Clinical trial NCT02720744
Conditions: Excessive Daytime Sleepiness Cataplexy Narcolepsy
Sponsor: Avadel
Start date: 2016-11-17; Completion date: 2020-03-25
Enrollment: 212 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether once-nightly FT218 is safe and effective for the treatment of excessive daytime sleepiness and cataplexy in subjects with narcolepsy.

Detailed description:

Arms: arm 1: Patients will undergo a screening period and will then be titrated to the following once-nightly doses: 4.5 g sodium oxybate, 6.0 g sodium oxybate, 7.5 g sodium oxybate, and 9.0 g sodium oxybate. arm 2: Patients will undergo a screening period and will then be titrated to the following once-nightly doses: 4.5 g placebo, 6.0 g placebo, 7.5 g placebo, and 9.0 g placebo.
Interventions: intervention 1: FT218 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 


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1 
PROTOCOL APPROVAL SIGNATURES 
 


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2 
STUDY PERSONNEL 
Sponsor Personnel 
Clinical Operations 
Name: 
Courtney Wells 
Title: 
Vice President, Clinical Operations 
Address: 
Flamel Ireland Limited trading under the business name Avadel Ireland 
Blanchardstown Corporate Park 
Block 10-1, Ballycoolin 
Dublin 15 
Ireland 
Medical Director 
Name: 
Jordan Dubow , MD 
Title: 
Chief Medical Officer  
Address: 
Flamel Ireland Ltd trading under the business name Avadel Ireland 
Block 10, Unit 1, Blanchardstown Corporate Park 
Ballycoolin 
Dublin 15  
Ireland 
Statistician 
 


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CRO Personnel 
Project Manager 
Medical Monitor  
Name: 
David Seiden, MD 
Title: 
Senior Medical Director 
Address: 
Flamel Ireland Ltd trading under the business name Avadel Ireland 
 


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Other Personnel 
Drug Supply 
Central Clinical Laboratory 
Interactive Response Technology (IRT) 
Central Scoring Laboratory 
 




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to dosing will be no more than 7 days). For subjects randomized to the active arm of the study the maximum 
duration of treatment with FT218 will be 13 weeks incorporating up-titration over a period of 8 weeks with 5 weeks 
on stable dosing at 9.0 g/night. For subjects randomized to placebo, there is no exposure to the study treatment.  
A follow-up visit will occur at least 1 week after the last dose of FT218 or placebo (i.e. Period 4, Visit 9, Week 15, 
Day 1 [+4/-0 (i.e. a minimum of 7 days after the last on study dose)]). Additional follow-up for safety surveillance 
and management will be done for unresolved adverse events (AEs) as determined by the study investigator. 
Number of Subjects:  
Treatment: 
FT218 or placebo dosing will follow a 4 period up-titration as follows: FT218 4.5 g or placebo daily for 1 week, 
FT218 6.0 g or placebo daily for 2 weeks, FT218 7.5 g or placebo daily for 5 weeks, and FT218 9.0 g or placebo 
daily for 5 weeks. Study drug will be taken orally at bedtime. 
Study Duration: 
There will be a 3-week screening period, a 13-week treatment period and a 1-week follow-up period. Total duration 
of the study will be approximately17 weeks. 
Study Population: 
Male or female subjects 16 years of age or older; documented evidence of a diagnosis of NT1 or NT2 as, in part, 
determined by an overnight PSG and next-day multiple sleep latency test (MSLT) with 2 or more sleep-onset rapid 
eye movement (REM) periods with mean sleep latency in the pathological range i.e. < 8 minutes (screening, Visit 1) 
and MWT < 11 minutes (after 3-week screening period); current continuing presence of EDS as defined by subject 
report for the last 3 months and an ESS > 10; for NT1 only, current continuing presence of cataplexy as defined by 
subject report for the last 3 months; subjects may use concomitant stimulants, but must comply with the following: 
they must be on a stable dose of stimulants for at least 3 weeks prior to starting the screening process for this study; 
AND they must use the same stimulant regimen throughout the entire study period, including during screening and 
posttreatment periods. 
Primary Endpoints: 
The primary criteria that efficacy determination will be based on include: 
• 
Longer MWT sleep latency 
• 
Improvement in CGI sleepiness scores 
• 
Fewer cataplexy attacks as recorded by Sleep and Symptom Daily Diary 
Secondary/Exploratory Endpoints: 
Efficacy: 
Efficacy assessments include MWT, CGI, Sleep and Symptom Daily Diary, nocturnal PSG, and ESS 


