries. Similarly, if the subject has a T-score of “90+”, then a 90 will be 
used in the numeric summaries.  
 
T-scores will be categorized as:  
• 
≤ 40 = Low  
• 
41-59 = Average 
• 
60-64 = High Average  
• 
65-69 = Elevated  
• 
≥ 70 = Very Elevated  
 
In the event of multiple recordings of CDI 2: SR[S] at an analysis visit, the highest 
reported T-score at the visit will be utilized in the analysis.  
Summaries of observed values and changes from baseline, and categorized T-Scores will 
be completed for all treatment periods. 
A graphical presentation of the mean CDI T-Score, with error bars for +/- 1 SD (or 
Standard Error), will be presented covering all dosing periods, using the Safety 
Population who Took Study Drug in any period. For the DB Period and OL Period, means 
and error bars will be separated for those who received Placebo in the DB Period vs. 
those who received Xyrem. The graphical presentation will also be provided by Age 
Group and Xyrem status at study entry. 
11.12. 
TANNER STAGE  
During Part 1, the assessment of Tanner stage for sexual maturity is assessed at 
Screening and at Visit 15 (Week 52) or Early Termination. The Tanner Stage is not 
scheduled for collection during Part 2. For Part 1, a shift table of Tanner stage at 
Screening vs. End of Study will be completed using the Safety Population. The 
summarization will be done by Age Group and sex.  
11.13. 
PHYSICAL EXAMINATION 
Physical examination data will be presented only in a listing and won’t otherwise be 
summarized.  


 
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12. 
INTERIM ANALYSES 
As described in Section 9.1, an interim analysis of the primary outcome was completed 
after 35 randomized subjects had completed the DB Treatment Period. The analysis was 
completed by the unblinded INC biostatistician and presented to the DSMB.  


 
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13. 
DSMB  
The DSMB will function according to the DSMB charter. Periodic summaries of selected 
safety endpoints will be provided to the DSMB. Summarizations of DT Period, SD Period, 
blinded DB period, OL Period, and Part 2 summaries will be provided to representatives 
of Jazz Pharmaceuticals and the DSMB during their open session. Presentations of the 
DB Period safety endpoints will be presented by the unblinded 
 
biostatistician to DSMB members only during the closed session of each meeting. 
Analyses to be performed for the DSMB are specified in the DSMB charter. 


 
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14. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
• 
In the study protocol, Section 9.1, it states “PK parameters will be assessed by 
analysis of variance (ANOVA) models using natural log transformed data.”  The 
analysis was to assess dose proportionality of Cmax and AUC0-4.  After further 
consideration, given the range of potential doses, it was decided that a different 
method would be used to assess dose proportionality.  The method is described 
in Section 10.2 of the SAP under the dose proportionality section. 
• 
In Protocol Amendment 4, section 9.6.1,  it states:  
“However, 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. Since the primary efficacy 
endpoint was reached and the Double-Blind Randomized treatment is 
discontinued, the sample size to assess the secondary efficacy endpoints will be 
reduced. Given the positive primary efficacy results and with the expected 
treatment benefit of Xyrem on the secondary endpoints based on the adult 
studies, tiered testing on secondary endpoints will be conducted with a 
significance level of 0.05, with all tests being one-sided, …”. 
After review of change in testing by the FDA, it was decided that all tiered 
testing of the secondary endpoints will be conducted using two-sided testing.  
• 
Section 9.3 of the protocol states:  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. 
After Amendment 4, the Safety Population who had Study Drug Dispensed in the 
DB Treatment Period will be used to assess demographics and baseline 
characteristics, safety and efficacy of subjects who were randomized into 
Double-Blind Treatment Period, but will further include subjects who were 
continued on Open-label Xyrem during the DB Treatment Period.  Inferential 
comparisons of demographic and baseline characteristics will be completed using 
the Randomized Population. 
• 
In section 9.3 of the protocol Amendment 5, the Continued Access Population is 
defined. In the SAP, this population is called the Safety Population who Took 
Study Drug in the Part 2 Open-Label Continuation Period. 


