Clinical trial NCT02348593
Conditions: Narcolepsy
Sponsor: Jazz Pharmaceuticals
Start date: 2015-05-01; Completion date: 2017-02-01
Enrollment: 239 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is a 12-week, randomized, double-blind, placebo controlled, multicenter, 4-treatment parallel group study of the safety and efficacy of JZP-110 in the treatment of excessive sleepiness in adult subjects with narcolepsy.

Detailed description:

Arms: arm 1: Once Daily Dosing arm 2: Once Daily Dosing arm 3: Once Daily Dosing arm 4: Once Daily Dosing
Interventions: intervention 1: JZP-110 intervention 2: Placebo oral tablet
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
Signature Date: 20160210
JP: Protocol 14-002 Amendment 3.pdf
Signature Date:
JP: Protocol 14-002 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-002 Amendment 3 
 
  
 
 
 
 
CONFIDENTIAL 
Page 1 of 101 
 
Clinical Trial Protocol: 14-002 
Study Title: 
A Twelve-week, Double-blind, Placebo-controlled, Randomized, 
Parallel-group, Multicenter Study of the Safety and Efficacy of 
JZP-110 [(R)-2-amino-3-phenylpropylcarbamate hydrochloride] in the 
Treatment of Excessive Sleepiness in Subjects with Narcolepsy 
Study Phase: 
3 
Product Name: 
JZP-110 [(R)-2-amino-3-phenylpropylcarbamate hydrochloride] 
IND Number: 
107,203 
EUDRACT 
Number: 
2014-005487-15 
Indication: 
Treatment of excessive sleepiness in adult patients with narcolepsy; to 
increase the ability to stay awake throughout the day. 
Investigators: 
Multicenter 
Sponsor: 
Jazz Pharmaceuticals 
3180 Porter Drive 
Palo Alto, CA 94304 
Tel: (650) 496-3777 
 
Sponsor’s 
Medical 
Directors: 
    
   
   
    
    
Contract 
Research 
Organization: 
 
Original Protocol: 
18 December 2014 
Amendment 1: 
18 February 2015 
Amendment 2: 
10 September 2015 
Amendment 3: 
08 February 2016 
Confidentiality Statement 
The information in this document is Jazz Pharmaceuticals confidential information. This material may 
be used only for evaluating or conducting clinical investigations; any other proposed use requires 
written consent from Jazz Pharmaceuticals. Acceptance of this document constitutes an agreement by 
the recipient(s) that no unpublished information contained herein will be published or disclosed 
without first obtaining written approval from Jazz Pharmaceuticals. This document may be disclosed 
to appropriate Investigational Review Boards/Ethics Committees under the condition of 
confidentiality. 
This study will be conducted under Good Clinical Practice guidelines. 
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Signature Date:
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JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-002 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
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SYNOPSIS 
SPONSOR 
Jazz Pharmaceuticals 
PRODUCT 
JZP-110 [(R)-2-amino-3-phenylpropylcarbamate 
hydrochloride] 
TITLE 
A Twelve-week, Double-blind, Placebo-controlled, 
Randomized, Parallel-group, Multicenter Study of the Safety 
and Efficacy of JZP-110 [(R)-2-amino-3-
phenylpropylcarbamate hydrochloride] in the Treatment of 
Excessive Sleepiness in Subjects with Narcolepsy 
STUDY NUMBER 
14-002 
STUDY PHASE 
Phase 3 
LOCATION 
This trial will be conducted at approximately 60 sites in North 
America and Europe. 
PRIMARY 
OBJECTIVE 
To evaluate the efficacy of JZP-110 administered once daily 
for up to 12 weeks in doses of 75, 150, and 300 mg compared 
to placebo in the treatment of excessive sleepiness in adult 
subjects with narcolepsy. 
SECONDARY 
OBJECTIVES 
To evaluate the safety and tolerability of JZP-110 
administered once daily for up to 12 weeks in doses of 75, 
150, and 300 mg compared to placebo in the treatment of 
excessive sleepiness in adult subjects with narcolepsy. 
To characterize the pharmacokinetics (PK) of JZP-110 in 
subjects with narcolepsy using sparse sampling methods. 
DESIGN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This trial is a 12-week, randomized, double-blind, placebo-
controlled, multicenter, 4-treatment parallel group study of the 
safety and efficacy of JZP-110 in the treatment of excessive 
sleepiness in adult subjects with narcolepsy as defined by The 
International Classification of Sleep Disorders, Third Edition 
(ICSD-3) or Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5). Following the successful 
completion of Screening and Baseline visits, stratified 
randomization on the basis of the presence or absence of 
cataplexy will occur. Subjects will be assigned to receive 
JZP-110 75, 150, or 300 mg or placebo in a 1:1:1:1 ratio once 
daily over a 12-week Treatment Phase. Subjects randomized 
to the 150 mg dose will initially receive 75 mg from Day 1 
through Day 3 of the first week of the Treatment Phase and 
will receive 150 mg starting on Day 4.  Subjects randomized 
to the 300 mg dose will initially receive 150 mg from Day 
1 through Day 3 of the first week of the Treatment Phase and 
will receive 300 mg starting on Day 4. Subjects randomized to 
the 75 mg group will not require titration. 
During the Treatment Phase, subjects will return to the 
investigative site to complete efficacy and safety assessments 
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JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-002 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
Page 3 of 101 
 
at the end of Weeks 1, 4, 8, and 12; the Week 4 and 12 visits 
will include an overnight stay at the investigational site for 
nocturnal polysomnography (PSG) followed by a 
Maintenance of Wakefulness Test (MWT), and the Week 8 
Visit will include 24-hour ambulatory blood pressure 
monitoring. Subjects will take their final dose of study drug at 
the Week 12 visit prior to the Week 12 visit assessments. 
Subjects will return at the end of Week 14 for follow-up 
assessments. Unless there are any outstanding safety issues 
that require follow-up, subjects will be discharged from the 
study at the Week 14 visit. 
Efficacy will be assessed by changes in the mean sleep 
latency on the first 4 trials of a 5-trial, 40-minute MWT and 
by changes in the mean Epworth Sleepiness Scale (ESS) score 
as co-primary endpoints, percentage of patients improved on 
the Patient Global Impression of Change (PGIc) as a key 
secondary endpoint, and Clinical Global Impression of 
Change (CGIc), Functional Outcomes of Sleep Questionnaire 
Short Version (FOSQ-10), 36-Item Short Form Health Survey 
(SF-36v2), EuroQoL EQ-5D-5L, and the Work Productivity 
and Activity Impairment Questionnaire: Specific Health 
Problem V2.0 (WPAI:SHP) as other endpoints. 
Four blood samples will be collected from each subject for PK 
evaluations; one sample during the Week 1 visit, one sample 
during the Week 4 visit, and two samples during the Week 
8 visit. The samples collected at the Week 1 and Week 8 visits 
will be within 1-8 hours of dosing. The samples collected at  
the Week 4 visit will be within 8-12 hours after dosing. 
Safety will be assessed by the incidence of observed and 
reported adverse events (AEs), and changes in physical 
examination findings, electrocardiograms (ECGs), clinical 
laboratory tests, vital sign measurements, 24-hour ambulatory 
blood pressure monitoring at the Week 8 visit, and the 
Columbia-Suicide Severity Rating Scale (C-SSRS). Safety 
will be assessed throughout the study. 
ESTIMATED 
DURATION OF 
STUDY 
Up to 31 days for Screening and Baseline visits, 12 weeks for 
the Treatment Phase, and 2 weeks for a Safety Follow-up (the 
2 week Safety Follow-up visit is not required for subjects who 
enter the Open-label Safety Study [14-005] at the Final Clinic 
Visit). 
It is estimated that enrollment across all sites will be 
completed in 12 months. 
STUDY POPULATION Subjects must have a documented diagnosis of narcolepsy 
according to the ICSD-3 or DSM-5 and have sleepiness and 
an inability to stay awake as demonstrated by objective and 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-002 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
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subjective criteria.  
Approximately 240 subjects are planned for enrollment. 
Approximately 60 subjects will be randomized to each 
treatment group. These sample sizes will provide at least 80% 
power to detect a difference of 6 minutes in the mean sleep 
latency time as determined from the MWT (mean of the first 
four trials) and a difference of 4 points on the ESS changes 
from Baseline to Week 12 between each JZP-110 treatment 
group and placebo. This calculation assumes common 
standard deviations of 10 minutes for the MWT and 6 points 
for the ESS changes from Baseline and a two-sided 
significance level of 0.05 using a t-test.   
DIAGNOSIS AND 
MAIN CRITERIA FOR 
INCLUSION 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in 
the study. 
1. Males and females between 18 and 75 years of age, 
inclusive. 
2. Diagnosis of narcolepsy according to ICSD-3 or 
DSM-5 criteria. 
3. Baseline mean sleep latency <25 minutes as 
documented by the mean of the first four trials of the 
Baseline 5-trial MWT. 
4. Baseline Epworth Sleepiness Scale (ESS) score ≥10. 
5. Usual nightly total sleep time of at least 6 hours. 
6. Body mass index from 18 to <45 kg/m2. 
7. Consent to use a medically acceptable method of 
contraception for at least 2 months prior to the first 
dose of study drug, throughout the entire study period, 
and for 30 days after the study is completed. 
8. Willing and able to comply with the study design 
schedule and other requirements. 
9. Willing and able to provide written informed consent. 
 
Exclusion Criteria 
Subjects who meet any of the following criteria will be 
excluded from the study. 
1. Female subjects who are pregnant, nursing, or 
lactating. 
2. Usual bedtime later than 1 AM (0100 hours). 
3. Occupation requiring nighttime or variable shift work. 
4. Moderate or severe obstructive sleep apnea (OSA) on 
the baseline PSG. 
5. Any other clinically relevant medical, behavioral, or 
psychiatric disorder other than narcolepsy that is 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-002 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
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associated with excessive sleepiness. 
6. History or presence of bipolar disorder, bipolar related 
disorders, schizophrenia, schizophrenia spectrum 
disorders, or other psychotic disorders according to 
DSM-5 criteria. 
7. History or presence of any acutely unstable medical 
condition, behavioral or psychiatric disorder 
(including active suicidal ideation), or surgical history 
that could affect the safety of the subject or interfere 
with study efficacy, safety, PK assessments, or the 
ability of the subject to complete the trial per the 
judgment of the Investigator. 
8. History of bariatric surgery within the past year or a 
history of any gastric bypass procedure. 
9. Presence of renal impairment or calculated creatinine 
clearance <60 mL/min. 
10. Clinically significant ECG abnormality in the opinion 
of the Investigator.  
11. This criterion has been removed.  
12. Presence of significant cardiovascular disease 
including but not limited to: myocardial infarction 
within the past year, unstable angina pectoris, 
symptomatic congestive heart failure (ACC/AHA 
stage C or D), revascularization procedures within the 
past year, ventricular cardiac arrhythmias requiring 
automatic implantable cardioverter defibrillator 
(AICD) or medication therapy, uncontrolled 
hypertension, systolic blood pressure ≥155 mmHg or 
diastolic blood pressure ≥95 mmHg (at screening, or 
consistently across Baseline measures according to 
protocol specifications), or any history of 
cardiovascular disease or any significant 
cardiovascular condition that in the investigator’s 
opinion may jeopardize subject safety in the study. 
13. Laboratory value(s) outside the laboratory reference 
range that are considered to be clinically significant by 
the Investigator (clinical chemistry, hematology, and 
urinalysis); NOTE: Screening labs may be repeated 
once. 
14. Excessive caffeine use one week prior to Baseline 
assessments or anticipated excessive use during the 
study defined as >600 mg/day of caffeine. 
15. Use of any over-the-counter (OTC) or prescription 
medications that could affect the evaluation of 
excessive sleepiness within a time period prior to the 
Baseline visit corresponding to at least five half-lives 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-002 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
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of the drug(s) or planned use of such drug(s) at some 
point throughout the duration of the study. Examples 
of excluded medications include OTC sleep aids or 
stimulants (e.g., pseudoephedrine), methylphenidate, 
amphetamines, modafinil, armodafinil, sodium 
oxybate, pemoline, trazodone, hypnotics, 
benzodiazepines, barbiturates, and opioids. 
Medications should be discontinued such that the 
subject has returned to his/her baseline level of 
daytime sleepiness at least 7 days prior to the Baseline 
visit, in the opinion of the Investigator. 
16. Use of any medications that could affect the evaluation 
of cataplexy within a time period prior to the Baseline 
visit corresponding to at least five half-lives of the 
drug(s) or planned use of such drug(s) at some point 
throughout the duration of the study. Examples of 
excluded anti-cataplectic medications include selective 
serotonin reuptake inhibitors (SSRIs), serotonin-
norepinephrine reuptake inhibitors (SNRIs), tricyclic 
antidepressants (TCAs), monoamine oxidase inhibitors 
(MAOIs), anti-convulsant agents, and sodium oxybate. 
These drugs will be discontinued if they are taken for 
the treatment of narcolepsy and discontinuation is 
deemed safe by the Investigator. Medications should 
be sufficiently washed out such that the subject has 
returned to his/her baseline level of cataplexy at least 
7 days prior to the Baseline visit, in the opinion of the 
Investigator. 
17. Received an investigational drug in the past 30 days or 
five half-lives (whichever is longer) prior to the 
Baseline visit, or plans to use an investigational drug 
(other than the study drug) during the study. 
18. Previous exposure to or participation in a previous 
clinical trial of JZP-110 (ADX-N05, R228060, 
YKP10A). 
19. Current or past (within the past 2 years) diagnosis of a 
moderate or severe substance use disorder according 
to DSM-5 criteria. 
20. Nicotine dependence that has an effect on sleep (e.g., a 
subject who routinely awakens at night to smoke). 
21. Current, past (within the past 2 years), or seeking 
treatment for a substance related disorder. 
22. Urine drug screen positive for an illicit drug of abuse 
(including cannabinoids) at screening or at any point 
throughout the duration of the study, except for a 
prescribed drug (e.g., amphetamine) at screening. 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-002 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
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23. History of phenylketonuria (PKU) or history of 
hypersensitivity to phenylalanine-derived products. 
TEST PRODUCT, 
DOSE, AND MODE OF 
ADMINISTRATION 
JZP-110 [(R)-2-amino-3-phenylpropylcarbamate 
hydrochloride] will be supplied as 75 mg, 150 mg, and 
300 mg tablets that will be overencapsulated in identical 
opaque gelatin capsules. The doses of JZP-110 will be based 
on the free base of the molecule. Subjects will be instructed to 
take a single oral daily dose of study drug in the morning, on 
an empty stomach, within one hour of awakening. Subjects 
will also be instructed to abstain from eating or drinking 
(except for water) for 30 minutes after taking the study drug. 
REFERENCE 
THERAPY, DOSE, 
AND MODE OF 
ADMINISTRATION 
Placebo tablets will also be overencapsulated in opaque 
gelatin capsules that will be identical to those used for the 
active JZP-110 treatments. Mode of administration will be the 
same as for the test product above. 
DURATION OF 
TREATMENT 
The treatment duration of the study for each subject will be 
approximately 12 weeks. 
EFFICACY 
ASSESSMENTS 
 
Co-primary Efficacy Endpoints: 
• MWT: Change in the mean sleep latency time (in 
minutes) as determined from the first four trials of a 
40-minute MWT from Baseline to Week 12 
• ESS: Change in ESS score from Baseline to Week 12  
Key Secondary Efficacy Endpoint: 
• PGIc: Percentage of subjects reported as improved 
(minimally, much, or very much) on the PGIc at 
Week 12 
PHARMACOKINETIC 
ASSESSMENTS 
Concentration data for JZP-110 will be tabulated by sampling 
time point and will be included in a population PK analysis. 
The population PK model will be used to characterize 
JZP-110 PK profile in narcolepsy patients and to explore 
exposure-efficacy correlations. 
SAFETY 
ASSESSMENTS 
Safety and tolerability evaluations will consist of treatment-
emergent adverse events (TEAEs) and changes in clinical 
laboratory tests (chemistry, hematology, and urinalysis), vital 
signs, 24-hour ambulatory blood pressure monitoring, 12-lead 
ECGs, physical exams, and C-SSRS assessments. 
STATISTICAL 
ANALYSIS 
For the analysis of the co-primary efficacy endpoints, a 
mixed-effect repeated measures (MMRM) model will be used 
as the primary method of analysis. This model will include 
fixed effects for treatment (i.e., dose group), time (as a 
discrete factor), treatment-by-time interaction, baseline value 
of the efficacy endpoint, and randomization stratification 
factor. SAS procedure PROC MIXED will be used to carry 
out this analysis. All available data will be included in the 
model. An unstructured covariance matrix will be used to 
model the correlation among repeated measurements. The 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-002 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
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estimates of treatment difference vs. placebo and their 95% 
confidence intervals will be presented. In addition to the 
MMRM model, an analysis of covariance (ANCOVA) model 
will be used to analyze MWT and ESS to provide sensitivity 
analyses. This ANCOVA model will include the effect for 
treatment (i.e., dose group) as a fixed effect, and baseline 
value of the efficacy endpoint as the covariate.  
The chi-squared test will be used to test the hypotheses 
associated with the analysis of PGIc. 
DATE OF ORIGINAL 
PROTOCOL 
18 December 2014 
Amendment 1 
18 February 2015 
Amendment 2 
10 September 2015 
Amendment 3 
08 February 2016 
 
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Signature Date: 20160210
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Signature Date:
JP: Protocol 14-002 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-002 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
TABLE OF CONTENTS ...........................................................................................................9 
LIST OF IN-TEXT TABLES ..................................................................................................13 
LIST OF IN-TEXT FIGURES.................................................................................................13 
LIST OF APPENDIXES..........................................................................................................13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................14 
1 
INTRODUCTION ...........................................................................................................17 
1.1 
Background and Rationale .....................................................................................18 
1.2 
Nonclinical Experience ..........................................................................................19 
1.3 
Clinical Experience ................................................................................................19 
1.3.1 
Pharmacokinetics of JZP-110 ......................................................................20 
1.3.2 
Efficacy of JZP-110 in Clinical Studies of Narcolepsy ...............................20 
1.3.3 
Safety of JZP-110 in Clinical Studies of Narcolepsy ..................................21 
1.3.4 
Safety of JZP-110 in Clinical Studies of Major Depression and in Healthy 
Subjects ........................................................................................................22 
1.4 
Summary of Potential Benefits and Risks .............................................................23 
2 
STUDY OBJECTIVES ....................................................................................................24 
2.1 
Primary Objective ..................................................................................................24 
2.2 
Secondary Objectives.............................................................................................24 
3 
STUDY DESIGN.............................................................................................................24 
3.1 
Overall Study Design and Plan ..............................................................................24 
3.1.1 
Rationale for Study Design and Control Group ...........................................27 
3.2 
Study Duration and Dates ......................................................................................27 
3.3 
End of Trial ............................................................................................................27 
4 
STUDY POPULATION SELECTION ...........................................................................27 
4.1 
Selection of Study Population ................................................................................27 
4.2 
Inclusion Criteria ...................................................................................................27 
4.3 
Exclusion Criteria ..................................................................................................28 
4.4 
Screening and Randomization Eligibility ..............................................................29 
5 
STUDY TREATMENTS .................................................................................................30 
5.1 
Description of Treatments......................................................................................30 
5.1.1 
JZP-110 ........................................................................................................30 
5.1.2 
Placebo .........................................................................................................30 
5.2 
Treatments Administered .......................................................................................30 
5.3 
Selection and Timing of Dose for Each Subject ....................................................30 
5.4 
Method of Assigning Subjects to Treatment Groups .............................................31 
5.5 
Randomization .......................................................................................................31 
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Clinical Trial Protocol: 14-002 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
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5.6 
Blinding..................................................................................................................31 
5.7 
Prior and Concomitant Therapy .............................................................................31 
5.8 
Restrictions ............................................................................................................32 
5.8.1 
Prior Therapy ...............................................................................................32 
5.8.2 
Fluid and Food Intake ..................................................................................32 
5.8.3 
Other Restrictions ........................................................................................32 
5.9 
Investigational Medicinal Product Treatment Compliance ...................................33 
5.10 
Packaging and Labeling .........................................................................................33 
5.11 
Storage and Accountability ....................................................................................33 
5.12 
Investigational Medicinal Product Retention at Study Site ...................................33 
6 
STUDY PROCEDURES .................................................................................................34 
6.1 
Informed Consent...................................................................................................34 
6.2 
Demographics ........................................................................................................34 
6.3 
Medical History .....................................................................................................34 
6.4 
Physical Examination.............................................................................................34 
6.5 
Vital Signs ..............................................................................................................34 
6.6 
24-Hour Ambulatory Blood Pressure Monitoring .................................................35 
6.7 
Electrocardiography ...............................................................................................35 
6.8 
Polysomnography (PSG) .......................................................................................35 
6.9 
Columbia-Suicide Severity Rating Scale (C-SSRS) ..............................................36 
6.10 
Clinical Laboratory Tests .......................................................................................36 
6.10.1 
Laboratory Parameters .................................................................................36 
6.10.2 
Sample Collection, Storage, and Shipping ..................................................38 
6.10.2.1 
Clinical Laboratory Test Samples ......................................................38 
6.10.2.2 
Blood Samples for Pharmacokinetic (PK) Analysis ..........................39 
6.11 
Dispensing Study Drug ..........................................................................................39 
6.12 
Efficacy Assessments.............................................................................................39 
6.12.1 
Maintenance of Wakefulness Test (MWT) ..................................................39 
6.12.2 
Epworth Sleepiness Scale (ESS) ..................................................................40 
6.12.3 
Clinician Global Impression of Severity (CGIs) .........................................40 
6.12.4 
Clinician Global Impression of Change (CGIc) ..........................................40 
6.12.5 
Patient Global Impression of Change (PGIc) ..............................................40 
6.12.6 
Functional Outcomes of Sleep Questionnaire Short Version (FOSQ-10) ...41 
6.12.7 
36-Item Short Form Health Survey Version 2 (SF-36v2) ...........................41 
6.12.8 
EuroQoL EQ-5D-5L ....................................................................................41 
6.12.9 
Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem V2.0 (WPAI:SHP) .........................................................................41 
6.12.10 Cataplexy Diary ...........................................................................................42 
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6.13 
Pharmacokinetic Assessments ...............................................................................42 
6.13.1 
Blood Samples .............................................................................................42 
6.13.2 
Pharmacokinetic Parameters ........................................................................42 
6.14 
Adverse Event Reporting .......................................................................................42 
6.14.1 
Adverse Events (AEs) ..................................................................................42 
6.14.1.1 
Severity Assessment ..........................................................................43 
6.14.1.2 
Serious Adverse Events and Seriousness Assessment .......................43 
6.14.1.3 
Causal Relationship to Study Drug or Procedure ..............................44 
6.14.1.4 
Other Immediately Reportable Experiences ......................................45 
6.14.1.5 
Adverse Events Recording and Reporting .........................................46 
6.14.1.6 
Follow-up of Adverse Events and Serious Adverse Events ..............46 
6.14.2 
Post-Study Reporting Requirements ............................................................46 
6.14.3 
Pregnancy .....................................................................................................46 
6.14.4 
Emergency Unblinding ................................................................................47 
6.15 
Removal of Subjects from the Trial or Study Drug ...............................................47 
6.15.1 
Handling of Early Terminations ..................................................................48 
6.15.2 
Jazz Pharmaceuticals’ Termination of Study ...............................................48 
6.16 
Appropriateness of Measurements .........................................................................48 
7 
STUDY ACTIVITIES .....................................................................................................49 
7.1 
Screening Clinic Visit(s) ........................................................................................49 
7.1.1 
Screening Visit 1, Days -31 to -3 .................................................................49 
7.1.2 
Rescreening ..................................................................................................50 
7.2 
Baseline Clinic Visit ..............................................................................................50 
7.3 
End of Week 1 Clinic Visit ....................................................................................52 
Visit 3, Day 7 (-1 and +2 days) ..........................................................................................52 
7.4 
End of Week 4 Clinic Visit ....................................................................................53 
7.5 
Phone Contact at the end of Weeks 2, 3, 5, 6, 7, 9, 10 and 11 ...............................55 
7.6 
End of Week 8 Clinic Visit ....................................................................................55 
7.7 
Final Clinic Visit Week 12 ....................................................................................56 
7.8 
Follow-up Clinic Visit Week 14 ............................................................................58 
7.9 
Early Termination Clinic Visit ...............................................................................59 
7.10 
Discontinuations ....................................................................................................59 
8 
QUALITY CONTROL AND ASSURANCE .................................................................60 
9 
PLANNED STATISTICAL METHODS ........................................................................60 
9.1 
General Considerations ..........................................................................................60 
9.2 
Tests of Hypotheses and Significance Levels ........................................................60 
9.3 
Determination of Sample Size ...............................................................................60 
9.4 
Analysis Populations ..............................................................................................61 
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9.5 
Demographics and Baseline Characteristics ..........................................................61 
9.6 
Handling of Dropouts and Missing Data ...............................................................61 
9.7 
Pooling of Investigation Centers ............................................................................61 
9.8 
Efficacy Endpoints .................................................................................................62 
9.8.1 
Co-primary Efficacy Endpoint .....................................................................62 
9.8.2 
Key Secondary Efficacy Endpoint ...............................................................62 
9.8.3 
Other Secondary Endpoints .........................................................................62 
9.8.4 
Functional Outcomes and Quality of Life Endpoints ..................................62 
9.8.5 
Exploratory Endpoints .................................................................................63 
9.9 
Safety Endpoints ....................................................................................................63 
9.10 
Multiplicity Issue ...................................................................................................63 
9.11 
Efficacy Analyses ..................................................................................................64 
9.12 
Safety Analyses ......................................................................................................65 
9.12.1 
Adverse Events ............................................................................................65 
9.12.2 
Vital Signs and 24-Hour Ambulatory Blood Pressure Monitoring .............66 
9.12.3 
Laboratory Evaluation .................................................................................66 
9.12.4 
12-Lead Electrocardiograms ........................................................................66 
9.12.5 
Physical Examinations .................................................................................66 
9.12.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) ....................................66 
9.13 
Analysis of Pharmacokinetic and Pharmacodynamic Variables ...........................66 
9.14 
Subgroup Analyses ................................................................................................67 
9.15 
Interim Analysis and Data Monitoring ..................................................................67 
10 DATA QUALITY ASSURANCE ...................................................................................67 
10.1 
Data Management ..................................................................................................67 
10.2 
Case Report Forms .................................................................................................67 
10.3 
Retention of Data ...................................................................................................67 
10.4 
Data Safety Monitoring Board ...............................................................................68 
11 ADMINISTRATIVE CONSIDERATIONS ....................................................................68 
11.1 
Investigators and Study Administrative Structure .................................................68 
11.1.1 
Contract Research Organization ..................................................................68 
11.1.2 
Jazz Pharmaceuticals Medical Monitors ......................................................68 
11.1.3 
EU Medical Monitor ....................................................................................68 
11.1.4 
Investigator ..................................................................................................68 
11.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................68 
11.3 
Ethical/Legal Conduct of the Study .......................................................................69 
11.4 
Subject Information and Consent...........................................................................69 
11.5 
Subject Confidentiality ..........................................................................................70 
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11.6 
Protocol Adherence – Amendments ......................................................................70 
11.7 
Required Documents ..............................................................................................70 
11.8 
Study Monitoring ...................................................................................................70 
11.9 
Protocol Violations/Deviations ..............................................................................71 
11.10 Access to Source Documentation ..........................................................................71 
11.11 Publication and Disclosure Policy .........................................................................71 
12 REFERENCE LIST .........................................................................................................72 
13 LIST OF UNPUBLISHED STUDY REPORTS .............................................................75 
 
LIST OF IN-TEXT TABLES 
Table 1 
List of Laboratory Tests ...............................................................................37 
Table 2 
Schedule of Clinical Laboratory Samples and Estimated Blood Volume ...38 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Schema...............................................................................................26 
Figure 2 
Multiplicity Strategy ....................................................................................64 
 