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Safety: 
Safety assessments include AEs, laboratory parameters, vital signs, physical examination, 12-lead 
electrocardiogram, Columbia-Suicide Severity Rating Scale 
Statistical Analysis: 
A mixed-effects means model with repeated measures (MMRM) will be used to analyze change from baseline for 
each of the coprimary endpoints. Each model will include treatment, time, treatment–by time interaction, site and 
baseline score as fixed effects and subjects as random effects. 
 
 
The primary hypothesis tests of the efficacy of individual doses will be performed as contrasts within the mixed 
models. The hypothesis testing will proceed in the following order: first, to test hypotheses for EDS, both MWT and 
CGI will be examined for statistical significance for the 9.0 g dose using the data collected during Periods 3c(i), and 
3c(ii). If both tests are significant, NCA for the same dose will be tested. If the first test fails (either MWT or CGI 
not significant), the data for the 9.0 g dose was not able to reject the null hypothesis of equality to placebo for either 
symptom. If the first test is significant (both MWT and CGI significant) but the second test (NCA) fails, the dose 
has been demonstrated to exceed placebo for EDS treatment but not for cataplexy. If both tests are statistically 
significant, the dose has been shown to be effective for EDS and cataplexy.  
If the 9.0 g dose demonstrates efficacy for both EDS and cataplexy, the same sequence of testing will be followed for 
the 7.5 g dose using the data collected during Periods 3b(i) and 3b(ii). If  the 7.5 g dose demonstrates efficacy for both 
EDS and cataplexy, the same sequence of testing will be followed for the 6 g dose using the data collected during 
Period 3a.  
Each dose will be tested in a hierarchical order starting at the 9.0 g dose level at the 2-sided α level of 0.05. Efficacy 
tests for MWT and for CGI within a dose need not be adjusted, since both are required for demonstrating efficacy 
for EDS at that dose. Efficacy tests for NCA within a dose for demonstrating efficacy for cataplexy also need not be 
adjusted because the test is reached via a step down procedure. Within each step, rejection terminates all subsequent 
hypothesis tests, which will be deemed to be nonsignificant. A strictly exploratory analysis examining 
secondary/exploratory endpoints is also proposed to provide evidence of consistency. The type I error rate for these 
endpoints will all be tested at the α level of 0.05. 


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4 
TABLE OF CONTENTS 
1 
Protocol Approval Signatures ....................................................................................... 2 
2 
Study Personnel .............................................................................................................. 3 
3 
Synopsis ........................................................................................................................... 6 
4 
Table of Contents ............................................................................................................ 9 
5 
List of Abbreviations and Definition of Terms .......................................................... 12 
6 
Introduction................................................................................................................... 15 
6.1 
Scientific Background .................................................................................................. 15 
6.1.1 
Summary ........................................................................................................ 15 
6.1.2 
Disease Under Treatment .............................................................................. 15 
6.1.2.1 
Symptoms of Narcolepsy ............................................................................... 16 
6.1.2.2 
Pharmacologic Treatment Options ................................................................ 17 
6.2 
Background to FT218 Controlled-Release Technology ............................................ 18 
6.2.1 
Sodium Oxybate Drug Metabolism and Pharmacokinetics ........................... 18 
6.2.2 
FT218 Development ...................................................................................... 19 
6.3 
Preclinical Experience and Animal Models ............................................................... 19 
..................... 20 
6.5 
Study Rationale ............................................................................................................. 24 
6.6 
Potential Risks and Benefits ........................................................................................ 25 
7 
Study Objectives ........................................................................................................... 28 
7.1 
Primary Objective ........................................................................................................ 28 
7.2 
Secondary/Exploratory Objectives ............................................................................. 28 
7.3 
Safety Objective ............................................................................................................ 28 
8 
Investigational Plan ...................................................................................................... 29 
8.1 
Overall Study Design and Plan: Description .............................................................. 29 
8.1.1 
Study Design .................................................................................................. 30 
 