 
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15. 
REFERENCE LIST 
Benjamini, Y., and Y. Hochberg. 1995. Controlling the false discovery rate: a practical 
and powerful approach to multiple testing. Journal of the Royal Statistical Society B 57: 
289-300. 
Conover, W.J. and Iman, R.L. 1981. Rank Transformation as a Bridge Between 
Parametric and Nonparametric Statistics. The American Statistician, Volume 35 Issue 3 
(August 1981), 124-129. 
Johns, M.W. A New Method for Measuring Daytime Sleepiness: The Epworth Sleepiness 
Scale. Sleep, 14(6): 540-545 (1991). 
Kuczmarski RJ, Ogden CL, Guo SS, et al. 2000 CDC growth charts for the United States: 
Methods and development. National Center for Health Statistics. Vital Health Stat 
11(246). 2002.  
Lan, K.K.G., and Wittes, J. (1988). The B-value: A tool for monitoring data. Biometrics 
44: 579-585. 
 


 
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16. 
PROGRAMMING CONSIDERATIONS 
All tables, data listings, figures (TLFs), and statistical analyses will be generated using 
SAS® for Windows, Release 9.3 (SAS® Institute Inc., Cary, NC, USA) or higher.  
Non-compartmental PK parameters, i.e. Cmax, Tmax, AUC0-4, AUC0-infinity, Half-life, will be 
calculated using SAS® for Windows, Release 9.3 (SAS® Institute Inc., Cary, NC, USA) or 
higher. 
16.1. 
GENERAL CONSIDERATIONS 
• 
One SAS program may create several outputs. 
• 
Each output will be stored in a separate file.  
• 
Individual output files will be delivered in RTF format. Combined outputs will be 
delivered in PDF format. 
• 
Numbering of tables, figures, and listings (TFLs) will follow ICH E3 guidance. 
 
16.2. 
TABLE, LISTING, AND FIGURE FORMAT 
16.2.1. 
General 
• 
All TLFs will be produced in landscape format. 
• 
All TLFs will be produced using the Courier New font, size 8.  
The data displays for all TLFs will be produced on a landscape oriented page with 
the following margins specified in inches: Top 1.6”, Bottom, 1.15”, Left 1”, Right 
1”.  
• 
Headers and footers for figures will be in Courier New font, size 8. 
• 
Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
• 
Tables and Listings will be in black and white; Colors may be used for figures to aid 
interpretation.  
• 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified. On 
some occasions, superscripts 1, 2, or 3 may be used. 
• 
Only standard keyboard characters will be used in the TLFs. Special characters, such 
as non-printable control characters, printer-specific, or font-specific characters, will 
not be used. Hexadecimal-derived characters may be used, where possible, if they 


 
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are appropriate to help display math symbols (e.g., μ). Certain subscripts and 
superscripts (e.g., cm2, Cmax) may be employed on a case-by-case basis. 
• 
Mixed case will be used for all titles, footnotes, column headers, and programmer-
supplied formats, as appropriate. 
 
16.2.2. 
Headers and Footers 
• 
All output should have the following header at the top left of each page: 
Jazz Pharmaceuticals 
Protocol 13-005      
• 
All output should have Page n of N at the top right corner of each page. TLFs will be 
internally paginated in relation to the total length (i.e., the page number should 
appear sequentially as page n of N, where N is the total number of pages in the 
table). 
• 
The date of output generation should appear along with program name and output 
name as the last footer on each page. 
 
16.2.3. 
Display Titles 
• 
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). 
ICH E3 numbering will be used. A decimal system (x.y and x.y.z) will be used to 
identify TLFs with related contents. The study Period of analysis will be included in 
the title. The title will be centered. The analysis population will be identified on 
the line immediately following the title. The title and table designation are single 
spaced. A solid line spanning the margins will separate the display titles from the 
column headers. There will be 1 blank line between the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
Safety Population 
 
16.2.4. 
Column Headers 
• 
Column headings should be displayed immediately below the solid line described 
above in initial upper-case characters.  
• 
In the case of efficacy tables, the variable (or characteristic) column will be on the 
far left followed by the treatment group columns and total column (if applicable). 
P-values may be presented under the total column or in separate p-value column (if 
applicable).  