LIST OF APPENDIXES 
Appendix 1 
Schedule of Events .............................................................................76 
Appendix 2 
Example Schedule of Times for Procedures During MWT Visits ....79 
Appendix 3 
Cataplexy Frequency Diary ...............................................................80 
Appendix 4 
DSM-5 Criteria for Psychiatric Disorders .........................................81 
Appendix 5 
DSM-5 Substance Use Disorder Diagnostic Criteria .........................88 
Appendix 6 
Epworth Sleepiness Scale (ESS) ........................................................89 
Appendix 7 
Functional Outcomes of Sleep Questionnaire Short Version 
                        (FOSQ-10)...........................................................................................91
Appendix 8 
36-Item Short Form Health Survey Version 2 (SF-36v2) .................94 
Appendix 9 
EuroQoL EQ-5D-5L .........................................................................101 
Appendix 10 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
                        Baseline/Screening Version ..............................................................105 
Appendix 11 
Work Productivity and Activity Impairment Questionnaire: Specific 
                        Health Problem V2.0 (WPAI:SHP) ..................................................109 
Appendix 12 
Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last Visit 
                        Version................................................................................................112 
Appendix 13 
Clinical Global Impression of Severity (CGIs) ................................113 
Appendix 14 
Clinical Global Impression of Change (CGIc) .................................117 
Appendix 15 
Patient Global Impression of Change (PGIc) ...................................118 
Appendix 16 
Diagnostic Criteria for Narcolepsy ...................................................119 
Appendix 17 
Signatures of Agreement for Protocol ..............................................121 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AASM 
American Academy of Sleep Medicine 
AE 
Adverse event 
ACC 
AHA 
AHI 
American College of Cardiology 
American Heart Association 
Apnea hypopnea index 
AICD 
ALB 
Automatic Implantable Cardioverter Defibrillator 
Albumin 
ALK-P 
Alkaline phosphatase 
ALT 
Alanine aminotransferase (SGPT) 
ANCOVA 
Analysis of covariance 
AR 
Adverse reaction 
AST 
Aspartate aminotransferase (SGOT) 
βHCG 
Βeta human chorionic gonadotropin 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
Ca 
Calcium 
CBC 
Complete blood count 
C-CASA 
Columbia Classification Algorithm of Suicide Assessment 
CFR 
Code of Federal Regulations 
CGIc 
Clinical Global Impression of Change 
CGIs 
Clinical Global Impression of Severity 
cGMP 
Current Good Manufacturing Practice 
Cl 
Chloride 
CNS 
Central nervous system 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
CRO 
Contract Research Organization 
CRF 
Case report form 
DMP 
Data Management Plan 
DNS 
Disrupted nighttime sleep 
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DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
EQ-5D-5L 
EuroQoL  
EU 
European Union 
ESS 
Epworth Sleepiness Scale 
FDA 
Food and Drug Administration 
FOSQ-10 
Functional Outcomes of Sleep Questionnaire Short Version 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization  
ICSD-3 
International Classification of Sleep Disorders, 3rd Edition 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
K 
Potassium 
MAOI 
Monoamine Oxidase Inhibitor 
MCC 
Microcrystalline cellulose 
MDD 
Major depressive disorder 
mITT 
Modified Intent-to-treat 
MMRM 
Mixed-effect Repeated Measures 
MSLT 
Multiple Sleep Latency Test 
MWT 
Maintenance of Wakefulness Test 
OSA 
Obstructive Sleep Apnea 
OTC 
Over the counter 
PGIc 
Patient Global Impression of Change 
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PK 
Pharmacokinetics 
PKU 
Phenylketonuria 
PSG 
Polysomnography 
QTc interval 
Q-T interval corrected for heart rate  
QTcB 
Q-T interval corrected for heart rate using Bazett’s formula 
QTcF 
Q-T interval corrected for heart rate using Fridericia’s formula 
REM 
Rapid eye movement 
SAE 
Serious adverse event 
SF-36v2 
36-Item Short Form Health Survey Version 2 
SGOT 
Serum glutamic oxaloacetic transaminase (AST) 
SGPT 
Serum glutamic pyruvic transaminase (ALT) 
SNRI 
Serotonin–norepinephrine reuptake inhibitor 
SOREMP 
Sleep onset REM period 
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  
TEAE 
Treatment emergent adverse event 
TCA 
Tricyclic antidepressant 
TST 
Total sleep time  
ULN 
Upper limit of normal 
UK 
United Kingdom 
US 
United States 
VAS 
Visual analogue scale 
WASO 
Wake after sleep onset  
WBC 
White blood cell (count) 
WPAI:SHP 
Work Productivity and Activity Impairment Questionnaire: Specific 
Health Problem V2.0 
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1 
INTRODUCTION 
JZP-110 [(R)-2-amino-3-phenylpropylcarbamate hydrochloride] is a phenylalanine derivative 
(previously known as ADX-N05, R228060, and YKP10A) that is currently being 
investigated as a potential treatment for excessive daytime sleepiness in narcolepsy and 
obstructive sleep apnea (OSA). Nonclinical data indicate that JZP-110 is a wake-promoting 
agent that lacks the noradrenergic releasing effects of amphetamines 
(EDMS PSDB-4956838, EDMS-PSDB-2735318, EDMS-PSDB-5305783) and does not 
produce rebound hypersomnia in rodent models (Hasan et al. 2009). Pharmacologically, 
JZP-110 appears to be a low-potency reuptake inhibitor at dopamine and norepinephrine 
transporters. 
JZP-110 was originally synthesized by SK Life Science (South Korea). The molecule has 
been under development for the treatment of depression and for the treatment of excessive 
sleepiness in narcolepsy under various sponsors. Jazz Pharmaceuticals intends to complete 
development of JZP-110 for the treatment of excessive sleepiness in adult patients with 
narcolepsy and in adult patients with OSA by demonstrating increased ability to stay awake 
throughout the day using the validated maintenance of wakefulness test (MWT) and 
decreased subjective sleepiness using the Epworth Sleepiness Scale (ESS). 
Narcolepsy is a life-long neurologic disease for which no cure has been identified. It affects 
an estimated 0.02% to 0.067% of the population worldwide, approximately 1 in 
2000 individuals in the United States (Ohayon 2007, Majid & Hirshkowitz 2010), and 4.7 of 
10,000 (0.047%) individuals in the general population of five European countries (United 
Kingdom [UK], Germany, Italy, Portugal, and Spain) (Ohayon et al. 2002). The 
symptomatology of this condition is well described in the literature, with consensus on the 
five core symptoms of narcolepsy: excessive daytime sleepiness, cataplexy, sleep paralysis, 
sleep-related (hypnagogic and hypnopompic) hallucinations, and disrupted nighttime sleep 
(DNS) (Morgenthaler et al. 2007), with excessive daytime sleepiness and cataplexy being the 
most common symptoms. 
Based on the interim analysis of a survey conducted in 2013 by Wake Up Narcolepsy, Inc., a 
nonprofit organization working to improve the diagnosis and treatment of narcolepsy, 
excessive daytime sleepiness was the symptom most commonly endorsed as having the most 
significant impact on patients’ lives (77% of patients) (Unite Narcolepsy 2013). Wake Up 
Narcolepsy, Inc., conducted the survey through a special patient education and engagement 
initiative called Unite Narcolepsy. The survey, which is the largest survey ever conducted by 
a narcolepsy patient organization (1,350 individuals, including more than 1,000 people 
diagnosed with narcolepsy by a physician), was conducted in preparation for a public 
meeting held by the FDA on Patient-Focused Drug Development for narcolepsy. At the 
meeting, patients surveyed “overwhelmingly” selected daytime sleepiness as their narcolepsy 
symptom having the most significant impact on their daily lives (93% was displayed on the 
webcast clicker count) (FDA Narcolepsy Public Meeting 2013). These surveys demonstrate 
that a clear unmet medical need remains for the adequate treatment of excessive sleepiness in 
narcolepsy and that patients with narcolepsy endorse the symptom of excessive sleepiness as 
having the most significant impact on their daily lives. 
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Currently approved medications to improve wakefulness and to treat excessive daytime 
sleepiness in narcolepsy include dextroamphetamine (Dexedrine®), methylphenidate 
(Ritalin®), sodium oxybate (Xyrem®), modafinil (Provigil®), and armodafinil (Nuvigil®). 
Each of these medications has limitations, including those related to efficacy and safety. 
Dextroamphetamine and methylphenidate are C-II stimulant medications with high potential 
for abuse. Sodium oxybate is a C-III CNS depressant that requires twice nightly dosing. 
Modafinil and armodafinil do not appear to adequately promote wakefulness throughout the 
day with once daily dosing (Harsh et al. 2006, Schwartz et al. 2003). 
As a result of the findings of significant decreases in excessive sleepiness (lower ESS scores) 
and significant increases in the ability to stay awake throughout the day (higher MWT sleep 
latencies) when adult patients with narcolepsy were treated with JZP-110, as well as the 
urgent clinical need reported by patients for therapies that better treat the excessive 
sleepiness that significantly impacts their daily lives (Unite Narcolepsy 2013, FDA 
Narcolepsy Public Meeting 2013), Jazz Pharmaceuticals is conducting this study with 
JZP-110 to generate efficacy, safety, and pharmacokinetic (PK) information in this 
population. 
1.1 
Background and Rationale 
The MWT is the standard objective measure of an individual’s ability to remain awake 
during the daytime in a darkened, quiet environment and is commonly used to assess 
response to treatment (International Classification of Sleep Disorders, Third Edition 
[ICSD-3], American Academy of Sleep Medicine [AASM 2014]). Previous studies of 
modafinil and armodafinil in patients with narcolepsy have demonstrated statistically 
significant increases in mean sleep latency using a 20-minute MWT with maximal 
differences in the means between drug and placebo groups ranging from 2.3 to 4.5 minutes 
(US Modafinil in Narcolepsy Multicenter Study Group 1998, US Modafinil in Narcolepsy 
Multicenter Study Group 2000, Harsh et al. 2006). In contrast, data for the 300 mg dose of 
JZP-110 from the Phase 2a Study ADX-N05 201 using a 40-minute MWT resulted in a 
maximal difference in the means between drug and placebo of 11.8 minutes. Similarly, data 
from the Phase 2b Study ADX-N05 202 resulted in maximal differences in the means of 
8.1 and 10.7 minutes between 150 mg or 300 mg JZP-110 and placebo, respectively, on a 
40 minute MWT. These data suggest that doses of 150 and 300 mg JZP-110 could serve a 
significant unmet medical need to treat excessive sleepiness and to increase patients’ ability 
to stay awake throughout the day beyond what has been demonstrated with current available 
therapies. 
Another limitation of modafinil and armodafinil is that the therapeutic effects of these drugs 
do not appear to last throughout the day and are markedly reduced by the fifth trial of a 5- or 
6-trial, 20-minute MWT (Schwartz et al. 2003, Harsh et al. 2006, Roth et al. 2006). For 
example, the effects of 200 and 400 mg modafinil diminished throughout the day, and the 
mean changes from baseline in sleep latency were almost zero on the fifth and sixth trials of 
a 6-trial, 20-minute MWT (5-7 PM) when modafinil was given once daily in the morning 
(Schwartz et al. 2003). Modafinil does appear to last throughout the day if given in split 
doses, which is not an approved dosing regimen (Schwartz et al. 2003; Provigil Prescribing 
Information). 
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Similarly, the effects of 150 and 250 mg armodafinil began to diminish by the fifth trial of a 
6-trial, 20-minute MWT, resulting in a mean change from baseline in sleep latency of almost 
zero for 250 mg armodafinil at 1700 hours (5 PM) (Harsh et al. 2006). In addition, the effects 
of 150 and 250 mg modafinil on mean sleep latency across the last three trials (3-7 PM) were 
not statistically different from placebo (for the individual doses or when combined) at the end 
of this 12-week trial (Harsh et al. 2006). 
In contrast to the limited effects of modafinil and armodafinil on sleep latency on the fifth 
trial of a 20-minute MWT (Schwartz et al. 2003, Harsh et al. 2006), data from the 12-week, 
Phase 2b study of JZP-110 (ADX-N05 202) in 93 subjects with narcolepsy (44 subjects 
randomized to receive JZP-110) showed that the mean change from baseline in sleep latency 
on the fifth trial of a 5-trial, 40-minute MWT was 8.2 minutes for the 300 mg dose of JZP-
110 (significantly greater than placebo at p=0.0007). The mean change from baseline on the 
fifth trial of a 5-trial, 40-minute MWT was also significantly greater than placebo (p=0.0002) 
for the 150 mg dose of JZP-110 at 5.4 minutes. The 4- and 12-week JZP-110 studies found 
no unexpected drug-related toxicities and demonstrated that JZP-110 was safe and well 
tolerated in narcolepsy patients under the parameters tested. Taken together, these data 
suggest that JZP-110 might offer an important advance in the treatment of excessive 
sleepiness in narcolepsy by increasing patients’ ability to stay awake throughout the day.  
1.2 
Nonclinical Experience  
Nonclinical studies have been conducted to characterize primary pharmacology, secondary 
and safety pharmacology, abuse liability, absorption, distribution, metabolism, excretion, and 
toxicology of JZP-110. 
JZP-110 was extensively absorbed and showed high oral bioavailability (71 to 100%) in 
mice, rats, and dogs. In humans, bioavailability was >90% as evidenced by plasma AUC for 
parent drug essentially matching AUC for total radioactivity in a human mass balance study, 
along with urinary recovery of >90% of the dose as unchanged drug. Plasma protein binding 
was low (8 to 17%) in mouse, rat, rabbit, dog, and human plasma. In the in vitro metabolism 
studies, no notable inhibition of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2E1 and CYP3A4 occurred (15%) with concentrations up to 1000 μM. Notable 
inhibition of CYP1A2 (73%) and CYP2D6 (56%) activity was observed only at the highest 
concentration (1000 μM) investigated. However, this level of inhibition is unlikely to result 
in clinically significant drug-drug interactions with CYP1A2 or CYP2D6 substrates. The 
plasma Cmax level after oral administration to humans at 400 mg/day is approximately 7.6 μM 
(1482 ng/mL). JZP-110 (5 to 100 μM) did not inhibit P-glycoprotein–mediated transport. 
More detailed information is provided in the JZP-110 Investigators Brochure. 
1.3 
Clinical Experience 
At the start of the Phase 3 program, nine clinical studies (six Phase 1 and three Phase 2a 
studies) had been conducted in 262 healthy subjects and 602 subjects (two of whom did not 
receive study drug) with major depressive disorder (MDD). Of these 862 subjects, 
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555 received JZP-110, 185 received placebo, and 122 received paroxetine. Two Phase 2 
studies have been conducted in 126 subjects with narcolepsy, in which 77 subjects received 
JZP-110 and 49 subjects received placebo. 
1.3.1 
Pharmacokinetics of JZP-110 
JZP-110 is eliminated primarily via the renal route, with at least 90% of the dose being 
excreted as unchanged drug within 48 hours. Following repeated doses administered once or 
twice daily, JZP-110 exposure was dose proportional, absorption (tmax: 1.3 to 2.5 hours) and 
elimination (t½: 6 to 7.6 hours) were rapid, and steady state was reached in 3 days. 
Pharmacokinetics were linear over the multiple-dose (14 day) range of 200 to 1000 mg/day. 
Limited accumulation and no enzyme induction were evident.  
Doses of JZP-110 previously studied in human subjects have ranged from 50 to 1200 mg per 
day in healthy subjects, from 200 to 900 mg per day in subjects with MDD, and have 
included 150 and 300 mg in subjects with narcolepsy.  
1.3.2 
Efficacy of JZP-110 in Clinical Studies of Narcolepsy 
Two randomized, double-blind, placebo-controlled studies were conducted in 126 adult 
subjects with narcolepsy. In these studies, once daily doses included 150 and 300 mg/day 
JZP-110; the doses were based on the free base of the molecule. 
Study ADX-N05 201 was a 4-week, double-blind, placebo-controlled, crossover study of 
JZP-110 150 and 300 mg given once daily in adult subjects with narcolepsy (N=33). The 
primary efficacy endpoint was the change from Baseline in the mean sleep latency time (in 
minutes) averaged across the first four trials of the MWT at the end of 2 weeks of treatment. 
At the end of 2 weeks of treatment, the mean sleep latency on the MWT increased by 
12.7 minutes for the JZP-110 300 mg/day treatment period versus 0.9 minutes for the placebo 
period. The difference in mean change from Baseline was both statistically and clinically 
significant in favor of the active treatment period (mixed model analysis of variance; 
p=0.0002). All secondary endpoints in this study were also positive including the mean 
change in the ESS. 
Study ADX-N05 202 was a 12-week, double-blind, placebo-controlled, parallel-group study 
of JZP-110 150 and 300 mg given once daily in adult subjects with narcolepsy (N=93). The 
primary efficacy endpoints were the change from Baseline in the mean sleep latency time (in 
minutes) averaged across the first four trials of the MWT and the Clinical Global Impression 
of Change (CGIc) scores for JZP-110 versus placebo at the last (Week 12) assessment at the 
300 mg dose. At Week 12/Last Assessment, the mean sleep latency increased by 
12.8 minutes for the JZP-110 group (300 mg/day) versus 2.1 minutes for the placebo group. 
The difference in mean change from Baseline was both statistically and clinically significant 
in favor of the active treatment group (two-sample t-test; p<0.0001). All secondary endpoints 
in this study were also positive. 
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1.3.3 
Safety of JZP-110 in Clinical Studies of Narcolepsy 
In Study ADX-N05 201, 1 week of treatment with JZP-110 150 mg/day followed by an 
increase to 300 mg/day for a second week was safe and well tolerated. The most common 
treatment-emergent adverse events (TEAEs) with JZP-110 treatment included nausea (12%), 
chest discomfort (9%), headache (9%), anxiety (6%), decreased appetite (6%), initial 
insomnia (6%), insomnia (6%), and muscle tightness (6%). None of these events were 
reported during placebo treatment. There were no deaths, treatment-emergent serious AEs 
(SAEs), or discontinuations due to AEs. Severe TEAEs were limited to two subjects (one 
with intermittent nausea and one with insomnia). JZP-110 treatment was associated with a 
modest effect on heart rate and blood pressure, and TEAEs suggested a profile of effects 
consistent with those of a wake-promoting drug (decreased appetite, headache, anxiety, 
insomnias, and gastrointestinal complaints). Palpitations were reported by one subject (3%) 
and chest pain was reported by 3 subjects (9%; all reported as non-cardiac pain) while on 
JZP-110. There were no reports of palpitations or chest pain while subjects were on placebo. 
In Study ADX-N05 202, the JZP-110 dose regimen of 150 mg/day for 4 weeks followed by 
300 mg/day for 8 weeks appeared to be safe and well tolerated. The most common TEAEs 
with JZP-110 treatment included headache (16%), nausea (14%), insomnia (14%), decreased 
appetite (14%), diarrhea (11%), and anxiety (11%); all of these events were more common in 
the combined JZP-110 group than in the placebo group. There were no deaths in this study. 
Treatment-emergent SAEs occurred in two subjects (both in the JZP-110 group): one subject 
had conversion disorder and one had acute cholecystitis. Three subjects (6.8%) in the 
JZP-110 group and two subjects (4.1%) in the placebo group had TEAEs that led to study 
discontinuation. It appears likely that JZP-110 is causally associated with insomnia, 
decreased appetite, anxiety, irritability, palpitations, and perhaps nausea and diarrhea.  
In the ADX-N05 202 study, JZP-110 treatment was associated with small effects on placebo-
corrected changes in heart rate (both measured and from ECGs), blood pressure, and 
quantitative ECG parameters (mean heart rate increased from Baseline at 2 hours after dosing 
by 3 to 5 beats per minute (bpm) with little or no change at 9 to 10 hours after dosing; mean 
PR, QRS, QT, QTcB and QTcF demonstrated no significant changes). There were no 
clinically significant effects on the ECG parameters of PR, QRS, QTcF or QTcB in any 
subject. Palpitations were reported by 4 subjects (9%) and chest pain was reported by 
2 subjects (both appeared to be non-cardiac pain) while on JZP-110. There was one report of 
palpitations and one report of chest pain from subjects who were on placebo in the ADX-N05 
202 study. There were two subjects who had TEAEs that were related to vital signs: mildly 
elevated blood pressure beginning on Day 17 in one subject on JZP-110 and elevated blood 
pressure at the Week 4 visit and intermittent elevated systolic and diastolic pressures 
beginning at the Week 6 visit in one subject on placebo. There were two subjects who had 
TEAEs related to ECG findings: one subject had a TEAE of “heart rate increased” on 
JZP-110 that may have been related to ECG-derived measurements, and another subject on 
placebo was reported to have a TEAE of “occasional ventricular premature complexes.” 
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1.3.4 
Safety of JZP-110 in Clinical Studies of Major Depression and in Healthy 
Subjects 
Three randomized, double-blind, placebo-controlled studies (SKUP- 9801, R228060-USA-
10, and R228060-MDD-201) have been conducted in a total of 600 adult subjects with MDD. 
In these studies, doses ranged from 100 to 900 mg/day JZP-110 with the dose based on the 
hydrochloride salt of the drug. These studies did not demonstrate efficacy for JZP-110 in 
treating MDD.  
• 
Study SKUP-9801 was an 8-week, double-blind, placebo-controlled, parallel-group pilot 
study in adults with MDD of low (100 to 300 mg/day; N=8), intermediate (400 to 
600 mg/day; N=9), and high (700 to 900 mg/day; N=10) doses (given twice daily) of 
JZP-110 versus placebo (N=8) (total N=35) (EDMS-PSDB-2275504).  
• 
Study R228060-USA-10 was a 3-week, double-blind, placebo-controlled, parallel-group 
study to assess the tolerability of JZP-110 200 mg/day (100 mg morning, 100 mg evening) 
and 500 mg/day (300 mg morning, 200 mg evening) in adult subjects with MDD (N=77), 
with efficacy as an exploratory objective (R228060-USA-10). 
• 
Study R228060-MDD-201 was a large-scale (27 centers, N=488), 6-week, double-blind, 
active- (paroxetine) and placebo-controlled, parallel-group study of JZP-110 100 and 200 mg 
given twice daily in adult subjects with MDD (N=488) (EDMS-PSDB-3696001). 
Most of the 219 healthy subjects and 600 subjects with MDD reported adverse events (AEs), 
the majority of which were mild or moderate. The AEs from these 219 healthy subjects do 
not include data from a recently completed Phase 1 human abuse liability study in 
43 subjects because data analysis from that study is ongoing (preliminary data will be 
included in the JZP-110 Investigators Brochure). The most common TEAEs that occurred 
≥5% and more often with JZP-110 than placebo across doses of 200 to 1200 mg/day 
included: insomnia (34%), headache (23%), dizziness (16%), anorexia (16%), dry mouth 
(16%), nervousness (15%), nausea (14%), palpitation (11%), agitation (10%), abdominal 
pain (10%), anxiety (9%), fatigue (9%), concentration impaired (8%), and diarrhea (6%). 
There were no deaths. One healthy JZP-110-treated subject (1000 mg/day) reported a serious 
adverse event (SAE, confusion) that was considered unrelated to study drug. Four JZP-110-
treated subjects with MDD reported SAEs: cellulitis (100 to 300 mg/day), aggravated 
depression (200 mg/day), aggravated depression and suicidal ideation (400 mg/day), and 
myocardial infarction (200 mg). The myocardial infarction was the only SAE that was 
classified as possibly related to study drug (see the JZP-110 Investigators Brochure for 
additional information on this SAE).  
In addition, there were reports of mostly mild cardiovascular AEs in other studies (see the 
JZP-110 Investigators Brochure for additional information). Palpitations were reported by 
one subject in each of the YUKIC 9603-01 and SKUP-9801 studies and by seven subjects in 
the MDD-201 study. Chest pain was reported by one subject in the YUKIC 9603-01 study 
and by four subjects in the MDD-201 study. T-wave inversions were observed in one subject 
in each of the YUKIC-9603 and YUKIC-9702-01 studies and in three subjects in the 
MDD-201 study (which includes the myocardial infarction described above). Ventricular 
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ectopy (seen on 12-lead ECG) was reported in one patient in YUKIC-9702-01 and one 
patient in MDD-201. One patient reported orthostatic hypotension and two patients reported 
hypertension in MDD-201, all three on JZP-110. There were occasional ECG reports of 
intermittent fascicular blocks, intraventricular conduction defects, and 1st degree AV block, 
about equally common in JZP-110 and controls, and rarely new and sustained. These were 
usually considered not clinically significant findings or adverse events.  
Three healthy subjects (two on 200 mg and one on 800 mg JZP-110) and two subjects with 
MDD (both on 500 mg JZP-110) had treatment-emergent reversible elevations of liver 
enzymes (alanine aminotransferase and/or aspartate aminotransferase) of 1.1 to 4.1 × the 
upper limit of normal (ULN). Two placebo-treated subjects also developed mild elevations in 
liver enzymes. There were no other findings in laboratory safety tests. 
1.4 
Summary of Potential Benefits and Risks 
The potential benefits of JZP-110 to subjects randomized to the 150 mg or 300 mg treatment 
arms in this study are expected to be a clinically significant increase in the ability to stay 
awake and a clinically significant decrease in subjective sleepiness. These benefits are 
anticipated from the MWT and ESS data, respectively, from previous studies of JZP-110 in 
narcolepsy patients. However, not every subject in the 150 or 300 mg treatment arms is 
anticipated to benefit. It is not known if the 75 mg dose will provide a clinical benefit. 
Placebo is not anticipated to provide any benefit; however, some patients receiving placebo 
might benefit from their participation in the study. 
The risks to subjects in this study who are randomized to the 150 mg or 300 mg treatment 
arms are expected to be similar to those seen in prior clinical studies that evaluated the 
effects of 150 mg and 300 mg JZP-110 in narcolepsy patients (Section 1.3.3). It is not known 
if the 75 mg dose will be associated with the same type or magnitude of AEs that were 
associated with the higher doses that were previously studied. Risks for subjects who are 
randomized to the placebo treatment arm may include those associated with untreated 
narcolepsy symptoms.  
Subjects treated with JZP-110 might also experience small increases in blood pressure and 
heart rate in the first 8 hours after dosing. To date those increases have been on the order of 
up to 5 beats per minute, up to 6 mmHg in systolic blood pressure, and up to 3 mmHg in 
diastolic blood pressure. In a recently completed thorough QT study, JZP-110 did not cause 
QT interval prolongation above the threshold of regulatory concern when given at either the 
300 mg or 900 mg dose (International Conference on Harmonisation [ICH] E14 Clinical 
Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-
Antiarrhythmic Drugs, 2005). 
 
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2 
STUDY OBJECTIVES 
2.1 
Primary Objective  
To evaluate the efficacy of JZP-110 administered once daily for up to 12 weeks in doses of 
75, 150, and 300 mg compared to placebo in the treatment of excessive sleepiness in adult 
subjects with narcolepsy. 
2.2 
Secondary Objectives  
To evaluate the safety and tolerability of JZP-110 administered once daily for up to 12 weeks 
in doses of 75, 150, and 300 mg compared to placebo in the treatment of excessive sleepiness 
in adult subjects with narcolepsy. 
To characterize the pharmacokinetics (PK) of JZP-110 in subjects with narcolepsy using 
sparse sampling methods. 
3 
STUDY DESIGN 
3.1 
Overall Study Design and Plan 
The Schedule of Events is presented in Appendix 1, and the Study Schema in Figure 1. 
This trial is a 12-week, randomized, double-blind, placebo-controlled, multicenter, 
4 treatment parallel group study of the safety and efficacy of JZP-110 in the treatment of 
excessive sleepiness in adult subjects with narcolepsy as defined by The ICSD-3 or the 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Following the 
successful completion of Screening and Baseline visits, stratified randomization on the basis 
of the presence or absence of cataplexy will occur. Subjects will be assigned to receive 
JZP-110 75, 150, or 300 mg or placebo in a 1:1:1:1 ratio once daily over a 12-week 
Treatment Phase. Subjects randomized to the 150 mg dose will initially receive 75 mg from 
Day 1 through Day 3 of the first week of the Treatment Phase and will receive 150 mg 
starting on Day 4. Subjects randomized to the 300 mg dose will initially receive 150 mg from 
Day 1 through Day 3 of the first week of the Treatment Phase and will receive 300 mg 
starting on Day 4. Subjects randomized to the 75 mg group will not require titration. 
During the Treatment Phase, subjects will return to the investigative site to complete efficacy 
and safety assessments at the end of Weeks 1, 4, 8, and 12; the Week 4 and 12 visits will 
include an overnight stay at the investigational site for nocturnal polysomnography (PSG) 
followed by an MWT, and the Week 8 Visit will include 24-hour ambulatory blood pressure 
monitoring. Subjects will take their final dose of study drug at the Week 12 visit prior to the 
Week 12 visit assessments. Subjects will return at the end of Week 14 for follow-up 
assessments. Unless there are any outstanding safety issues that require follow-up, subjects 
will be discharged from the study at the Week 14 visit. 
Efficacy will be assessed by changes in the mean sleep latency on the first 4 trials of a 5 trial, 
40-minute MWT and by changes in the mean ESS score as co-primary endpoints, percentage 
of patients improved on the Patient Global Impression of Change (PGIc) as a key secondary 
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endpoint, and the CGIc, Functional Outcomes of Sleep Questionnaire Short Version 
(FOSQ-10), 36-Item Short Form Health Survey Version 2 (SF-36v2), EuroQoL EQ-5D-5L, 
and the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem 
V2.0 (WPAI:SHP) as other endpoints. 
Four blood samples will be collected from each subject for PK evaluations; one sample 
during the Week 1 visit, one sample during the Week 4 visit, and two samples during the 
Week 8 visit. The samples collected at the Week 1 and Week 8 visits will be within 1-8 hours 
of dosing. The sample collected at the Week 4 visit will be within 8-12 hours after dosing.  
Safety will be assessed by the incidence of observed and reported AEs, and changes in 
physical examination findings, ECGs, clinical laboratory tests, vital sign measurements, 
24-hour ambulatory blood pressure monitoring at the Week 8 visit, and the Columbia-Suicide 
Severity Rating Scale (C-SSRS). Safety will be assessed throughout the study. 
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Figure 1 
Study Schema 
 
 
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3.1.1 
Rationale for Study Design and Control Group 
This study was designed to be consistent with the United States (US) Food and Drug 
Administration (FDA) Guidance for Industry on Providing Clinical Evidence of 
Effectiveness for Human Drug and Biological Products, with The International Conference 
on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) Guidance on The Extent of Population Exposure to Assess Clinical Safety for 
Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions, and with the 
ethical principles given in these guidances which have their origins in the Declaration of 
Helsinki. The inclusion of a placebo control group in this study is necessary to determine the 
efficacy and safety of this new investigational medicinal product.  
3.2 
Study Duration and Dates 
Each subject will participate for up to 31 days for Screening and Baseline evaluations, for 
12 weeks in the Treatment Phase, and for 2 weeks in the Safety Follow-up Phase (the 2 week 
Safety Follow-up visit is not required for subjects who enter the Open-label Safety Study 
[14-005] at the Final Clinic Visit). It is estimated that enrollment across all sites will be 
completed in 12 months. 
3.3 
End of Trial 
The end of the trial will be the date of the last visit of the last subject enrolled in the trial. 
4 
STUDY POPULATION SELECTION 
4.1 
Selection of Study Population 
Subjects must have a documented diagnosis of narcolepsy according to the ICSD-3 or 
DSM-5 and have sleepiness and an inability to stay awake as demonstrated by objective and 
subjective criteria. 
4.2 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in the study. 
1. Males and females between 18 and 75 years of age, inclusive. 
2. Diagnosis of narcolepsy according to ICSD-3 or DSM-5 criteria (Appendix 16). 
3. Baseline mean sleep latency <25 minutes as documented by the mean of the first four 
trials of the Baseline 5-trial MWT. 
4. Baseline Epworth Sleepiness Scale (ESS) score ≥10. 
5. Usual nightly total sleep time of at least 6 hours. 
6. Body mass index from 18 to <45 kg/m2. 
7. Consent to use a medically acceptable method of contraception for at least 2 months 
prior to the first dose of study drug, throughout the entire study period, and for 
30 days after the study is completed.  
8. Willing and able to comply with the study design schedule and other requirements. 
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9. Willing and able to provide written informed consent. 
4.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study. 
1. Female subjects who are pregnant, nursing, or lactating. 
2. Usual bedtime later than 1 AM (0100 hours). 
3. Occupation requiring nighttime or variable shift work. 
4. Moderate or severe obstructive sleep apnea (OSA) on the baseline PSG. 
5. Any other clinically relevant medical, behavioral, or psychiatric disorder other than 
narcolepsy that is associated with excessive sleepiness. 
6. History or presence of bipolar disorder, bipolar related disorders, schizophrenia, 
schizophrenia spectrum disorders, or other psychotic disorders according to DSM-5 
criteria (Appendix 4). 
7. History or presence of any acutely unstable medical condition, behavioral or 
psychiatric disorder (including active suicidal ideation), or surgical history that could 
affect the safety of the subject or interfere with study efficacy, safety, PK 
assessments, or the ability of the subject to complete the trial per the judgment of the 
Investigator. 
8. History of bariatric surgery within the past year or a history of any gastric bypass 
procedure. 
9. Presence of renal impairment or calculated creatinine clearance <60 mL/min. 
10. Clinically significant ECG abnormality in the opinion of the Investigator. 
11. This criterion has been removed.  
12. Presence of significant cardiovascular disease including but not limited to: 
myocardial infarction within the past year, unstable angina pectoris, symptomatic 
congestive heart failure (ACC/AHA stage C or D), revascularization procedures 
within the past year, ventricular cardiac arrhythmias requiring automatic implantable 
cardioverter defibrillator (AICD) or medication therapy, uncontrolled hypertension, 
systolic blood pressure ≥155 mmHg or diastolic blood pressure ≥95 mmHg (at 
screening, or consistently across Baseline measures according to protocol 
specifications), or any history of cardiovascular disease or any significant 
cardiovascular condition that in the investigator’s opinion may jeopardize subject 
safety in the study. 
13. Laboratory value(s) outside the laboratory reference range that are considered to be 
clinically significant by the Investigator (clinical chemistry, hematology, and 
urinalysis); NOTE: Screening labs may be repeated once. 
14. Excessive caffeine use one week prior to Baseline assessments or anticipated 
excessive use during the study defined as >600 mg/day of caffeine. 
15. Use of any over-the-counter (OTC) or prescription medications that could affect the 
evaluation of excessive sleepiness within a time period prior to the Baseline visit 
corresponding to at least five half-lives of the drug(s) or planned use of such drug(s) 
at some point throughout the duration of the study. Examples of excluded 
medications include OTC sleep aids or stimulants (e.g., pseudoephedrine), 
methylphenidate, amphetamines, modafinil, armodafinil, sodium oxybate, pemoline, 
trazodone, hypnotics, benzodiazepines, barbiturates, and opioids. Medications should 
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be discontinued such that the subject has returned to his/her baseline level of daytime 
sleepiness at least 7 days prior to the Baseline visit, in the opinion of the Investigator. 
16. Use of any medications that could affect the evaluation of cataplexy within a time 
period prior to the Baseline visit corresponding to at least five half-lives of the drug(s) 
or planned use of such drug(s) at some point throughout the duration of the study. 
Examples of excluded anti-cataplectic medications include selective serotonin 
reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), 
tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), anti-
convulsant agents, and sodium oxybate. These drugs will be discontinued if they are 
taken for the treatment of narcolepsy and discontinuation is deemed safe by the 
Investigator. Medications should be sufficiently washed out such that the subject has 
returned to his/her baseline level of cataplexy at least 7 days prior to the Baseline 
visit, in the opinion of the Investigator. 
17. Received an investigational drug in the past 30 days or five half-lives (whichever is 
longer) prior to the Baseline visit, or plans to use an investigational drug (other than 
the study drug) during the study. 
18. Previous exposure to or participation in a previous clinical trial of JZP-110 (ADX-
N05, R228060, YKP10A). 
19. Current or past (within the past 2 years) diagnosis of a moderate or severe substance 
use disorder according to DSM-5 criteria. 
20. Nicotine dependence that has an effect on sleep (e.g., a subject who routinely 
awakens at night to smoke). 
21. Current, past (within the past 2 years), or seeking treatment for a substance related 
disorder (Appendix 5). 
22. Urine drug screen positive for an illicit drug of abuse (including cannabinoids) at 
screening or at any point throughout the duration of the study, except for a prescribed 
drug (e.g., amphetamine) at screening. 
23. History of phenylketonuria (PKU) or history of hypersensitivity to phenylalanine-
derived products. 
 
For the purpose of this study, medically acceptable methods of contraception include 
estrogen-progestin oral contraceptive pills, patches, or vaginal ring (if one of these methods 
is chosen it must have been used consistently for 2 months prior to the first dose of study 
drug); progestin implant or injection; diaphragm with spermicide; male condom plus vaginal 
spermicide; surgical sterilization; intrauterine device; post-menopausal (defined as age >50 
and >1 year of amenorrhea); medically documented ovarian failure (defined as age <50 with 
serum estradiol and follicle-stimulating hormone [FSH] levels within the institutional 
postmenopausal range and a negative serum or urine βHCG); vasectomy (>6 months prior to 
baseline); or abstinence. 
4.4 
Screening and Randomization Eligibility  
Subjects will be considered eligible for screening if they meet the inclusion criteria and do 
not meet any exclusion criteria. 
Subjects who do not meet all eligibility criteria will not be randomized. 
 
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5 
STUDY TREATMENTS 
5.1 
Description of Treatments 
5.1.1 
JZP-110 
The investigational medicinal product JZP-110 [(R)-2-amino-3-phenylpropylcarbamate 
hydrochloride] will be supplied as 75 mg, 150 mg, and 300 mg tablets (based on the free base 
of the molecule) that will be overencapsulated in an opaque gelatin capsule. The tablets 
contain the excipients hydroxypropyl cellulose and magnesium stearate, and a polymer film 
coat (Opadry®). The capsule backfill will be microcrystalline cellulose (MCC). 
JZP-110 is not a controlled substance under the United States Controlled Substances Act or 
under the United Nations Convention on Psychotropic Substances. 
5.1.2 
Placebo 
Placebo tablets are composed of mannitol, MCC, and magnesium stearate, and a polymer 
film coat (Opadry®). Placebo tablets will be overencapsulated in the same opaque gelatin 
capsules that will be used for the active JZP-110 treatments. MCC will be used as the capsule 
backfill. 
5.2 
Treatments Administered 
Subjects will receive JZP-110 75, 150, or 300 mg or placebo once daily as a single gelatin 
capsule over a Treatment Phase of 12 weeks. 
 
5.3 
Selection and Timing of Dose for Each Subject 
Data from the ADX-N05 201 and ADX-N05 202 trials that were conducted in patients with 
narcolepsy demonstrated that doses of 150 mg and 300 mg JZP-110 increased the mean sleep 
latency on the first four trials of the MWT by 9.5 and 12.8 minutes from baseline, 
respectively, and increased the sleep latency on the fifth trial of the MWT by 5.4 and 
8.2 minutes from baseline, respectively. Based on these findings and the safety and 
tolerability profiles of 150 and 300 mg JZP-110 in adult patients with narcolepsy in these 
trials, this study will further evaluate of the safety and efficacy of 150 and 300 mg, in 
addition to a lower dose of 75 mg JZP-110 given once a day in the morning.  
In this study, subjects will be randomized 1:1:1:1 to receive either JZP-110 75, 150, 300 mg, 
or placebo as described in Section 5.5. Subjects will be instructed to take a single daily dose 
of study drug in the morning, on an empty stomach within one hour of awakening. Subjects 
will also be instructed to abstain from eating or drinking (except for water) for 30 minutes 
after taking the study drug. If a subject fails to take the study drug within an hour of 
awakening, the subject should be instructed to take the study drug, if he/she is able to do so, 
at least 12 hours before his/her anticipated bedtime. If the subject cannot take the study drug 
at least 12 hours before his/her anticipated bedtime, the subject should not take the study 
drug for that day. 
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The titration schedule in this protocol is based on the pharmacokinetics of the JZP-110 as 
well as the titration experience in clinical trials to date. Steady state levels of JZP-110 are 
reached within 3 days (Section 1.3.1). In the previous ADX-N05 201 and ADX-N05 202 
studies in narcolepsy patients, subjects received 150 mg JZP-110 for 1 or 4 weeks, 
respectively, prior to receiving 300 mg JZP-110. In this study, subjects randomized to receive 
the 300 mg dose will initially receive 150 mg from Day 1 through Day 3 of the first week of 
the Treatment Phase and will receive 300 mg starting on Day 4. This titration schedule is 
similar to those that were used in previous studies of JZP-110 in MDD (Section 1.3.4). 
Although previous studies have shown that the 150 mg dose is tolerated as a starting dose in 
patients with narcolepsy, subjects randomized to receive the 150 mg dose in this study will 
initially receive 75 mg from Day 1 through Day 3 of the first week of the Treatment Phase 
and will receive 150 mg starting on Day 4 to evaluate whether titration to the 150 mg dose in 
this study will result in fewer AEs as compared to a starting dose of 150 mg without titration. 
Subjects randomized to the 75 mg or placebo groups will not require titration. 
5.4 
Method of Assigning Subjects to Treatment Groups 
Following the successful completion of Screening and Baseline visits, stratified 
randomization on the basis of the presence or absence of cataplexy will be used to assign 
subjects in a 1:1:1:1 ratio to one of the following four treatment groups: JZP-110 75, 150, or 
300 mg, or placebo. The investigator will access an Interactive Voice Response System 
(IVRS) or an Interactive Web Response System (IWRS) to randomize subjects. 
5.5 
Randomization 
A statistician selected by Jazz Pharmaceuticals will prepare and retain the master 
randomization code for the entire study. This statistician will not be involved in the analysis 
of this study. A copy of the master randomization code will be provided to the head of the 
Quality Department at Jazz Pharmaceuticals, or a designee in the Quality Department. The 
Head of Quality at Jazz Pharmaceuticals will sequester the master randomization code. 
Unless there is an emergency that requires the release of the subject’s assigned treatment, the 
code will not be broken or released until all study data are collected and accepted for 
analysis.   
 
5.6 
Blinding 
A double-blind approach will be used during the Treatment Phase. All study drugs will be 
prepared in identical opaque gelatin capsules to ensure adequate blinding. All study 
personnel will be blinded to the study treatments. 
5.7 
Prior and Concomitant Therapy 
During the Screening Phase, prior (30 days) and concomitant medication use and any 
therapies for the treatment of narcolepsy since diagnosis will be recorded on the case report 
form (CRF).  
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Any medications that are included under the exclusion criteria for entry into the study must 
be discontinued prior to the Baseline visit as specified in Section 4.3 and are prohibited for 
use throughout the study as well. 
Subjects may continue to take their usual medications during the study other than the 
excluded medications described in Section 4.3. All drugs other than study drugs that are 
taken during the course of study (approved or unapproved; prescription, over-the-counter 
[including health and dietary supplements], or illicit drugs) will be documented in the 
concomitant medications CRF. Jazz Pharmaceuticals must be notified in advance (or as soon 
as possible thereafter) of any instances in which excluded therapies are administered. 
 