 ............................................................................... 31 
8.2 
Discussion of Study Design .......................................................................................... 35 
8.3 
Selection of Study Population ...................................................................................... 35 
8.3.1 
Number of Planned Subjects ......................................................................... 35 
8.3.2 
Inclusion Criteria ........................................................................................... 35 
8.3.3 
Exclusion Criteria .......................................................................................... 36 


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8.3.4 
Removal of Subjects From Therapy or Assessments .................................... 38 
8.3.4.1 
Pregnancy ...................................................................................................... 39 
8.4 
Investigational Product ................................................................................................ 40 
8.4.1 
Investigational Products Administered .......................................................... 40 
8.4.1.1 
Definition of a Schedule I/Controlled Drug Substance ................................. 40 
8.4.1.2 
FT218 Study Drug Risk Management ........................................................... 40 
8.4.1.3 
Specification for Managing Controlled Substances ...................................... 41 
8.4.1.4 
Drug Accountability ...................................................................................... 41 
8.4.1.5 
FT218/Placebo ............................................................................................... 42 
8.4.2 
Identity of Investigational Products ............................................................... 43 
8.4.3 
Packaging and Labelling ................................................................................ 43 
8.4.4 
Method of Assigning Subjects to Treatment Groups .................................... 44 
8.4.5 
Selection of Doses in the Study ..................................................................... 45 
8.4.6 
Selection and Timing of Dose for Each Subject ............................................ 45 
8.4.7 
Study Blinding and Unblinding Procedures .................................................. 46 
8.4.8 
Prior and Concomitant Therapy ..................................................................... 47 
8.4.8.1 
Prohibited Medication/Therapy ..................................................................... 47 
8.4.9 
Treatment Compliance ................................................................................... 48 
9 
Timing of Study Procedures ........................................................................................ 49 
9.1 
Pre-treatment – Periods 1 and 2 .................................................................................. 50 
9.1.1 
Period 1: Visit 1 (Week -3, Day 1) Screening and Assessment .................... 50 
9.1.2 
Period 2: Visit 2 (Week -1, Day 7) Baseline Visit ........................................ 51 
9.1.2.1 
Central Scoring Laboratory: PSG and MWT (+ 2 Days for results) ............. 52 
9.1.2.2 
Randomization ............................................................................................... 52 
9.2 
Treatment Period – Period 3 (Dose Titration and Stabilization) ............................. 53 
9.2.1 
Period 3a: Visit 3 (Week 1, Day 1) Dose Titration to 6.0 g/Night ................ 53 
9.2.2 
Period 3b(i): Visit 4 (Week 3, Day 7) Dose Titration to 7.5 g /Night ........... 54 
9.2.3 
Period 3b(ii): Visit 5 (Week 6, Day 1) 7.5 g/Night ....................................... 55 
9.2.4 
Period 3c(i): Visit 6 (Week 8, Day 7) Dose Titration to 9.0 g/Night, 
Stabilization ................................................................................................... 56 
9.2.5 
Period 3c(ii): Visit 7 (Week 11, Day 1) Stabilization ................................... 57 
9.2.6 
Period 3c(iii) Visit 8 (Week 13, Day 7) End of Study (EOS) ....................... 58 
9.3 
Follow-up Period – Period 4 ........................................................................................ 59 
9.3.1 
Period 4: Visit 9 (Week 15, Day 1) Follow-up .............................................. 59 
9.4 
Unscheduled Visits ........................................................................................................ 60 
9.5 
Duration of Treatment ................................................................................................. 61 
10 
Efficacy and Safety Variables ...................................................................................... 61 
10.1 Efficacy and Safety Measurements Assessed ............................................................. 61 
 