 
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• 
For numeric variables, include “unit” in column or row heading when appropriate. 
• 
Analysis set sizes will be presented for each treatment group or category in the 
column heading as (N=xxx) (or in the row headings if applicable). This is distinct 
from the ‘n’ used for the descriptive statistics representing the number of subjects 
in the analysis set with a value for the variable being analyzed. 
• 
For the DT Period tables, the columns for presentation of summaries will include: 
Age Group 7-11, Age Group 12-17, and Total. 
• 
For the SD Period, the columns for presentation will include: Age Group 7-11, Age 
Group 12-17, Xyrem Naïve, On Xyrem at Entry, and Total. 
• 
For the DB Period presentations of efficacy endpoints for subjects randomized prior 
to the implementation of Amendment 4, the columns for presentation will include: 
Placebo, Xyrem, and Total.  
• 
For the DB Period presentations of efficacy endpoints for subjects entering the 
period after the implementation of Amendment 4, the columns for presentation will 
include: Age Group 7-11, Age Group 12-17, Xyrem Naive, On Xyrem at Entry, and 
Total Open-Label Xyrem.  
• 
For DB Period presentations of safety endpoints, the columns for presentation will 
include: Randomized to Placebo, Randomized to Xyrem, OL Xyrem, All Xyrem, and 
Total. 
• 
For the OL Period, in general the columns for presentation will include: Age Group 
7-11, Age Group 12-17, Xyrem Naïve, On Xyrem at Entry, and Total. For efficacy 
parameters collected in the OL Period, the columns for presentation will include: 
Age Group 7-11, Age Group 12-17, Xyrem Naïve, On Xyrem at Entry, Received 
Placebo during DB, Received Xyrem during DB, and Total. 
• 
For the OL Continuation Period, the columns for presentation will include: Age 
Group 7-11, Age 12-17, and Total. When presenting results across Part 1 and Part2, 
the columns for presentation will include: Age Group 7-11, Age Group 12-17, Xyrem 
Naïve, On Xyrem at Entry, and Total. 
 
16.2.5. 
Body of the Data Display 
16.2.5.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (e.g., counts) are right-justified;  
16.2.5.2. Table Conventions 
• 
Units will be included where available 


 
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• 
If the categories of a parameter are ordered, then all categories between the 
maximum and minimum category will be presented in the table, even if n=0 for all 
treatment groups in a given category that is between the minimum and maximum 
level for that parameter. For example, the frequency distribution for symptom 
severity would appear as: 
Severity 
Rating 
n 
Severe 
0 
Moderate 
8 
Mild 
3 
 
• 
Percentage values should be rounded and presented to one decimal place (including 
100.0%). Percentages will be presented in parentheses, one space after the count 
(e.g., 7 ( 12.8), 13 ( 5.4), 100 (100.0)). Unless otherwise noted, percentages will be 
calculated using the number of subjects in the analysis set as the denominator.  
• 
If the categories for a categorical variable are not ordered (e.g., Medical History, 
Adverse Events, etc.), then only those categories for which there is at least 1 
subject represented in 1 or more groups should be included. 
• 
Unless otherwise specified, the estimated mean, median, 1st quartile, and 3rd 
quartile for a set of values should be printed out to 1 more significant digit than the 
original values, and standard deviations or standard error should be printed out to 2 
more significant digits than the original values. The minimum and maximum should 
report the same significant digits as the original values. For example, for systolic 
blood pressure: 
n 
  XX 
Mean 
XXX.X 
Std Dev 
XXX.XX 
Median 
XXX.X 
Q1 
XXX.X 
Q3 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
• 
P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 
4 decimal places. Any p-value less than 0.0001 will be presented as <0.0001. If the 
p-value is returned as >0.9999 then present as >0.9999. 
• 
Tabular display of data for prior / concomitant medications, and adverse event data 
should be presented ordered alphabetically by the class variable (ATC4 level or 
SOC). Within the class or SOC, drugs or adverse event terms will be presented in 
descending order by preferred name or preferred term. If the incidence is the same 
for 2 or more terms, terms will be sorted alphabetically within that incidence level. 


 
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• 
Any percentage calculated using a denominator other than the analysis set 
population count will be documented on the table using a footnote. 
• 
For categorical summaries (number and percentage of subjects) where a subject can 
be included in more than one category, a footnote will be added to indicate that 
subjects may be counted in more than 1 category.  
16.2.5.3. Listing Conventions 
• 
Listings will be sorted in order of Xyrem Status at Study Entry, randomized 
treatment (or not randomized), country, subject identifier, period of collection, 
visit number, date and study day of collection.  
• 
Dates should be printed in Year/Month/Day format (“YYYY-MM-DD”: 2015-01-25). 
Missing portions of dates will be represented by blanks. 
• 
All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the study. 
• 
Units will be included where available. 
 