5.8 
Restrictions 
5.8.1 
Prior Therapy 
Subjects may continue prescription and OTC medications with the exception of the excluded 
medications described in Section 4.3. Subjects being treated with medications for narcolepsy 
must be tapered off these medications prior to the Baseline visit.  
5.8.2 
Fluid and Food Intake  
Subjects will be instructed to take a single oral daily dose of study drug in the morning, on an 
empty stomach, within one hour of awakening. Subjects will also be instructed to abstain 
from eating or drinking (except water) for 30 minutes after taking the study drug. Subjects 
will be encouraged not to increase caffeine use during the study. 
The day after the overnight stay at Weeks 4 and 12, study drug will be administered at the 
investigative site with approximately 240 mL water (subjects may receive an additional 
240 mL of water if necessary).  
Subjects will also be given a light breakfast and light lunch at times indicated in the Schedule 
of Events (Appendix 1) and Sections 7.2, 7.4, and 7.7. On days when blood samples for 
clinical laboratory tests are drawn, the blood samples will be drawn prior to breakfast (i.e., 
fasting). On visits for Weeks 4 and 12, the light breakfast should be served approximately 
30 minutes after dosing and should be consumed within 15-20 minutes. Caffeine 
consumption will not be allowed during the Baseline and Week 4 and 12 visits.  
5.8.3 
Other Restrictions 
On the nights that PSGs are being conducted, subjects will remain in bed, and if they need to 
go to the toilet during the night they may be assisted by the lab tech or other study staff 
member. On the day following the PSG, subjects should be seated in bed in a darkened room 
during the MWT trials (Section 6.12.1). In between the MWT trials, subjects will be free to 
move about while staying at the sleep lab. At other times during the study there are no 
restrictions on activity. Cigarette smokers will be allowed to smoke one cigarette in the 
evening prior to initiation of the PSG, one cigarette in the morning at least 1 hour prior to the 
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first trial of the MWT, and one cigarette during the day immediately following the end of an 
MWT trial. 
5.9 
Investigational Medicinal Product Treatment Compliance 
Study drug will be dispensed and collected at clinic visits and, if applicable, at intervals 
specified by State or local regulations. Subjects will be instructed to return any unused drug 
to the study site. Treatment compliance will be assessed at each clinic visit based on the day 
of the visit and the amount of study drug that is returned to the site. Overall treatment 
compliance will be calculated at the end of the trial when the trial is unblinded. PK data may 
be used to interpret findings of non-compliance 
5.10 Packaging and Labeling 
Jazz Pharmaceuticals will provide the clinical sites with a supply of clinical trial material 
(study drug) as described in Section 5.1. Clinical trial material will consist of tablets that 
have been overencapsulated in opaque gelatin capsules and packaged in blister cards. 
All packaging and labeling operations will be performed according to Current Good 
Manufacturing Practices (cGMP), Good Clinical Practices (GCP), and local requirements and 
regulations. 
5.11 Storage and Accountability 
The drug product should be stored in the supplied packaging according to the label. 
The Investigator or qualified designee will maintain accurate records of the receipt of all 
study drugs from Jazz Pharmaceuticals, including the date(s) of receipt. Study drug must be 
kept in a secure area and dispensed as described in Section 6.11. Unused (or partially used) 
supplies must be accounted for on the drug inventory record. The receipt and dispensing of 
new study drug and the collection of unused study drug from subjects must be documented 
throughout the study and reconciled at study completion.  
Following study completion and notification by Jazz Pharmaceuticals, all labels, blister 
cards, and unused JZP-110 and JZP-110 placebo must be destroyed or returned to Jazz 
Pharmaceuticals according to written instructions from Jazz Pharmaceuticals or its designee 
at the completion of the study for reconciliation and destruction. Used blister cards of study 
drug will be destroyed upon Jazz Pharmaceuticals’ instruction following the review of study 
drug accountability. The Investigator must provide a written explanation for any missing 
study drug. After review of the drug inventory record at the site at study completion, one 
copy of the drug inventory record will be retained by the Investigator/site and the other will 
be retained by Jazz Pharmaceuticals. 
5.12 Investigational Medicinal Product Retention at Study Site 
Investigational medicinal product (JZP-110) does not need to be retained at the study site for 
FDA testing purposes.  
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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
All subjects will provide written informed consent before the performance of any study 
related procedures. Each subject will be given a copy of his or her signed informed consent 
form (ICF). 
Each subject’s chart will include his or her signed ICF. After the conclusion of the study and 
the CRF has been monitored, the ICF will be kept in the Investigator’s central study file. 
Regulatory authorities may check the existence of the signed ICF in this central study folder.  
6.2 
Demographics 
Demographic information will be collected at Screening (Visit 1) as permitted by regional or 
national regulations. Demographics will include the date the subject signed the informed 
consent, and the subject’s age (as indicated by date of birth, month and year of birth, year of 
birth, or age at screening), sex, ethnicity, and race.  
6.3 
Medical History  
A complete medical history for each subject will be collected during the Screening Phase. 
The information will include, but is not limited to, symptoms of narcolepsy (current and past, 
including symptoms experienced prior to any narcolepsy treatment); concomitant medication 
use; any medications used for the treatment of narcolepsy since diagnosis; any prior reaction 
to drugs; history and treatment (if any) of cardiovascular, pulmonary, gastrointestinal, 
hepatic, renal, immunologic, neurologic, or psychiatric disease; reproductive status; and 
confirmation of relevant inclusion and exclusion criteria. Any updates to the medical history 
will be assessed at the Baseline Visit.  
6.4 
Physical Examination 
A full review of body systems should be obtained for each subject during the Screening 
Phase and at the Final Visit (Week 12) or early termination. Physical examinations will 
include a full examination of body systems (except genitourinary), height (at screening only), 
and body weight measurements. Height and weight should be assessed in ordinary indoor 
clothes without shoes. A qualified investigator or designee should perform the examination. 
6.5 
Vital Signs  
Vitals signs (systolic and diastolic blood pressure, pulse, respiratory rate, and body 
temperature) will be obtained at every clinic visit after the subject has been resting and seated 
for at least 5 minutes. For blood pressure and pulse rate measurement, the subject should be 
seated comfortably with the back supported and the upper arm bared without constrictive 
clothing. The subject’s legs should not be crossed. The arm should be supported at heart 
level, and the bladder of the cuff should encircle at least 80% of the arm circumference. 
Neither the subject nor the observer should talk during the measurement. 
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A minimum of 2 blood pressure and pulse rate measurements should be taken, and the 
measurements should be separated by approximately 5 minutes. If there is >5 mm Hg 
difference between the first and second blood pressure measurement (systolic or diastolic 
reading), an additional measurement should be taken (Pickering et al. 2005). Vital signs will 
be recorded on the CRF. 
The mean of the two or three blood pressure assessments taken at the Screening visit will be 
used to meet entrance criteria to the study. Body temperature, respiratory rate, and blood 
pressure and pulse will be obtained on admission to the site the evenings before the PSG 
nights at Baseline and the end of Weeks 4 and 12; at Week 8; and at the Follow-up visit or at 
Early Termination. 
On the Baseline MWT day (Day -1), body temperature, respiratory rate, blood pressure, and 
pulse measurements will be taken approximately 30 minutes after awakening (prior to the 
start of the MWT). Blood pressure and pulse will also be taken approximately 2, 3, 5, 7, 9, 
and 11 hours after awakening. 
On MWT days at the end of Weeks 4 and 12 (or Early Termination if PSG/MWT is 
performed), body temperature, respiratory rate, blood pressure, and pulse will be taken 
approximately 1 hour before dosing (shortly before the first MWT trial). Blood pressure and 
pulse will be taken at approximately 1, 2, 4, 6, 8, and 10 (approximately 10 minutes after 
completion of the last MWT trial) hours after dosing. The schedule of assessment for vital 
signs during PSG/MWT visits is described in Section 7 and Appendix 2.  
6.6 
24-Hour Ambulatory Blood Pressure Monitoring 
Ambulatory blood pressure monitoring is a non-invasive method of obtaining blood pressure 
readings over a 24-hour period while the subject is in his/her own environment. Subjects will 
undergo 24-hour blood pressure monitoring after discontinuation of excluded medication (at 
least 5 half-lives) during the Screening Period and at Week 8. Blood pressure and pulse 
readings taken at 30-minute intervals will be recorded over a period of 24 hours. A manual 
with instructions for ambulatory blood pressure monitoring will be provided separately. 
6.7 
Electrocardiography 
Standard 12-lead ECGs will be recorded with the subject resting supine for at least 5 minutes. 
ECGs will be performed at Screening, Baseline, and at every clinic visit. The schedule of 
ECG assessment is described in Section 7 and Appendix 2. 
6.8 
Polysomnography (PSG) 
A PSG followed by an MWT will be performed at Baseline and at Weeks 4 and 12 (or Early 
Termination if the subject is willing and able to take study drug for the assessments). If a 
subject is allowed to be rescreened, a repeat PSG and MWT will not be required if the results 
of the previous PSG and MWT in the study meet the current inclusion/exclusion criteria and 
there have been no changes to medical history or concomitant medications that would likely 
affect the MWT results. 
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The PSG and MWT procedures will be performed according to standard protocols, which 
will be provided in a manual to each site. The manual will include all parameters to be 
recorded, methods, and a scoring appendix. Oxygen saturation will be monitored according 
to the study center’s standard procedures. Standard PSG parameters will be recorded. All 
polysomnographic data will be read by a central reader. 
An experienced sleep technologist must be present to monitor the PSG during PSG nights. 
6.9 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
At the Screening Visit, the Baseline/Screening Version of the C-SSRS will be administered 
to subjects to exclude any individuals with active suicidal ideation or behavior  
(Appendix 10). The C-SSRS is a widely used measure of suicidal ideation and behavior. The 
instrument reliably predicts a potential suicide attempt in those who had previously attempted 
suicide and is able to determine clinically meaningful points at which a person may be at risk 
for an impending suicide attempt (Posner et al. 2011). Suicidal ideation will be assessed for 
lifetime and over the past 12 months, and suicidal behavior will be assessed for lifetime and 
over the past 5 years with the Baseline/Screening Version of the C-SSRS. The Since Last 
Visit Version of the C-SSRS will be administered to subjects at every clinic visit after their 
Screening Visit including the Baseline and Follow-up visits (Appendix 12). 
6.10 Clinical Laboratory Tests 
6.10.1 
Laboratory Parameters 
Subjects will be in a seated or supine position during blood collection. Screening labs may be 
repeated one time. Clinical laboratory tests to be conducted are listed in Table 1. 
The clinical laboratory tests will be performed at a central laboratory. An authorized back-up 
laboratory, as indicated on the Form FDA 1572 or equivalent, may be used if necessary as an 
emergency laboratory. The investigator will supply Jazz Pharmaceuticals or its designee with 
the back-up laboratory’s current licensure and laboratory reference ranges.  
Please note exclusionary clinical laboratory parameters listed in the exclusion criteria 
(Section 4.3). In addition, any laboratory parameter that is out of range and considered 
clinically significant (as determined by the investigator) at the end of treatment must be re-
evaluated. The investigator will provide an explanation of all clinically significant 
observations. These findings will be reported as adverse events. 
At Screening, the investigator will calculate the estimated creatinine clearance rate using the 
Cockcroft-Gault formula (FDA Guidance for Industry. Pharmacokinetics in Patients with 
Impaired Renal Function – Study Design, Data Analysis, and Impact on Dosing and 
Labeling, May 1998). 
 
CLcr (mL/min)  = [140 – age (years)] x weight (kg) x (0.85 if female)  
                                                72 x serum creatinine (mg/dL) 
 
If serum creatinine is reported in µmol/L, the value should be divided by 88.4 for conversion 
to mg/dL.  
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Clinical laboratory tests will include the following: 
Table 1 List of Laboratory Tests  
Hematology: 
- 
Complete blood count (CBC), 
including platelet count and white 
blood cell count (WBC) with 
differential 
- 
Hemoglobin 
- 
Hematocrit 
 
Urinalysis:  
- 
Appearance 
- 
Bilirubin 
- 
Color 
- 
Glucose 
- 
Ketones 
- 
Nitrite  
- 
Occult blood 
- 
pH 
- 
Protein 
- 
Specific gravity 
- 
Urobilinogen 
 
Urine Drug Screen:  
- 
Amphetamines 
- 
Barbiturates 
- 
Benzodiazepines 
- 
Cannabinoids 
- 
Cocaine metabolites 
- 
Opiates 
- 
Phencyclidine-PCP 
- 
Methadone 
Serum Chemistry: 
- 
Albumin (ALB) 
- 
Alkaline phosphatase (ALK-P) 
- 
Alanine aminotransferase (ALT; 
SGPT) 
- 
Aspartate aminotransferase (AST; 
SGOT) 
- 
Blood urea nitrogen (BUN) 
- 
Calcium (Ca) 
- 
Chloride (Cl) 
- 
Creatinine 
- 
Creatine kinase  
- 
Glucose 
- 
Phosphorus 
- 
Potassium (K) 
- 
Sodium (Na) 
- 
Total bilirubin 
- 
Direct bilirubin 
- 
Total cholesterol 
- 
Total protein 
- 
Triglycerides 
- 
Uric acid 
 
Pregnancy Screen:*  
- 
Serum (at Screening [or 
Rescreening] and following a 
positive urine test) 
- 
Urine (at Baseline and Week 12 or 
Early Termination) 
*Pregnancy screening is required for all females of childbearing potential. Female 
subjects who have undergone surgical sterilization, who are post-menopausal (defined 
as age >50 and >1 year of amenorrhea), who have medically documented ovarian failure 
(defined as age <50 with serum estradiol and follicle-stimulating hormone [FSH] levels 
within the institutional postmenopausal range and a negative serum or urine βHCG) do 
not need to undergo pregnancy screening. 
 
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Table 2 Schedule of Clinical Laboratory Samples and Estimated Blood 
Volume 
Clinical chemistry: 
Screening  
Baseline* and Week 12 
 
3 × 6 mL 
 
 
18 mL 
 
Hematology: 
Screening, Baseline*, Week 12 
 
3 × 4 mL 
 
12 mL 
Serum pregnancy test (for females of 
childbearing potential) 
Screening 
 
1 × 1 mL 
 
1 mL 
Pharmacokinetics: 
1 sample Week 1 
1 sample Week 4 
2 samples Week 8 
 
1 × 4 mL 
1 × 4 mL 
2 × 4 mL 
 
 
4 mL 
4 mL 
8 mL 
 
Approximate total blood volume per 
subject: 
females of childbearing potential 
males and females who are not of 
childbearing potential 
 
 
 
47 mL 
46 mL 
*Required if Baseline visit occurs outside of the screening window (i.e., >29 days after the Screening Visit). 
Repeat Screening labs may be fasting or nonfasting. 
6.10.2 
Sample Collection, Storage, and Shipping 
6.10.2.1 
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. 
Blood samples for hematology and serum chemistry tests will be collected while the subject 
is fasting at Screening (or Rescreening) and Week 12 or Early Termination. If the Baseline 
visit occurs outside of the screening window (i.e., >29 days after the Screening Visit), 
hematology and serum chemistry tests should be collected at the Baseline visit and may be 
drawn with the subject fasting or nonfasting. Table 2 shows the schedule for collection of 
blood and the total estimated blood volume to be collected during the study. 
Urine samples for urinalysis will be collected at Screening (or Rescreening) and Week 12 or 
Early Termination. A repeat urinalysis should be obtained if the Baseline visit occurs outside 
of the screening window (i.e., >29 days after the Screening Visit). 
A urine sample for urine drug screen will be obtained at every clinic visit except at the 
Follow-up visit. Samples collected at Screening (or Rescreening), Baseline, and Week 12 (or 
Early Termination) will be analyzed. Samples collected at other visits may be analyzed at the 
investigator’s discretion.  
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A serum pregnancy test for females of childbearing potential will be performed at Screening 
(or Rescreening), and urine pregnancy tests will be performed at Baseline and Week 12 or 
Early Termination (Table 2).  
6.10.2.2 
Blood Samples for Pharmacokinetic (PK) Analysis 
Blood samples to measure plasma JZP-110 concentrations will be collected at four time 
points per subject as described in Table 2 and Section 6.13.1. These blood samples will be 
drawn within the time windows indicated in Section 6.13.1 and dispensed into labeled 
K2EDTA tubes. The actual time of blood collection for all samples will be recorded on the 
CRF. 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 Jazz Pharmaceuticals. 
The bioanalysis will be performed by a central bioanalytical laboratory. 
6.11 Dispensing Study Drug 
Study drug will be dispensed to subjects at the end of the Baseline visit and at the end of the 
Week 1, 4, and 8 visits or at alternative intervals if necessary to comply with State and local 
laws and regulations. Subjects will be instructed to begin daily dosing with the new supply of 
study drug the day after the completion of the Baseline, Week 1, Week 4, and Week 8 visits. 
Subjects will also be provided with dosing instructions consistent with the restrictions 
described in Section 5.8. On the day after the overnight PSG and on the morning of the 
MWT at Weeks 4 and 12 (or Early Termination if PSG/MWT is performed), study drug will 
be administered by qualified study site personnel as described in Section 7 and Appendix 2. 
6.12 Efficacy Assessments 
6.12.1 
Maintenance of Wakefulness Test (MWT) 
The MWT is the standard objective measure of an individual’s ability to remain awake 
during the daytime in a darkened, quiet environment and is commonly used to assess 
response to treatment (Doghramji et al. 1997, Mitler et al. 1982, AASM 2014). A five-trial, 
40 minute MWT will be performed at Baseline and at the Week  4 and 12 visits (or Early 
Termination if the subject is willing and able to take study drug for the assessments) on the 
morning after an overnight PSG according to a standard protocol, which will be provided in a 
manual to each site.  
Each MWT during the study should be started at approximately the same time of the day. 
During the MWT trials, subjects should be seated in bed in a darkened room with their back 
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and head supported by a bedrest (bolster pillow) such that their neck is not uncomfortably 
flexed or extended (Littner et al. 2005). Subjects will be instructed to sit still and remain 
awake for as long as possible during each of the 5 40-minute trials separated by 2-hour 
intervals. Following a light breakfast, the subject will be allowed to relax prior to initiating 
the first MWT trial. The first MWT trial should occur approximately 2 hours after “lights on” 
at the Baseline visit and approximately 1 hour after dosing with study drug at all other visits 
at which the MWT will be conducted. If the subject falls asleep during a trial, they will be 
awakened and instructed to remain awake until the next trial. If the subject does not fall 
asleep, then the specific trial is terminated at 40 minutes and a sleep latency of 40 minutes is 
recorded. The subject is then instructed to remain awake (and will be awoken if they fall 
asleep) until the next trial.  
Data from the MWT should be recorded and saved electronically, and any technician notes 
should also be maintained for potential transfer to Jazz Pharmaceuticals at the end of the 
study. 
6.12.2 
Epworth Sleepiness Scale (ESS) 
The ESS is a self-administered questionnaire with 8 questions asking the subject how likely 
they would be to doze off or fall asleep in different situations. Responses range from 
0 = would never doze to 3 = high chance of dozing (Appendix 6). Subjects will be asked to 
complete the ESS with regard to the level of sleepiness they experienced over the past 7 days 
at the Baseline and Week 1, 4, 8, and 12 visits (or Early Termination). It provides a measure 
of a person’s general level of daytime sleepiness, or their average sleep propensity in daily 
life. The ESS is a validated measure with high specificity and sensitivity for assessing 
subjective sleepiness in narcolepsy (Johns 1991, 2000, Broderick et al. 2013).  
6.12.3 
Clinician Global Impression of Severity (CGIs)  
The CGIs is a 7-point Likert-type rating scale and a widely used assessment in clinical 
psychopharmacology trials to assess severity of illness (Appendix 13). The responses of this 
investigator-completed scale range from 1 = normal, no signs of illness to 7 = among the 
most extremely ill patients. The Investigator will rate his/her impression of the severity of the 
subject’s current condition at Baseline relative to his/her experience with this patient 
population.  
6.12.4 
Clinician Global Impression of Change (CGIc)  
The CGIc is a 7-point Likert-type rating scale and a widely used assessment to assess 
efficacy in clinical drug trials. Investigators will rate their impression of any change in the 
subject’s condition from baseline (before the subject started treatment) on a 7-point scale 
ranging from 1 = very much improved to 7 = very much worse at the Week 1, 4, 8, and 12 
visits (or Early Termination) (Appendix 14).  
6.12.5 
Patient Global Impression of Change (PGIc) 
The PGIc is a 7-point Likert-type rating scale and a widely used measure to assess efficacy in 
clinical drug trials. Subjects will rate the change in their condition since they started 
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treatment on a 7-point scale ranging from 1 = very much improved to 7 = very much worse at 
the Week 1, 4, 8, and 12 visits (or Early Termination) (Appendix 15). 
6.12.6 
Functional Outcomes of Sleep Questionnaire Short Version (FOSQ-10) 
The FOSQ is a 30-item disease specific quality of life questionnaire to determine functional 
status in adults; measures are designed to assess the impact of disorders of excessive 
sleepiness on multiple activities of everyday living and the extent to which these activities 
are improved by effective treatment (Weaver et al. 1997). The FOSQ-10 is a short version of 
the original 30-item FOSQ that has been shown to perform similarly to the longer version 
(Chasens et al. 2009). The FOSQ-10 has been shown to exhibit high internal consistency, and 
effect sizes and pre- and post-treatment differences that are highly correlated with the longer 
version (Chasens et al. 2009). Subjects will complete the FOSQ-10 at the Baseline and 
Week 1, 4, 8, and 12 visits (or Early Termination) (Appendix 7). 
6.12.7 
36-Item Short Form Health Survey Version 2 (SF-36v2) 
The SF-36v2 is a multi-purpose, short-form health survey with 36 questions. It yields an 
8-scale profile of functional health and well-being scores as well as psychometrically-based 
physical and mental health summary measures and a preference-based health utility index 
(Hays & Stewart 1992, Ware & Sherbourne 1992). Subjects will complete the SF-36v2 at the 
Baseline and Week 4, 8, and 12 visits (or Early Termination) (Appendix 8). 
6.12.8 
EuroQoL EQ-5D-5L 
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome that 
includes a descriptive system consisting of 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) and an EQ visual analogue scale (VAS) (EuroQol 
Group, 2013). It is applicable to a wide range of health conditions and treatments, it provides 
a simple descriptive profile and a single index value for health status. The EQ-5D-5L 
includes five levels of severity for each of the 5 dimensions of the descriptive system and 
was developed to improve the instrument’s reliability and sensitivity and to reduce ceiling 
effects. Subjects will complete the EQ-5D-5L at the Baseline and Week 1, 4, 8, and 12 visits 
(or Early Termination) (Appendix 9). 
6.12.9 
Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem V2.0 (WPAI:SHP) 
The WPAI:SHP questionnaire is a 6-item self-administered questionnaire that measures work 
time missed and work and activity impairment because of a specified health problem during 
the past 7 days. The WPAI:SHP will be used with “narcolepsy” as the specified health 
problem. The validity of the WPAI has been established in a number of diseases 
(Reilly et al. 1993). Subjects will complete the WPAI:SHP at the Baseline and Week 1, 4, 8, 
and 12 visits (or Early Termination) (Appendix 11). 
 
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6.12.10 Cataplexy Diary 
Subjects who experience cataplexy will complete a daily cataplexy frequency diary 
(Appendix 3) to record the occurrence and number of cataplexy attacks that they had each 
day beginning after discontinuation of narcolepsy medication and throughout the 12-week 
Treatment Phase of the study. The study staff will review the diary at each study visit and 
discuss it with the subject at each phone contact. 
6.13 Pharmacokinetic Assessments 
6.13.1 
Blood Samples 
Four blood samples will be collected from each subject for PK evaluations. One sample will 
be collected at Week 1 and two samples will be collected at Week 8 (one sample at the 
beginning of the visit and one sample at the end of the visit before the subject leaves the 
clinic) within 1-8 hours after dosing to characterize the absorption phase of the PK curve. 
One sample will be collected at Week 4 within 8-12 hours after dosing on the day that 
subjects check in for the overnight PSG to characterize the trough of the PK curve. PK 
samples should be taken within the time windows indicated. The actual time of blood 
collection for all samples and the exact time that the subject dosed on each morning that 
samples are collected will be recorded. To the extent possible, investigators should schedule 
the Week 8 clinic visit in the morning to facilitate characterization of the absorption phase of 
the PK curve. 
6.13.2 
Pharmacokinetic Parameters  
Four blood samples will be collected from each subject for an assessment of population PK 
parameters using sparse sampling. These data may be pooled with PK data from other 
JZP-110 studies to establish a population PK model. This approach is expected to permit 
characterization of the JZP-110 PK profile, specifically in the narcolepsy patient population. 
6.14 Adverse Event Reporting 
6.14.1 
Adverse Events (AEs) 
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered related to study drug or procedure.  
Adverse events include, but are not limited to: (1) a worsening or change in nature, severity, 
or frequency of conditions present at the start of the study; (2) subject deterioration due to 
primary illness; (3) intercurrent illness; (4) drug interaction; and/or (5) abnormal clinically 
significant laboratory values. 
• Symptoms of the underlying medical condition of narcolepsy are not considered as 
adverse events unless there is an exacerbation of the symptoms from baseline. 
• During the study, clinically significant adverse changes in ECGs, routine laboratory 
tests, and physical examinations are considered AEs. Any subject complaint 
associated with such an abnormal finding will also be reported as an AE.  
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All AEs, whether observed by the investigator, reported by the subject, determined from 
laboratory findings, or other means, will be recorded on the AE CRF, with each individual 
AE to be listed as a separate entry on the AE CRF. 
Subjects should be questioned in a general way, without asking about the occurrence of any 
specific symptom. The investigator should attempt to establish a diagnosis of the event based 
on signs, symptoms, and/or other clinical information. In such cases, the diagnosis, not the 
individual signs/symptoms, should be documented as the AE.  
Following questioning and evaluation, all AEs, whether believed by the investigator to be 
related or unrelated to the study drug or procedure, must be documented in the subject’s 
medical records, in accordance with the investigator’s normal clinical practice, and on the 
AE CRF. Each AE is to be evaluated for duration, severity, seriousness, and causal 
relationship to the study drug or procedure.  
6.14.1.1 
Severity Assessment 
Adverse events will be classified by the investigator as mild, moderate, or severe as defined 
below. When the severity of the AE changes over time, the change in severity will be 
recorded on the AE CRF as a new AE, and the original AE will stop when the new AE starts. 
Mild 
Symptom(s) barely noticeable to subject or does not make subject 
uncomfortable; does not influence performance or functioning; prescription 
drug not ordinarily needed for relief of symptom(s) but may be given. 
Moderate 
Symptom(s) of a sufficient severity to make subject uncomfortable; 
performance of daily activities is influenced; treatment for symptom(s) may 
be needed. 
Severe 
Symptom(s) causes severe discomfort; symptom(s) incapacitate or 
significantly affect subject’s daily life; treatment for symptom(s) may be 
given and/or subject hospitalized.  
 
6.14.1.2 
Serious Adverse Events and Seriousness Assessment 
An SAE is an AE that fulfills any of the following criteria, as per Title 21 CFR 312.32 and 
ICH E2A.II.B. Events meeting the following seriousness criteria must be reported to Jazz 
Pharmaceuticals or its designee using the SAE Report form within 24 hours of the site being 
notified of the event. The event must also be entered on the AE CRF. 
• Is fatal (results in death) 
• Is life-threatening (Note: the term “life-threatening” refers to an event in which the 
subject was at immediate risk of death at the time of the event; it does not refer to an 
event that could hypothetically have caused death had it been more severe) 
• Requires inpatient hospitalization or prolongs existing hospitalization 
• Results in persistent or significant incapacity or disability, defined as substantial 
disruption of the ability to conduct normal life functions 
• Is a congenital anomaly/birth defect 
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• Is medically significant or requires intervention to prevent one of the outcomes listed 
above   
− Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered an SAE when, based on appropriate 
medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above in the definition 
of an SAE.  
− Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, and the development of 
drug dependency or drug abuse. 
• Suspected transmission of an infectious agent via a medicinal product [for EU sites only; 
EMA Guideline on Good Pharmacovigilance Practices (GVP) Module VI] 
 
Hospitalization is NOT considered an SAE if: 
• It is planned prior to subject entering trial 
• It is for social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• It is elective in nature and not related to worsening of an underlying condition 
 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is an SAE. 
 
“In-patient hospitalization” means the subject has been formally admitted to a hospital for 
medical reasons, for any length of time. Emergency room care without admission to a 
hospital is considered outpatient care. 
 
Overdose, medication errors, and drug misuse of the study drug are SAEs only if any of the 
seriousness criteria are met. Details of signs and symptoms, clinical management, and 
outcome should be reported. 
6.14.1.3 
Causal Relationship to Study Drug or Procedure 
The investigator’s assessment of an AE’s relationship to study drug or procedure is required. 
The relationship or association of the study drug or procedure in causing or contributing to 
the AE will be characterized using the following classification and criteria:  
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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. 
 
6.14.1.4 
Other Immediately Reportable Experiences 
The following immediately reportable experiences may occur during participation in this 
clinical trial and must be entered on the AE CRF and SAE Report form and reported within 
24 hours of first knowledge of the event by study personnel to the appropriate Jazz 
Pharmaceuticals contact or designee: 
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) with a 3-fold or 
greater elevation above the upper limit of normal (ULN) in addition to an elevation of 
serum total bilirubin greater than two times the ULN, with no other identifiable etiology 
• Liver enzyme (AST, ALT) value greater than or equal to 5 times the ULN 
 
As with other SAEs (Section 6.14.1.2), immediately reportable experiences must be reported 
on the SAE Report form, which should be completed as thoroughly as possible and signed by 
the investigator or his/her designee before transmittal to the contact provided on the form. 
The investigator must provide his/her assessment of causality to study drug or procedure at 
the time of the initial report. Where the investigator does not provide causality assessment of 
the SAE at the time of the initial report, the event by default will be presumed “Related.” If 
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the investigator’s assessment of causality changes, then a follow-up SAE form must be 
submitted. 
The source document to determine expectedness of an SAE, is the JZP-110 Investigator’s 
Brochure. 
6.14.1.5 
Adverse Events Recording and Reporting 
The investigator must report to Jazz Pharmaceuticals or its designee all AEs that occur during 
the study from the time written informed consent is obtained until the final study visit or 
early termination, regardless of their relationship to study drug or procedure. 
6.14.1.6 
Follow-up of Adverse Events and Serious Adverse Events 
Adverse events assessed as not related to study drug or procedure, including clinically 
significant laboratory tests, ECGs, or physical examination findings, must be followed until 
the event resolves, the condition stabilizes, the event is otherwise explained, or the final 
study visit occurs, whichever comes first. AEs and SAEs assessed as related to study drug or 
procedure will be followed for as long as necessary to adequately evaluate the subject’s 
safety, or until the event stabilizes, or the subject is lost to follow up. If resolved, a resolution 
date should be provided, and for SAEs, a follow-up SAE Report form must be submitted 
indicating the resolution date. The investigator is responsible for ensuring that follow-up 
includes any supplemental investigations indicated to elucidate the nature and/or causality of 
the AE. This may include additional clinical laboratory testing or investigations, 
examinations, histopathological examinations, or consultation with other health care 
professionals as is practical. 
6.14.2 
Post-Study Reporting Requirements 
If an investigator becomes aware of an SAE within 30 days after the last dose of study 
medication, the event must be documented and reported as described in Section 6.14.1.2. 
Any AE or SAE assessed as related to study drug or procedure by the investigator must be 
reported regardless of time after study termination. 
6.14.3 
Pregnancy   
If a subject or a male subject’s partner becomes pregnant any time after the first dose of 
study drug is taken until 30 days after the last dose of study drug is taken, the pregnancy 
form should be used to report the pregnancy to Jazz Pharmaceuticals or its designee. 
Pregnancy of a subject or a male subject’s partner is an immediately reportable event and 
should be reported within 24 hours of first knowledge of the event by study personnel to the 
appropriate Jazz Pharmaceuticals contact or designee. The pregnancy of a subject or a male 
subject’s partner will be followed until the outcome of the pregnancy is known, and in the 
case of a live birth, for 6 months following the birth of the child. The infant follow-up form 
should be used to report information regarding the status of the infant. 
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6.14.4 Emergency Unblinding 
A subject’s treatment assignment should only be unblinded when knowledge of the treatment 
is necessary for the immediate medical management of the subject or to ensure subject safety 
in the trial. In the case of an immediate medical emergency, an Investigator or his/her 
designee will be able to unblind a subject at any time via the IVRS. Every attempt should be 
made to contact Jazz Pharmaceuticals or its designee before unblinding a subject as long as 
this does not compromise the safety of the subject. If a request for unblinding is received 
from an Investigator, the Medical Director/Medical Monitor will discuss with the 
Investigator the rationale for the request. If the treatment assignment is unblinded, then any 
broken blinding code must be clearly justified and explained by a comment in the source 
documentation, along with the date on which the code was broken and the identity of the 
person authorizing the unblinding. In addition, the study biostatistician will document the 
occurrence of investigator-initiated unblinding in the section of “Documentation of Statistical 
Method” in the final study report. Subjects for whom the blind is broken will be withdrawn 
from the study. 
If the request for unblinding is related to the occurrence of an SAE, all procedures for the 
reporting of an SAE must be followed (Section 6.14). The blinded SAE will be reviewed by 
Jazz Pharmaceuticals Drug Safety to assess the expectedness and relationship to the study 
drugs and to assess whether there is a potential safety concern for the individual subject or 
the other subjects in the study.  
6.15 Removal of Subjects from the Trial or Study Drug 
All subjects are free to withdraw from participation in this study at any time, for any reason, 
and without prejudice. The investigator must withdraw any subject from the study if the 
subject states that he/she wants to stop participating in the study. 
The investigator, Jazz Pharmaceuticals or its designee may remove a subject from the study 
at any time and for any reason.  
If any of the following criteria are met during the study, study drug administration must be 
stopped and the subject discontinued from the study: 
• Suicide risk reported or assessed by C-SSRS 
• 3-fold or greater elevation above the upper limit of normal (ULN) of alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) accompanied by an 
elevation of serum total bilirubin greater than two times the ULN 
• Liver enzyme (AST, ALT) value greater than or equal to 5 times the ULN 
• Creatinine ≥2 mg/dL 
• Positive urine drug screen 
• Positive pregnancy test 
• Subject demonstrates a QTc value above 500 msec (determinations should be based on at 
least two ECG recordings performed in close temporal proximity) 
• Subject experiences a serious adverse event that is considered related to study drug or 
procedure  
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For all subjects who prematurely discontinue, an attempt should be made to perform all early 
termination assessments (same assessments as those performed at the final study visit). 
Subjects should be asked to return 2 weeks later for a safety follow-up visit.  
The specific reason for the discontinuation should be carefully documented on the 
termination CRF. If a subject withdraws informed consent, the specific reason for 
withdrawing the informed consent should be stated. 
Adverse events resulting in termination will be followed to the satisfactory resolution and 
determination of outcome as ascertained by the investigator (and/or Jazz Pharmaceuticals or 
its designee). The data will be recorded on the CRF. 
6.15.1 
Handling of Early Terminations 
If a subject terminates early from the study, either at his or her request or at the investigator’s 
discretion, the investigator will record the reason(s) for early termination on the relevant CRF 
page and notify Jazz Pharmaceuticals immediately. All subjects who terminate from the 
study early should undergo final study visit assessments indicated in Section 7.9. 
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. 
6.15.2 
Jazz Pharmaceuticals’ Termination of Study 
Jazz Pharmaceuticals reserves the right to discontinue the study at any time for clinical or 
administrative reasons. 
Such a termination must be implemented by the investigator, if instructed to do so by Jazz 
Pharmaceuticals in a time frame that is compatible with the subject’s well-being. 
 
6.16 Appropriateness of Measurements 
The MWT is a validated objective measure of the ability to stay awake for a defined period 
of time and is particularly useful for determining efficacy of treatment (Doghramji et al. 
1997, Mitler et al. 1982). The ESS is a validated measure with high specificity and sensitivity 
for assessing subjective sleepiness in narcolepsy (Johns 1991, 2000; Broderick et al. 2013). 
Additionally, the CGIc, PCIc, SF-36v2, FOSQ-10, EQ-5D-5L and the WPAI:SHP have been 
used extensively in clinical trials to assess efficacy and quality of life. 
Sparse samples (4 samples per subject) are being drawn at various time points following drug 
administration to use a population approach to characterize the PK profile of JZP-110 in the 
narcolepsy patient population.  
The use of vital signs including 24-hour ambulatory blood pressure monitoring, clinical 
laboratory tests, standard AE reporting, and the questionnaires that have been selected to 
assess the safety of the study drug are appropriate since they are routinely used to assess the 
safety profile of drugs in clinical studies and pertinent to known risks of JZP-110. The 
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C-SSRS is able to determine clinically meaningful points at which a person may be at risk for 
an impending suicide attempt (Posner et al. 2011). 
7 
STUDY ACTIVITIES 
Visit windows and approximate times for assessments are provided below and in Appendix 1 
and Appendix 2. In the case that an efficacy assessment is missed, not conducted within the 
specified time window, failed, or conducted incorrectly, the investigator may conduct the 
assessment outside of the specified time window or repeat the assessment only with prior 
permission from Jazz Pharmaceuticals. Scheduled safety assessments should always be 
conducted, even if outside of the specified time windows, and the time of their conduct 
should be recorded. Sites should complete informed consent procedures and collect a signed 
ICF from the subject prior to the conduct of any study procedures (Section 6.1). 
7.1 
Screening Clinic Visit(s) 
7.1.1 
Screening Visit 1, Days -31 to -3 
Subjects may be screened over a maximum period of 29 days. 
• Review the inclusion (Section 4.2) and exclusion (Section 4.3) criteria. 
• Obtain demographics (Section 6.2) and a medical history, including past (prior to any 
narcolepsy treatment) and current symptoms of narcolepsy (Section 6.3). 
• Record all prior and concomitant medications, including OTC medications, health, 
and dietary supplements taken during the 30 days before Screening; also record any 
medications used for the treatment of narcolepsy since diagnosis (Sections 4.3 and 
5.7). 
• Perform a physical examination including a full examination of body systems 
(excluding a full genitourinary exam) and a brief neurological examination. Record 
height and weight in ordinary indoor clothes (without shoes) (Section 6.4). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature) including at least two sets of blood pressure and pulse rate 
measurements in the seated position, as described in Section 6.5. 
• Obtain a 12-lead ECG after the subject has been resting supine for at least 5 minutes 
(Section 6.7). 
• Administer the Columbia-Suicide Severity Rating Scale (C-SSRS) 
Baseline/Screening version (Section 6.9) and record results. 
• Complete clinical laboratory tests (Section 6.10 and Table 1). 
o Obtain fasting blood samples for serum chemistry and hematology tests  
including a serum pregnancy test for all females of childbearing potential 
(Table 1 see footnote for definitions of childbearing potential). 
o Obtain a urine sample for urinalysis and urine drug screens. 
• Provide a light breakfast after blood samples are collected. 
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• After screening procedures have been completed and eligibility criteria have been 
confirmed, provide eligible subjects with instructions on how to discontinue any 
excluded medications. (See Section 4.3). 
• Dispense Cataplexy Diary and instruct on use (for subjects who have cataplexy; 
diaries should be completed for at least 7 days prior to the Baseline visit). 
• Dispense the 24 hour ambulatory blood pressure monitoring equipment after 
demonstrating how it should be used. Provide instructions for use, guidance for when 
and how the subject should record 24 hour ambulatory blood pressure following 
medication washout, and instructions for returning the equipment. 
• Schedule a Baseline visit after the Investigator has thoroughly reviewed results of all 
screening procedures and has confirmed all eligibility criteria. 
7.1.2 
Rescreening  
Subjects may be allowed to rescreen if the rescreening is approved by the Medical Monitor. 
Subjects who are approved for rescreening must be re-consented and must repeat all 
screening procedures in Section 7.1.1. For subjects who are being rescreened, a repeat PSG 
and MWT are not required at Visit 2 if the results of the previous PSG and MWT meet the 
current inclusion/exclusion criteria and there have been no changes to medical history or 
concomitant medications that would likely affect the MWT results. 
7.2 
Baseline Clinic Visit  
Visit 2, Days -2 and -1 
After a subject has successfully completed the screening procedures he or she will return to 
the investigative site for an overnight stay to complete his or her baseline procedures. If the 
subject is being rescreened and does not require a repeat PSG and MWT, perform all other 
Visit 2 procedures listed below (with the exception of the repeated vital signs during the 
MWT conduct and the provision of meals) during a single visit on one day. If a subject is 
being rescreened and does require a repeat PSG and MWT, perform all procedures for Visit 2 
as listed below. 
On admission to the investigative site in the evening (Day -2), complete the following: 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain a urine sample for a pregnancy test for all females of childbearing potential 
(see footnote of Table 1 for definitions of childbearing potential). 
• Obtain a urine sample for a urine drug screen (Section 6.10.2.1 and Table 1). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and oral temperature) including at least two sets of blood pressure and pulse rate 
measurements in the seated position, as described in Section 6.5. 
• Administer the C-SSRS Since Last Visit version and record the results (Section 6.9). 
• If the Baseline visit occurs outside of the screening window (i.e., >29 days after the 
Screening Visit), obtain blood samples for serum chemistry, hematology tests and a 
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urine sample for urinalysis (Section 6.10.2.1 and Table 1). Record if samples were 
collected with the subject fasted or nonfasted. 
• For subjects with cataplexy, review Cataplexy Diary and review instructions for 
continued use (Section 6.12.10). 
• Record the date(s) that narcolepsy medications were discontinued (Sections 4.3 and 
5.7) and any other changes to concomitant medications since screening on the 
concomitant medication CRF. 
• Assess if there are any updates to the subject’s medical history (Section 6.3). 
• Prepare subject for the overnight PSG. 
• At “lights out” initiate the overnight PSG (Section 6.8). 
 