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10.1.1.1 Maintenance of Wakefulness Test ................................................................. 61 
10.1.1.2 Clinical Global Impression of Sleepiness ...................................................... 61 
10.1.1.3 Sleep and Symptoms Daily Diary .................................................................. 61 
.............. 62 
10.1.1.5 Epworth Sleepiness Scale .............................................................................. 62 
10.1.2 
Safety Assessments ........................................................................................ 62 
10.1.2.1 Adverse Events .............................................................................................. 62 
10.1.2.2 Clinical Laboratory Evaluation ...................................................................... 69 
10.1.2.3 Vital Signs ..................................................................................................... 70 
10.1.2.4 Physical Examination .................................................................................... 70 
10.1.2.5 Electrocardiogram .......................................................................................... 70 
10.1.3 
Appropriateness of Measurements ................................................................ 70 
11 
Statistical Methods ........................................................................................................ 71 
11.1 Statistical and Analytical Plans ................................................................................... 71 
11.2 Definition of the Analysis Populations ........................................................................ 71 
11.2.1 
Determination of Sample Size ....................................................................... 71 
11.2.2 
Randomization and Blinding ......................................................................... 71 
11.2.3 
Interim Analysis and Unblinding ................................................................... 72 
11.2.4 
Data and Safety Monitoring Board ................................................................ 72 
11.3 Analysis Sets .................................................................................................................. 72 
11.3.1 
Intent-to-Treat (ITT) Population .................................................................... 72 
11.3.2 
Per Protocol (PP) Population ......................................................................... 72 
11.3.2.1 Safety (S) Population ..................................................................................... 72 
11.4 Description of Statistical Analysis ............................................................................... 72 
11.4.1 
General Considerations .................................................................................. 73 
11.4.2 
Use of Analysis Sets ...................................................................................... 73 
11.4.3 
Analysis of Subgroups ................................................................................... 73 
 
............................................................................. 73 
11.5 Subject Disposition ....................................................................................................... 73 
11.6 Demographic and Other Baseline Characteristics .................................................... 73 
11.7 Medical History ............................................................................................................. 73 
11.8 Study Drug Exposure and Compliance ...................................................................... 74 
11.9 Efficacy Analysis ........................................................................................................... 74 
11.9.1 
Description of Primary Endpoints ................................................................. 74 
11.9.1.1 Primary Analysis ........................................................................................... 74 
11.9.1.2 Sequential Testing Approach for Comparing FT219 and Placebo ................ 74 
.................................. 75 
.................................. 75 
.................................. 76 


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11.10 Safety Analysis .............................................................................................................. 76 
11.10.1.1 Laboratory Data ............................................................................................. 76 
11.11 Data and Safety Monitoring Board ............................................................................. 76 
11.12 Central Scoring Laboratory ........................................................................................ 77 
11.13 Protocol Deviations ....................................................................................................... 77 
12 
Quality Assurance and Quality Control ..................................................................... 77 
12.1 Audit and Inspection .................................................................................................... 77 
12.2 Monitoring ..................................................................................................................... 77 
12.3 Data Management and Coding .................................................................................... 78 
13 
Records and Supplies ................................................................................................... 79 
13.1 Financing and Insurance .............................................................................................. 79 
14 
Ethics .............................................................................................................................. 80 
14.1 Independent Ethics Committee or Institutional Review Board ............................... 80 
14.2 Regulatory Authorities ................................................................................................. 80 
14.3 Ethical Conduct of the Study ....................................................................................... 80 
14.4 Informed Consent and Assent ..................................................................................... 80 
14.5 Subject Confidentiality ................................................................................................. 81 
15 
Reporting and Publication, Including Archiving ...................................................... 82 
16 
References ...................................................................................................................... 83 
17 
Appendices..................................................................................................................... 85 
17.1 Investigator Signature Page ......................................................................................... 86 
17.2 Study Drug Kit Dispensing .......................................................................................... 87 
 ................................................................................. 88 
17.4 Columbia-Suicide Severity Rating Scale (C-SSRS) – Since Last Visit 
Version 92 
17.5 Columbia-Suicide Severity Rating Scale (C-SSRS) – Baseline/Screening 
Version 93 
17.6 CGI-Severity (CGI-S) / CGI-Improvement (CGI-I) ................................................. 96 
17.7 Epworth Sleepiness Scale ............................................................................................. 97 
5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
AUC 
area under the curve 
BMI 
body mass index 
BP 
blood pressure 
CGI 
clinical global impression 
CNS 
central nervous system 
Cmax 
maximum concentration 
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DNS 
disturbed nocturnal sleep 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EDS 
excessive daytime sleepiness 
EMA 
European Medicines Agency 
ESS 
Epworth Sleepiness Scale 
FDA 
United States Food and Drug Administration 
FT218 
sodium oxybate for extended-release oral suspension 
GABA 
gamma-aminobutyric acid 
cGCP 
current Good Clinical Practice 
GHB 
gamma-hydroxybutyric acid (sodium oxybate) 
GI 
gastrointestinal 
HBs Ag 
hepatitis B surface antigen 
HCVAb 
hepatitis C virus antibody 
HH 
hypnagogic hallucinations 
HLA 
human leukocytes antigen 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
MAOI 
monoamine oxidase inhibitor 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSLT 
multiple sleep latency test 
MWT 
maintenance of wakefulness test 
n 
number of subjects with an observation 
N 
number of subjects in the dataset or population 
NCA 
number of cataplexy attacks 
NT1 
type 1 narcolepsy 
NT2 
type 2 narcolepsy 
PI 
principal investigator 
PK 
pharmacokinetic 
PP 
per protocol 
PSG 
polysomnography 
REM 
rapid eye movement 
SAE 
serious adverse event 
SOC 
system organ class 