16.2.5.4. Figure Conventions 
• 
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis 
and endpoint (e.g., treatment mean change from baseline) values will be displayed 
on the Y-axis. Going forward all figures will indicate the number of observations 
available at the study visit. 
• 
By-subject plots of PK concentrations will identify the subject identifier, age, sex, 
body weight, Xyrem dosage level in g/night. Separate lines will be produced on the 
page for each PK night. Y axes will always initiate at 0. Nominal elapsed times from 
first dosing on the PK night will be used. 
 
16.2.5.5. Footnotes  
• 
A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
• 
All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display. 
• 
Footnotes should always begin with “Note:” if an informational footnote, or [1], [2], 
‘[3], etc. if a reference footnote. Each new footnote should start on a new line 
where possible. 


 
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• 
Footnotes provided on the table, listing and figure shells will be, in general, 
presented on each page of the output. Subject specific footnotes will not be used. 
• 
Footnotes will be used sparingly and must add value to the table, figure, or data 
listing.  
• 
The last line of the footnote section will be a standard source line that indicates the 
name of the program used to produce the data display and the date the program 
was run. 


 
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17. 
QUALITY CONTROL 
SAS programs are developed to produce clinical trial output such as analysis data sets, 
summary tables, data listings, figures or statistical analyses. 
 SOP 
03.010.00 and 03.013.00 provide an overview of the development of such SAS programs. 
 SOP 03.009.00 describes the quality control procedures that are 
performed for all SAS programs and output. Quality control is defined here as the 
operational techniques and activities undertaken to verify that the SAS programs 
produce the proper clinical trial output by checking for their logic, efficiency and 
commenting and by review of the produced output. 
Each provided analysis dataset (i.e. CDISC ADaM), output table, and output listing will 
be checked for accuracy using double programming. An independent programmer or 
biostatistician will reprogram the results and compare using the SAS procedure PROC 
COMPARE. Values and order of presentation will be compared. The outputs will be 
compared to the table, listing, and figure shells for accuracy. The quality control of 
figures will be achieved using a comparison of figure results to already created 
summarization tables or with double-programming. 


 
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18. 
INDEX OF TABLES 
The index of tables will be provided in a separate document. 


 
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19. 
INDEX OF FIGURES 
The index of figures will be provided in a separate document.  
 


 
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20. 
INDEX OF LISTINGS 
The index of listings will be provided in a separate document. 


 
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21. 
MOCK-UPS 
21.1. 
TABLE MOCK-UPS 
Table mockups will be provided in a separate document. 
21.2. 
FIGURE MOCK-UPS 
Figure mockups will be provided in a separate document. 
A detailed description of the figure may be used in lieu of a figure template. Here is an 
example: 
Figures 14.4.1.4:  Mean Plasma Concentration Over Time by Treatment Group (PK 
Analysis Set) 
PROGRAMMING NOTES: 
• 
This figure is a line plot and corresponds to Data Listing XXXXX Drug Concentration Data. 
• 
Axes: Vertical axis:  Mean plasma drug concentration (units),. Include vertical axes on both 
the left and right sides of the figure. Horizontal axis: Nominal time Post-Dose (hours), with 
range from 0 hour (pre-dose) to X hours post-dose. 
• 
Solid lines should connect the data points for the means. One line per treatment group will 
be plotted.  
• 
Solid circles will be used for mean values in treatment group X; triangles will be used for 
mean values in treatment group Y. Include a legend that indicates which treatment group a 
circle represents and which treatment group a triangle represents. 
• 
Error bars should be used at each visit that represents standard deviations. 
• 
Include the number of subjects with data at each time point below the horizontal axis. 
• 
Include footnote “Values below limit of quantification were imputed to xxxxx.” 
• 
The 
 stamp (program name, date, etc.) should appear at the bottom of the 
figure. 
21.3. 
LISTING MOCK-UPS 
Listing mockups are provided in a separate document. 


 
Jazz Pharmaceuticals 
13-005 
4.0 
Statistical Analysis Plan 
 
 
 
03.007A.01     
  
 
Page 115 of 115 
22. 
APPENDICES 
Not applicable.