On the morning of the following day (Day -1), complete the following procedures. The time 
for these procedures should occur relative to “lights on” (see Appendix 2 for an example 
schedule). 
• “Lights on” (waking). 
• Approximately 30 minutes after “lights on,” obtain vital signs (systolic and diastolic 
blood pressure, pulse and respiratory rate, and body temperature), including at least 
two sets of blood pressure and pulse rate measurements in the seated position, as 
described in Section 6.5. 
• Approximately 1.5 hours after “lights on,” subjects should be served a light breakfast. 
Breakfast should be completed within 15 to 20 minutes (Section 5.8.2). 
• Approximately 1 hour and 50 minutes after “lights on,” obtain at least two sets of 
blood pressure and pulse rate measurements in the seated position, as described in 
Section 6.5. 
• Approximately 2 hours after “lights on,” initiate the first trial of the MWT 
(Section 6.12.1). 
• Approximately 2 hours and 50 minutes after “lights on,” obtain at least two sets of 
blood pressure and pulse rate measurements in the seated position, as described in 
Section 6.5. 
• Approximately 3 hours after “lights on,” obtain a 12-lead ECG after the subject has 
been resting supine for at least 5 minutes (Section 6.7). 
• Administer the following questionnaires to the subject in the order specified below: 
• ESS (Section 6.12.2) 
• FOSQ-10 (Section 6.12.6) 
• SF-36v2 (Section 6.12.7) 
• EQ-5D-5L (Section 6.12.8) 
• WPAI:SHP questionnaire (Section 6.12.9) 
• Complete the CGIs (Section 6.12.3). 
• Approximately 4 hours after “lights on,” initiate the second trial of the MWT.  
• Subjects should be served a light lunch immediately after the second or third trial of 
the MWT. 
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• Approximately 5 hours after “lights on,” obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Approximately 6 hours after “lights on,” initiate the third trial of the MWT. 
• Approximately 7 hours after “lights on,” obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Approximately 8 hours after “lights on,” initiate the fourth trial of the MWT. 
• Approximately 9 hours after “lights on,” obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Approximately 10 hours after “lights on,” initiate the fifth trial of the MWT. 
• Approximately 11 hours after “lights on,” obtain at least two sets of blood pressure 
and pulse rate measurements in the seated position, as described in Section 6.5. 
• Record all AEs on the AE CRF that occurred after the ICF was signed (Section 6.14).  
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the ICF was signed (Section 5.7). 
• Review the inclusion (Section 4.2) and exclusion (Section 4.3) criteria, including 
MWT and ESS results and medical history to determine the subject’s eligibility to 
continue participating in the study. 
• Randomize to study treatment (Access IVRS/IWRS). 
• Dispense study drug and instruct subject on the daily dose administration to begin on 
the following morning (Day 1) (Section 6.11). 
• Schedule the subject to return to the site for Visit 3 at the end of Week 1 of dosing.  
7.3 
End of Week 1 Clinic Visit 
Visit 3, Day 7 (-1 and +2 days) 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain a urine sample for a urine drug screen (Section 6.10.2.1 and Table 1). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure and pulse rate 
measurements in the seated position, as described in Section 6.5. 
• Administer the C-SSRS Since Last Visit version and record the results (Section 6.9). 
• Obtain a single PK sample (1-8 hours postdose), record the exact time of collection, 
and record the exact time that the subject dosed that morning (Section 6.13). 
• Collect study drug and assess compliance (Section 5.9). 
• For subjects with cataplexy, review Cataplexy Diary and review instructions for 
continued use (Section 6.12.10). 
• Obtain a 12-lead ECG after the subject has been resting supine for at least 5 minutes 
(Section 6.7). 
• Administer the following questionnaires to the subject in the order specified below: 
• ESS (Section 6.12.2) 
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• PGIc (Section 6.12.5) 
• FOSQ-10 (Section 6.12.6) 
• EQ-5D-5L (Section 6.12.8) 
• WPAI:SHP questionnaire (Section 6.12.9) 
• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.14). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the last visit or phone contact (Section 5.7). 
• Complete the CGIc (Section 6.12.4). 
• Dispense study drug and instruct subject on the daily dose administration to begin on 
the following morning (Section 6.11). 
• Schedule the next Phone Contact times and return clinic visit. 
7.4 
End of Week 4 Clinic Visit 
Visit 6, Days 27&28 (±3 days) 
On admission to the investigative site in the evening on Day 27 (±3), complete the following: 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain a urine sample for a urine drug screen (Section 6.10.2.1 and Table 1). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure and pulse rate 
measurements in the seated position, as described in Section 6.5. 
• Administer the C-SSRS Since Last Visit version and record the results (Section 6.9). 
• Obtain a single PK sample (8-12 hours postdose), record the exact time of collection, 
and record the exact time that the subject dosed that morning (Section 6.13). 
• Collect study drug and assess compliance (Section 5.9). 
• For subjects with cataplexy, review Cataplexy Diary and review instructions for 
continued use (Section 6.12.10). 
• Prepare the subject for the PSG. 
• “Lights out” and initiate the overnight PSG (Section 6.8). 
On the morning of the following day, complete the following procedures. The time for these 
procedures should occur relative to dosing (see Appendix 2 for an example schedule). 
• “Lights on” (waking) should occur approximately 1 hour before dosing. 
• Approximately 30 minutes before dosing, obtain vital signs (systolic and diastolic 
blood pressure, pulse and respiratory rate, and body temperature), including at least 
two sets of blood pressure and pulse rate measurements in the seated position, as 
described in Section 6.5. 
• Administer study drug to the subject (dosing) on an empty stomach at least 1 hour 
after waking (Section 5.8.2). 
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• Approximately 30 minutes after dosing, subjects should be served a light breakfast. 
Breakfast should be completed within 15 to 20 minutes (Section 5.8.2). 
• Approximately 50 minutes after dosing, obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Approximately 1 hour after dosing, initiate the first trial of the MWT (Section 6.12.1 
and Appendix 2). 
• Approximately 1 hour and 50 minutes after dosing, obtain at least two sets of blood 
pressure and pulse rate measurements in the seated position, as described in 
Section 6.5. 
• Approximately 2 hours after dosing, obtain a 12-lead ECG after the subject has been 
resting supine for at least 5 minutes (Section 6.7). 
• Administer the following questionnaires to the subject in the order specified below: 
• ESS (Section 6.12.2) 
• PGIc (Section 6.12.5) 
• FOSQ-10 (Section 6.12.6) 
• SF-36v2 (Section 6.12.7) 
• EQ-5D-5L (Section 6.12.8) 
• WPAI:SHP questionnaire (Section 6.12.9) 
• Approximately 3 hours after dosing, initiate the second trial of the MWT. 
• Subjects should be served a light lunch immediately after the second or third trial of 
the MWT. 
• Approximately 4 hours after dosing, obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Approximately 5 hours after dosing, initiate the third trial of the MWT. 
• Approximately 6 hours after dosing, obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Approximately 7 hours after dosing, initiate the fourth trial of the MWT. 
• Approximately 8 hours after dosing, obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Approximately 9 hours after dosing, initiate the fifth trial of the MWT. 
• Approximately 10 hours after dosing, obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.14). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the last visit or phone contact (Section 5.7). 
• Complete the CGIc (Section 6.12.4). 
• Dispense study drug and instruct subject on the daily dose administration to begin on 
the following morning (Section 6.11). 
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• Schedule the next Phone Contact times and return clinic visit. To the extent possible, 
the Week 8 clinic visit should be scheduled in the morning to facilitate 
characterization of the absorption phase of the PK curve. 
 
7.5 
Phone Contact at the end of Weeks 2, 3, 5, 6, 7, 9, 10 and 11 
 
Visits 
4 
5 
7 
8 
9 
11 
12 
13 
Days 
14±3 
21±3 
35±3 
42±3 
49±3 
63±3 
70±3 
77±3 
Weeks 
2 
3 
5 
6 
7 
9 
10 
11 
 
• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.14). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the last visit or phone contact (Section 5.7). 
• For subjects with cataplexy, review the Cataplexy Diary with the subject, and remind 
the subject to complete the Cataplexy Diary at the end of each day (Section 6.12.10). 
• Remind subject of next Phone Contact time or return clinic visit. 
 
7.6 
End of Week 8 Clinic Visit 
Visit 10, Day 56 ±3 days  
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain a urine sample for a urine drug screen (Section 6.10.2.1 and Table 1). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure and pulse rate 
measurements in the seated position, as described in Section 6.5. 
• Obtain a 12-lead ECG after the subject has been resting supine for at least 5 minutes 
(Section 6.7). 
• Obtain two PK samples within 1-8 hours postdose (one sample at beginning of visit 
and one sample at the end of the visit before the subject leaves the clinic), record the 
exact time of collection, and record the exact time that subject dosed that morning 
(Section 6.13). 
• Collect study drug and assess compliance. 
• For subjects with cataplexy, review Cataplexy Diary and review instructions for 
continued use (Section 6.12.10). 
• Administer the following questionnaires to the subject in the order specified below:  
• ESS (Section 6.12.2) 
• PGIc (Section 6.12.5) 
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• FOSQ-10 (Section 6.12.6) 
• SF-36v2 (Section 6.12.7) 
• EQ-5D-5L (Section 6.12.8) 
• WPAI:SHP questionnaire (Section 6.12.9) 
• Administer the C-SSRS Since Last Visit version and record the results (Section 6.9) 
• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.14). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the last visit or phone contact (Section 5.7). 
• Complete the CGIc (Section 6.12.4). 
• Dispense study drug and instruct subject on the daily dose administration to begin on 
the following morning (see Section 6.11). 
• Dispense the 24-hour ambulatory blood pressure monitoring equipment after 
demonstrating how it should be used. Provide instructions for use and for returning 
the equipment (Section 6.6). 
• Schedule the next Phone Contact times and return clinic visit. 
• Assess whether the subject is interested in participating in the Open-Label Safety 
Study (14-005). If the subject is interested, the Investigator should provide the subject 
with a copy of the 14-005 ICF for their review prior to the Final Week 12 visit in this 
study. 
 
7.7 
Final Clinic Visit Week 12  
Visit 14, Days 83 & 84 (±3 days) 
On admission to the investigative site in the evening, complete the following: 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain a urine sample for a pregnancy test for all females of childbearing potential 
(Section 6.10, Table 1 footnote for definitions of childbearing potential). 
• Obtain a urine sample for urinalysis and urine drug screens (Section 6.10.2.1 and 
Table 1). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure and pulse rate 
measurements in the seated position, as described in Section 6.5. 
• Administer the C-SSRS Since Last Visit version and record the results (Section 6.9). 
• Collect study drug and assess compliance (Section 5.9). 
• For subjects with cataplexy, review the Cataplexy Diary (Section 6.12.10). 
• Prepare the subject for the PSG. 
• “Lights out” and initiate the overnight PSG (Section 6.8). 
On the morning of the following day, complete the following procedures. The time for these 
procedures should occur relative to dosing (Appendix 2 for an example schedule). 
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• “Lights on” (waking) should occur approximately 1 hour before dosing. 
• Approximately 30 minutes before dosing, obtain vital signs (systolic and diastolic 
blood pressure, pulse and respiratory rate, and body temperature), including at least 
two sets of blood pressure and pulse rate measurements in the seated position, as 
described in Section 6.5. 
• Obtain fasting blood samples for laboratory serum chemistry and hematology tests 
(see Section 6.10.2.1 and Table 1). 
• Administer study drug to the subject (dosing) on an empty stomach at least 1 hour 
after waking (Section 5.8.2). 
• Approximately 30 minutes after dosing subjects should be served a light breakfast. 
Breakfast should be completed within 15 to 20 minutes (Section 5.8.2). 
• Approximately 50 minutes after dosing, obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Approximately 1 hour after dosing, initiate the first trial of the MWT 
(Section 6.12.1). 
• Approximately 1 hour and 50 minutes after dosing, obtain at least two sets of blood 
pressure and pulse rate measurements in the seated position, as described in 
Section 6.5. 
• Approximately 2 hours after dosing, obtain a 12-lead ECG after the subject has been 
resting supine for at least 5 minutes (Section 6.7). 
• Administer the following questionnaires to the subject in the order specified below: 
• ESS (Section 6.12.2) 
• PGIc (Section 6.12.5) 
• FOSQ-10 (Section 6.12.6) 
• SF-36v2 (Section 6.12.7) 
• EQ-5D-5L (Section 6.12.8) 
• WPAI:SHP questionnaire (Section 6.12.9) 
• Approximately 3 hours after dosing, initiate the second trial of the MWT. 
• Subjects should be served a light lunch immediately after the second or third trial of 
the MWT. 
• Approximately 4 hours after dosing, obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Approximately 5 hours after dosing, initiate the third trial of the MWT. 
• Approximately 6 hours after dosing, obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Approximately 7 hours after dosing, initiate the fourth trial of the MWT. 
• Approximately 8 hours after dosing, obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Approximately 9 hours after dosing, initiate the fifth trial of the MWT. 
• Approximately 10 hours after dosing, obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
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• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.14). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the last visit or phone contact (Section 5.7). 
• Complete the CGIc (Section 6.12.4). 
• Perform a physical examination including a full examination of body systems 
(excluding a full genitourinary exam) and a brief neurological examination 
(Section 6.4). 
• If the subject is interested in enrolling in the Open-Label Safety Study, the 
Investigator should follow procedures for enrollment in Study 14-005. Subjects who 
enroll in Study 14-005 will not have a Safety Follow-up Visit in this study. 
• If the subject is not interested in participating in the Open-Label Safety Study, the 
Investigator should schedule the (Week 14) Safety Follow-up visit. 
 
7.8 
Follow-up Clinic Visit Week 14 
Visit 15, Day 98 (±3 days) 
The Follow-up Period is not required for subjects who agreed to enter the Open-label Safety 
Study (14-005) at the Final Clinic Visit. 
Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure and pulse rate 
measurements in the seated position, as described in Section 6.5.  
• Obtain a 12-lead ECG after the subject has been resting supine for at least 5 minutes 
(Section 6.7). 
• Administer the C-SSRS Since Last Visit version and record the results (Section 6.9). 
• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.14). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the last visit or phone contact (Section 5.7). 
 
Unless any safety issues are identified that require follow-up, the study will be considered 
completed and the subject will be discharged from the study. Subjects will be instructed to 
follow-up with their healthcare provider regarding the resumption of any medications that 
were discontinued prior to study participation. 
A subject who did not agree to enter Study 14-005 at the Final Clinic Visit of this study may 
decide to enroll in Study 14-005 at any time prior to this Follow-up visit; however, that 
subject must first complete the Follow-up visit in this study before enrolling in Study 14-005. 
In that case, enrollment in Study 14-005 will occur concurrently with the Follow-up visit in 
this study.  
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7.9 
Early Termination Clinic Visit 
If a subject intends to withdraw and is willing and able to safely take additional study drug, 
schedule a clinic visit and complete all final visit assessments indicated at the Final Visit 
Week 12 (Section 7.7), except for assessing whether the subject is interested in participating 
in Study 14-005. Subjects who withdraw from this study are not eligible for Study 14-005. 
If a subject withdraws and is unable or unwilling to take additional study drug, the following 
safety and final assessments should be conducted.  
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain a urine sample for a pregnancy test for all females of childbearing 
potential (Section 6.10, Table 1 footnote for definitions of childbearing potential). 
• Obtain a urine sample for urinalysis and urine drug screens (Section 6.10.2.1 and 
Table 1). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory 
rate, and body temperature), including at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Obtain a 12-lead ECG after the subject has been resting supine for at least 
5 minutes (Section 6.7). 
• Obtain fasting blood samples for laboratory serum chemistry and hematology 
tests (see Section 6.10.2.1 and Table 1). 
• Provide a light breakfast after blood samples are collected. 
• Administer the C-SSRS Since Last Visit version and record the results 
(Section 6.9). 
• Collect study drug and assess compliance (Section 5.9). 
• Review the Cataplexy Diary (if the patient has cataplexy) (Section 6.12.10). 
• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.14). 
• Record all concomitant medications on the concomitant medications CRF that 
were taken after the last visit or phone contact (Section 5.7). 
• Perform a physical examination including a full examination of body systems 
(excluding a full genitourinary exam) and a brief neurological examination 
(Section 6.4). 
• Schedule a 2-week Follow-up visit if the subject is willing to continue with 
follow-up procedures (Section 7.8). 
7.10 Discontinuations 
If a subject is withdrawn before completing the study, the reason for withdrawal will be 
entered on the appropriate CRF. The specific reason for the withdrawal should be carefully 
documented on the CRF. For instance, rather than stating “withdrew informed consent”, the 
specific reason for withdrawing the informed consent should be stated. Whenever possible 
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and reasonable, the evaluations that were to be conducted during the final study visit should 
be performed at the time of premature discontinuation as noted above.  
It is vital to obtain follow-up data on any subject who terminated because of an AE, 
abnormal laboratory test, or ECG finding.  In any case, every effort must be made to ensure 
safety follow-up procedures are completed. 
8 
QUALITY CONTROL AND ASSURANCE 
The study will be conducted according to GCP guidelines and according to national law. 
Quality Assurance audits may be performed at the discretion of Jazz Pharmaceuticals. 
9 
PLANNED STATISTICAL METHODS  
9.1 
General Considerations 
All study data will be summarized by treatment using descriptive statistics. Categorical 
variables will be reported as frequency and percent (e.g., gender, race). Continuous variables 
will be reported as number of subjects, mean, standard deviation, median, minimum, and 
maximum (e.g., age, weight). All summaries, statistical analyses, and individual subject data 
listings described below will be completed using Version 9.3 or later of the SAS Statistical 
Analysis System (SAS Institute, Inc. Cary, NC). 
9.2 
Tests of Hypotheses and Significance Levels 
The primary objective of the study is to evaluate the efficacy of JZP-110 administered once 
daily for up to 12 weeks in doses of 75, 150, and 300 mg compared to placebo in the 
treatment of excessive sleepiness in adult subjects with narcolepsy.  To address this 
objective, pairwise treatment difference between each of the 3 doses and placebo will be 
tested.  The family-wise error rate will be controlled at a significance level of 0.05. To 
address the multiplicity issue due to the multiple efficacy endpoints and doses, a fixed 
hierarchical testing sequence will be employed (Section 9.10). 
9.3 
Determination of Sample Size 
Approximately 240 subjects are planned for enrollment. Approximately 60 subjects will be 
randomized to each treatment group. A sample size of 54 subjects per group will provide at 
least 80% power to detect a difference of 6 minutes in the mean sleep latency time as 
determined from the MWT (mean of the first four trials) and a difference of 4 points on the 
ESS changes from Baseline to Week 12 between each JZP-110 treatment group and placebo. 
This calculation assumes common standard deviations of 10 minutes for the MWT and 
6 points for the ESS changes from Baseline and a two-sided significance level of 0.05 using a 
t-test. To account for dropouts without evaluable data, a sample size of 60 subjects per 
treatment group is planned. 
 
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9.4 
Analysis Populations 
The Safety Population will consist of all subjects who received at least one dose of study 
medication. This population will be analyzed for safety evaluation and will be presented in 
the tables and listings of safety data. 
 
The Modified Intent-to-Treat (mITT) Population will include subjects who received at least 
one dose of study medication and have baseline and at least one post-baseline evaluation of 
MWT or ESS. This population will be evaluable for the co-primary endpoints. This 
population will also be analyzed for other efficacy endpoints. If a subject in the mITT 
Population does not have an assessment for a particular secondary efficacy endpoint, that 
subject will be excluded in the analysis of that endpoint. 
 
The Per-Protocol population will include subjects who completed the trial according to 
protocol specifications without a major violation. The type of protocol violations that will 
result in exclusion from the Per-Protocol Population will be identified in the statistical 
analysis plan.  This population will be identified before unblinding the study, and will only 
be used in a secondary analysis of the co-primary endpoints. 
 
The PK Population will include subjects who have evaluable PK data for the population PK 
analysis. 
9.5 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for the Safety Population, the 
mITT Population, and the Per-Protocol Population. The summaries of data will include 
frequencies and percentages for categorical variables and mean, standard deviation, median, 
minimum, and maximum for continuous variables. 
 
9.6 
Handling of Dropouts and Missing Data 
For the analysis of the co-primary efficacy parameter of MWT and ESS, the key secondary 
efficacy parameter of PGIc, and secondary efficacy parameter of CGIc, multiple imputation 
methods will be used to impute the missing data in order to assess the sensitivity of the 
results. These methods will be described in the statistical analysis plan.  
The assumptions important to the validity of these imputation methods will be examined and 
discussed in the final study report where the sensitivity analysis is presented. 
9.7 
Pooling of Investigation Centers 
Data from all investigational centers will be pooled for primary analyses. Data may also be 
pooled by region of country as appropriate for exploratory analyses.  
 
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9.8 
Efficacy Endpoints 
9.8.1 
Co-primary Efficacy Endpoint 
• MWT: Change in the mean sleep latency time (in minutes) as determined from the 
first four trials of a 40-minute MWT from Baseline to Week 12 
• ESS: Change in ESS score from Baseline to Week 12  
9.8.2 
Key Secondary Efficacy Endpoint 
• PGIc: Percentage of subjects reported as improved (minimally, much, or very much) 
at Week 12 
9.8.3 
Other Secondary Endpoints 
• Time course of efficacy on the MWT: Change in sleep latency time (in minutes) on 
each of the 5 MWT trials 
• CGIc: Percentage of subjects reported as improved (minimally, much, or very much) 
at Week 12 
• MWT: Change in the mean sleep latency time (in minutes) as determined from the 
first four trials of a 40-minute MWT from Baseline to Week 4 
• ESS: Change in ESS score from Baseline to Week 1, Week 4, and Week 8  
• PGIc: Percentage of subjects reported as improved at Week 1, Week 4, and Week 8 
• CGIc: Percentage of subjects reported as improved at Week 1, Week 4, and Week 8 
9.8.4 
Functional Outcomes and Quality of Life Endpoints 
• FOSQ-10: Change in the total score from Baseline to Week 1, Week 4, Week 8, and 
Week 12 
• SF-36v2: Change in the total score and change in the 8 subscales from Baseline to 
Week 4, Week 8, and Week 12 
o EQ-5D-5L: EQ-5D Dimensions:  
 Number and percentage of subjects in each of the 5 levels (e.g., no 
problem, slight problem, moderate problem, severe problem, unable) 
for each dimension (e.g., mobility, self-care) over time  
 Number and percentage of subjects reporting any problems (levels 2-
5) for each dimension (e.g., mobility, self-care) over time  
o EQ VAS: Mean and SD or median with 25th and 75th percentiles for the VAS 
at Baseline, Week 1, Week 4, Week 8 and Week 12. Change in the mean VAS 
scores from Baseline to Week 1, Week 4, Week 8, and Week 12 
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o EQ-5D-5L Index: Index value at Baseline to Week 1, Week 4, Week 8, and 
Week 12 
• WPAI:SHP: Percent work time missed due to problem over time, percent impairment 
while working due to problem over time, percent overall work impairment due to 
problem over time, and percent activity impairment due to problem over time  
9.8.5 
Exploratory Endpoints 
• Number of Cataplexy Attacks: Change in the mean weekly number of cataplexy 
attacks in the subset of subjects who report the presence of cataplexy at 
randomization from Baseline to Week 1, Week 4, Week 8, and Week 12 
• Change in PSG parameters including total sleep time (TST), Stages N1, N2, N3, 
wake after sleep onset (WASO), number of awakenings, AI, AHI, number of central 
apneas, SaO2 nadir, and SaO2 mean from Baseline to Week 4 and Week 12. 
9.9 
Safety Endpoints 
To evaluate the safety and tolerability evaluations as determined by the occurrence of and/or 
changes in: 
• Treatment-emergent adverse events 
• Change in clinical laboratory tests (chemistry, hematology, and urinalysis) 
• Vital signs 
• 24 hour ambulatory blood pressure monitoring 
• 12-lead electrocardiograms (ECGs) 
• Physical examination 
• C-SSRS 
9.10 Multiplicity Issue 
To address the multiplicity issue of multiple endpoints and dose groups, the fixed 
hierarchical testing sequence in Figure 2 will be used. The testing will begin with the 
comparison of 300 mg dose versus placebo for the co-primary efficacy endpoints MWT and 
ESS.  Since they are co-primary endpoints, both have to be significant at the 0.05 level 
before the test can proceed to the next level. The testing will stop when a significant level 
exceeds 0.05. This gate keeping approach will control the family-wise error rate at 0.05 for 
the comparisons of the three JZP-110 doses versus placebo in MWT, ESS, and PGIc. The 
dose(s) that show(s) significant difference versus placebo in both MWT and ESS will be 
considered efficacious doses and additional testing to characterize the time course of efficacy 
will be performed (Section 9.11). 
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Figure 2 
Multiplicity Strategy 
 
9.11 Efficacy Analyses 
Efficacy analyses will be performed for the mITT Analysis Population. The per-protocol 
analysis will only be used in a secondary analysis of the co-primary endpoints. For the 
analysis of the co-primary efficacy endpoints, a mixed-effect repeated measures (MMRM) 
model will be used as the primary method of analysis. This model will include fixed effects 
for treatment (i.e., dose group), time (as a discrete factor), treatment-by-time interaction, 
baseline value of the efficacy endpoint, and randomization stratification factor. SAS 
procedure PROC MIXED will be used to carry out this analysis. All available data will be 
included in the model. An unstructured covariance matrix will be used to model the 
correlation among repeated measurements. The estimates of treatment difference versus 
placebo and their 95% confidence intervals will be presented. In addition to the MMRM 
model, an analysis of covariance (ANCOVA) model will be used to analyze MWT and ESS 
to provide sensitivity analyses. This ANCOVA model will include the effect for treatment as 
a fixed effect, and baseline value of the efficacy endpoint as the covariate.  
The chi-squared test will be used to test the hypotheses associated with the analysis of the 
key secondary efficacy endpoint of PGIc and the secondary efficacy endpoint of CGIc at 
Week 12.  
For the time course efficacy analysis, the dose(s) that show(s) significant difference versus 
placebo in both MWT and ESS will be considered efficacious dose(s). For each of these 
doses, additional testing to characterize the time course of efficacy using MWT will be 
performed.  The mean and standard error of the mean MWT data will be displayed 
graphically for the dose and placebo. Pairwise comparison vs. placebo for each of the 
5 MWT trials will be conducted at a significance level of 0.05. Characterizing the time 
MWT and ESS  
300 mg vs. placebo; proceed to next test if both are significant at α=0.05 
PGIc 
300 mg vs. placebo; proceed to next test if significant α=0.05 
PGIc 
75 mg vs. placebo; use α=0.05 
PGIc 
150 mg vs. placebo; proceed to next test if significant α=0.05 
MWT, ESS  
75 mg vs. placebo; proceed to next test if both are significant at α=0.05 
MWT, ESS  
150 mg vs. placebo; proceed to next test if both are significant at α=0.05 
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course of efficacy will begin with identifying the first trial that demonstrates significant 
difference from placebo. If such a trial is identified, the treatment difference at the next trial 
will be examined. If the treatment difference for the next trial is also significant at the 
0.05 level, the treatment will be considered efficacious at the time of the next trial. This 
procedure will continue as long as significance for each subsequent trial is observed or until 
trial 5 is examined. 
For the other MWT and ESS endpoints, FOSQ-10 endpoints, SF-36v2 endpoints, EQ VAS 
endpoints, EQ-5D-5L Index endpoints, and WPAI:SHP endpoints, a similar MMRM model 
will be used as the method of analysis; the other PGIc and CGIc endpoints, and EQ-5D-5L: 
EQ-5D Dimensions endpoints will be analyzed using the chi-squared test. 
No sensitivity analyses and no multiplicity adjustments will be employed for these endpoints. 
9.12 Safety Analyses 
Safety analyses will be performed for the Safety Analysis Population. No formal statistical 
testing will be performed for the safety analyses. 
9.12.1 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities system 
to classify events under primary system organ class and preferred term. 
The number and percent of subjects who experienced TEAEs, TEAEs related to study drug, 
or SAEs; who died during the study; or who discontinued study drug or withdrew from the 
study due to an AE will be summarized by treatment. Results will be presented by system 
organ class and preferred term. The overview will also report TEAEs by maximum severity. 
A TEAE is defined as an AE that either began after first study drug dose or worsened after 
the first dose. When determining the percent of subjects who experience an AE, multiple 
increases in severity are only counted as one AE. For example, a subject who develops a mild 
headache after the first study drug dose (that was not present during screening or at baseline), 
which subsequently worsens to moderate, then severe, is only counted once under the 
preferred term of headache. The increase in severity will be accounted for in the maximum 
severity analysis. 
For all AE summaries, if a subject has more than one AE within a preferred term, the subject 
is counted only once at the maximum severity and with the closest relationship to study drug. 
If a subject has more than one AE within a system organ class, the subject is similarly 
counted once when reporting results for that system organ class. 
All AE data will be listed. The information presented will include subject number, treatment, 
primary system organ class and preferred term, date of onset, severity, relationship to study 
drug, action taken, and stop date (if available). 
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9.12.2 
Vital Signs and 24-Hour Ambulatory Blood Pressure Monitoring 
Abnormal vital signs will be counted by treatment. The number and percent of subjects with 
any post-baseline vital sign readings above and/or below specified levels will be presented 
for each treatment. In addition, summary statistics (i.e., mean, median, minimum, maximum, 
standard deviation, and number of subjects) will be presented by treatment for each vital sign 
as per protocol schedule. An additional listing will be provided of those subjects who have 
clinically significant vital sign values. 
9.12.3 
Laboratory Evaluation 
The number and percent of subjects with abnormal values post-baseline will be tabulated by 
treatment. In addition, summary statistics (i.e., mean, minimum, maximum, standard 
deviation, and number of subjects) will be presented by treatment for each laboratory 
parameter as per protocol schedule. An additional listing will be provided of those subjects 
who have clinically significant laboratory values. 
9.12.4 
12-Lead Electrocardiograms 
Electrocardiogram intervals and durations will be reviewed for notable abnormalities, and 
clinically notable abnormalities and findings considered to be clinically significant will be 
listed. The number and percent of patients who have a clinically notable ECG interval 
abnormality or other clinically significant ECG finding will be summarized. A listing of 
abnormal ECG values will also be provided. 
9.12.5 
Physical Examinations 
A finding identified by the investigator as abnormal on the physical examination at the 
Screening visit will be recorded on the Medical History eCRF. A clinically significant 
adverse change (i.e., worsening) of a physical examination finding after screening will be 
recorded as an AE. 
9.12.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Data from the Since Last Visit Version of the C-SSRS will be summarized by treatment 
group according to the Columbia Classification Algorithm of Suicide Assessment (C-CASA) 
(Posner et al. 2007). 
9.13 Analysis of Pharmacokinetic and Pharmacodynamic Variables 
PK analyses will be performed for the PK Analysis Population. 
Concentration data for JZP-110 will be tabulated by sampling time point, and will be 
included in a population PK analysis. The population PK model will be used to characterize 
JZP-110 PK profile in narcolepsy patients, and to explore exposure-efficacy correlations. 
Available subject characteristics (such as demographics, labs, etc.) will be tested as potential 
covariates, as appropriate. 
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9.14 Subgroup Analyses 
Exploratory analyses of the efficacy and safety endpoints will be conducted in the subgroups 
of subjects who report the presence or absence of cataplexy at randomization.  
9.15 Interim Analysis and Data Monitoring 
No interim analyses are planned. 
10 DATA QUALITY ASSURANCE 
Steps to assure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator 
and associated personnel prior to the study, and periodic monitoring visits by Jazz 
Pharmaceuticals or its designee. Data will be reviewed for accuracy and completeness by 
Jazz Pharmaceuticals or its representatives during and after onsite monitoring visits, and any 
discrepancies will be resolved with the investigator or designees as appropriate. 
10.1 Data Management 
The standard procedures for handling and processing records will be followed in compliance 
with 21 CFR 11, Good Clinical Practices, ICH Guidelines, and the Standard Operating 
Procedures (SOPs) of Jazz Pharmaceuticals or the Contract Research Organization (CRO). A 
comprehensive Data Management Plan (DMP) will be developed, which may include but is 
not limited to a Data Management Overview, Database Contents, annotated CRF, Query 
Contacts, and Consistency Checks. A central laboratory will review all PSG data. 
10.2 Case Report Forms 
Jazz Pharmaceuticals or its designee will supply electronic case report forms (eCRFs) for the 
recording of all trial data not recorded in subject diaries, ECG or generated by laboratory 
report. All data recorded must be completed in the eCRFs. 
The principal investigator must review the eCRFs and provide his/her signature certifying 
that he/she has reviewed the data and considers the data accurate to the best of his/her 
knowledge. Regardless of who completes the forms, it is the principal investigator’s 
responsibility to ensure the accuracy of the forms. 
10.3 Retention of Data 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Trial (ICH E6 Good Clinical Practice) and as required by the 
applicable regulatory requirement(s). The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents.  
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
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should be retained for a longer period if required by the applicable regulatory requirements or 
by an agreement with Jazz Pharmaceuticals. It is the responsibility of Jazz Pharmaceuticals to 
inform the investigator/institution when these documents no longer need to be retained. 
10.4 Data Safety Monitoring Board 
A data safety monitoring board is not planned for this trial. 
11 ADMINISTRATIVE CONSIDERATIONS 
11.1 Investigators and Study Administrative Structure 
11.1.1 
Contract Research Organization  
11.1.2 
Jazz Pharmaceuticals Medical Monitors  
11.1.3 
EU Medical Monitor  
Contact information for the EU Medical Monitor will be provided separately.  
11.1.4 
Investigator 
Multicenter 
11.2 Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval 
The final approved protocol and the informed consent form will be reviewed by the IRB/IEC.  
In addition, the IRB/IEC will review any other written information to be provided to the 
subject, advertisements for subject recruitment (if used), and subject compensation (if any). 
The committee’s decision concerning conduct of the study will be sent in writing to the 
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investigator and a copy will be forwarded to Jazz Pharmaceuticals. The investigator agrees to 
make any required progress reports, as well as reports of SAEs, life-threatening problems, 
death, or any significant protocol deviations, as required by the IRB/IEC. 
A list of the IRB/IEC members who actually participated in the review, their respective titles 
(occupational identification), and institutional affiliations or an IRB/IEC assurance number 
must be provided to Jazz Pharmaceuticals. The approval letter or notice must be provided on 
IRB/IEC letterhead and contain the date of the meeting and sufficient information to identify 
the version of the protocol unambiguously (by name and number) and state that the informed 
consent form was also reviewed. 
A clinical trial may not be initiated before the proposed protocol and informed consent form 
have been reviewed and unconditionally approved by an IRB meeting federal regulations. 
The clinical study remains subject to continuing review by the IRB. Jazz Pharmaceuticals or 
its designee will supply all necessary data for the investigator to submit to the IRB/IEC. Jazz 
Pharmaceuticals will not ship clinical supplies to an investigational site until written signed 
approval from the site’s IRB/IEC has been received by Jazz Pharmaceuticals. 
The investigator is responsible for ensuring initial and continued review and approval of the 
clinical trial by the IRB/IEC at his/her site. The investigator must also ensure that he/she will 
promptly report to the IRB/IEC and Jazz Pharmaceuticals all changes in the research activity 
and all unanticipated problems involving risk to human subjects or others, and that he/she 
will not make any changes in the research without IRB/IEC approval, except where 
necessary to eliminate apparent hazards to human subjects. If the trial remains in progress for 
more than 1 year, documentation of annual renewal must be submitted to Jazz 
Pharmaceuticals or its designee. Within 3 months of trial completion or termination, a final 
report must be provided to the IRB/IEC by the clinical site. 
11.3 Ethical/Legal Conduct of the Study 
The study will be conducted in accordance with applicable local regulations relating to Good 
Clinical Practice (GCP) and with the SOPs of the CRO or Jazz Pharmaceuticals, as 
applicable.  These standards respect the following guidelines or laws: 
• Guideline for Good Clinical Practice E6 (R1): ICH, May 1996. 
• United States (US) Code of Federal Regulations (CFR) pertaining to conduct and 
reporting of clinical studies (Title 21_ CFR Parts 11, 50, 54, 56, 312, and 314). 
• Clinical Trials Directive (European Medicines Agency) Directive 2001/20/EC. 
Endorsement of the ethical principles embedded in the above guidances and regulations 
ensures that the rights, safety, and well-being of trial subjects are protected and are consistent 
with the principles that have their origin in the Declaration of Helsinki, World Medical 
Association –“Ethical Principles for Medical Research Involving Human Subjects.” 
11.4 Subject Information and Consent 
All subjects will provide their written informed consent before the performance of any 
study-related procedures. Subjects will be given a copy of their signed ICF. 
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Each subject's chart will have his/her signed ICF for study participation attached to it.  When 
the study treatment is completed and the CRF has been monitored, the ICF will be kept in the 
investigator’s central study file. Regulatory authorities may check the existence of the signed 
ICF in this central study folder if not having done so during the performance of the trial. 
11.5 Subject Confidentiality  
All reports and communications relating to the subjects in the study will identify each subject 
only by his/her initials and by the subject’s study number. These documents will be treated 
with strict adherence to professional standards of confidentiality and will be filed at the study 
site under adequate security and restricted access.  
Portions of the subject's medical records pertinent to the study will be reviewed by Jazz 
Pharmaceuticals personnel or its designee and possibly by governmental agency personnel to 
ensure adequate source documentation, accuracy, and completeness of the CRFs. The IRB 
has the authority to review subject records. 
11.6 Protocol Adherence – Amendments 
The protocol must be read thoroughly and the instructions must be followed exactly. 
Any changes in the protocol will require a formal amendment. Such amendments will be 
agreed upon and approved in writing by the investigator and the Jazz Pharmaceuticals 
designees.  The IRB/IEC will be notified of all amendments to the protocol. Amendments to 
the protocol will not be implemented until written IRB/IEC approval has been received.  
11.7 Required Documents 
The investigator must provide Jazz Pharmaceuticals or its designee with the applicable 
regulatory documents before the enrollment of any subject (copies should be kept by the 
investigator in the investigator’s regulatory document binder).  
11.8 Study Monitoring 
Throughout the course of the study, the study monitor will make frequent contacts with the 
investigator.  This will include telephone calls and onsite visits.  During the onsite visits, the 
eCRFs will be reviewed for completeness and adherence to the protocol.  As part of the data 
audit, source documents will be made available for review by the site.  The study monitor 
will also perform drug accountability checks and may periodically request review of the 
investigator study file to assure completeness of documentation in all respects of clinical trial 
conduct. 
Upon completion of the study, the study monitor will arrange for a final review of the study 
files after which the files should be secured for the appropriate time period.  The investigator 
or appointed delegate will receive the study monitor during these onsite visits and will 
cooperate in providing the documents for inspection and respond to inquiries.  In addition, 
the investigator will permit inspection of the study files by authorized representatives of the 
regulatory agencies. 
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11.9 Protocol Violations/Deviations 
All major protocol violations must be reported to the IRB in an expedited fashion. It is the 
responsibility of the principal investigator to ensure proper reporting to the IRB. Protocol 
violations and deviations should be reported to Jazz Pharmaceuticals or designee. 
11.10 Access to Source Documentation  
Jazz Pharmaceuticals (or its designee) will be responsible for monitoring this clinical trial. 
Jazz Pharmaceuticals will monitor the study conduct, proper CRF and source documentation 
completion and retention, and accurate study drug accountability. To this end, a monitor will 
visit the study site at suitable intervals and be in frequent contact with the site through verbal 
and written communication. It is essential that the monitor have access to all documents 
(related to the study and the individual participants) at any time they are requested. In turn, 
the monitor will adhere to all requirements for subject confidentiality as outlined in the 
informed consent form. The investigator and his/her staff will be expected to cooperate with 
the monitor, to be available during a portion of the monitoring visit to answer questions, and 
to provide any missing information. 
In addition, representatives of the Clinical Quality Assurance Department of Jazz 
Pharmaceuticals (or equivalent), or appointed monitoring organization(s), and representatives 
of the FDA or other regulatory agencies may request to inspect the study documents (e.g., 
study protocol, CRFs, study drug, original medical records/files). All subject data will be 
treated confidentially. 
11.11 Publication and Disclosure Policy  
Please refer to individual site contracts for specific contractual obligations and requirements. 
All information concerning JZP-110, Jazz Pharmaceuticals’ operations, patent applications, 
formulas, manufacturing processes, basic scientific data, and formulation information 
supplied by Jazz Pharmaceuticals to the investigator and not previously published, are 
considered confidential and remain the sole property of Jazz Pharmaceuticals. CRFs also 
remain the property of Jazz Pharmaceuticals. The investigator agrees to use this information 
only to complete this study and will not use it for other purposes without written consent of 
Jazz Pharmaceuticals as further detailed in the Clinical Study Agreement signed by the 
investigator and/or institution. 
It is understood by the investigator that Jazz Pharmaceuticals will use the information 
obtained in this clinical trial in connection with the study of JZP-110, and therefore may 
disclose this information as required to other Jazz Pharmaceuticals investigators; appropriate 
international regulatory agencies; or others. In agreeing to participate in this study, the 
investigator understands that he/she has an obligation to provide complete test results and all 
data developed during this trial to Jazz Pharmaceuticals. Jazz Pharmaceuticals requires that 
permission to publish details of this study must be obtained in writing as further detailed in 
the Clinical Study Agreement signed by the investigator and/or institution. It is intended that 
the results of this trial will be published in scientific literature. The conditions noted here are 
intended to protect commercial confidential materials (patents, etc.) and not to restrict 
publication.   
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12 REFERENCE LIST 
American Academy of Sleep Medicine (AASM). International Classification of Sleep 
Disorders-Third Edition (ICSD-3), Darien, IL. American Academy of Sleep Medicine, 2014; 
53-62, 143-155.   
American Psychiatric Association. (2013) Diagnostic and statistical manual of mental 
disorders (5th ed.), Washington DC. 
Broderick JE, Junghaenel DU, Schneider S, Pilosi JJ, Stone AA. Pittsburgh and Epworth 
sleep scale items: accuracy of ratings across different reporting periods. 2013; Behav Sleep 
Med. 11:173-88. 
Chasens E, Ratcliffe S, Weaver T. Development of the FOSQ-10: A short version of the 
Functional Outcomes of Sleep Questionnaire. 2009; Sleep 32: 915-919. 
Doghramji K, Mitler MM, Sangal B, Shapiro C, Taylor S, Walsleben J, Belisle C, Erman M, 
Hayduk R, Hosn R, O’Malley E, Sangal J, Schutte S and Youakim J. A normative study of 
the maintenance of wakefulness test (MWT). Electroencephalogr Clin Neurophysiol 1997; 
103:554-562. 
EQ-5D-5L User Guide. 2013. Available at: 
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/UserGuide
_EQ-5D-5L_v2.0_October_2013.pdf.   Accessed November 19, 2014. 
FDA Narcolepsy Public Meeting on Patient-Focused Drug Development. September 24, 
2013, pages 76-77. Accessed March 12, 2014 at FDA website. 
Harsh JR, Hayduk R, Rosenberg R, Wesnes KA, Walsh JK, Arora S, Niebler GE, Roth T. 
The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness 
associated with narcolepsy. Curr Med Res Opin. 2006;22:761-74. 
Hasan S, Pradervand S, Ahnaou A, Drinkenburg W, Tafti M, Franken P. How to keep the 
brain awake? The complex molecular pharmacogenetics of wake promotion. 
Neuropsychopharmacology. 2009;34:1625-1640. 
Hays RD, Stewart AL. (1992). Construct validity of MOS health measures. In A. L. Stewart 
& J. E. Ware (eds.), Measuring functioning and well-being: The Medical Outcomes Study 
approach (pp. 325-342), Durham, NC: Duke University Press. 
Johns MW. 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. 
Littner MR, Kushida C, Wise M, et al. Practice parameters for clinical use of the multiple 
sleep latency test and the maintenance of wakefulness test. Sleep. 2005; 28: 113-21. 
Majid H, Hirshkowitz M. Therapeutics of narcolepsy. Sleep Med Clin 2010; 5:659-673. 
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Mitler MM, Gujavarty KS, and Broman C. Maintenance of wakefulness test: A 
polysomnographic technique for evaluating treatment efficacy in patients with excessive 
somnolence. Electroencephalogr Clin Neurophysiol. Jun 1982; 53(6): 658–661. 
Morgenthaler TI, Kapur VK, Brown TM, Swick TJ, Alessi C, Aurora RN, Boehlecke B, et 
al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central 
origin. SLEEP 2007; 30:1705-1711. 
Ohayon MM. Epidemiology of narcolepsy. In Narcolepsy and Hypersomnia 2007. C 
Bassetti, M Billiard, E Mignot, eds. New York: Informa Healthcare: pp 125-132. 
Ohayon MM, Priest RG, Zulley J, Smirne S, Paiva T. Prevalence of narcolepsy 
symptomatology and diagnosis in the European general population. Neurology 
2002;58:1826-1833. 
Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, Jones DW, Kurtz T, Sheps 
SG, Roccella EJ; Subcommittee of Professional and Public Education of the American Heart 
Association Council on High Blood Pressure Research. Recommendations for blood pressure 
measurement in humans and experimental animals: Part 1: blood pressure measurement in 
humans: a statement for professionals from the Subcommittee of Professional and Public 
Education of the American Heart Association Council on High Blood Pressure Research. 
Hypertension. 2005; 45:142-61. 
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm 
of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric 
suicidal risk analysis of antidepressants. Am J Psychiatry. 2007;164:1035-1043. 
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, Frazer, PA: Cephalon 2010. 
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity 
and activity impairment instrument. PharmacoEconomics 1993; 4(5):353-65. 
Roth T, White D, Schmidt-Nowara W, Wesnes KA, Niebler G, Arora S, Black J. Effects of 
armodafinil in the treatment of residual excessive sleepiness associated with obstructive sleep 
apnea/hypopnea syndrome: a 12-week, multicenter, double-blind, randomized, placebo-
controlled study in nCPAP-adherent adults. Clin Ther. 2006 28:689-706. 
Schwartz JR, Feldman NT, Bogan RK, Nelson MT, Hughes RJ. Dosing regimen effects of 
modafinil for improving daytime wakefulness in patients with narcolepsy. Clin 
Neuropharmacol. 2003;26(5):252-257. 
Unite Narcolepsy. Patient-Focused Narcolepsy Survey Interim Analysis as of September 16, 
2013. Available at: http://www.unitenarcolepsy.org/wp-content/uploads/Interim-Survey-
Analysis-v1.pdf. Accessed April 23, 2014. 
US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil for the 
treatment of pathological somnolence in narcolepsy. Ann Neurol. 1998;43(1):88-97. 
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Clinical Trial Protocol: 14-002 Amendment 3 
 