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SOREM 
Sleep-onset REM 
SNRI 
serotonin and norepinephrine re-uptake inhibitors 
SP 
sleep paralysis 
SSRI 
selective serotonin re-uptake inhibitors 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
half-life 
TCA 
tricyclic antidepressants 
Tmax 
time to maximum concentration  
US 
United States 
VAS 
visual analog scale 
WHO 
World Health Organization 
 


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6 
INTRODUCTION 
6.1 
Scientific Background 
6.1.1 
Summary 
Sodium oxybate, also known as gamma-hydroxybutyric acid (GHB), was discovered in 1960. 
Sodium oxybate (GHB) is a metabolite of γ-aminobutyric acid (GABA) which is synthesized by 
neurons in the brain and functions as a neurotransmitter. Sodium oxybate is a central nervous 
system (CNS) depressant and produces dose-dependent sedation and anesthesia in laboratory 
animals. Sodium oxybate is currently indicated for the treatment of cataplexy and excessive 
daytime sleepiness (EDS) in subjects with narcolepsy at doses up to 9.0 g/night. In 2002, the US 
Food and Drug Administration (FDA) approved Xyrem® (sodium oxybate) oral solution as an 
orphan drug for the treatment of cataplexy in adult subjects with narcolepsy. In 2005, this 
approval was extended to the treatment of EDS for adults with narcolepsy. In Europe, sodium 
oxybate was granted Orphan Drug Designation in February 2003 (however, the orphan 
designation request has since been withdrawn), and the European Commission issued a decision 
in 2005 for its marketing authorization for the treatment of cataplexy in adult subjects with 
narcolepsy that was extended in 2007 to treating EDS in adults with narcolepsy.  
As part of a recent meeting for the narcolepsy community initiated by the Food and Drug 
Administration (FDA), the FDA inquired “Assuming there is no complete cure for your 
condition, what specific things would you look for in an ideal therapy for your condition?” In an 
interim report circulated from the patient advocacy community, Unite Narcolepsy, summarizing 
the results from a patient survey with 1350 responses in preparation for the FDA meeting, the 
first statement responding to the FDA’s question was an excerpt from a patient response stating 
“A drug that would provide consistent and adequate control of the daytime sleepiness without the 
hard crash and one that would require 1 dose taken at bedtime resulting in 8 hours of restorative 
sleep”.1 
Flamel Technologies has developed a drug delivery technology designed to extend and/or delay 
the absorption of a drug in order to control its pharmacokinetic (PK) profile. Based on this 
proprietary controlled-release delivery technology, Micropump®, Flamel Technologies has 
developed a new formulation of sodium oxybate which is more convenient for the subject in that 
it is dosed only once (i.e. at bedtime). The once nightly dosing is an improvement beyond the 
current approved dosing regimen for Xyrem that requires narcolepsy subjects to wake up in the 
middle of the night to take a second dose.  
6.1.2 
Disease Under Treatment 
Narcolepsy is a chronic, life-disrupting neurologically-based sleep disorder characterized by 5 
major symptoms, EDS, cataplexy, hypnagogic hallucinations (HH), sleep paralysis (SP), and 
disturbed nocturnal sleep (DNS). Narcolepsy is associated with increased morbidity,2,3 increased 
mortality,4 and reduced quality of life.5 In addition, there are significant social6,7 and economic8,9 
impacts for subjects with narcolepsy, their families, and the healthcare system.10 
Narcolepsy is currently dichotomized by the International Classification of Sleep Disorders-3 as 
either type 1 narcolepsy (NT1) or type 2 narcolepsy (NT2).11 Type 1 narcolepsy is diagnosed by 