  
 
 
 
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US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil as a 
treatment for the excessive daytime somnolence of narcolepsy. Neurology. 2000;54(5):1166-
1175.  
Ware JE, Jr, Sherbourne CD. The MOS 36-Item Short-Form Health Survey (SF-36): I. 
Conceptual Framework and Item Selection. Medical Care, 30:473-483, 1992. 
Weaver TE, Laizner AM, Evans LK, et al. An instrument to measure functional status 
outcomes for disorders of excessive sleepiness. Sleep 1997;20:835-43. 
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13  LIST OF UNPUBLISHED STUDY REPORTS 
Document ID or Report No. 
Unpublished Study Report Citation 
EDMS-PSDB-4956838 
Dupuis P, Neliat G. Study of BZ-818730-000-D and BZ-
10A000-301-A in various receptor binding and cell 
biology assays (870189) (03 July 2001). 
EDMS-PSDB-5305783 
Janowsky A.  In vitro receptor, transporter, and release 
assay for NIDA medications discovery and abuse liability 
testing (Release Assays) (March 2006a). 
EDMS-PSDB-2735318 
Mailman R. Assessment of dopaminergic actions of YK-
10A (May 2003). 
EDMS-PSDB-2275504 
Newton K. A double-blind, placebo-controlled, 
randomized, single center, parallel-design study to 
evaluate the preliminary efficacy and safety of three dose 
ranges of YKP10A in outpatients with major depressive 
disorder (Protocol SKUP-9801) PPD Development, Inc. 
Final Report (03 July 2001). 
EDMS-PSDB-3696001 
Sporn J, Ness S, Gassmann-Mayer C, Grattan J. 6-week, 
randomized, double-blind, parallel- group, active- and 
placebo-controlled study to assess the efficacy of 
R228060 in adult subjects with major depressive disorder 
(MDD) (Protocol R228060-MDD-201); J&JPRD, 
Clinical Study Report (2004). 
R228060-USA-10 
Sutherland S, Okamoto A, Boom S, Hedli C, Kusumakar 
V, Grossman F. Three-week, randomized study to assess 
the tolerability of 2 fixed doses (200 mg and 500 mg) of 
R228060 (2003). 
 
 
 
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Appendix 1 
Schedule of Events  
 
Screen-
ing 
Baseline 
Treatment Phase 
Early 
Term 
Safety 
Follow-
upa 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
15 
Day/ End of 
Week 
Day 
-31 to -3 
Day  
-2&-1 
Day 7 (-
1, +2) 
Wk 1 
Day 
14±3 
Wk 
2 
Day 
21±3
Wk 
3 
Day 
27&28 
(±3) 
Wk 4 
Day 
35±3 
Wk 
5 
Day 
42±3 
Wk 
6 
Day 
49±3
Wk 
7 
Day 
56±3  
Wk 
8 
Day 
63±3
Wk 
9 
Day 
70±3
Wk 
10 
Day 
77±3
Wk 
11 
Day 
83&84 
(±3) 
Wk 12 
 
Day 
98±3 
Wk 
14 
Clinic visit 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Phone Contact 
 
 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination  
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight  
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Vital signs  
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
ECG  
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Fasting serum 
chemistry, 
hematology, 
urinalysis  
X 
Xb 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Urine sample for 
possible drug 
screen  
X 
X 
Xc 
 
 
Xc 
 
 
 
Xc 
 
 
 
X 
X 
 
Serum pregnancy 
test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Light breakfast 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Light lunch 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
Xd 
 
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Screen-
ing 
Baseline 
Treatment Phase 
Early 
Term 
Safety 
Follow-
upa 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
15 
Day/ End of 
Week 
Day 
-31 to -3 
Day  
-2&-1 
Day 7 (-
1, +2) 
Wk 1 
Day 
14±3 
Wk 
2 
Day 
21±3
Wk 
3 
Day 
27&28 
(±3) 
Wk 4 
Day 
35±3 
Wk 
5 
Day 
42±3 
Wk 
6 
Day 
49±3
Wk 
7 
Day 
56±3  
Wk 
8 
Day 
63±3
Wk 
9 
Day 
70±3
Wk 
10 
Day 
77±3
Wk 
11 
Day 
83&84 
(±3) 
Wk 12 
 
Day 
98±3 
Wk 
14 
Clinic visit 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Phone Contact 
 
 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
C-SSRS 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cataplexy Diary  
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Instruct how to 
discontinue 
excluded 
medications  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense 24-hour 
ambulatory blood 
pressure 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Overnight stay 
PSG/MWT  
 
Xe 
 
 
 
X 
 
 
 
 
 
 
 
X 
Xd 
 
ESS  
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Xd 
 
FOSQ-10  
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Xd 
 
SF-36v2 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xd 
 
EQ-5D-5L  
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Xd 
 
WPAI:SHP  
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Xd 
 
CGIs  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense study 
drug 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Collect Study 
drug/Assess 
Compliance 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
PGIc 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Xd 
 
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Clinical Trial Protocol: 14-002 Amendment 3 
 
 
 
 
 
 
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Screen-
ing 
Baseline 
Treatment Phase 
Early 
Term 
Safety 
Follow-
upa 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
15 
Day/ End of 
Week 
Day 
-31 to -3 
Day  
-2&-1 
Day 7 (-
1, +2) 
Wk 1 
Day 
14±3 
Wk 
2 
Day 
21±3
Wk 
3 
Day 
27&28 
(±3) 
Wk 4 
Day 
35±3 
Wk 
5 
Day 
42±3 
Wk 
6 
Day 
49±3
Wk 
7 
Day 
56±3  
Wk 
8 
Day 
63±3
Wk 
9 
Day 
70±3
Wk 
10 
Day 
77±3
Wk 
11 
Day 
83&84 
(±3) 
Wk 12 
 
Day 
98±3 
Wk 
14 
Clinic visit 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Phone Contact 
 
 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
CGIc  
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Xd 
 
Study drug 
administration 
prior to MWT 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Xd 
 
Blood draws for 
PK 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Assess interest in 
Study 14-005  
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Adverse Events  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Schedule next 
clinic visit and/or 
phone contact 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Shaded columns indicate clinic visits. 
a 
The 2 week Safety Follow-up is not required for subjects who enter the Open-label Safety Study (14-005) at the Final Clinic Visit. 
b 
If the Baseline visit occurs outside of the screening window (i.e. >29 days after the Screening Visit), obtain blood samples for serum chemistry, 
hematology tests and a urine sample for urinalysis. Record if the subject was fasting or nonfasting at the time of the collection. 
c 
Samples collected at Screening, Baseline, and Week 12 or Early Termination will be analyzed. Samples collected at other visits may be analyzed at the 
investigator’s discretion. 
d 
These assessments are not required for subjects who are withdrawing early from the study and are unable or unwilling to take additional study drug to 
complete a final PSG/MWT. 
e 
For subjects who are being rescreened, a repeat PSG and MWT is not required at Visit 2 if the results of the previous PSG and MWT meet the current 
inclusion/exclusion criteria and there have been no changes to medical history or concomitant medications that would likely affect the MWT results 
 
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Clinical Trial Protocol: 14-002 Amendment 3  
 
 
 
 
 
 
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Appendix 2 
Example Schedule of Times for Procedures During 
MWT Visits 
Baseline Visit – Day -1 (following overnight PSG)* 
Time relative to 
“lights on” 
Approximate 
time 
Procedure/activity 
0 h 
7:00 
Lights on 
~0.5 h 
7:30 
Body temperature, respiratory rate, and at least 2 sets of blood 
pressure and pulse 
~1.5 h 
8:30 
Light breakfast 
~2 
8:50 
At least 2 sets of blood pressure and pulse 
~2 h 
9:00 
Start 1st MWT Trial 
~3 
9:50 
At least 2 sets of blood pressure and pulse 
~3 h 
10:00 
ECG 
~3-4 h 
10:00-11:00 
Administer Questionnaires 
~4 h 
11:00 
Start 2nd MWT Trial 
 
 
Light lunch served immediately after the end of the 2nd or 3rd trial 
~5 h 
12:00 
At least 2 sets of blood pressure and pulse 
~6 h 
13:00 
Start 3rd MWT Trial 
~7 h 
14:00 
At least 2 sets of blood pressure and pulse 
~8 h 
15:00 
Start 4th MWT Trial 
~9 h 
16:00 
At least 2 sets of blood pressure and pulse 
~10 h 
17:00 
Start 5th MWT Trial 
~11 h 
~18:00 
At least 2 sets of blood pressure and pulse 
Week 4 and 12 Visits or Early Termination – MWT (following overnight PSG) 
Time relative to 
dosing 
Approximate 
time 
Procedure/activity 
~-1 h 
7:00 
Lights on 
~-0.5 h 
7:30 
Body temperature, respiratory rate, and at least 2 sets of blood 
pressure and pulse) 
 
 
Obtain fasting blood samples (Week 12 or Early Termination only) 
0 h 
8:00 
Dosing 
~0.5 h 
8:30 
Light breakfast 
~1 h 
8:50 
At least 2 sets of blood pressure and pulse 
~1 h 
9:00 
Start 1st MWT Trial 
~2 h 
9:50 
At least 2 sets of blood pressure and pulse 
~2 h 
10:00 
ECG 
~2-3 h 
10:00-11:00 
Administer Questionnaires 
~3 h 
11:00 
Start 2nd MWT Trial 
 
 
Light lunch served immediately after the end of the 2nd or 3rd trial 
~4 h 
12:00 
At least 2 sets of blood pressure and pulse  
~5 h 
13:00 
Start 3rd MWT Trial 
~6 h 
14:00 
At least 2 sets of blood pressure and pulse 
~7 h 
15:00 
Start 4th MWT Trial 
~8 h 
16:00 
At least 2 sets of blood pressure and pulse 
~9 h 
17:00 
Start of 5th MWT Trial 
~10 h 
~18:00 
At least 2 sets of blood pressure and pulse) 
*For subjects who are being rescreened, a repeat PSG and MWT will not be required at Visit 2 if the results of 
the previous PSG and MWT meet the current inclusion/exclusion criteria and there have been no changes to 
medical history or concomitant medications that would likely affect the MWT results.
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Appendix 3 
Cataplexy Frequency Diary 
To be completed in the evening 
Cataplexy Diary 
Subject Number/Initials 
Week(s) of Treatment: 
Day 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Date: 
 
 
 
 
 
 
 
Number of 
Cataplectic 
Episodes 
 
 
 
 
 
 
 
Date: 
 
 
 
 
 
 
 
Number of 
Cataplectic 
Episodes 
 
 
 
 
 
 
 
Date: 
 
 
 
 
 
 
 
Number of 
Cataplectic 
Episodes 
 
 
 
 
 
 
 
Date: 
 
 
 
 
 
 
 
Number of 
Cataplectic 
Episodes 
 
 
 
 
 
 
 
Date: 
 
 
 
 
 
 
 
Number of 
Cataplectic 
Episodes 
 
 
 
 
 
 
 
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Appendix 4 
DSM-5 Criteria for Psychiatric Disorders 
The following selected psychiatric DSM-5 criteria are presented as a resource, if needed 
when screening subjects. The full DSM Edition 5 (DSM-5) criteria for psychiatric conditions 
should be consulted for diagnoses not listed here. 
Bipolar and Related Disorders 
Bipolar I Disorder 
For a diagnosis of bipolar I disorder, it is necessary to meet the following criteria for a manic 
episode. The manic episode may have been preceded by and may be followed by hypomanic 
or major depressive episodes. 
Manic Episode 
A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood 
and abnormally and persistently increased goal-directed activity or energy, lasting at 
least 1 week and present most of the day, nearly every day (or any duration if 
hospitalization is necessary). 
B. During the period of mood disturbance and increased energy or activity, three (or more) 
of the following symptoms (four if the mood is only irritable) are present to a significant 
degree and represent a noticeable change from usual behavior: 
1. Inflated self-esteem or grandiosity. 
2. Decreased need for sleep (e.g., feels rested after only 3 hours of sleep). 
3. More talkative than usual or pressure to keep talking. 
4. Flight of ideas or subjective experience that thoughts are racing. 
5. Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external 
stimuli), as reported or observed. 
6. Increase in goal-directed activity (either socially, at work or school, or sexually) or 
psychomotor agitation (i.e., purposeless non-goal-directed activity). 
7. Excessive involvement in activities that have a high potential for painful 
consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or 
foolish business investments). 
C. The mood disturbance is sufficiently severe to cause marked impairment in social or 
occupational functioning or to necessitate hospitalization to prevent harm to self or 
others, or there are psychotic features. 
D. The episode is not attributable to the physiological effects of a substance (e.g., a drug of 
abuse, a medication, other treatment) or to another medical condition. 
 
Hypomanic Episode 
A. A distinct period of abnormally and persistently elevated, expansive, or irritable 
mood and abnormally and persistently increased activity or energy, lasting at least 4 
consecutive days and present most of the day, nearly every day. 
B. During the period of mood disturbance and increased energy and activity, three (or 
more) of the following symptoms (four if the mood is only irritable) have persisted, 
represent a noticeable change from usual behavior, and have been present to a 
significant degree: 
1. Inflated self-esteem or grandiosity. 
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2. Decreased need for sleep (e.g., feels rested after only 3 hours of sleep). 
3. More talkative than usual or pressure to keep talking. 
4. Flight of ideas or subjective experience that thoughts are racing. 
5. Distractibility (i.e., attention too easily drawn to unimportant or irrelevant 
external stimuli), as reported or observed. 
6. Increase in goal-directed activity (either socially, at work or school, or 
sexually) or psychomotor agitation. 
7. Excessive involvement in activities that have a high potential for painful 
consequences (e.g., engaging in unrestrained buying sprees, sexual 
indiscretions, or foolish business investments). 
C. The episode is associated with an unequivocal change in functioning that is 
uncharacteristic of the individual when not symptomatic. 
D. The disturbance in mood and the change in functioning are observable by others. 
E. The episode is not severe enough to cause marked impairment in social or 
occupational functioning or to necessitate hospitalization. If there are psychotic 
features, the episode is, by definition, manic. 
F. The episode is not attributable to the physiological effects of a substance (e.g., a drug 
of abuse, a medication, other treatment). 
 
Major Depressive Episode 
A. Five (or more) of the following symptoms have been present during the same 2-week 
period and represent a change from previous functioning; at least one of the 
symptoms is either (1) depressed mood or (2) loss of interest or pleasure. 
1. Depressed mood most of the day, nearly every day, as indicated by either 
subjective report (e.g., feels sad, empty, or hopeless) or observation made by 
others (e.g., appears tearful). (Note: In children and adolescents, can be 
irritable mood.) 
2. Markedly diminished interest or pleasure in all, or almost all, activities most 
of the day, nearly every day (as indicated by either subjective account or 
observation). 
3. Significant weight loss when not dieting or weight gain (e.g., a change of 
more than 5% of body weight in a month), or decrease or increase in appetite 
nearly every day. (Note: In children, consider failure to make expected weight 
gain.) 
4. Insomnia or hypersomnia nearly every day. 
5. Psychomotor agitation or retardation nearly every day (observable by others; 
not merely subjective feelings of restlessness or being slowed down). 
6. Fatigue or loss of energy nearly every day. 
7. Feelings of worthlessness or excessive or inappropriate guilt (which may be 
delusional) nearly every day (not merely self-reproach or guilt about being 
sick). 
8. Diminished ability to think or concentrate, or indecisiveness, nearly every day 
(either by subjective account or as observed by others). 
9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation 
without a specific plan, or a suicide attempt or a specific plan for committing 
suicide. 
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B. The symptoms cause clinically significant distress or impairment in social, 
occupational, or other important areas of functioning. 
C. The episode is not attributable to the physiological effects of a substance or another 
medical condition.  
 
Bipolar I Disorder 
A. Criteria have been met for at least one manic episode (Criteria A–D under “Manic 
Episode” above). 
B. The occurrence of the manic and major depressive episode(s) is not better explained 
by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional 
disorder, or other specified or unspecified schizophrenia spectrum and other 
psychotic disorder. 
Bipolar II Disorder 
Diagnostic Criteria 
For a diagnosis of bipolar II disorder, it is necessary to meet the following criteria for a 
current or past hypomanic episode and the following criteria for a current or past major 
depressive episode: 
Hypomanic Episode 
A. A distinct period of abnormally and persistently elevated, expansive, or irritable 
mood and abnormally and persistently increased activity or energy, lasting at least 4 
consecutive days and present most of the day, nearly every day. 
B. During the period of mood disturbance and increased energy and activity, three (or 
more) of the following symptoms have persisted (four if the mood is only irritable), 
represent a noticeable change from usual behavior, and have been present to a 
significant degree: 
1. Inflated self-esteem or grandiosity. 
2. Decreased need for sleep (e.g., feels rested after only 3 hours of sleep). 
3. More talkative than usual or pressure to keep talking. 
4. Flight of ideas or subjective experience that thoughts are racing. 
5. Distractibility (i.e., attention too easily drawn to unimportant or irrelevant 
external stimuli), as reported or observed. 
6. Increase in goal-directed activity (either socially, at work or school, or 
sexually) or psychomotor agitation. 
7. Excessive involvement in activities that have a high potential for painful 
consequences (e.g., engaging in unrestrained buying sprees, sexual 
indiscretions, or foolish business investments). 
C. The episode is associated with an unequivocal change in functioning that is 
uncharacteristic of the individual when not symptomatic.  
D. The disturbance in mood and the change in functioning are observable by others. 
E. The episode is not severe enough to cause marked impairment in social or 
occupational functioning or to necessitate hospitalization. If there are psychotic 
features, the episode is, by definition, manic. 
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F. The episode is not attributable to the physiological effects of a substance (e.g., a drug 
of abuse, a medication or other treatment). 
 
Major Depressive Episode 
A. Five (or more) of the following symptoms have been present during the same 2-week 
period and represent a change from previous functioning; at least one of the 
symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Note: Do 
not include symptoms that are clearly attributable to a medical condition. 
1. Depressed mood most of the day, nearly every day, as indicated by either 
subjective report (e.g., feels sad, empty, or hopeless) or observation made by 
others (e.g., appears tearful). (Note: In children and adolescents, can be 
irritable mood.) 
2. Markedly diminished interest or pleasure in all, or almost all, activities most 
of the day, nearly every day (as indicated by either subjective account or 
observation). 
3. Significant weight loss when not dieting or weight gain (e.g., a change of 
more than 5% of body weight in a month), or decrease or increase in appetite 
nearly every day. (Note: In children, consider failure to make expected weight 
gain.) 
4. Insomnia or hypersomnia nearly every day. 
5. Psychomotor agitation or retardation nearly every day (observable by others; 
not merely subjective feelings of restlessness or being slowed down). 
6. Fatigue or loss of energy nearly every day. 
7. Feelings of worthlessness or excessive or inappropriate guilt (which may be 
delusional) nearly every day (not merely self-reproach or guilt about being 
sick). 
8. Diminished ability to think or concentrate, or indecisiveness, nearly every day 
(either by subjective account or as observed by others). 
9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation 
without a specific plan, a suicide attempt, or a specific plan for committing 
suicide. 
B. The symptoms cause clinically significant distress or impairment in social, 
occupational, or other important areas of functioning.  
C. The episode is not attributable to the physiological effects of a substance or another 
medical condition. 
Bipolar II Disorder 
A. Criteria have been met for at least one hypomanic episode (Criteria A–F under 
“Hypomanic Episode” above) and at least one major depressive episode (Criteria A–
C under “Major Depressive Episode” above). 
B. There has never been a manic episode. 
C. The occurrence of the hypomanic episode(s) and major depressive episode(s) is not 
better explained by schizoaffective disorder, schizophrenia, schizophreniform 
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disorder, delusional disorder, or other specified or unspecified schizophrenia 
spectrum and other psychotic disorder. 
D. The symptoms of depression or the unpredictability caused by frequent alternation 
between periods of depression and hypomania causes clinically significant distress or 
impairment in social, occupational, or other important areas of functioning. 
Schizophrenia Spectrum and Other Psychotic Disorders 
Delusional Disorder 
Diagnostic Criteria 
A. The presence of one (or more) delusions with a duration of 1 month or longer. 
B. Criterion A for schizophrenia has never been met.  
Note: Hallucinations, if present, are not prominent and are related to the 
delusional theme (e.g., the sensation of being infested with insects associated 
with delusions of infestation). 
C. Apart from the impact of the delusion(s) or its ramifications, functioning is not 
markedly impaired, and behavior is not obviously bizarre or odd. 
D. If manic or major depressive episodes have occurred, these have been brief relative to 
the duration of the delusional periods. 
E. The disturbance is not attributable to the physiological effects of a substance or 
another medical condition and is not better explained by another mental disorder, 
such as body dysmorphic disorder or obsessive-compulsive disorder. 
 
Brief Psychotic Disorder 
Diagnostic Criteria 
A. Presence of one (or more) of the following symptoms. At least one of these must be 
(1), (2), or (3): 
1. Delusions. 
2. Hallucinations. 
3. Disorganized speech (e.g., frequent derailment or incoherence). 
4. Grossly disorganized or catatonic behavior. 
o Note: Do not include a symptom if it is a culturally sanctioned response.  
B. Duration of an episode of the disturbance is at least 1 day but less than 1 month, with 
eventual full return to premorbid level of functioning. 
C. The disturbance is not better explained by major depressive or bipolar disorder with 
psychotic features or another psychotic disorder such as schizophrenia or catatonia, 
and is not attributable to the physiological effects of a substance (e.g., a drug of 
abuse, a medication) or another medical condition. 
 
Schizophreniform Disorder 
Diagnostic Criteria 
A. Two (or more) of the following, each present for a significant portion of time during a 
1-month period (or less if successfully treated). At least one of these must be (1), (2), 
or (3): 
1. Delusions. 
2. Hallucinations. 
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3. Disorganized speech (e.g., frequent derailment or incoherence). 
4. Grossly disorganized or catatonic behavior. 
5. Negative symptoms (i.e., diminished emotional expression or avolition). 
B. An episode of the disorder lasts at least 1 month but less than 6 months. When the 
diagnosis must be made without waiting for recovery, it should be qualified as 
“provisional.” 
C. Schizoaffective disorder and depressive or bipolar disorder with psychotic features 
have been ruled out because either 1) no major depressive or manic episodes have 
occurred concurrently with the active-phase symptoms, or 2) if mood episodes have 
occurred during active-phase symptoms, they have been present for a minority of the 
total duration of the active and residual periods of the illness.  
D. The disturbance is not attributable to the physiological effects of a substance (e.g., a 
drug of abuse, a medication) or another medical condition. 
Schizophrenia 
Diagnostic Criteria 
A. Two (or more) of the following, each present for a significant portion of time during a 
1-month period (or less if successfully treated). At least one of these must be (1), (2), 
or (3): 
1. Delusions. 
2. Hallucinations. 
3. Disorganized speech (e.g., frequent derailment or incoherence). 
4. Grossly disorganized or catatonic behavior. 
5. Negative symptoms (i.e., diminished emotional expression or avolition). 
B. For a significant portion of the time since the onset of the disturbance, level of 
functioning in one or more major areas, such as work, interpersonal relations, or self-
care, is markedly below the level achieved prior to the onset (or when the onset is in 
childhood or adolescence, there is failure to achieve expected level of interpersonal, 
academic, or occupational functioning). 
C. Continuous signs of the disturbance persist for at least 6 months. This 6-month period 
must include at least 1 month of symptoms (or less if successfully treated) that meet 
Criterion A (i.e., active-phase symptoms) and may include periods of prodromal or 
residual symptoms. During these prodromal or residual periods, the signs of the 
disturbance may be manifested by only negative symptoms or by two or more 
symptoms listed in Criterion A present in an attenuated form (e.g., odd beliefs, 
unusual perceptual experiences). 
D. Schizoaffective disorder and depressive or bipolar disorder with psychotic features 
have been ruled out because either 1) no major depressive or manic episodes have 
occurred concurrently with the active-phase symptoms, or 2) if mood episodes have 
occurred during active-phase symptoms, they have been present for a minority of the 
total duration of the active and residual periods of the illness. 
E. The disturbance is not attributable to the physiological effects of a substance (e.g., a 
drug of abuse, a medication) or another medical condition. 
F. If there is a history of autism spectrum disorder or a communication disorder of 
childhood onset, the additional diagnosis of schizophrenia is made only if prominent 
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delusions or hallucinations, in addition to the other required symptoms of 
schizophrenia, are also present for at least 1 month (or less if successfully treated). 
Schizoaffective Disorder 
Diagnostic Criteria 
A. An uninterrupted period of illness during which there is a major mood episode (major 
depressive or manic) concurrent with Criterion A of schizophrenia. 
o Note: The major depressive episode must include Criterion A1: Depressed mood. 
B. Delusions or hallucinations for 2 or more weeks in the absence of a major mood episode 
(depressive or manic) during the lifetime duration of the illness.  
C. Symptoms that meet criteria for a major mood episode are present for the majority of the 
total duration of the active and residual portions of the illness. 
D. The disturbance is not attributable to the effects of a substance (e.g., a drug of abuse, a 
medication) or another medical condition. 
 
American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental 
Disorders (5th ed.). Washington, DC. 
 
 
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Appendix 5 
DSM-5 Substance Use Disorder Diagnostic Criteria 
The following criteria are adapted from the DSM-5 criteria for substance use disorders and 
are presented as a resource, if needed for screening subjects. The full DSM Edition 5 
(DSM-5) criteria for substance use disorders should be consulted for further information. 
 
A. A pattern of ________use leading to clinically significant impairment or distress, as 
manifested by at least two of the following, occurring within a 12-month period: 
1. The _______ is often taken in larger amounts or over a longer period than was 
intended. 
2. There is a persistent desire or unsuccessful efforts to cut down or control _______ 
use. 
3. A great deal of time is spent in activities necessary to obtain the _______ use the 
_______, or recover from its effects. 
4. Craving, or a strong desire or urge to use the _______. 
5. Recurrent _______ use resulting in a failure to fulfill major role obligations at work, 
school, or home. 
6. Continued _______ use despite having persistent or recurrent social or interpersonal 
problems caused or exacerbated by the effects of the _______. 
7. Important social, occupational, or recreational activities are given up or reduced 
because of _______ use. 
8. Recurrent _______ use in situations in which it is physically hazardous. 
9. _______ use is continued despite knowledge of having a persistent or recurrent 
physical or psychological problem that is likely to have been caused or exacerbated 
by the _______. 
10. Tolerance, as defined by either of the following: 
a. A need for markedly increased amounts of the _______ to achieve intoxication or 
desired effect. 
b. A markedly diminished effect with continued use of the same amount of the 
_______. 
Note: This criterion is not considered to be met for those taking _______ medications under 
appropriate medical supervision.  
11. Withdrawal, as manifested by either of the following:  
a. The characteristic withdrawal syndrome for the _______ (refer to Criteria A and 
B of the criteria set for _______withdrawal – see full DSM-5 criteria). 
b. The _______ (or a closely related substance) is taken to relieve or avoid 
withdrawal symptoms. 
Severity: 
 
Mild: Presence of 2–3 symptoms. 
 
Moderate: Presence of 4–5 symptoms. 
 
Severe: Presence of 6 or more symptoms. 
 
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental 
disorders (5th ed.). Washington, DC. 
 
 
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Appendix 6 
Epworth Sleepiness Scale (ESS) 
 
 
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Epworth Sleepiness Scale 
 
 
 
Name:   
 Today’s date:   
 
 
Your age (Yrs):   
 Your  sex (Male = M, Female = F):   
 
 
 
 
How likely are you to doze off or fall asleep in the following situations, in contrast to feeling just 
tired? 
 
This refers to your usual way of life in the past week. 
 
Even if you haven’t done some of these things recently try to work out how they would have affected 
you. 
 
Use the following scale to choose the most appropriate number for each situation: 
 
0  =  would never doze 
1  =  slight chance of dozing 
2  =  moderate chance of dozing 
3  =  high chance of dozing 
 
It is important that you answer each question as best you can. 
 
Situation  
Chance of Dozing (0-3) 
 
 
 
Sitting and reading 
  
 
 
Watching TV 
  
 
 
Sitting, inactive in a public place (e.g. a theatre or a meeting) 
  
 
 
As a passenger in a car for an hour without a break 
  
 
 
Lying down to rest in the afternoon when circumstances permit     
 
 
Sitting and talking to someone     
 
 
Sitting quietly after a lunch without alcohol     
 
 
In a car, while stopped for a few minutes in the traffic    
 
 
 
 
 
THANK YOU FOR YOUR COOPERATION 
 
 M.W. Johns 1990-
97 
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Appendix 7 
Functional Outcomes of Sleep Questionnaire Short 
Version (FOSQ-10) 
 
 
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©Weaver, June, 2004 
fosq.97 updated 6/04 
Functional Outcomes of Sleep Questionnaire (FOSQ ) short 
Page 1 
FUNCTIONAL OUTCOMES OF SLEEP QUESTIONNAIRE 
(FOSQ) 
Some people have difficulty performing everyday activities when they feel tired or sleepy.  The 
purpose of this questionnaire is to find out if you generally have difficulty carrying out certain 
activities because you are too sleepy or tired.  In this questionnaire, when the words “sleepy” or 
“tired” are used, it means the feeling that you can’t keep your eyes open, your head is droopy, 
that you want to “nod off”, or that you feel the urge to take a nap.  These words do not refer to 
the tired or fatigued feeling you may have after you have exercised. 
DIRECTIONS: Please put a (X) in the box for your answer to each question.  Select only one 
answer for each question.  Please try to be as accurate as possible.  All information will be kept 
confidential.  
(0) 
I don’t do 
this 
activity 
for other 
reasons 
(4) 
No 
difficulty 
 (3) 
Yes, 
a little 
difficulty 
(2) 
Yes, 
moderate 
difficulty 
(1) 
Yes, 
extreme 
difficulty 
1. Do you have difficulty concentrating on the
things you do because you are sleepy or tired? 
! 
! 
! 
!
2. Do you generally have difficulty
remembering things, because you are sleepy or 
tired? 
! 
! 
! 
!
3. Do you have difficulty operating a motor
vehicle for short distances (less than 100 miles) 
because you become sleepy or tired? 
! 
! 
! 
! 
!
4. Do you have difficulty operating a motor
vehicle for long distances (greater than 100  
miles) because you become sleepy or tired? 
! 
! 
! 
! 
!
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Functional Outcomes of Sleep Questionnaire (FOSQ ) short 
Page 2 
(0) 
I don’t do this 
activity for 
other reasons 
(4) 
No 
difficulty 
 (3) 
Yes, 
a little 
difficulty 
(2) 
Yes, 
moderate 
difficulty 
(1) 
Yes, 
extreme 
difficulty 
5. Do you have difficulty visiting with your
family or friends in their home because you 
become sleepy or tired? 
! 
! 
! 
! 
!
6. Has your relationship with family, friends
or work colleagues been affected because you 
are sleepy or tired?
! 
! 
! 
!
!
7. Do you have difficulty watching a movie
or videotape because you become sleepy or 
tired? 
! 
! 
! 
! 
!
8. Do you have difficulty being as active as
you want to be in the evening because you are 
sleepy or tired? 
! 
! 
! 
!
9. Do you have difficulty being as
active as you want to be in the morning 
because you are sleepy or tired? 
! 
! 
! 
!
(0) 
I don’t 
engage in 
sexual 
activity for 
other reasons 
(4) 
No 
(3) 
Yes, 
a 
little 
(2) 
Yes, 
moderately 
(1) 
Yes, 
extremely 
10. Has your desire for intimacy or sex
been affected because you are sleepy or tired? 
!
! 
! 
! 
!
Thank you for completing this questionnaire.
CONFIDENTIAL
Page 93 of 121


Signature Date: 20160210
JP: Protocol 14-002 Amendment 3.pdf
Signature Date:
JP: Protocol 14-002 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-002 Amendment 3  
 
 
 
 
 
 
CONFIDENTIAL 
Page 91 of 101 
 
Appendix 8 
36-Item Short Form Health Survey Version 2 (SF-36v2) 
 
 
 
 
CONFIDENTIAL
Page 94 of 121


Signature Date: 20160210
JP: Protocol 14-002 Amendment 3.pdf
Signature Date:
JP: Protocol 14-002 Amendment 3.pdf
 
SF-36v2™ Health Survey  1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
 
Your Health and Well-Being 
 
 
This survey asks for your views about your health.  This information will help 
keep track of how you feel and how well you are able to do your usual 
activities.  Thank you for completing this survey! 
For each of the following questions, please mark an 
 in the one box that best 
describes your answer. 
1. In general, would you say your health is: 
 
Excellent 
Very good 
Good 
Fair 
Poor 
 
 
 
 
 
  
1 
 
2 
 
3 
 
4 
 
5 
 
2. Compared to one year ago, how would you rate your health in general 
 
now? 
 
Much better 
now than one 
year ago 
Somewhat 
better now 
than one year 
ago 
About the 
same as one 
year ago 
Somewhat 
worse now 
than one year 
ago 
Much worse 
now than one 
year ago 
 
 
 
 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
CONFIDENTIAL
Page 95 of 121


Signature Date: 20160210
JP: Protocol 14-002 Amendment 3.pdf
Signature Date:
JP: Protocol 14-002 Amendment 3.pdf
 
SF-36v2™ Health Survey  1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
 
 
 
3. The following questions are about activities you might do during a typical 
day.  Does your health now limit you in these activities?  If so, how much? 
 
Yes, 
limited 
a lot 
Yes, 
limited 
a little 
No, not 
limited 
at all 
 
 
 
 
a  Vigorous activities, such as running, lifting  
 heavy objects, participating in strenuous  
 sports ....................................................................
1...................
2 ..................
3 
 
b   Moderate activities, such as moving a table,  
  pushing a vacuum cleaner, bowling, or  
 playing golf ...........................................................
1...................
2 ..................
3 
 
c   Lifting or carrying groceries ..................................
1...................
2 ..................
3 
 
d  Climbing several flights of stairs............................
1...................
2 ..................
3 
 
e  Climbing one flight of stairs...................................
1...................
2 ..................
3 
 
f  Bending, kneeling, or stooping...............................
1...................
2 ..................
3 
 
g Walking more than a mile ......................................
1...................
2 ..................
3
 
h Walking several hundred yards..............................
1...................
2 ..................
3
 
i Walking one hundred yards ....................................
1...................
2 ..................
3
 
j  Bathing or dressing yourself...................................
1...................
2 ..................
3
 
CONFIDENTIAL
Page 96 of 121


Signature Date: 20160210
JP: Protocol 14-002 Amendment 3.pdf
Signature Date:
JP: Protocol 14-002 Amendment 3.pdf
 
SF-36v2™ Health Survey  1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
 
4. During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of your physical health? 
 
 
All of 
the time
Most of 
the time
Some of 
the time 
A little 
of the 
time 
None of 
the time
 
 
 
 
 
a  Cut down on the amount of time you spent  
on work or other activities.......................................
1.........
2........
3.........
4.........
5 
b  Accomplished less than you would like .................
1.........
2........
3.........
4.........
5 
 
c  Were limited in the kind of work or other  
    activities.................................................................
1.........
2........
3.........
4.........
5 
d  Had difficulty performing the work or other  
  activities (for example, it took extra effort) ...........
1.........
2........
3.........
4.........
5 
 
5. During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of any emotional problems (such as feeling depressed or anxious)? 
 
All of 
the time
Most of 
the time
Some of 
the time 
A little 
of the 
time 
None of 
the time
 
 
 
 
 
 
a  Cut down on the amount of time you spent  
 on work or other activities ....................................
1 .........
2 ........
3..........
4.........
5 
b  Accomplished less than you would like................
1 .........
2 ........
3..........
4.........
5 
 
c  Did work or other activities less carefully  
 than usual...............................................................
1 .........
2 ........
3..........
4.........
5 
 
CONFIDENTIAL
Page 97 of 121


Signature Date: 20160210
JP: Protocol 14-002 Amendment 3.pdf
Signature Date:
JP: Protocol 14-002 Amendment 3.pdf
 
SF-36v2™ Health Survey  1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
6. During the past 4 weeks, to what extent has your physical health or 
emotional problems interfered with your normal social activities with 
family, friends, neighbors, or groups? 
Not at all 
Slightly 
Moderately 
Quite a bit 
Extremely 
 
 
 
 
 
 
1 
 
2 
 
3 
  
4 
 
5 
 
7. How much bodily pain have you had during the past 4 weeks? 
None 
Very mild 
Mild 
Moderate 
Severe 
Very Severe 
 
 
 
 
 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
8. During the past 4 weeks, how much did pain interfere with your normal 
work (including both work outside the home and housework)? 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 
 
 
 
 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
CONFIDENTIAL
Page 98 of 121


Signature Date: 20160210
JP: Protocol 14-002 Amendment 3.pdf
Signature Date:
JP: Protocol 14-002 Amendment 3.pdf
 
SF-36v2™ Health Survey  1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
 
9. These questions are about how you feel and how things have been with you 
during the past 4 weeks.  For each question, please give the one answer that 
comes closest to the way you have been feeling.  How much of the time 
during the past 4 weeks... 
 
All of 
the time
Most of 
the time
Some of 
the time 
A little 
of the 
time 
None of 
the time
 
 
 
 
 
 
 
a   Did you feel full of life? ......................................
1..........
2 ..........
3..........
4 ..........
5
b  Have you been very nervous?..............................
1..........
2 ..........
3..........
4 ..........
5
 
c  Have you felt so down in the dumps  
 that nothing could cheer you up? .........................
1..........
2 ..........
3..........
4 ..........
5
d  Have you felt calm and peaceful?........................
1..........
2 ..........
3..........
4 ..........
5
 
e  Did you have a lot of energy?..............................
1..........
2 ..........
3..........
4 ..........
5
 
f  Have you felt downhearted and  
 depressed?............................................................
1..........
2 ..........
3..........
4 ..........
5
 
g  Did you feel worn out? ........................................
1..........
2 ..........
3..........
4 ..........
5
 
h  Have you been happy?.........................................
1..........
2 ..........
3..........
4 ..........
5
 
i  Did you feel tired?................................................
1..........
2 ..........
3..........
4 ..........
5
 
 
10.  During the past 4 weeks, how much of the time has your physical health  
or emotional problems interfered with your social activities (like visiting 
friends, relatives, etc.)? 
All of the 
time 
Most of the 
time 
Some of the 
time 
A little of the 
time 
None of the 
time 
 
 
 
 
 
 
1 
 
2 
 
3 
  
4 
 
5 
 
CONFIDENTIAL
Page 99 of 121


Signature Date: 20160210
JP: Protocol 14-002 Amendment 3.pdf
Signature Date:
JP: Protocol 14-002 Amendment 3.pdf
 
SF-36v2™ Health Survey  1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
11.   How TRUE or FALSE is each of the following statements for you? 
 
Definitely 
true 
Mostly 
true 
Don't 
know 
Mostly 
false 
Definitely 
false 
 
 
 
 
 
 
a  I seem to get sick a little easier  
 than other people....................................
1............
2 ...........
3 ...........
4 ...........
5 
b  I am as healthy as anybody I know........
1............
2 ...........
3 ...........
4 ...........
5 
c  I expect my health to get worse .............
1............
2 ...........
3 ...........
4 ...........
5 
d  My health is excellent............................
1............
2 ...........
3 ...........
4 ...........
5
 
 
THANK YOU FOR COMPLETING THESE QUESTIONS! 
 
CONFIDENTIAL
Page 100 of 121


Signature Date: 20160210
JP: Protocol 14-002 Amendment 3.pdf
Signature Date:
JP: Protocol 14-002 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-002 Amendment 3  
 
 
 
 
 
 
CONFIDENTIAL 
Page 92 of 101 
 
Appendix 9 
EuroQoL EQ-5D-5L 
The version attached is an example. The US English language version will be used in the US.  
 
 
CONFIDENTIAL
Page 101 of 121


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CONFIDENTIAL
Page 102 of 121


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CONFIDENTIAL
Page 103 of 121


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CONFIDENTIAL
Page 104 of 121


Signature Date: 20160210
JP: Protocol 14-002 Amendment 3.pdf
Signature Date:
JP: Protocol 14-002 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-002 Amendment 3  
 
 
 
 
 
 
CONFIDENTIAL 
Page 93 of 101 
 
Appendix 10 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Baseline/Screening Version 
 
 
 
CONFIDENTIAL
Page 105 of 121


Signature Date: 20160210
JP: Protocol 14-002 Amendment 3.pdf
Signature Date:
JP: Protocol 14-002 Amendment 3.pdf
 
 
 
 
 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS)  
Baseline/Screening Version 
Version 1/14/09 
 
  
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained in 
the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of suicidal 
ideation or behavior depends on the judgment of the individual administering the scale. 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History Form, 
developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
CONFIDENTIAL
Page 106 of 121


Signature Date: 20160210
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Signature Date:
JP: Protocol 14-002 Amendment 3.pdf
SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to 
question 2 is “yes”, ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete 
“Intensity of Ideation” section below. 
Lifetime: Time 
He/She Felt 
Most Suicidal 
Past __ 
Months 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
If yes, describe: 
 
Yes       No 
□    □ 
 
Yes     No 
□   □ 
2.  Non-Specific Active Suicidal Thoughts 
General non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts 
of ways to kill oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
    Yes       No 
   □    □ 
 
Yes     No 
□   □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a 
specific plan with time, place or method details worked out (e.g.  thought of method to kill self but not a specific plan).  Includes person 
who would say, “I thought about taking an overdose but I never made a specific plan as to when, where or how I would actually do 
it…and I would never go through with it.” 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 
    Yes      No 
 □    □ 
 
Yes     No 
□   □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the 
thoughts but I definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
 
If yes, describe: 
 
 
   Yes      No 
□    □ 
 
Yes     No 
□   □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
   
If yes, describe: 
 
 
   Yes       No 
 □    □ 
 
Yes     No 
□   □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being 
the least severe and 5 being the most severe).  Ask about time he/she was feeling the most suicidal.  
                                   
Lifetime -           Most Severe Ideation:  _______                  ________________________________________ 
                                                                       Type # (1-5)                                                 Description of  Ideation 
 
Past X Months - Most Severe Ideation:  _______                   ________________________________________ 
                                                                      Type # (1-5)                                                 Description of  Ideation 
Most  
Severe 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
 
 
____ 
 
 
____ 
Duration 
When you have the thoughts how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time 
____ 
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts  with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to 
die or acting on thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
____ 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain 
or stop the way you were feeling (in other words you couldn’t go on living with this pain or how you were 
feeling) or was it to get attention, revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain                                                                         living with the pain or  how you were feeling) 
                                                                                                                 (0)  Does not apply 
 
 
____ 
 
 
____ 
 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Baseline/Screening (Version 1/14/09)    
 
 
                             Page 1 of 2     
CONFIDENTIAL
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Signature Date: 20160210
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SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
 
Lifetime 
Past __ 
Years 
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill 
oneself. Intent does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide 
attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in 
mouth but gun is broken so no injury results, this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a 
highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a 
high floor/story). Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or Did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better,  
get sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes     No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
□   □ 
Yes     No 
□   □ 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would 
have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted 
attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once 
they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. 
Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before 
you actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
 
Total # of 
interrupted 
 
______ 
 
Yes     No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-
destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by 
something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
aborted 
 
______ 
Yes     No 
□   □ 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as 
assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a 
suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, 
getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
 
Yes      No 
□   □ 
 
 
Yes     No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Yes     No 
□   □ 
Answer for Actual Attempts Only 
Most Recent 
Attempt 
Date: 
Most Lethal        
Attempt 
Date: 
Initial/First 
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes 
intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree 
burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had 
potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying 
on train tracks with oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Baseline/Screening (Version 1/14/09)    
 
 
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Signature Date:
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JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-002 Amendment 3  
 
 
 
 
 
 
CONFIDENTIAL 
Page 94 of 101 
 
Appendix 11 
Work Productivity and Activity Impairment 
Questionnaire: Specific Health Problem V2.0 
(WPAI:SHP)  
 
 
 
 
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Work Productivity and Activity Impairment Questionnaire: 
Specific Health Problem V2.0 (WPAI:SHP) 
 
 
 
The following questions ask about the effect of your narcolepsy on your ability to work 
and perform regular activities.  Please fill in the blanks or circle a number, as indicated. 
 
1. 
 Are you currently employed (working for pay)?  _____ NO ___ YES 
  If NO, check “NO” and skip to question 6. 
The next questions are about the past seven days, not including today. 
 
 
2. During the past seven days, how many hours did you miss from work because of 
problems associated with your narcolepsy?  Include hours you missed on sick days, 
times you went in late, left early, etc., because of your narcolepsy.  Do not include 
time you missed to participate in this study. 
 
_____ HOURS 
 
 
3. During the past seven days, how many hours did you miss from work because of 
any other reason, such as vacation, holidays, time off to participate in this study? 
 
_____HOURS 
 
 
4. During the past seven days, how many hours did you actually work? 
 
_____HOURS  (If “0”, skip to question 6.) 
 
 
 
 
 
 
 
 
 
 
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Reilly MC, Zbrozek AS, Dukes E: The validity and reproducibility of a work productivity and activity impairment measure.  
PharmacoEconomics 1993; 4(5):353-365. 
 
2
 
 
 
5. During the past seven days, how much did your narcolepsy affect your productivity 
while you were working?   
 
Think about days you were limited in the amount or kind of work you could do, days 
you accomplished less than you would like, or days you could not do your work as 
carefully as usual.  If narcolepsy affected your work only a little, choose a low 
number.  Choose a high number if narcolepsy affected your work a great deal.   
Consider only how much narcolepsy affected  
productivity while you were working. 
narcolepsy had 
no effect on my 
work 
 
 
 
 
 
 
 
 
 
 
 
narcolepsy 
completely 
prevented me 
from working 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CIRCLE A NUMBER 
 
6. During the past seven days, how much did your narcolepsy affect your ability to do 
your regular daily activities, other than work at a job?   
 
By regular activities, we mean the usual activities you do, such as work around the 
house, shopping, childcare, exercising, studying, etc.  Think about times you were 
limited in the amount or kind of activities you could do and times you accomplished 
less than you would like.  If narcolepsy affected your activities only a little, choose a 
low number.  Choose a high number if narcolepsy affected your activities a great 
deal.   
 
Consider only how much narcolepsy affected your ability  
to do your regular daily activities, other than work at a job. 
narcolepsy had 
no effect on my 
daily activities 
 
 
 
 
 
 
 
 
 
 
 
narcolepsy 
completely 
prevented me 
from doing my 
daily activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
                           
CIRCLE A NUMBER 
 
WPAI:SHP  V2.0 (US English)      
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Signature Date:
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JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-002 Amendment 3  
 
 
 
 
 
 
CONFIDENTIAL 
Page 95 of 101 
 
Appendix 12 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Since Last Visit Version 
 
 
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Signature Date:
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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 
 
 
 
 
____ 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Since Last Visit (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 
 
 
 
______ 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Since Last Visit (Version 1/14/09)    
 
 
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Signature Date: 20160210
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Signature Date:
JP: Protocol 14-002 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-002 Amendment 3  
 
 
 
 
 
 
CONFIDENTIAL 
Page 96 of 101 
 
Appendix 13 
Clinical Global Impression of Severity (CGIs) 
 
Check if Not Done □ 
(Choose only one) 
 
CGI – SEVERITY 
Considering your total clinical experience with this patient population, how ill is the patient at this 
time? 
 
□  
1. Normal, not at all ill 
□  
2. Borderline ill 
□  
3. Mildly ill 
□  
4. Moderately ill 
□  
5. Markedly ill 
□  
6. Severely ill 
□  
7. Among the most extremely ill patients 
 
 
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Signature Date: 20160210
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Signature Date:
JP: Protocol 14-002 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-002 Amendment 3  
 
 
 
 
 
 
CONFIDENTIAL 
Page 97 of 101 
 
Appendix 14 
Clinical Global Impression of Change (CGIc) 
 
Check if Not Done □ 
CGI – CHANGE 
Compared to the subject’s condition at BASELINE,  
how much has he/she  changed?  
(Choose only one) 
 
□  1. Very much improved 
□  2. Much improved 
□  3. Minimally improved 
□  4. No change 
□  5. Minimally worse 
□  6. Much worse 
□  7. Very much worse 
CONFIDENTIAL
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Signature Date:
JP: Protocol 14-002 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-002 Amendment 3  
 
 
 
 
 
 
CONFIDENTIAL 
Page 98 of 101 
 
Appendix 15 
Patient Global Impression of Change (PGIc) 
 
Check if Not Done □ 
PGI – CHANGE 
 (Choose only one) 
Since you STARTED study treatment, your OVERALL condition is:  
 
 
□  
1. Very much improved 
□  
2. Much improved 
□  
3. Minimally improved 
□  
4. No change 
□  
5. Minimally worse 
□  
6. Much worse 
□  
7. Very much worse 
 
 
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Signature Date: 20160210
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Signature Date:
JP: Protocol 14-002 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-002 Amendment 3  
 
 
 
 
 
 
CONFIDENTIAL 
Page 99 of 101 
 
Appendix 16 
Diagnostic Criteria for Narcolepsy 
ICSD-3 Diagnostic Criteria for Narcolepsy 
Narcolepsy Type 1 
Criteria A and B must be met: 
A. The patient has daily periods of irrepressible need to sleep or daytime lapses into 
sleep occurring for at least three months. 
B. The presence of one or both of the following: 
1. Cataplexy (as defined under Essential Features) 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 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. 
Note 
If narcolepsy type I is strongly suspected clinically but the MSLT criteria of B1 are 
not met, a possible strategy is to repeat the MSLT. 
 
Narcolepsy Type 2 
Criteria A-E must be met 
A. The patient has daily periods of irrepressible need to sleep or daytime lapses into 
sleep occurring for at least three months.  
B. A mean sleep latency of ≤ 8 minutes and two or more sleep onset REM periods 
(SOREMPs) are found on a MSLT performed according to standard techniques. A 
SOREMP (within 15 minutes of sleep onset) on the preceding nocturnal 
polysomnogram may replace one of the SOREMPs on the MSLT. 
C. Cataplexy is absent. 
 D. Either CSF hypocretin-1 concentration has not been measured or 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.2 
E. The hypersomnolence and/or MSLT findings are not better explained by other causes 
such as insufficient sleep, obstructive sleep apnea, delayed sleep phase disorder, or 
the effect of medication or substances or their withdrawal. 
Notes 
1. If cataplexy develops later, then the disorder should be reclassified as narcolepsy type 1. 
2. If the CSF Hcrt-1 concentration is tested at a later stage and found to be either ≤ 110 
pg/mL or < 1/3 of mean values obtained in normal subjects with the same assay, then the 
disorder should be reclassified as narcolepsy type 1. 
American Academy of Sleep Medicine (AASM). Central disorders of hypersomnolence. In: 
International Classification of Sleep Disorders-Third Edition (ICSD-3), Darien, IL. American 
Academy of Sleep Medicine, 2014:146, 155. 
 
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Signature Date:
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JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-002 Amendment 3  
 
 
 
 
 
 
CONFIDENTIAL 
Page 100 of 101 
 
DSM-5 Diagnostic Criteria for Narcolepsy 
A. Recurrent periods of an irrepressible need to sleep, lapsing into sleep, or napping 
occurring within the same day. These must have been occurring at least three times 
per week over the past 3 months.  
B. The presence of at least one of the following: 
1. Episodes of cataplexy, defined as either (a) or (b), occurring at least a few times per 
month:  
a. In individuals with long-standing disease, brief (seconds to minutes) episodes of 
sudden bilateral loss of muscle tone with maintained consciousness that are 
precipitated by laughter or joking. 
b. In children or in individuals within 6 months of onset, spontaneous grimaces or 
jaw-opening episodes with tongue thrusting or a global hypotonia, without any 
obvious emotional triggers. 
2. Hypocretin deficiency, as measured using cerebrospinal fluid (CSF) hypocretin-1 
immunoreactivity values (less than or equal to one-third of values obtained in healthy 
subjects tested using the same assay, or less than or equal to 110 pg/mL). Low CSF 
levels of hypocretin-1 must not be observed in the context of acute brain injury, 
inflammation, or infection. 
3. Nocturnal sleep polysomnography showing rapid eye movement (REM) sleep latency 
less than or equal to 15 minutes, or a multiple sleep latency test showing a mean sleep 
latency less than or equal to 8 minutes and two or more sleep-onset REM periods. 
American Psychiatric Association. (2013) Diagnostic and Statistical Manual of Mental 
Disorders (5th ed.), Washington DC: 372-373. 
 
 
 
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Signature Date: 20160210
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Signature Date:
JP: Protocol 14-002 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-002 Amendment 3  
 
 
 
 
 
 
CONFIDENTIAL 
Page 101 of 101 
 
Appendix 17 
Signatures of Agreement for Protocol 
Study Title: 
A Twelve-week, Double-blind, Placebo-controlled, Randomized, 
Parallel-group, Multicenter Study of the Safety and Efficacy of 
JZP-110 [(R)-2-amino-3-phenylpropylcarbamate hydrochloride] in 
the Treatment of Excessive Sleepiness in Subjects with Narcolepsy 
Study Number: 
14-002 
Original Protocol: 
18 December 2014 
Amendment 1: 
18 February 2015 
Amendment 2: 
Amendment 3: 
10 September 2015 
08 February 2016 
This clinical study protocol was subject to critical review and has been approved by Jazz 
Pharmaceuticals.  
 
Signed:  {Please see appended electronic signature page}  
Date: 
 
 
 
 
Signed:  {Please see appended electronic signature page}  
Date: 
 
 
 
Signed:  {Please see appended electronic signature page}  
Date: 
 
 
 
 
 
 
CONFIDENTIAL
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Signature Date: 20160210
JP: Protocol 14-002 Amendment 3.pdf
 
 
 
Signature Manifestation 
 
 

SAP_001.pdf: 
 
Jazz Pharmaceuticals 
Protocol: 14-002 
Version 1.0 
Statistical Analysis Plan 
 
Page 1 of 59 
Sponsor Name:  
Jazz Pharmaceuticals 
Protocol Number: 
14-002 
Protocol Title:  
A Twelve-week, Double-blind, Placebo-controlled, 
Randomized, Parallel-group, Multicenter Study of 
the Safety and Efficacy of JZP-110 [(R)-2-amino-3-
phenylpropylcarbamate hydrochloride] in the 
Treatment of Excessive Sleepiness in Subjects with 
Narcolepsy 
 
 
Protocol Version and Date: 
Original protocol, 18 December 2014 
Protocol Amendment 1, 18 February 2015 
 
Protocol Amendment 2, 10 September 2015 
Protocol Amendment 3, 08 February 2016 
 
 
 
SAP Version: 
 1.0 
SAP Version Date:  
2 Mar 2017 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Jazz Pharmaceuticals. 
Acceptance of this document constitutes agreement by the recipient that no information 
contained herein will be published or disclosed without prior written authorization from an 
official of Jazz Pharmaceuticals.  However, this document may be disclosed to appropriate 
Institutional Review Board and Ethics Committees or duly authorized representatives of a 
national regulatory authority under the condition that they are requested to keep it confidential. 
In the event of an actual or suspected breach of this obligation, 
 should be notified 
promptly. 
 
 


 
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Version: 
1.0 
Version Date: 
2 Mar 2017 
 
I confirm that I have reviewed this document and agree with the content. 
 
APPROVALS 
 
 
 
 
Written by:
                   
                   
 
 
Date  
Approved by
                     
                     
 
Date  
Jazz Pharmaceuticals 
 
 
 
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TABLE OF CONTENTS 
 
ABBREVIATION ............................................................................................. 7 
1.
 
PURPOSE ....................................................................................................... 9 
2.
 
STUDY OBJECTIVES ................................................................................... 10 
3.
 
Primary Objective .............................................................................................................. 10 
3.1.
 
Secondary Objective(s) ..................................................................................................... 10 
3.2.
 
Study Design ...................................................................................................................... 10 
3.3.
 
Determination of Sample Size .......................................................................................... 15 
3.4.
 
Randomization and Stratification ..................................................................................... 15 
3.5.
 
Administration of Study Drug ........................................................................................... 15 
3.6.
 
ENDPOINTS .................................................................................................. 16 
4.
 
Co-Primary Efficacy Endpoints ........................................................................................ 16 
4.1.
 
Key Secondary Efficacy Endpoint ................................................................................... 16 
4.2.
 
Other Secondary Efficacy Endpoints .............................................................................. 16 
4.3.
 
Functional Outcomes and Quality of Life Endpoints ..................................................... 16 
4.4.
 
Exploratory Endpoints ...................................................................................................... 17 
4.5.
 
Pharmacokinetic Endpoints ............................................................................................. 17 
4.6.
 
Pharmacodynamic Endpoints .......................................................................................... 17 
4.7.
 
Safety Endpoints ................................................................................................................ 17 
4.8.
 
STATISTICAL HYPOTHESES FOR TRIAL OBJECTIVES .......................... 19 
5.


 
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ANALYSIS POPULATIONS .......................................................................... 20 
6.
 
Safety Population ............................................................................................................... 20 
6.1.
 
Modified Intent-to-Treat Population ................................................................................. 20 
6.2.
 
Per Protocol Population .................................................................................................... 20 
6.3.
 
Pharmacokinetic Population ............................................................................................ 20 
6.4.
 
EFFICACY ASSESSMENTS ......................................................................... 21 
7.
 
Maintenance of Wakefulness Test (MWT) ....................................................................... 21 
7.1.
 
Epworth Sleepiness Scale (ESS) ...................................................................................... 21 
7.2.
 
Clinician Global Impression of Severity(CGIs) ............................................................... 21 
7.3.
 
Clinician Global Impression of Change (CGIc) ............................................................... 22 
7.4.
 
Patient Global Impression of Change (PGIc) .................................................................. 22 
7.5.
 
Functional Outcomes of Sleep Questionnaire Short Version (FOSQ-10) .................... 22 
7.6.
 
36-Item Short Form Health Survey Version 2 (SF-36v2) ................................................ 22 
7.7.
 
EuroQoL EQ-5D-5L ............................................................................................................ 22 
7.8.
 
Work Productivity and Activity Impairment Questionnaire: Specific Health Problem 
7.9.
V2.0 (WPAI:SHP) ............................................................................................................................. 23 
 
Cataplexy Diary .................................................................................................................. 23 
7.10.
 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ................................ 24 
8.
 
General Methods ................................................................................................................ 24 
8.1.
 
KEY Definitions .................................................................................................................. 24 
8.2.
 
Baseline ........................................................................................................................... 24 
8.2.1.
 
Study Day ........................................................................................................................ 24 
8.2.2.
 
JZP-110 Exposure ........................................................................................................... 25 
8.2.3.
 
Visit Windows ..................................................................................................................... 25 
8.3.
 
Missing Data ....................................................................................................................... 26 
8.4.


 
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Level of Significance and Multiplicity Adjustment ......................................................... 26 
8.5.
 
Pooling of Centers and Region ........................................................................................ 27 
8.6.
 
Subgroups and Subgroups Analyses .............................................................................. 28 
8.7.
 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
9.
MEDICATION ....................................................................................................... 29 
 
Subject Disposition and Withdrawals .............................................................................. 29 
9.1.
 
Demographic and Other Baseline Characteristics ......................................................... 29 
9.2.
 
Medical/Surgical History ................................................................................................... 29 
9.3.
 
Medication/Procedure ....................................................................................................... 30 
9.4.
 
Prior Medication ............................................................................................................... 30 
9.4.1.
 
Concomitant Medication and Procedure ......................................................................... 30 
9.4.2.
 
Protocol Deviations ........................................................................................................... 30 
9.5.
 
EFFICACY ................................................................................................. 32 
10.
 
Co-Primary Efficacy Endpoints and Analyses ................................................................ 32 
10.1.
 
Primary Analysis ......................................................................................................... 32 
10.1.1.
 
Secondary Analysis ..................................................................................................... 33 
10.1.2.
 
Sensitivity Analyses .................................................................................................... 33 
10.1.3.
 
Subgroup Analyses ..................................................................................................... 38 
10.1.4.
 
Key Secondary Efficacy Endpoint and Analyses ........................................................... 38 
10.2.
 
Primary Analysis ......................................................................................................... 38 
10.2.1.
 
Secondary Analysis ..................................................................................................... 38 
10.2.2.
 
Sensitivity Analyses .................................................................................................... 38 
10.2.3.
 
Subgroup Analyses ..................................................................................................... 39 
10.2.4.
 
Other Secondary Efficacy EndpointS and Analyses ...................................................... 39 
10.3.
 
Time Course of Efficacy on the MWT: Change in Sleep Latency Time (in Minutes) on 
10.3.1.
Each of the 5 MWT Trials ............................................................................................................. 39 
 
CGIc: Percentage of Subjects Reported as Improved (Minimally, Much, or Very 
10.3.2.
Much) at Weeks 1, 4, 8, and 12.................................................................................................... 39 
 
MWT: Change in the Mean Sleep Latency Time (in Minutes) as Determined from the 
10.3.3.
First Four Trials of a 40-minute MWT from Baseline to Week 4 .................................................. 40 
 
ESS: Change in ESS Score from Baseline to Weeks 1, 4, and 8 ............................... 40 
10.3.4.
 
PGIc: Percentage of Subjects Reported as Improved (Minimally, Much, or Very Much) 
10.3.5.
at Weeks 1, 4 and 8 ...................................................................................................................... 40 
 
Functional Outcomes and Quality of Life Endpoints ..................................................... 40 
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FOSQ-10: Change in the Total Score and 5 Subscales from Baseline to Weeks 1, 4, 
10.4.1.
8, and 12 40 
 
SF-36v2: Change in 8 Domain Scores, Physical Component Summary (PCS) Score, 
10.4.2.
and Mental Component Summary (MCS) Score from Baseline to Weeks 4, 8, and 12 .............. 41 
 
EQ-5D-5L: EQ-5D Dimensions at Week 1, 4, 8, and 12 ............................................. 42 
10.4.3.
 
EQ VAS:  Change in the VAS Score from Baseline to Weeks 1, 4, 8, and 12 ........... 42 
10.4.4.
 
EQ-5D-5L Index: Index Value from Baseline to Week 1, 4, 8, and 12........................ 42 
10.4.5.
 
WPAI:SHP: Change in WPAI:SHP Endpoints from Baseline to Week 1,4,8, and 12 . 43 
10.4.6.
 
Exploratory Endpoints ...................................................................................................... 44 
10.5.
 
Number of Cataplexy Attacks ...................................................................................... 44 
10.5.1.
 
Change in PSG Parameters from Baseline to Week 4 and 12 ................................... 44 
10.5.2.
 
Categorical Analysis for Maintenance of Wakefulness Test ....................................... 45 
10.5.3.
 
Summary of Efficacy Analysis Methods.......................................................................... 45 
10.6.
 
ANALYSIS OF PHARMACOKINETICS .................................................... 49 
11.
 
SAFETY ..................................................................................................... 50 
12.
 
Extent of Exposure ............................................................................................................ 50 
12.1.
 
Treatment Compliance ...................................................................................................... 50 
12.2.
 
Adverse Events .................................................................................................................. 50 
12.3.
 
Subgroup Analyses ..................................................................................................... 51 
12.3.1.
 
Laboratory Evaluations ..................................................................................................... 51 
12.4.
 
Vital Signs and 24-Hour ambulatory Blood Pressure monitoring ................................ 52 
12.5.
 
Regular Vital Signs ...................................................................................................... 52 
12.5.1.
 
Blood Pressure and Pulse on the MWT day ............................................................... 53 
12.5.2.
 
24 hour Ambulatory Blood Pressure Monitoring (ABPM) ........................................... 54 
12.5.3.
 
ECG ..................................................................................................................................... 54 
12.6.
 
Columbia-Suicide Severity Rating Scale ......................................................................... 55 
12.7.
 
C-SSRS Outcomes/Composite Scores ....................................................................... 55 
12.7.1.
 
Analyses ...................................................................................................................... 56 
12.7.2.
 
INTERIM ANALYSES ................................................................................ 57 
13.
 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ......................... 58 
14.
 
REFERENCE ............................................................................................. 59 
15.


 
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ABBREVIATION 
1.
Abbreviation 
Description 
AE 
Adverse Event 
AHI 
Apnea Hypopnea Index 
ANCOVA 
Analysis of Covariance 
AI 
Apnea Index  
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CGIc 
Clinical Global Impression of Change 
CGIs 
Clinical Global Impression of Severity 
CI 
Confidence Interval 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
CV 
Coefficient of Variation 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
ECG 
Electrocardiogram 
ESS 
Epworth Sleepiness Scale  
ET 
Early Termination 
EQ VAS 
EuroQoL Visual Analog Scale 
FOSQ-10 
Functional Outcomes of Sleep Questionnaire Short Version 
ICSD-3 
International Classification of Sleep Disorders, 3rd Edition 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System  
LOCF 
Last Observation Carried Forward  
LOE 
Lack of Efficacy 
LS 
Least Square 
MAR 
Missing at Random 


 
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Abbreviation 
Description 
Max 
Maximum 
MCAR 
Missing Completely at Random  
MCS 
Mental Component Summary 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
Min 
Minimum 
mITT 
Modified Intent-to-Treat 
MMRM 
Mixed-Effect Model with Repeated Measures 
MNAR 
Missing Not at Random 
MWT 
Maintenance of Wakefulness Test 
PGIc 
Patient Global Impression of Change  
PAP 
Positive airway pressure 
PCS 
Physical Component Summary 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PSG 
Polysomnography 
QTcF 
QT Corrected with Fridericia’s Formula  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SF-36v2 
36-Item Short Form Health Survey Version 2  
SI 
Single Imputation 
TEAE 
Treatment Emergent Adverse Event 
TST 
Total Sleep Time  
WASO 
Wake after Sleep Onset  
WHO 
World Health Organization 
WPAI:SHP 
Work Productivity and Activity Impairment Questionnaire: 
Specific Health Problem  


 
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PURPOSE 
2.
This Statistical Analysis Plan (SAP) is created based on Protocol 14-002, Amendment 3 
(08 February 2016) and it describes in detail the statistical methodology and the 
statistical analyses to be conducted for the above mentioned protocol.  
 
Results obtained from the analyses outlined in this document will become the basis of 
the final clinical study report (CSR) for this protocol.  The purpose of this plan is to 
provide specific instructions as to how each analysis will be conducted.  Any deviations 
from these guidelines must be substantiated by sound statistical reasoning and 
documented in the final CSR. 
 
 
 
 
 


 
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STUDY OBJECTIVES 
3.
 
PRIMARY OBJECTIVE 
3.1.
To evaluate the efficacy of JZP-110 administered once daily for up to 12 weeks in daily 
doses of 75, 150, and 300 mg compared to placebo in the treatment of excessive 
sleepiness in adult subjects with narcolepsy. 
 
 
SECONDARY OBJECTIVE(S) 
3.2.
To evaluate the safety and tolerability of JZP-110 administered once daily for up to 12 
weeks in daily doses of 75, 150, and 300 mg compared to placebo in the treatment of 
excessive sleepiness in adult subjects with narcolepsy. 
 
To characterize the pharmacokinetics (PK) of JZP-110 in subjects with narcolepsy using 
sparse sampling methods. 
 
STUDY DESIGN 
3.3.
The Schedule of Events is presented in Table 1, and the Study Schema in Figure 1. 
 
This trial is a 12-week, randomized, double-blind, placebo-controlled, multicenter, 4 
treatment parallel group study of the safety and efficacy of JZP-110 in the treatment of 
excessive sleepiness in adult subjects with narcolepsy as defined by the International 
Classification of Sleep Disorders, 3rd Edition (ICSD-3) or the Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5). Following the successful completion 
of Screening and Baseline visits, stratified randomization on the basis of the presence or 
absence of cataplexy will occur. Subjects will be assigned to receive JZP-110 75, 150, or 
300 mg daily or placebo in a 1:1:1:1 ratio once daily over a 12-week Treatment Phase. 
Subjects randomized to the 150 mg daily dose will initially receive 75 mg daily from Day 
1 through Day 3 of the first week of the Treatment Phase and will receive 150 mg daily 
starting on Day 4. Subjects randomized to the 300 mg daily dose will initially receive 
150 mg daily from Day 1 through Day 3 of the first week of the Treatment Phase and 
will receive 300 mg daily starting on Day 4. Subjects randomized to the 75 mg daily 
group will not require titration.  
 
During the Treatment Phase, subjects will return to the investigative site to complete 
efficacy and safety assessments at the end of Weeks 1, 4, 8, and 12; the Week 4 and 12 
visits will include an overnight stay at the investigational site for nocturnal 
polysomnography (PSG) followed by a Maintenance of Wakefulness Test (MWT), and the 
Week 8 Visit will include 24-hour ambulatory blood pressure monitoring. Subjects will 
take their final dose of study drug at the Week 12 visit prior to the Week 12 visit 
assessments. Subjects will return at the end of Week 14 for follow-up assessments. 


 
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Unless there are any outstanding safety issues that require follow-up, subjects will be 
discharged from the study at the Week 14 visit. 
 