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the presence of EDS, cataplexy, a Multiple Sleep Latency Test (MSLT) indicating 2 or more 
sleep-onset rapid eye movement (REM) periods (SOREMs) and a mean sleep latency in the 
pathological range (i.e. < 8 minutes), and/or low hypocretin (≤ 110 pg/mL). Type 2 narcolepsy is 
diagnosed in the absence of cataplexy and when hypocretin levels are greater than 110 pg/mL, 
but the other diagnostic criteria for NT1 are met, including EDS, a MSLT indicating 2 or more 
SOREMs and a mean sleep latency in the pathological range (i.e. < 8 minutes), as well as the 
absence of another sleep disorder that better explains the EDS.  
Narcolepsy is a rare disease, with 65,000 of the approximately 100,000 to 200,000 cases 
currently diagnosed in the US. Type 1 narcolepsy or narcolepsy with cataplexy is estimated to 
have a prevalence of 25 to 50 per 100,000 people and an incidence of 0.74 per 100,000 person-
years internationally.12,13,14 Evidence indicates that NT1 is caused by the loss of hypocretin (also 
called orexin) cells in the hypothalamus. Thus, the best biological marker for NT1 is the 
reduction or complete deficiency of hypocretin in the cerebrospinal fluid. 
Over 92% of Caucasian subjects with NT1 carry the human leukocytes antigen 
(HLA)-DQB1*06:02, while HLA-DQB1*06:03 allele confers a strong protection.15,16 The 
association with specific HLA alleles has allowed for the hypothesis that narcolepsy is an 
autoimmune disease, and progress has been made further substantiating an autoimmune origin 
for NT1 including: 1) anti-TRIBBLES-2 antibodies17, 2) elevated antistreptolysin O titers 
discovered close to disease onset18, and 3) the association with a polymorphism of T-cell 
receptor alpha gene and a polymorphism of the purinergic receptor P2RY11 gene.19 However, 
the mechanism for this autoimmune process remains unknown. 
6.1.2.1 
Symptoms of Narcolepsy 
The hallmark symptom of narcolepsy is EDS, and is hence required for the diagnosis of 
narcolepsy. It is also the most troublesome symptom and the one for which subjects most 
commonly seek treatment. Excessive daytime sleepiness is defined as the inability to stay awake 
and alert during the day, resulting in periods of involuntary sleep episodes or unintended lapses 
into “drowsiness” during activities of daily living. In narcolepsy, EDS can exist despite adequate 
nighttime sleep, is not caused by another disease or condition which better explains the EDS, or 
persists when other conditions known to also cause EDS are treated. The chronic and severe 
nature of EDS predisposes these subjects to deficits in multiple areas of functioning. When 
alertness is compromised (i.e. sleepiness is pervasive), performance may be diminished across a 
variety of cognitive functions, work related safety may be compromised, and productivity and 
overall quality of life may suffer. It is possible the performance deficits may precipitate reduced 
patient-reported quality of life and difficulty with achievement in work and/or school. Beyond 
this, the sleepiness can be so omnipresent as to cause subjects to socially withdraw, making 
relationships with family and friends difficult to maintain and potentially strained. 
Cataplexy, in the presence of EDS, is suggestive of NT1 and an indication for objective testing to 
confirm the diagnosis. Cataplexy is defined as a sudden muscle weakness episode and can affect 
a few muscles (for example, facial muscles) or all skeletal muscles at once. As a result of the 
muscle weakness, subjects momentarily have head nodding from weakness in the neck muscles, 
sagging of the jaw, buckling of the knees, dropping of objects from hands, and/or dysarthria or 