Efficacy will be assessed by changes in the mean sleep latency on the first 4 trials of a 5 
trial, 40-minute MWT and by changes in the mean Epworth Sleepiness Scale (ESS) score 
as co-primary endpoints, percentage of patients improved on the Patient Global 
Impression of Change (PGIc) as a key secondary endpoint, and the Clinical Global 
Impression of Change (CGIc), Functional Outcomes of Sleep Questionnaire Short Version 
(FOSQ- 10), 36-Item Short Form Health Survey Version 2 (SF-36v2), EuroQoL EQ-5D-5L, 
and the Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem V2.0 (WPAI:SHP) as other endpoints. 
 
Four blood samples will be collected from each subject for PK evaluations; one sample 
during the Week 1 visit, one sample during the Week 4 visit, and two samples during the 
Week 8 visit. The samples collected at the Week 1 and Week 8 visits will be within 
1-8 hours of dosing. The samples collected at the Week 4 visit will be within 8-12 hours 
after dosing. 
 
Safety will be assessed by the incidence of observed and reported adverse events (AEs), 
and changes in physical examination findings, electrocardiograms (ECGs), clinical 
laboratory tests, vital sign measurements, 24-hour ambulatory blood pressure 
monitoring at the Week 8 visit, and the Columbia-Suicide Severity Rating Scale (C-SSRS). 
Safety will be assessed throughout the study. 
 
Figure 1 Study Schema 
 


 
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Table 1 Schedule of events 
 
 
 


 
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DETERMINATION OF SAMPLE SIZE 
3.4.
Approximately 240 subjects are planned for enrollment. Approximately 60 subjects will 
be randomized to each treatment group. A sample size of 54 subjects per group will 
provide at least 80% power to detect a difference of 6 minutes in the mean sleep 
latency time as determined from the MWT (mean of the first four trials) and a 
difference of 4 points on the ESS changes from Baseline to Week 12 between each JZP-
110 treatment group and placebo. This calculation assumes common standard deviations 
of 10 minutes for the MWT and 6 points for the ESS changes from Baseline and a two-
sided significance level of 0.05 using a t-test. To account for dropouts without evaluable 
data, a sample size of 60 subjects per treatment group is planned. 
 
 
RANDOMIZATION AND STRATIFICATION 
3.5.
All subjects will be randomly assigned to treatments via an interactive voice response 
system (IVRS) or an Interactive Web Response System (IWRS).  Subjects will be 
randomized to JZP-110 75 mg, 150 mg, 300 mg or placebo in a 1:1:1:1 ratio using 
stratified randomization. The stratification factor is the presence or absence of 
cataplexy at the screening.   
 
 
ADMINISTRATION OF STUDY DRUG 
3.6.
Subjects will receive JZP-110 75, 150, or 300 mg or placebo once daily as a single oral 
dose over a Treatment Phase of 12 weeks. 


 
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ENDPOINTS 
4.
 
CO-PRIMARY EFFICACY ENDPOINTS 
4.1.
 
MWT: Change in the mean sleep latency time (in minutes) as determined 
from the first four trials of a 40-minute MWT from Baseline to Week 12 
 
 
ESS: Change in ESS score from Baseline to Week 12 
 
KEY SECONDARY EFFICACY ENDPOINT 
4.2.
 
PGIc: Percentage of subjects reported as improved (minimally, much, or very 
much) at Week 12 
 
OTHER SECONDARY EFFICACY ENDPOINTS 
4.3.
 
Time course of efficacy on the MWT: Change in sleep latency time (in 
minutes) on each of the 5 MWT trials at Week 4, and Week 12 
 
CGIc: Percentage of subjects reported as improved (minimally, much, or very 
much) at Week 12 
 
MWT: Change in the mean sleep latency time (in minutes) as determined 
from the first four trials of a 40-minute MWT from Baseline to Week 4 
 
ESS: Change in ESS score from Baseline to Week 1, Week 4, and Week 8 
 
PGIc: Percentage of subjects reported as improved at Week 1, Week 4, and 
Week 8  
 
CGIc: Percentage of subjects reported as improved at Week 1, Week 4, and 
Week 8 
 
FUNCTIONAL OUTCOMES AND QUALITY OF LIFE ENDPOINTS 
4.4.
 
FOSQ-10: Change in the total score and 5 FOSQ-10 subscales from Baseline to 
Week 1, Week 4, Week 8, and Week 12 
 
SF-36v2: Change in the physical component summary (PCS) and the mental 
component summary (MCS) and change in the 8 subscales from Baseline to 
Week 4, Week 8, and Week 12 
 
EQ-5D-5L:  


 
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o EQ-5D Dimensions: 
• 
Number and percentage of subjects in each of the 5 levels (e.g., 
no problem, slight problem, moderate problem, severe problem, 
unable) for each dimension (e.g., mobility, self-care) over time 
• 
Number and percentage of subjects reporting any problems (levels 
2-5) for each dimension (e.g., mobility, self-care) over time 
o EuroQoL Visual Analog Scale (EQ VAS): Mean and SD or median with 25th 
and 75th percentiles for the VAS at Baseline, Week 1, Week 4, Week 8 
and Week 12. Change in the VAS scores from Baseline to Week 1, Week 4, 
Week 8, and Week 12 
o EQ-5D-5L Index: Index value at Baseline to Week 1, Week 4, Week 8, and 
Week 12 
 
WPAI:SHP: Percent work time missed due to problem over time, percent 
impairment while working due to problem over time, percent overall work 
impairment due to problem over time, and percent activity impairment due 
to problem over time 
 
EXPLORATORY ENDPOINTS  
4.5.
 
Number of Cataplexy Attacks: Change in the mean and median weekly 
number of cataplexy attacks in the subset of subjects who report the 
presence of cataplexy at randomization from Baseline to each subsequent 
analysis period (e.g., Week 1, Weeks 2-4, Weeks 5-8, and Weeks 9-12) 
 
Change in PSG parameters including total sleep time (TST), time in Stages 
N1, N2, N3, wake after sleep onset (WASO), number of awakenings, apnea 
index (AI), Apnea Hypopnea Index (AHI), number of central apneas, SaO2 
nadir, and SaO2 mean from Baseline to Week 4, and Week 12. 
 
PHARMACOKINETIC ENDPOINTS 
4.6.
 
Concentration of JZP-110 at Weeks 1, 4 and 8. 
 
PHARMACODYNAMIC ENDPOINTS  
4.7.
Not applicable 
 
SAFETY ENDPOINTS  
4.8.
To evaluate safety and tolerability as determined by the occurrence of and/or changes 
in: 


 
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 
Treatment-emergent adverse events (TEAEs) 
 
Change in clinical laboratory tests (chemistry, hematology, and urinalysis) 
 
Vital signs 
 
24 hour ambulatory blood pressure monitoring 
 
12-lead electrocardiograms (ECGs) 
 
C-SSRS 


 
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STATISTICAL HYPOTHESES FOR TRIAL OBJECTIVES 
5.
The two co-primary hypotheses, corresponding to the two co-primary efficacy variables 
(MWT and ESS), are the following:  
 
JZP-110 is superior to placebo as measured by change in the mean sleep latency 
time (in minutes) as determined from the first four trials of a 40-minute MWT 
from Baseline to Week 12 
 
The statistical null hypothesis is that for the MWT, the mean change in the mean 
sleep latency time (in minutes) from Baseline to Week 12 for each JZP-110 dose 
group is the same as the mean change in the mean sleep latency time (in 
minutes) from Baseline to Week 12 for placebo group.  
 
 
JZP-110 is superior to placebo as measured by change in ESS score from Baseline 
to Week 12 
 
The statistical null hypothesis is that for the ESS score, the mean change from 
Baseline to Week 12 for each JZP-110 dose group is the same as the mean 
change from Baseline to Week 12 for the placebo group. 
 
In addition to the two co-primary hypotheses, the key secondary hypothesis is: 
 
 
JZP-110 is superior to placebo as measured by Patient Global Impression of 
Change (PGIc) at Week 12 
 
The statistical null hypothesis is that for the PGIc, the proportion of subjects 
reported as improved (minimally, much, or very much) at Week 12 for each JZP-
110 dose group is the same as the proportion of subjects reported as improved 
(minimally, much, or very much) at Week 12 for the placebo group.   
 


 
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ANALYSIS POPULATIONS 
6.
 
SAFETY POPULATION 
6.1.
The Safety Population will consist of all subjects who received at least one dose of 
study medication. This population will be used for safety analyses and will be presented 
in the tables and listings of safety data. 
 
 
MODIFIED INTENT-TO-TREAT POPULATION  
6.2.
The Modified Intent-to-Treat (mITT) Population will include subjects who were 
randomized, received at least one dose of study medication and have baseline and at 
least one post-baseline evaluation of MWT or ESS. If a subject in the mITT Population 
does not have an assessment for a particular endpoint, that subject will be excluded in 
the analysis of that endpoint. 
 
The mITT population will be used for efficacy and functional outcomes and quality of 
life analyses.  
 
PER PROTOCOL POPULATION  
6.3.
The Per-Protocol (PP) population will include subjects who completed the trial 
according to protocol specifications without a major protocol violation. Based on the 
protocol deviation management plan, a major violation can be identified by an 
exclusion from Per Protocol population flag in the study protocol deviation report. The 
reasons for exclusion will also be detailed in the study protocol deviation report.  
The categories of major protocol deviations will be defined in the protocol deviation 
management plan, and the plan will be approved before unblinding of the study.  
The PP population will be used in a secondary analysis of the co-primary endpoints and 
the key secondary endpoint. 
 
PHARMACOKINETIC POPULATION   
6.4.
The PK Population will include subjects who received at least one dose of JZP-110 and 
have evaluable PK data for the PK analysis. 
 


 
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EFFICACY ASSESSMENTS 
7.
 
MAINTENANCE OF WAKEFULNESS TEST (MWT) 
7.1.
The MWT is the standard objective measure of an individual’s ability to remain awake 
during the daytime in a darkened, quiet environment and is commonly used to assess 
response to treatment. A five-trial, 40 minute MWT will be performed at Baseline and at 
the Week 4 and 12 visits (or Early Termination if the subject is willing and able to take 
study drug for the assessments) on the morning after an overnight PSG according to a 
standard protocol, which will be provided in a manual to each site. 
 
Each MWT during the study should be started at approximately the same time of the 
day. During the MWT trials, subjects should be seated in bed in a darkened room with 
their back and head supported by a bedrest such that their neck is not uncomfortably 
flexed or extended. Subjects will be instructed to sit still and remain awake for as long 
as possible during each of the 5 40-minute trials separated by 2-hour intervals. 
Following a light breakfast, the subject will be allowed to relax prior to initiating the 
first MWT trial. The first MWT trial should occur approximately 2 hours after “lights on” 
at the Baseline visit and approximately 1 hour after dosing with study drug at all other 
visits at which the MWT will be conducted. If the subject falls asleep during a trial, they 
will be awakened and instructed to remain awake until the next trial. If the subject 
does not fall asleep, then the specific trial is terminated at 40 minutes and a sleep 
latency of 40 minutes is recorded. The subject is then instructed to remain awake (and 
will be awoken if they fall asleep) until the next trial. 
 
 
EPWORTH SLEEPINESS SCALE (ESS) 
7.2.
The ESS is a self-administered questionnaire with 8 questions asking the subject how 
likely they would be to doze off or fall asleep in different situations. Responses range 
from 0 = would never doze to 3 = high chance of dozing (Protocol Appendix 6). Subjects 
will be asked to complete the ESS with regard to the level of sleepiness they 
experienced over the past 7 days at the Baseline and Week 1, 4, 8, and 12 visits (or 
Early Termination). It provides a measure of a person’s general level of daytime 
sleepiness, or their average sleep propensity in daily life. The ESS is a validated 
measure with high specificity and sensitivity for assessing subjective sleepiness in 
narcolepsy. 
 
 
CLINICIAN GLOBAL IMPRESSION OF SEVERITY(CGIs) 
7.3.
The CGIs is a 7-point Likert-type rating scale and a widely used assessment in clinical 
psychopharmacology trials to assess severity of illness (Protocol Appendix 13). The 
responses of this investigator-completed scale range from 1 = normal, no signs of illness 
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impression of the severity of the subject’s current condition at Baseline relative to 
his/her experience with this patient population. 
 
 
CLINICIAN GLOBAL IMPRESSION OF CHANGE (CGIc) 
7.4.
The CGIc is a 7-point Likert-type rating scale and a widely used assessment to assess 
efficacy in clinical drug trials. Investigators will rate their impression of any change in 
the subject’s condition from baseline (before the subject started treatment) on a 7-
point scale ranging from 1 = very much improved to 7 = very much worse at the Week 1, 
4, 8, and 12 visits (or Early Termination) (Protocol Appendix 14). 
 
 
PATIENT GLOBAL IMPRESSION OF CHANGE (PGIc) 
7.5.
The PGIc is a 7-point Likert-type rating scale and a widely used measure to assess 
efficacy in clinical drug trials. Subjects will rate the change in their condition since they 
started treatment on a 7-point scale ranging from 1 = very much improved to 7 = very 
much worse at the Week 1, 4, 8, and 12 visits (or Early Termination) (Protocol Appendix 
15). 
 
 
FUNCTIONAL OUTCOMES OF SLEEP QUESTIONNAIRE SHORT 
7.6.
VERSION (FOSQ-10)  
The FOSQ is a 30-item disease specific quality of life questionnaire to determine 
functional status in adults; measures are designed to assess the impact of disorders of 
excessive sleepiness on multiple activities of everyday living and the extent to which 
these activities are improved by effective treatment. The FOSQ-10 is a short version of 
the original 30-item FOSQ that has been shown to perform similarly to the longer 
version. The FOSQ-10 has been shown to exhibit high internal consistency, effect sizes, 
and pre- and post-treatment differences that are highly correlated with the longer 
version. Subjects will complete the FOSQ-10 at the Baseline and Week 1, 4, 8, and 12 
visits (or Early Termination) (Protocol Appendix 7). 
 
 
36-ITEM SHORT FORM HEALTH SURVEY VERSION 2 (SF-36v2) 
7.7.
The SF-36v2 is a multi-purpose, short-form health survey with 36 questions. It yields an 
8-scale profile of functional health and well-being scores as well as psychometrically-
based physical and mental health summary measures and a preference-based health 
utility index. Subjects will complete the SF-36v2 at the Baseline and Week 4, 8, and 12 
visits (or Early Termination) (Protocol Appendix 8). 
 
 
EuroQoL EQ-5D-5L 
7.8.
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome that 
includes a descriptive system consisting of 5 dimensions (mobility, self-care, usual 


 
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activities, pain/discomfort, and anxiety/depression) and an EQ visual analogue scale 
(VAS). It is applicable to a wide range of health conditions and treatments. It provides a 
simple descriptive profile and a single index value for health status. The EQ-5D-5L 
includes five levels of severity for each of the 5 dimensions of the descriptive system 
and was developed to improve the instrument’s reliability and sensitivity and to reduce 
ceiling effects. Subjects will complete the EQ-5D-5L at the Baseline and Week 1, 4, 8, 
and 12 visits (or Early Termination) (Protocol Appendix 9). 
 
 
WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT 
7.9.
QUESTIONNAIRE: SPECIFIC HEALTH PROBLEM V2.0 
(WPAI:SHP) 
The WPAI:SHP questionnaire is a 6-item self-administered questionnaire that measures 
work time missed and work and activity impairment because of a specified health 
problem during the past 7 days. The WPAI:SHP will be used with “narcolepsy” as the 
specified health problem. The validity of the WPAI has been established in a number of 
diseases (Reilly et al. 1993). Subjects will complete the WPAI:SHP at the Baseline and 
Week 1, 4, 8, and 12 visits (or Early Termination) (Protocol Appendix 11). 
 
 
CATAPLEXY DIARY 
7.10.
Subjects who experience cataplexy will complete a daily cataplexy frequency diary 
(Protocol Appendix 3) to record the occurrence and number of cataplexy attacks that 
they had each day beginning after discontinuation of narcolepsy medication and 
throughout the 12-week Treatment Phase of the study. The study staff will review the 
diary at each study visit and discuss it with the subject at each phone contact. 
 
 


 
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GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
8.
 
GENERAL METHODS 
8.1.
Unless otherwise specified, for numeric data, descriptive statistics will include the 
number of subjects with data to be summarized (n), mean, standard deviation (SD), 
median, minimum (min) and maximum (max). The same number of decimal places as in 
the raw data will be presented when reporting min and max, 1 more decimal place than 
in the raw data will be presented when reporting mean and median, and 2 more 
decimal places than in the raw data will be presented when reporting SD. If the raw 
data have 3 decimals or more, 3 decimals will be presented for mean, median, min and 
max, and SD.  
All categorical/qualitative data will be presented using absolute and relative frequency 
counts and percentage. All percentages will be presented with one-decimal point. 
Percentages equal to 100 will be presented as 100% and percentages will not be 
presented for zero frequencies but the categories whose counts are zero will be 
displayed for the sake of completeness. 
P-value > 0.9999 will be presented as ‘>0.9999’ and p-value < 0.0001 will be presented 
as ‘< 0.0001’. 
All analyses and summary outputs will be generated by treatment group (Placebo, JZP-
110 75 mg, JZP-110 150 mg, JZP-110 300 mg, and combined JZP-110) using SAS® version 
9.3 (or higher). 
All data collected in this study will be presented in by-subject listings.    
 
 KEY DEFINITIONS 
8.2.
 
Baseline  
8.2.1.
The Baseline measurement for a variable is defined as the last non-missing value from 
the baseline visit measured prior to the first dose of the study drug. If a subject has 
repeated measurements from the baseline visit, then the last repeated non-missing 
value will be used. If there is not a value from the scheduled baseline visit, the last 
non-missing value from other screening or unscheduled visits measured prior to the first 
dose of study drug will be used.   
 
Study Day 
8.2.2.
A study day will be assigned as follows: 
 
The first dose of study drug is designated as Day 1. 


 
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 
For visit days after Day 1, study day = visit date - Day 1 date + 1. 
 
 
For visit days prior to Day 1, study day = visit date - Day 1 date.  Thus, study days 
for screening visit are negative numbers.  There is no “Day 0”. 
 
 
The end date of treatment is the last dose date in the study.  
 
The end date of the study is defined as the date of the subject’s last assessment 
including the safety follow-up in the study. 
 
 
JZP-110 Exposure 
8.2.3.
JZP-110 exposure is defined as the number of days that a dose of JZP-110 is taken, 
regardless of the JZP-110 dose level.  
 
 
VISIT WINDOWS 
8.3.
The unscheduled or early termination (ET) visit will be mapped to a scheduled visit for 
analysis using the date of collection/assessment as a basis to determine study day and 
then study day will be mapped to the intended visit. The table below contains the visit 
windows.  
 
Once analysis visit windows are assigned, all visits, including scheduled visits, 
unscheduled visits, and ET visits will be eligible for being flagged as the “analyzed 
record” within the analysis visit window, a subject’s individual analysis visit window 
could potentially contain more than one visit.  In the event of multiple visits falling 
within an analysis visit window or in case of a tie, the following rules will be used in 
sequence to determine the “analyzed record” for the analysis visit window: 
 
 
If there is a scheduled visit/week for the analysis visit window, then the 
scheduled visit/week data will be used. 
 
 
If there is no scheduled visit/week for the analysis visit window, the data closest 
to the scheduled day will be used.   
 
 
If there is no scheduled visit/week for the analysis visit window and there is a tie 
between the data in the number of days before and after the scheduled day, the 
later data will be used.   
 
The unscheduled or early termination (ET) visit will be mapped to a scheduled visit 
before the imputation methods will be used for handling dropouts and missing data for 
efficacy endpoints.  
 


 
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The data not flagged as the “analyzed record” will also be listed in subject listings.   
 
Study Day Window 
Scheduled day   
Scheduled Visit/Week 
Days (-31) to (-3) 
Day -3 
Visit 1/Screening  
Day (-2) to (-1) 
Day -2 & -1 
Visit 2/Baseline 
Day 1 -10 
Day 7 
Visit 3/Week 1 
Day 11 – 17 
Day 14 
Visit 4/Week 2 
Day 18 – 24 
Day 21 
Visit 5/Week 3 
Day 25 – 31 
Day 27 & 28 
Visit 6/Week 4 
Day 32 – 38 
Day 35 
Visit 7/Week 5 
Day 39 – 45 
Day 42 
Visit 8/Week 6 
Day 46 – 52 
Day 49 
Visit 9/Week 7 
Day 53 – 59 
Day 56 
Visit 10/Week 8 
Day 60 – 66 
Day 63 
Visit 11/Week 9 
Day 67 – 73 
Day 70 
Visit 12/Week 10 
Day 74 – 80 
Day 77 
Visit 13/Week 11 
Day 81 – 87 
Day 83 & 84 
Visit 14/Week 12 
Day > 87 
Day 98 
Visit 15/Week 14 
  
 
 
MISSING DATA 
8.4.
For the analysis of the co-primary efficacy parameters of MWT and the total ESS score, 
missing data will be handled by mixed effect model with repeated measure (MMRM) for 
the primary analysis. For sensitivity analyses, the following missing data approaches will 
be used to impute the missing data to assess the potential impact of missing data: two 
single imputation (SI) approaches [last observation carried forward (LOCF) and mean 
imputation] as described in section 10.1.3.1 and two multiple imputation (MI) 
approaches [MCMC with regression method and Pattern Mixture model using dropout 
pattern imputation method] as described in 10.1.3.2. 
  
For the key secondary efficacy parameter of PGIc and the other secondary efficacy 
parameter of CGIc, missing data will be imputed by the last observation carried forward 
(LOCF) for the primary analyses. Two SI approaches (worst case and varies by early 
termination reason) will be used to impute the missing data to assess potential impact 
of missing data as sensitivity analyses. See Section 10.2.1 and 10.2.3. 
 
 
LEVEL OF SIGNIFICANCE AND MULTIPLICITY ADJUSTMENT  
8.5.
To address the multiplicity issue of multiple endpoints and dose groups, the fixed 
hierarchical testing sequence in Figure 2 will be used. Testing will begin with the 
comparison of 300 mg daily dose versus placebo for the co-primary efficacy endpoints 
MWT and ESS. Since they are co-primary endpoints, both have to be significant at the 


 
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0.05 level from the primary analysis before the test can proceed to the next level (PGIc 
at 300 mg daily dose versus placebo). Testing will proceed from the highest JZP-110 
dose to the lowest dose and will stop when a significance level exceeds 0.05 (see Figure 
2). This gate keeping approach will control the family-wise error rate at 0.05 for the 
comparisons of the three JZP-110 doses versus placebo in MWT, ESS, and PGIc. The 
dose(s) that show(s) significant difference versus placebo in the primary analysis of both 
MWT and ESS will be considered efficacious doses and additional testing to characterize 
the time course of efficacy will be performed (Section 10.3.1). 
 
Figure 2. Multiplicity Strategy 
 
 
 
 
POOLING OF CENTERS AND REGION 
8.6.
Because of the large number of centers and the fact that many centers have a small 
number of subjects, analyses will not be performed by center and will not include an 
adjustment for center. Data from all investigational centers will be pooled.  
Data will also be summarized by region (North America and Europe) for specified 
analyses.   
 


 
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SUBGROUPS AND SUBGROUPS ANALYSES 
8.7.
Exploratory analyses of the key efficacy and safety endpoints will be conducted in the 
following subgroups of subjects: 
 
Subgroups of subjects who report the presence or absence of cataplexy  
 
Subgroups of subjects by region (North America and Europe) 
 
Subgroups of subjects by country (e.g., US, Canada, France, Germany  
Netherlands) 
 
The following endpoints will be included in the subgroup analyses: 
 
 
MWT: Change in the mean sleep latency time (in minutes) as determined from 
the first four trials of a 40-minute MWT from Baseline to each post-baseline time 
point 
 
ESS: Change in ESS score from Baseline to each post-baseline time point 
 
PGIc: Percentage of subjects reported as improved at each time point  
 
CGIc: Percentage of subjects reported as improved at each time point 
 
TEAEs 
 
EQ-5D-5L: 
o Number and percentage of subjects in each of the 5 levels (e.g., no 
problem, slight problem, moderate problem, severe problem, unable) for 
each dimension at Baseline and each post-baseline time point. 
o Number and percentage of subjects reporting any problems (levels 2-5) 
for each dimension at Baseline and each post-baseline time point. 
o EQ VAS score at each time point and change from Baseline to each post-
baseline time point 
o EQ-5D-5L index value at each time point and change from Baseline to 
each post-baseline time point 
 
 
FOSQ-10: Change in Total score and 5 subscales from Baseline to each post-
baseline time point 
 
For subgroups of subjects by country, only descriptive statistics will be performed. 
 
 


 
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DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
9.
MEDICATION 
 
SUBJECT DISPOSITION AND WITHDRAWALS 
9.1.
Number of all enrolled subjects and number and percentage of subjects in each analysis 
population will be presented. In addition, number of subjects who 
completed/prematurely discontinued, and reason for discontinuation will also be 
presented by treatment group for each analysis population and subgroup of subjects by 
region. 
The summary of disposition over time will show the number of subjects terminating the 
study in each week.   
For screen failure subjects, reasons for screen failure will be summarized separately.   
 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
9.2.
Demographics and baseline characteristics will be summarized by treatment group for 
the Safety Population, mITT Population, Per-Protocol Population, PK Population, and 
subgroups of subjects by region. 
 
Demographics and baseline characteristics include: age, gender, race, ethnicity, region, 
country, height, weight and body mass index (BMI). 
 
 
Height (in cm) = height (in inches) * 2.54 
 
Weight (in kg) = weight (in lbs) * 0.4536 
 
For screen failure subjects, demographics will be summarized separately.  
 
In addition, the following variables will be summarized: 
 
Baseline disease severity: mean MWT sleep latency time, total ESS score, and 
clinical global impression of severity (CGIs) 
 
Randomization stratification factor (presence or absence of cataplexy)  as 
collected on the CRF 
 
 
 
MEDICAL/SURGICAL HISTORY  
9.3.
Medical/surgical history collected at screening and baseline will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA), Version 18.  


 
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Medical/surgical data will be summarized by system organ class (SOC) and preferred 
term (PT) and treatment group for the safety population.  
 
MEDICATION/PROCEDURE 
9.4.
Medications will be coded using WHO DRUG dictionary, Version: March, 2015. 
Procedures will be coded using MedDRA, Version 18.0. 
 
Prior Medication 
9.4.1.
Prior medications will be defined as medications with a start date prior to the first dose 
of study drug.  The stop date of the medication should be before or after the first dose 
of study drug or the medication may be ongoing. If a start date is completely missing, 
then the medication will be considered a prior medication. 
Prior medications will be summarized by anatomical therapeutic chemical (ATC) level 3 
term, and preferred term based on the safety population.  
 
Concomitant Medication and Procedure 
9.4.2.
Concomitant medications will be defined as medications with a stop date on or after the 
first dose of study drug or any medication that is ongoing.  The start date of the 
medication may be before or after the first dose of study drug. A medication with 
completely missing use dates or partially missing use dates without evidence that the 
medication was stopped prior to the first dose of study drug will be considered a 
concomitant medication. Concomitant procedures will be defined as procedures with a 
procedure date on or after first dose of study drug. A procedure with a completely or 
partially missing use date without evidence that the procedure was conducted prior to 
the first dose of study drug will be considered a concomitant procedure.  
Concomitant medications will be summarized by ATC level 3 term, preferred term based 
on the safety population. Procedures will be summarized by MedDRA SOC and PT. The 
summaries will be based on the safety population. 
 
 
PROTOCOL DEVIATIONS 
9.5.
Before database lock, the cumulative protocol deviation report will be generated by the 
 clinical team and reviewed by the Jazz Medical Monitor and Lead Statistician per 
protocol deviation management plan. Source data will include both deviations reported 
directly from the sites and deviations identified from CRF data through programmatic 
edit checks. A flag of exclusion from the Per Protocol population due to major 
violation(s) will be identified and the reasons for exclusion from the Per Protocol 


 
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population will be documented based on discussion between the Jazz Medical Monitor, 
Lead Statistician, and Clinical Operations Lead. The flag of exclusion from the Per 
Protocol population and the reason for exclusion from the Per Protocol population will 
be included in the cumulative protocol deviation report and the final protocol deviation 
report. After database lock, the protocol deviation report will be filed in the TMF and 
will be used as source data for the clinical study database.  
Major protocol deviations will be summarized based on the safety and mITT populations.     
   


 
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EFFICACY 
10.
Observed data at each time point and change from baseline to each post-baseline 
visit/time point will be summarized by treatment group.  For categorical data, 
frequency counts and percentages will be presented in a similar manner.  
 
CO-PRIMARY EFFICACY ENDPOINTS AND ANALYSES 
10.1.
The co-primary efficacy endpoints are: 
 
MWT: Change in the mean sleep latency time (in minutes) as determined from 
the first four trials of a 40-minute MWT from Baseline to Week 12 
 
ESS: Change in ESS score from Baseline to Week 12 
The mean sleep latency time at each time point is the average of the sleep latency time 
(in minutes) from the first four trials of a 40-minute MWT at the specific time point. If 
two or more of the first four individual trials MWT sleep latencies are missing at a given 
time point, the mean sleep latency on the MWT will be set to missing at the specific 
time point. If one of the first four individual trials MWT sleep latency is missing, the 
mean of the remaining three of the first four MWT trials will be used for calculating the 
mean sleep latency on the MWT at that specific time point. 
The MWT sleep latency can range from 0 to 40 minutes, with higher latencies indicating 
greater ability to stay awake. Thus, an increase in mean sleep latency on the MWT from 
Baseline represents an improvement in the ability to stay awake.  
The ESS total score is the sum of eight item scores. If three or more item scores are 
missing at a specific time point, the ESS total score will be set to missing. If one or two 
ESS items are missing at specific time point, the mean of the remaining seven or six 
non-missing ESS items at that time point will be used to impute the missing ESS items. 
The ESS total score will be calculated as the sum of the observed and the imputed item 
scores. 
The ESS total score can range from 0 to 24 points, with higher scores indicating a 
greater chance of dozing. Thus, a decrease in ESS score represents an improvement in 
excessive sleepiness.  
 
Primary Analysis 
10.1.1.
For both co-primary efficacy endpoints, a mixed-effect model with repeated measures 
(MMRM) will be used as the primary method of analysis. The response variable will be 
the change from Baseline to each post-baseline visit and the co-primary endpoints will 
be the changes from Baseline to Week 12.  The model will include the following fixed 
effects: 


 
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 
Treatment (with four levels: JZP-110 75 mg, JZP-110 150 mg, JZP-110  300 mg, 
and placebo for the primary analysis or with 2 levels: Combined JZP-110 and 
placebo for the additional exploratory analysis) 
 
Visit (as a discrete and repeated factor) 
 
Treatment-by-visit interaction 
 
Baseline of the respective efficacy endpoint, a continuous covariate 
 
Randomization stratification factor (with 2 levels, presence or absence of 
cataplexy based on CRF data)  
“Baseline” refers to the baseline value of the response variable (mean MWT sleep 
latency time or total ESS score). SAS procedure PROC MIXED will be used to carry out 
this analysis. All available data will be included in the model. An unstructured 
covariance matrix will be used to model the correlation among repeated measurements 
unless convergence fails; in this case an auto-regressive (AR1) structure will be used. If 
the AR1 structure fails to converge, a compound symmetric structure will be used. The 
relative Hessian convergence criterion will be used in the MMRM model. Least square 
(LS) estimates of treatment differences (each JZP-110 dose group versus placebo for the 
primary analysis and combined JZP-110 group versus placebo for the additional 
exploratory analysis) and their 95% confidence intervals will be presented respectively.  
The primary analysis will be based on the mITT population. 
 
Secondary Analysis 
10.1.2.
For both co-primary efficacy endpoints, the analysis will be performed using the same 
statistical model as the primary analysis based on the PP population, instead of the 
mITT population. 
 
 
Sensitivity Analyses 
10.1.3.
This section describes analyses to explore the potential impact of missing data.  
Importantly, the analyses described in Section 10.1.1 are anticipated to be the most 
appropriate methods; the additional methods described in this section will be used to 
qualitatively evaluate the robustness of the primary analysis method.   
The sensitivity analyses will be based on the mITT population.  
10.1.3.1. Sensitivity Analyses using Single Imputation (SI) Approach 
The analysis of covariance (ANCOVA) model will be used to evaluate the change in co-
primary endpoints at Week 12 using the SI approaches described below. The ANCOVA 
model will include treatment as a fixed effect and the baseline value of the endpoint 
and randomization stratification factor as covariates. 


 
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 
SI Approach 1: Last observation carried forward 
SI approach 1 is a simple and common method for handling missing data. LOCF is used 
extensively in spite of the fact that it requires the following two strong assumptions: (1) 
missing data due to dropouts completely at random (MCAR) following early 
discontinuation, and (2) response following a subject dropping out remains constant 
following the last observed value prior to drop out. For each subject, missing data at 
Week 12 will be replaced with the last non-missing value.  
 
SI Approach 2: Mean Imputation 
SI approach 2 also assumes MCAR, meaning that the probability of an observed data 
point being missing does not depend either on the observed data or unobserved data. 
For each subject, missing data at Week 12 will be replaced with the corresponding 
treatment group mean. 
 
10.1.3.2. Sensitivity Analyses using Multiple Imputation (MI) Approach 
Instead of filling in a single value for each missing value, Rubin’s (1987) multiple 
imputation procedure replaces each missing value with a set of plausible values that 
represent the uncertainty about the right value to impute. 
 
Collected data are often incomplete, with a mixed monotone and non-monotone 
structure. For example, some subjects may drop out from the study, resulting in a 
monotone pattern of missing data. Alternatively, data may be missing intermittently 
due to invalid measurements; this non-monotone pattern is considered missing at 
random (MAR). 
 
Two MI methods are planned: 
 
Markov chain Monte Carlo (MCMC) method (Schafer 1997): For non-monotone missing 
data patterns, the MCMC assumes multivariate normality and generates multiple 
imputations using simulations from a Bayesian prediction distribution for normal data. 
Without prior information about the mean and covariance estimates, a noninformative 
prior will be used under the MCMC method. 
 
Regression method: For monotone missing data patterns, a regression model is fitted 
for each variable with missing values. Based on the resulting model, a new regression 
model is simulated to impute subsequent missing values for the variable (Rubin 1987, 
pp.166-167). The process is repeated sequentially for variables with missing values. 
  
Based on these two MI methods, the missing data will be imputed using the following 
approaches. 
 


 
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MI Approach 1: Multiple Imputation using MCMC and Regression Method 
 
Step 1: non-monotone missing data will be imputed using the MCMC method within each 
treatment group 
 
Step 2: monotone missing data in each treatment group will be imputed using the 
regression method on the basis of the predicted future pattern for the same treatment 
group  
 
MI Approach 2: Pattern Mixture Model using Dropout Pattern Imputation 
 
Pattern-Mixture Model using dropout pattern imputation is planned to explore the 
possibility of non-ignorable missing data. 
For the missing data due to dropout, pattern-mixture imputation will be considered 
based on the dropout patterns. 
Scenario 1:  
MNAR (missing not at random):  
 
dropout due to lack of efficacy (LOE) in JZP-110 treatment groups  
MAR (missing at random):  
 
dropout due to other reason (not LOE ) in JZP-110  treatment groups 
 
dropout due to any reason in the placebo group 
Scenario 2:  
MNAR (missing not at random): 
 
dropout due to AE in JZP-110 treatment groups 
MAR (missing at random):  
 
dropout due to other reason (not AE ) in JZP-110 treatment groups 
 
dropout due to any reason in the placebo group 
Scenario 3: 
MNAR (missing not at random): 


 
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 
dropout due to AE or LOE in JZP-110 treatment groups 
MAR (missing at random):  
 
dropout due to other reason (not AE or LOE ) in the treatment groups 
 
dropout due to any reason in the placebo group 
A tipping point method will be used to investigate the robustness of the primary analysis 
method. Imputed values in JZP-110 treatment groups that fall into a MNAR pattern will 
be adjusted under different scenarios above (Carpenter and Kenward 2013, pp. 237–239; 
van Buuren 2012, pp. 88–89) by using the delta adjustment imputation method. 
If missing data in the JZP-110 treatment groups falls into a MNAR pattern, the analysis 
will assume the treatment differences at the primary analysis visit (Week 12) 
progressively decrease from 0%, 10%, 20%, .., and up to 100% (i.e., equivalent to 
placebo). Otherwise, MCMC for the non-monotone missing data based on MAR 
assumption and regression method for monotone missing data on the basis of the 
predicted future pattern for the same treatment group will be applied. 
The tipping point analysis will be performed for each co-primary endpoint separately if 
the primary analysis results are statistically significant (p-value<0.05). The procedure 
will be implemented using the steps delineated below: 
Step 1: non-monotone missing data in JZP-110 treatment and placebo groups will be 
imputed using the MCMC method within each treatment group. 
Step 2: the monotone missing data in the placebo group and JZP-110 treatment groups 
that fall into MAR pattern will be imputed using the regression method on the basis of 
the predicted future pattern for the same treatment group. 
Step 3: for the monotone missing data in the JZP-110 treatment groups (e.g., 37.5mg, 
75 mg, 150 mg, and 300 mg) that fall into MNAR pattern: 
3.1 
For missing data at the visits (e.g., Week 1, Week 4, or Week 8) before 
the primary analysis visit at Week 12: 
Based on the observed data in the MNAR subgroup (e.g., AE, LOE, and (AE 
or LOE)), the following regression methods will be used in sequence to 
determine the applicable “imputation method” to impute the MNAR data 
prior to the primary analysis visit at Week 12: 


 
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 
The regression method on the basis of the predicted future pattern 
for the same subgroup (e.g., AE, LOE, or (AE or LOE)) by the JZP-110 
treatment groups (37.5mg, 75 mg, 150 mg, 300mg) 
 
The regression method on the basis of the predicated future pattern 
for the same subgroup (e.g., AE, LOE, or (AE or LOE)) while combining 
the JZP-110 treatment groups 
 
The regression method on the basis of the predicated future pattern 
for the early termination subgroup regardless of the ET reasons while 
combining the JZP-110 treatment groups 
 
The regression method on the basis of the predicted future pattern 
for the same treatment group, which is the same approach at step 2. 
3.2 For the  primary analysis visit (i.e. Week 12), missing data at Week 12 will be 
imputed by regression method by using the imputed data prior to the Week 12 
(Section 3.1) and all of the observed data from the treatment group  
3.3 The imputed value at the primary analysis visit (i.e. Week 12) for JZP-110 
treatment groups that fall into the MNAR pattern will be subtracted 
progressively by a delta = k (0%,  10%, 20%, ..,100%) * LS mean treatment 
difference at this visit (i.e. Week 12) obtained from the primary analysis 
method described in Section 10.1.1. 
Depending on the number of observed data in the JZP-110 treatment groups that fall 
into an MNAR pattern, step 3 will be performed for the three drop out scenarios 
separately: dropout due to LOE in the JZP-110 treatment groups, dropout due to AE in 
the JZP-110 treatment groups, and drop out due to LOE or AE in JZP-110 treatment 
groups. 
Step 4: One hundred (100) imputed datasets will be generated for each MI analysis. 
Each imputed dataset is analyzed separately using the MMRM model specified in Section 
10.1.1. The final estimate of treatment difference will be the average of the estimates 
based on the 100 individual imputed datasets. The pooling of the individual estimates 
and inferences based on the combined estimate will be handled by SAS procedure 
MIANALYZE. 
Step 3.3 will be repeated iteratively while increasing the penalty (e.g., 10%, 20%, …, 
100%) for the missing data in the JZP-110 treatment groups that fall into an MNAR 
pattern and keeping all the other imputed data unchanged, until the tipping point value 
(i.e., where p-value > 0.05) is identified. 