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inability to speak during the episode. Sometimes they may slump or fall forward onto the 
ground, either all at once or more gradually.  
Cataplexy attacks are typically brief, on average, lasting from milliseconds to 1 to 2 minutes. 
Cataplexy is typically triggered by emotions, most often by telling or hearing a joke, laughing, or 
becoming angry. These emotions have been combined to successfully identify cataplexy among 
cases and lack of cataplexy among controls with remarkable specificity. For those with 
cataplexy, though, a wide range of emotions may be triggers, including surprise, rage, fear, 
enjoyment, love, accomplishment, and/or satisfaction from accomplishment (e.g. winning in an 
athletic competition). Sometimes the emotions cause cataplexy in situations with a social 
component, meaning that others are involved in eliciting the emotion, including other family 
members, friends, children, and/or pets. At initial presentation and close to symptom onset, and 
especially in children and teenagers, the onset of a cataplexy attack may not be precipitated by an 
emotional trigger and can happen almost spontaneously, termed atypical cataplexy.    
Cataplexy is the most narcolepsy specific symptom, and it is unclear as to how and why the 
frequency or severity varies across subjects and may or may not change over time. Cataplexy is 
hypothesized to be a manifestation of REM atonia in waking. Thus when these episodes last for 
longer periods of time they evolve into REM sleep episodes and are perceived by the subject as 
sleep episodes with no memory of the cataplexy which preceded them. The onset of cataplexy 
typically occurs after the onset of EDS. Less frequently it can occur years after the EDS. Aside 
from the emotional triggers for cataplexy attacks, withdrawal from REM suppressing drugs may 
also cause them. 
Additional symptoms completing the narcolepsy pentad include HH (vivid dreams at sleep onset 
or offset that are more often associated with negative emotions), and SP (feeling unable to move 
the body during transition periods of sleep). These may occur simultaneously and are often 
frightening to the subject. More specific for narcolepsy is their occurrence at sleep onset. Like 
cataplexy, SP and HH are REM related phenomena. Thus, experiencing them at sleep onset is 
rare in the general population. Experiencing them at sleep offset may simply be an awakening 
from REM. Thus, their occurrence at sleep offset is seen in the general population. 
Disturbed nocturnal sleep (DNS) is the second most common symptom among narcolepsy 
subjects.20 The DNS observed in narcolepsy is distinct from that seen in insomnia. While 
subjects with insomnia have difficulty falling asleep at the beginning of the night and after 
nocturnal awakening, subjects with narcolepsy fall asleep faster than insomniacs and even the 
general population. Disturbed nocturnal sleep in narcolepsy is characterized by frequent brief 
awakenings or shifts to lighter stages of sleep during the sleep period that are transient, with 
increased Stage 1 sleep, and reduced deeper stages of sleep. Often this leaves subjects feeling 
poorly rested or that their sleep was not refreshing. The contribution of DNS to the EDS in 
narcolepsy is not well understood.  
6.1.2.2 
Pharmacologic Treatment Options  
Treatments for narcolepsy aim to relieve its symptoms, and are not directed towards any target 
known to be in the pathophysiological pathway of the disease. Thus, treatment includes 
stimulants to relieve EDS, sodium oxybate for EDS and cataplexy, and REM suppressing drugs 