 
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Subgroup Analyses 
10.1.4.
The primary analysis in Section 10.1.1 will be used for the subgroup analyses. However, 
the randomization stratification factor (with 2 levels, presence or absence of cataplexy 
based on the CRF data) will be removed from the model for the analysis by subgroups pf 
subjects with presence or absence of cataplexy. The analysis will be based on the mITT 
population. 
 
KEY SECONDARY EFFICACY ENDPOINT AND ANALYSES 
10.2.
The key secondary efficacy endpoint is the percentage of subjects reported as improved 
(minimally, much, or very much) on the PGIc at Week 12.  
 
Primary Analysis 
10.2.1.
The percentage of subjects reported as improved on the PGIc at Week 12 will be 
calculated and summarized by treatment group. Comparisons will be performed 
between each JZP-110 group vs placebo for primary analysis and combined JZP-110 vs 
placebo for additional explorative analysis using a chi-square test. 95% confidence 
intervals for the difference in proportions will be calculated.  Missing data at Week 12 
for the key secondary efficacy endpoint will be imputed using LOCF. The analysis will be 
based on the mITT population.  
 
Secondary Analysis 
10.2.2.
The secondary analysis of the key secondary endpoint will be performed using the same 
statistical method as the primary analysis based on the PP population, instead of mITT 
population.  
 
Sensitivity Analyses 
10.2.3.
Missing data at Week 12 will be imputed using the following single imputation 
approaches:  
Approach 1 – SI Varies by Early Termination Reason 
Subjects with missing data at Week 12 due to discontinuation by lack of efficacy or 
adverse events will be considered non-responders at Week 12. Subjects with missing 
data at Week 12 for other reasons will be imputed using LOCF. 
Approach 2 – SI by the Worst-Case  
Subjects with missing data at Week 12 will be considered non-responders.   


 
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The chi-square test will be used to test treatment difference between each JZP-110 
dose group vs placebo and combined JZP-110 vs placebo. 95% confidence intervals for 
the difference in the percentages between treatment groups will be calculated. These 
analyses will be based on the mITT population.  
 
Subgroup Analyses 
10.2.4.
The primary analysis in Section 10.2.1 will be used for the subgroup analyses. Analyses 
will be based on the mITT population. 
    
 
OTHER SECONDARY EFFICACY ENDPOINTS AND ANALYSES 
10.3.
Other secondary efficacy endpoints will be analyzed based on the mITT population. 
 Time Course of Efficacy on the MWT: Change in Sleep Latency Time 
10.3.1.
(in Minutes) on Each of the 5 MWT Trials  
For the time course of efficacy analysis, the dose(s) that show(s) significant difference 
versus placebo in both MWT and ESS will be considered efficacious dose(s). For each of 
these doses, additional testing to characterize the time course of efficacy on the MWT 
will be performed. The mean and standard error of the mean MWT data will be 
displayed graphically for the dose and placebo. Pairwise comparison vs. placebo for 
each of the 5 MWT trials will be conducted at a significance level of 0.05 using a similar 
MMRM model described in Section 10.1.1. Characterizing the time course of efficacy will 
begin with identifying the first trial that demonstrates a significant difference from 
placebo. If such a trial is identified, the treatment difference at the next trial will be 
examined. If the treatment difference for the next trial is also significant at the 0.05 
level, the treatment will be considered efficacious at the time of the next trial. This 
procedure will continue as long as significance for each subsequent trial is observed or 
until trial 5 is examined.  
 
 CGIc: Percentage of Subjects Reported as Improved (Minimally, Much, 
10.3.2.
or Very Much) at Weeks 1, 4, 8, and 12 
The percentage of subjects reported as improved on the CGIc at Week 1, 4, 8, and 12 
will be calculated and summarized by treatment group. Comparisons will be performed 
between each JZP-110 group vs placebo and combined JZP-110 vs placebo using a chi-
square test at each time point; 95% confidence intervals for the difference in 
proportions will be calculated.  LOCF will be used for subjects with missing data. 
Similar analyses will be conducted for the subgroups listed in Section 8.7.  


 
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 MWT: Change in the Mean Sleep Latency Time (in Minutes) as 
10.3.3.
Determined from the First Four Trials of a 40-minute MWT from 
Baseline to Week 4  
Change in mean sleep latency time (in minutes) as determined from the first four trials 
of a 40-minute MWT from Baseline to Week 4 will be analyzed using the methods 
described for the primary analysis of the co-primary efficacy endpoints (Section 10.1.1). 
Similar analyses will be conducted for the subgroups listed in Section 8.7.  
 ESS: Change in ESS Score from Baseline to Weeks 1, 4, and 8 
10.3.4.
Change in ESS score from Baseline to Weeks 1, 4, and 8 will be analyzed using the 
methods described for the primary analysis of the co-primary efficacy endpoints 
(Section 10.1.1). 
Similar analyses will be conducted for the subgroups listed in Section 8.7.  
 PGIc: Percentage of Subjects Reported as Improved (Minimally, Much, 
10.3.5.
or Very Much) at Weeks 1, 4 and 8  
The percentage of subjects reported as improved at Weeks 1, 4, and 8 will be analyzed 
using the methods described for the primary analysis of the key secondary endpoint 
(Section 10.2.1).   
Similar analyses will be conducted for the subgroups listed in Section 8.7.  
 
FUNCTIONAL OUTCOMES AND QUALITY OF LIFE 
10.4.
ENDPOINTS 
Analyses of functional outcomes and quality of life endpoints will be based on the mITT 
population. 
 FOSQ-10: Change in the Total Score and 5 Subscales from Baseline to 
10.4.1.
Weeks 1, 4, 8, and 12 
FOSQ-10 total score the mean of non-missing 5 subscales (General Productivity, Activity 
Level, Vigilance, Social Outcomes, Intimacy and Sexual Relationship) multiplied by 5.. 
Change from Baseline in the FOSQ-10 total score to Weeks 1, 4, 8, and 12 will be 
summarized and analyzed using a similar MMRM model as the primary analysis of the co-
primary efficacy endpoints (Section 10.1.1). Change from baseline in the 5 FOSQ-10 
subscales to Weeks 1, 4, 8, and 12 will also be summarized. 


 
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Similar analyses will be conducted for the subgroups listed in Section 8.7. 
 SF-36v2: Change in 8 Domain Scores, Physical Component Summary 
10.4.2.
(PCS) Score, and Mental Component Summary (MCS) Score from 
Baseline to Weeks 4, 8, and 12 
The survey is summarized into 8 domains/scales: physical functioning (PF), role-physical 
(RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role-
emotional (RE), and mental health (MH). From the eight domains, a physical component 
summary (PCS) (aggregate of the PF; RP; BP and GH scales) and a mental component 
summary (MCS) (aggregate of the VT; SF; RE and MH scales) measures are derived.  
 
SF-36 items and scales are scored so that a higher score indicates a better health state. 
Scoring the SF-36 involves several steps. First, 10 items are reverse-coded and an 
algorithm for an algebraic summation of item scores is applied to produce domain-
specific raw scales that account for missing item responses. Domain-specific raw scales 
are then transformed to a 0 to 100 range, after which a norm-based (T-score) 
transformation is applied so that each scale ranges from 0 to 100, with a mean of 50 
and a standard deviation of 10 in the 1998 general U.S. population (Ware et al 2000). 
The norm-based transformation is applied so that domain-specific scales can be 
meaningfully compared between each other.  
 
The mental and physical component summary scores (MCS/PCS) are computed by 
aggregating domain scores using factor score coefficients from the 1998 general U.S. 
population (Ware et al 2000). The aggregated summary scores are standardized to have 
a mean of 50 with a standard deviation of 10 in the general 1998 U.S. population (Ware 
et al 2000). 
 
When calculating the raw domain scores, if at least half the item scores for a domain 
are non-missing, the missing item scores will be replaced with the average of the non-
missing scores for the domain. Otherwise the raw domain score and corresponding 
norm-based domain scores will be set to missing. 
 
Domain scores and component summary scores will be calculated using the Quality 
Metric (QM) Certified Scoring software provided by Optum, Inc.  
 
Changes in domain scores (norm-based), the physical component summary (PCS) score, 
and the mental component summary (MCS) score from Baseline to Weeks 4, 8 and 12 
will be analyzed using a similar MMRM model as the primary analysis of the co-primary 
efficacy endpoints (Section 10.1.1). 
 


 
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 EQ-5D-5L: EQ-5D Dimensions at Week 1, 4, 8, and 12 
10.4.3.
EQ-5D-5L has 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression). Each dimension has 5 levels of response (e.g. 1=no problem, 
2=slight problem, 3=moderate problem, 4=severe problem, 5=unable). 
If multiple levels of response are checked for a single dimension, then the level of 
response will be treated as a “missing value” at the dimension.  
The chi-square test will be used to test the treatment differences between each JZP-
110 group (JZP-110 dose groups and combined JZP-110) and placebo in the endpoints 
below.    
 
Number and percentage of subjects in each of the 5 levels (e.g., no problem, 
slight problem, moderate problem, severe problem, unable) for each dimension 
at Baseline and Weeks 1, 4, 8, and 12. 
 
Number and percentage of subjects reporting any problems (levels 2-5) for each 
dimension at Baseline and Weeks 1, 4, 8, and 12. 
Similar analyses will be conducted for the subgroups listed in Section 8.7. 
 EQ VAS:  Change in the VAS Score from Baseline to Weeks 1, 4, 8, and 
10.4.4.
12 
EQ VAS score is ranged from 0 to 100, with a higher score indicating a better health 
condition. Change in the EQ VAS score from Baseline to Weeks 1, 4, 8, and 12 will be 
analyzed using a similar MMRM model as the primary analysis of co-primary efficacy 
endpoints (Section 10.1.1). 
The EQ VAS score at each time point and change from Baseline to each post-baseline 
time point will be summarized by treatment group using mean, SD, minimum , 25th 
percentile, median, 75th percentile, and maximum.  
Similar analyses will be conducted for the subgroups listed in Section 8.7.  
 EQ-5D-5L Index: Index Value from Baseline to Week 1, 4, 8, and 12 
10.4.5.
Health states in the EQ-5D-5L can be converted into a single index value, where index 
values are presented in the country specific value sets to facilitate the calculation of 
quality-adjusted life years (QALYs). EQ-5D-5L value sets can be used to obtain the EQ-
5D-5L index values based on the crosswalk for the respective countries: Denmark, 
France, Germany, Japan, the Netherlands, Spain, Thailand, UK, US, Zimbabwe. 
References: http://www.euroqol.org/about-eq-5d/valuation-of-eq-5d/eq-5d-5l-value-


 
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sets.html; van Hout B, Janssen MF, et al. Interim scoring for the EQ-5D-5L: Mapping the 
EQ-5D-5L to EQ-5D-3L value sets. Value in Health 2012 Jul-Aug; 15(5):708-15. 
Change in the EQ-5D-5L index value from Baseline to Weeks 1, 4, 8, and 12 will be 
analyzed using a similar MMRM model as the primary analysis of co-primary efficacy 
endpoints (Section 10.1.1). 
EQ-5D-5L index value at each time point and change from Baseline to each post-baseline 
time point will be summarized by treatment group using mean, SD, minimum , 25th 
percentile, median, 75th percentile, and maximum.  
Similar analyses will be conducted for the subgroups listed in Section 8.7.  
 WPAI:SHP: Change in WPAI:SHP Endpoints from Baseline to Week 
10.4.6.
1,4,8, and 12 
WPAI:SHP includes the following questions: 
 
1 = currently employed 
2a = hours missed from work due to narcolepsy 
2b = hours missed from work other reasons 
3 = hours actually worked 
4 = degree narcolepsy affected productivity while working 
5 = degree problem affected regular activities 
 
Endpoints and Scoring: 
 
The following four endpoints will be developed for evaluation of work productivity and 
activity impairment. Multiply scores by 100 to express in percentages. 
 
 
Percent work time missed due to problem: Score = Q2a/(Q2a+Q2b+Q3) 
 
 
Percent impairment while working due to problem: Score = Q4/10 
 
 
Percent overall work impairment due to problem:  
 Score = (Q2a+Q2b)/(Q2a+Q2b+Q3) + (1-(Q2a+Q2b)/(Q2a+Q2b+Q3)) x Q4/10 
 
 
Percent activity impairment due to problem: Score = Q5/10  
 
 
Analyses: 
 


 
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Change in the WPAI:SHP endpoints below from Baseline to Weeks 1, 4, 8, and 12 will be 
analyzed using a similar MMRM model as the primary analysis of co-primary efficacy 
endpoints (Section 10.1.1). 
 
 
Percent work time missed due to problem 
 
Percent impairment while working due to problem 
 
Percent overall work impairment due to problem  
 
Percent activity impairment due to problem 
 
 
EXPLORATORY ENDPOINTS 
10.5.
 Number of Cataplexy Attacks 
10.5.1.
The number of cataplexy attacks will be calculated by analysis periods, the duration of 
the analysis period is defined as below: 
 
Baseline period is the days prior to the day of first dose 
 
Week 1 period is from the first dose day to the End of Week 1 Visit Day  
 
Weeks 2 – 4  period is from the day after the Week 1 Visit to the End of Week 4 
Visit Day  
 
Weeks 5 – 8  period is from the day after the Week 4 Visit to the End of Week 8 
Visit Day 
 
Weeks 9 – 12 period is from the day after the Week 8 Visit to the End of Week 12 
Visit Day  
 
Change in the mean and median weekly number of cataplexy attacks from Baseline to 
each analysis period will be summarized. A Wilcoxon rank-sum test will be used to 
compare each treatment group vs placebo and combined JZP-110 vs placebo. 
 
The mean weekly number of cataplexy attacks during each analysis period will be 
calculated by counting the total number of cataplexy attacks reported during the 
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 mean weekly number of cataplexy 
attacks. The median weekly number of cataplexy attacks during each analysis period is 
calculated by calculating the median daily number of cataplexy attacks reported during 
the period. The median number is then multiplied by 7 to determine the median weekly 
number of cataplexy attacks.  
 
No imputation is needed and all available data will be used for the calculation of the 
above endpoints. 
 
 
 Change in PSG Parameters from Baseline to Week 4 and 12 
10.5.2.
PSG parameters include the following:  


 
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 
Total sleep time (TST, in minutes) 
 
Stage N1 time (in minutes) 
 
Stage N2 time (in minutes) 
 
Stage N3 time (in minutes)  
 
Wake time after sleep onset (WASO, in minutes), total minutes of wakefulness 
recorded after sleep onset, as scored by epochs. 
o WASO = Wake epochs/2 - (Sleep Latency {+ Final Wake Time}) 
 
Number of awakenings 
 
APNEA Index (AI), the average number of apneas (obstructive, central and 
mixed) in an hour of sleep 
o Calculated as:  60 x total # of apneas / total sleep time in minutes 
 
AHI, the average number of apneas and hypopneas in an hour of sleep. 
o Calculated as: 60 x total # of (apneas + hypopneas) / total sleep time in 
minutes 
 
Number of central apneas 
 
Post-baseline minimum SaO2 value 
 
SaO2 
 
Change in each PSG parameter, except for number of awakenings and number of central 
apneas, from Baseline to Week 4 and 12 will be analyzed using a similar MMRM model as 
the primary analysis of co-primary efficacy endpoints (Section 10.1.1). 
 
Change in the number of awakenings and the number of central apneas from Baseline to 
Week 4 and 12 will be analyzed using a Wilcoxon rank sum test to compare the 
treatment difference between each JZP-110 group vs placebo and combined JZP-110 vs 
placebo.  
 
 
Categorical Analysis for Maintenance of Wakefulness Test 
10.5.3.
Categorical summaries and accompanying figures will be provided for each treatment 
group as follows:  
 
Number and percentage of subjects with an increase in mean MWT sleep latency 
from Baseline to Week 4 and 12 will be summarized by increase every 5 minutes 
(e.g. >=5 min, >=10 min, >=15 min, >=20 min, >=25 min and >=30 min)  
 
 
SUMMARY OF EFFICACY ANALYSIS METHODS 
10.6.
Endpoint 
Time 
Point 
Analysis / 
Population 
Method 
Missing Data Imputation 


 
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Endpoint 
Time 
Point 
Analysis / 
Population 
Method 
Missing Data Imputation 
Co-primary 
Change from Baseline 
in MWT, ESS   
Week 12 
Primary/ 
mITT 
MMRM 
 
 
 
Secondary/ 
PP 
MMRM 
 
 
 
Sensitivity/ 
mITT 
ANCOVA 
SI: LOCF;  
SI: Mean Imputation;   
 
 
 
 
MMRM 
MI: Multiple Imputation 
Using MCMC and 
Regression Method 
 
MI: Pattern Mixture Model 
using Dropout Pattern 
Imputation 
 
 
Subgroup/ 
mITT 
MMRM 
 
Key Secondary 
Improvement in PGIc 
Week 12 
Primary/  
mITT 
Chi-
square 
SI:LOCF 
 
 
Secondary/ 
PP 
Chi-
square 
 
 
 
Sensitivity/ 
mITT 
Chi-
square 
SI: Varies by early 
termination reason;  
SI: Worst-case 
 
 
Subgroup/ 
mITT 
Chi-
square 
SI:LOCF 
Other Secondary 
Change from Baseline 
in MWT 
Week 4  
Primary/ 
mITT  
MMRM 
 
 
 
Subgroup/ 
mITT 
MMRM 
 
Change from Baseline 
in ESS 
Weeks 
1, 4, 
and 8 
Primary/ 
mITT 
MMRM 
 
 
 
Subgroup/ 
mITT 
MMRM 
 
Improvement in PGIc 
Weeks 
1, 4, 
and 8 
Primary/ 
mITT 
Chi-
square 
SI:LOCF 
 
 
Subgroup/ 
Chi-
SI:LOCF 


 
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Endpoint 
Time 
Point 
Analysis / 
Population 
Method 
Missing Data Imputation 
mITT 
square 
Improvement in CGIc 
Weeks 
1, 4, 8, 
and 12 
Primary/ 
mITT 
Chi-
square 
SI:LOCF 
 
 
Subgroup/ 
mITT 
Chi-
square 
SI: LOCF 
Time course on MWT 
Weeks 4 
and 12 
Primary/ 
mITT 
MMRM 
 
Functional and Quality of Life 
Change from Baseline 
in FOSQ-10 total score 
Weeks 
1, 4, 8 
and 12 
Primary/ 
mITT  
MMRM 
 
 
 
Subgroup/ 
mITT 
MMRM 
 
Change from Baseline 
in SF-36 domain and 
summary scores 
Weeks 
4, 8, 
and 12 
Primary/ 
mITT  
MMRM 
 
EQ-5D-5L Dimensions: 
number and 
percentage in each of 
the 5 levels and 
reporting any problem 
(levels 2-5) 
Weeks 
1, 4, 8, 
and 12 
Primary/ 
mITT 
Chi-
square 
 
 
 
Subgroup/ 
mITT 
Chi-
square 
 
Change from Baseline 
in EQ VAS 
Weeks 
1, 4, 8 
and 12 
Primary/ 
mITT 
MMRM 
 
 
 
Subgroup/ 
mITT 
MMRM 
 
Change from Baseline 
in EQ-5D-5L Index 
Weeks 
1, 4, 8 
and 12 
Primary/ 
mITT 
MMRM 
 
 
 
Subgroup/ 
mITT 
MMRM 
 
Change from Baseline 
in WPAI:SHP scores 
Weeks 
1, 4, 8 
and 12 
Primary/ 
mITT 
MMRM 
 
Exploratory 
Change from Baseline 
in mean and median 
Analysis 
periods 
Primary/Saf
ety 
Wilcoxo
n rank 
 


 
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Endpoint 
Time 
Point 
Analysis / 
Population 
Method 
Missing Data Imputation 
weekly number of 
cataplexy attacks 
after 
Baseline 
sum  
Change from Baseline 
in number of 
awakenings  
Weeks 4 
and 12 
Primary/ 
mITT 
Wilcoxo
n rank 
sum  
 
Change from Baseline 
in number of central 
apneas 
Weeks  
4 and 12 
Primary/ 
mITT 
Wilcoxo
n rank 
sum  
 
Change from Baseline 
in PSG Parameters, 
except for number of 
awakenings and 
number of central 
apneas 
Weeks  
4 and 12 
Primary/ 
mITT 
MMRM 
 


 
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ANALYSIS OF PHARMACOKINETICS 
11.
PK analyses will be performed for the PK Analysis Population. 
 
Concentration of JZP-110, date/time of PK sample collection, date/time of study drug 
dosing, the flag on whether the study drug was taken on the sampling day and on 
previous 2 days per schedule and all comments will be listed by nominal sampling time 
point (Week 1, Week 4 , Week 8 Sample 1 and Week 8 Sample 2), sorted by JZP-110 
treatment groups. In addition, scatter plot of JZP-110 concentrations over time (Week 
1, Week 4, Week 8 Sample 1 and Week 8 Sample 2) will be provided, sorted by JZP-110 
treatment groups. Spaghetti plot of each subject’s JZP-110 concentration over time 
(Week 1, Week 4, Week 8 Sample 1 and Week 8 Sample 2) will also be provided, sorted 
by JZP-110 treatment groups. 
 
Other PK analyses will be included in a separate population PK analysis plan. 
 
 
 
 


 
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SAFETY 
12.
Safety analyses will be based on the safety population. No inferential statistics will be 
performed; only summary statistics will be provided unless otherwise noted.  Missing 
safety data will not be imputed. 
 
EXTENT OF EXPOSURE 
12.1.
Exposure to study drug (in days) is calculated as last dose date of study drug – first dose 
date of study drug + 1 by treatment group.  In additional, overall exposure to JZP-
110 (in days) is calculated as last dose date of study drug – first dose date of 
study drug + 1 regardless of the JZP-110 dose level. 
  
 
TREATMENT COMPLIANCE  
12.2.
Study drug compliance (%) is calculated as: 100 x (total number of capsules dispensed – 
total number of capsules returned)/ total number of capsules expected to be taken 
during the study (once daily). 
 
Compliance will be summarized by treatment group. In addition, the number and 
percentage of subjects in pre-specified compliance categories (< 80%, 80-100%, >100%, 
>120%) will be summarized by treatment group.  
 
Overall Compliance will also be summarized, regardless of dose level. 
 
 
ADVERSE EVENTS 
12.3.
Adverse events will be coded using MedDRA 18 to classify events under primary SOC and 
PT. 
 
A TEAE is defined as an AE that either begins after the first dose of study drug or 
worsens after the first dose of study drug. 
  
TEAEs will be summarized by SOC and PT and by treatment groups with sorting based on 
alphabetical order for the SOC and frequency count (descending order) for the PT.  In 
addition, the incidence of all TEAEs and serious TEAEs will be summarized by PT with 
sorting based on the frequency count (descending order). 
 
An overview of adverse events will include the number and percent of subjects who had 
at least one TEAE, Serious TEAE, TEAE related/suspected to be related to study drug, 
TEAE related/suspected to be related to study procedure, study drug withdrawn due to 
TEAE, maximum severity of TEAE, or AE with fatal outcome. 
  


 
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Multiple occurrences of an AE are counted only once per subject per SOC and PT for 
summary tables. 
 
The following TEAEs will be summarized: 
 
 
Incidence of all TEAEs 
 
Incidence of all TEAEs by maximum severity (severe, moderate and mild) 
specified by investigators  
 
Incidence of TEAEs related/suspected to be related to study drug specified by 
investigators 
 
Incidence of TEAEs related/suspected to be related to study procedure specified 
by investigators 
 
Incidence of serious TEAEs 
 
Incidence of serious TEAEs related/suspected to be related to study drug 
specified by investigators 
 
Incidence of TEAEs leading to study drug dose reduction   
 
Incidence of TEAEs leading to study drug dose increase 
 
Incidence of TEAEs leading to study drug interruption 
 
Incidence of TEAEs leading to study drug withdrawn and withdrawn from study  
 
Incidence of TEAEs in which the outcome is fatal 
 
Incidence of TEAEs occurring in ≥ 5 and ≥ 10% of subjects in any treatment group will be 
tabulated.   
 
All data collected in the AE case report form (CRF) will be listed in by-subject listings.   
 
 
Subgroup Analyses 
12.3.1.
The following analyses will be also repeated for the subgroups listed in Section 8.7: 
 
 
Overview of AEs 
 
Incidence of all TEAEs 
 
Incidence of TEAEs related/suspected to be related to study drug specified by 
investigators 
 
Incidence of TEAEs leading to study drug withdrawn and withdrawn from study 
 
Incidence of Serious TEAEs 
 
Incidence of TEAEs in which outcome is fatal 
 
 
LABORATORY EVALUATIONS 
12.4.
If a continuous laboratory value is reported as either below or above the limits of 
quantification, the qualifiers should be dropped and the numeric value will be used in 
the analysis (e.g., “< 3” should be “3” and “> 200” should be “200”). 


 
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The observed data at each time point and change from baseline at each post-baseline 
time point in hematology, serum chemistry and quantitative urinalysis test results will 
be summarized by treatment group.  
For hematology and serum chemistry including calculated creatinine clearance, normal 
ranges for each parameter will be used to categorize the test result as low (value lower 
than the lower limit), normal (value within the normal range), or high (value higher 
than the upper limit). For urinalysis, test results will be categorized as normal and 
abnormal. Frequency counts and percentages will be presented at each time point by 
treatment groups for these categorical data. 
Additional information on clinical significance will also be included in the listing of lab 
values. 
 
VITAL SIGNS AND 24-HOUR AMBULATORY BLOOD PRESSURE 
12.5.
MONITORING 
 
Regular Vital Signs 
12.5.1.
For the vital signs obtained on the admission to the site in the evenings before the PSG 
nights at Baseline, Weeks 4 and 12 and for vital signs at Weeks 1, 8, and at the Follow-
up visit or Early Termination visit, the observed values at each time point and the 
change from Baseline in each vital sign parameter to each post-baseline time point will 
be summarized by treatment group. 
The number and percentage of subjects change from Baseline in blood pressure and 
heart rate to each post baseline time point in the following categories will be 
summarized:  
 
 
% of subjects with an increase in HR of ≥15 and ≥30   
 
% of subjects with a decrease in HR of ≥15 and ≥30   
 
% of subjects with an increase in SBP of ≥10, ≥20, and ≥30 
 
% of subjects with a decrease in SBP of ≥10, ≥20, and ≥30 
 
% of subjects with an increase in DBP of ≥10, ≥20, and ≥30 
 
% of subjects with a decrease in DBP of ≥10, ≥20, and ≥30 
  
Reference ranges for each vital sign parameter will be used to categorize the results as 
low  
(lower than the lower limit), within the reference range, or high (higher than the upper 
limit). In addition, shifts in categories from Baseline to each post-baseline time point 
for each parameter will be summarized by treatment group. 
 
Reference ranges: 


 
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Parameter 
Lower Limit of Reference 
Range 
Upper Limit of 
Reference Range 
Systolic Blood Pressure (mmHg) 
90 
155 
Diastolic Blood Pressure (mmHg) 
60 
95 
Heart Rate (beats/min) 
Female: 55, Male 50 
Female: 95, Male 90 
Respiration Rate (breaths/min) 
12 
30 
 
 
Blood Pressure and Pulse on the MWT day 
12.5.2.
On the MWT day at Baseline (Day -1), blood pressure and pulse will be taken 
approximately 30 minutes after awakening. Blood pressure and pulse will also be taken 
approximately 2, 3, 5, 7, 9 and 11 hours after awakening. 
 
On MWT days at the end of Weeks 4 and 12 (or Early Termination if PSG/MWT is 
performed), blood pressure and pulse will be taken approximately 0.5 hour before 
dosing. Blood pressure and pulse will be taken at approximately 1, 2, 4, 6, 8, and 10 
hours after dosing. 
 
The blood pressure and pulse parameter obtained on the MWT day will be summarized 
as follows: 
 
 
Observed values and change from Day -1 (~0.5 hr relative to “Light on”)  to 
Week 4 and 12 (~(-0.5 hr) relative to dosing) visit  
 
Observed value and changes from the pre-dose (~(-0.5 hr)) to post-dose (~ 1 hr, 
~2 hrs, ~4 hrs, ~6 hrs, ~8 hrs, and ~10 hrs) at Week 4 and Week 12 visit  and 
observed value and change from the (~(0.5 hr)) after awakening to the 2, 3, 5, 7, 
9 and 11 hours after awakening at baseline (Day -1) visit 
 
In addition, mean of blood pressure and pulse based on the seven measurements taken 
during the MWT day (e.g., Day -1 at ~0.5 hr, 2 hrs, 3 hrs, 5 hrs, 7 hr, 9 hrs, and 11 hrs 
after awakening, Week 4 and 12 at ~(-0.5 hr), ~ 1 hr, ~2 hrs, ~4 hrs, ~6 hrs, ~8 hrs, and 
~10 hrs relative to dosing) will be calculated and the mean and mean changes from the 
Day –1 to the Week 4 and 12 visit  will be summarized.  
 
The number and percentage of the subjects with maximum change in blood pressure 
and pulse from pre-dose to any post-dose time points at the Week 4 and Week 12 visit, 
and the maximum mean change from Day -1 to Week 4 and Week 12 visit  will be 
summarized by following categories:  
 
 
% of subjects with an increase in HR of ≥15 and ≥30   
 
% of subjects with a decrease in HR of ≥15 and ≥30   
 
% of subjects with an increase in SBP of ≥10, ≥20, and ≥30 
 
% of subjects with a decrease in SBP of ≥10, ≥20, and ≥30 


 
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 
% of subjects with an increase in DBP of ≥10, ≥20, and ≥30 
 
% of subjects with a decrease in DBP of ≥10, ≥20, and ≥30 
 
Additional information on clinical significance will also be included in the listing of 
regular and MWT day vital signs. 
 
 
24 hour Ambulatory Blood Pressure Monitoring (ABPM) 
12.5.3.
For the ABPM BP and HR data obtained during Screening and Week 8 at 30 minute 
interval during a 24 hour period, the overall mean, mean during the daytime period 
from 7:00 to 22:00 and mean during the nighttime period from 22:00 to 7:00 will be 
summarized  by treatment group. 
  
The following endpoints will also be summarized: 
 
Change from overall mean value at Screening to overall mean value at Week 8 
 
Change from daytime mean value (7:00 to 22:00) at Screening to daytime mean 
value (7:00 to 22:00) at Week 8 
 
Change from nighttime mean value (22:00 to 7:00) at Screening to nighttime 
mean value (22:00 to 7:00) at Week 8 
 
In addition, the number and percentage of subjects in the above change from Screening 
endpoints will also be summarized by the following categories: 
  
 
% of subjects with an increase in HR of ≥15 and ≥30   
 
% of subjects with a decrease in HR of ≥15 and ≥30   
 
% of subjects with an increase in SBP of ≥10, ≥20, and ≥30 
 
% of subjects with a decrease in SBP of ≥10, ≥20, and ≥30 
 
% of subjects with an increase in DBP of ≥10, ≥20, and ≥30 
 
% of subjects with a decrease in DBP of ≥10, ≥20, and ≥30 
 
 
ECG  
12.6.
Observed data at each time point and the change from Baseline to each post-baseline 
time point in ECG parameters [HR, RR, PR, QRS, QT, and QT corrected with Fridericia’s 
formula (QTcF)] will be summarized by treatment group. 
 
The number and percentage of patients with QT and QTcF values falling into the 
following categories at each post baseline time point will be summarized by treatment 
groups: 
 
 
Change from baseline of 30 – 60 msec in QT and QTcF 


 
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 
Change from baseline of > 60 msec in QT and QTcF 
 
Post-baseline value > 480 msec and baseline value <= 480 msec in QT and QTcF  
 
Post-baseline value > 500 msec and baseline value <= 500 msec in QT and QTcF 
 
Additional information on clinical significance will also be included in the listing of ECG 
measurements. 
 
 
COLUMBIA-SUICIDE SEVERITY RATING SCALE 
12.7.
Suicidal Ideation, Suicidal Behavior, and Self- Injurious Behavior without Suicidal Intent 
at each time point will be classified by C-SSRS outcomes and composite score.  
 
 
C-SSRS Outcomes/Composite Scores 
12.7.1.
The following C-SSRS outcomes have binary responses (yes/no).  
   
 
Suicidal Ideation (Categories 1 – 5) 
1. Wish to be dead 
2. Non-specific active suicidal thoughts 
3. Active suicidal ideation with any methods (not plan) without intent to act 
4. Active suicidal ideation with some intent to act, without specific plan 
5. Active suicidal ideation with specific plan and intent 
 
 
Suicidal Behavior (Categories 6 – 10) 
6. Preparatory acts or behavior 
7. Aborted attempt 
8. Interrupted attempt 
9. Non-fatal suicide attempt 
10. Completed suicide 
 
 
Suicidal Ideation or Behavior (1-10) 
 
Self-injurious behavior without suicidal intent 
 
Composite endpoints based on the above categories are defined below. 
 
 
Suicidal ideation:  A “yes” answer during treatment to any one of the five 
suicidal ideation questions (Categories 1-5) on the C-SSRS. 
 
Suicidal behavior:  A “yes” answer during treatment to any one of the five 
suicidal behavior questions (Categories 6-10) on the C-SSRS. 
 
Suicidal ideation or behavior: A “yes” answer during treatment to any one 
of the ten suicidal ideation and behavior questions (Categories 1-10) on 
the C-SSRS. 
 


 
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Composite scores based on the above categories are defined below:  
 
Suicidal Ideation score (0 to   5) is based on answers (Yes) to five suicidal ideation 
questions (Categories 1-5) on the C-SSRS. 
0 = No suicidal ideation 
1 = Wish to be dead 
2 = Non-specific active suicidal thoughts 
3 = Activity suicidal ideation with any methods (not plan) without intent to act 
4 = Activity suicidal ideation with some intent to act, without specific plan 
5 = Activity suicidal ideation with specific plan and intent 
 
Suicidal Behavior score (6 to 10) is based on answers (Yes) to the five suicidal behavior 
questions (Categories 6-10) on the C-SSRS:  
 
0 = No suicidal behavior 
6 = Preparatory acts or behavior 
7 = Aborted attempt 
8 = Interrupted attempt 
9 = Non-fatal suicide attempt  
10 = Completed suicide 
 
Suicidal Ideation or Behavior score (0 to 10) is based on answers (Yes) to the ten suicidal 
ideation and behavior questions (Categories 1-10) on the C-SSRS. 
 
 
Analyses 
12.7.2.
The number and percentage of subjects having a response of ‘Yes’ to above 
outcomes/composite endpoints will be summarized by category and treatment group at 
each time point. 
 
In addition, to demonstrate treatment emergence in C-SSRS, shift from Baseline (shift 
to maximum score) to any post-baseline time point in each of the C-SSRS composite 
scores (Suicidal Ideation, Suicidal Behavior, Suicidal Ideation or Behavior) will be 
summarized by treatment group. Shift from Baseline to the most serious outcome (No 
suicidal ideation or behavior, Suicidal Ideation, or Suicidal Behavior) at any post-
baseline time point in the C-SSRS outcomes  will also be summarized by treatment group 
 
A listing of subjects with Suicidal Ideation, Suicidal Behavior, or self-injurious behavior 
without suicidal intent based on the C-SSRS at each time point will be provided.      
 
 


 
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INTERIM ANALYSES 
13.
No interim analysis is planned. 


 
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CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
14.
Changes from analysis planned in protocol include the following: 
Item 
Category 
Protocol 
SAP 
1 
Functional 
outcomes and 
quality of 
Life 
endpoints 
SF-36v2: Change in the total 
score and change in the 8 
subscales from Baseline to 
Week 4, Week 8, and Week 
12 
SF-36v2: Change in the physical 
component summary (PCS) 
score and the mental 
component summary (MCS) 
score and change in the 8 
subscales from Baseline to 
Week 4, Week 8, and Week 12 
2 
Exploratory 
Endpoint  
Change in the mean and 
median weekly number of 
cataplexy attacks in the 
subgroup of subjects who 
report the presence of 
cataplexy at screening from 
Baseline to Weeks 1 to 12 
Change in the mean and median 
weekly number of cataplexy 
attacks in the subgroup of 
subjects who report the 
presence of cataplexy at 
screening from Baseline to 
analysis periods Week 1, Weeks 
2-4, Weeks 5-8 and Weeks 9-12 
 


 
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REFERENCE 
15.
Rubin D.B.: Multiple Imputation for Nonresponse in Surveys. New York: John Wiley and  
Sons, 1987 
  
Schafer: Analysis of Incomplete Multivariate Data. Chapman & Hall, New York, 1997  
 
Ware JE: SF-36 Health Survey update. Spine, 25(24):3130–3139, 2000  
 
Carpenter, J. R. and Kenward, M. G. (2013), Multiple Imputation and Its Application, 
New York: John Wiley & Sons.  
van Buuren, S. (2012), Flexible Imputation of Missing Data, Boca Raton, FL: Chapman & 
Hall/CRC.