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including tricyclic antidepressants (TCAs), selective serotonin re-uptake inhibitors (SSRIs), or 
monoamine oxidase inhibitors (MAOIs) to relieve cataplexy as well as HH and SP. The severity 
of the symptoms can vary greatly from one person to another, and thus the response to any given 
medication is similarly varied from subject to subject. 
Stimulants improve EDS in narcolepsy (eg, modafinil, armodafinil, methylphenidate, 
dextroamphetamine, or methamphetamine).21,22 In diagnosed subjects, modafinil, armodafinil, 
and methylphenidate are often prescribed first to reduce EDS. Dextroamphetamine and 
methamphetamine are potential alternatives for subjects who do not respond satisfactorily to the 
“front line” stimulant options. Some subjects may need a combination of drugs or a mixture of 
short- and longer -acting medications for optimal treatment. This evidences the fact that while 
stimulants improve EDS they do not normalize it. This is confirmed by patient reports in 
systematic studies.23, 24 
Potent REM suppressing drugs (i.e. SSRIs, TCAs and MAOIs) are used to treat cataplexy as well 
as HH and SP; however, the efficacy of these drugs in treating cataplexy has not been established 
in controlled clinical studies, but is based on experience from off-label use. Sodium oxybate 
(GHB), was approved by the FDA as Xyrem in 2002 for the treatment of cataplexy in adults with 
NT1. Subsequently, the improvement in daytime sleepiness led to a label extension to treat EDS 
in both types of narcolepsy. Sodium oxybate is administered in 2 divided doses at night, taken at 
bedtime and approximately 2.5 to 4 hours later. Disturbed nocturnal sleep is a symptom of 
narcolepsy that does not currently have any drugs indicated for its treatment.  
Despite the number of therapeutic options, narcolepsy medications are often not fully effective. 
It has been noted that there are drawbacks to the treatment regimen that can hinder compliance. 
Thus there remains a need for new agents. The twice nightly dosing regimen for Xyrem is 
inconvenient for subjects. With the availability of its drug delivery technology that allows for an 
extended release of drugs, Flamel Technologies has developed a new formulation of sodium 
oxybate, under investigation in this clinical study, with the objective to provide a therapy that is 
dosed only once at bedtime and provides subjects with the same level of efficacy and safety as 
the current twice nightly therapy. 
6.2 
Background to FT218 Controlled-Release Technology  
6.2.1 
Sodium Oxybate Drug Metabolism and Pharmacokinetics 
The active ingredient of FT218, sodium oxybate, is a CNS depressant. Sodium oxybate is the 
nonproprietary name for the sodium salt of GHB, a metabolite of GABA, which is synthesized 
and accumulated by neurons in the brain. It is present at μM concentrations in all brain regions 
investigated as well as in several peripheral organs, particularly in the gastrointestinal (GI) 
system. Sodium oxybate is rapidly absorbed after oral administration with an absolute 
bioavailability of about 25% due to a large hepatic first pass effect. Pharmacokinetics are 
nonlinear, following oral administration, the plasma levels of sodium oxybate increase more than 
proportionally with increasing dose. The clearance of sodium oxybate is almost entirely by 
biotransformation to carbon dioxide, which is then eliminated by expiration. On average, less 
than 5% of unchanged drug appears in human urine within 6 to 8 hours after dosing. Fecal 
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The efficacy and safety profiles of the currently marketed formulation of sodium oxybate, 
Xyrem, are well characterized. The molecular formula of FT218 active ingredient is C4H7Na03 
with molecular weight of 126.1. The chemical name is sodium 4-hydroxybutanoate. 
 
6.2.2 
FT218 Development 
Flamel has developed an extended-release oral suspension formulation of sodium oxybate, with 
the same active ingredient as the currently available and marketed product of sodium oxybate, 
Xyrem (NDA 021196) for treating EDS and cataplexy in subjects with narcolepsy. Flamel’s 
formulation provides for an extended-release of the active ingredient by utilizing its proprietary 
technology, Micropump. This technology is the same as that used for the marketed drug product 
Coreg CR® (carvedilol, NDA 022012) for the treatment of hypertension, left ventricular 
dysfunction, and mild to severe heart failure. Coreg CR has been marketed in the US since 2007. 
The Micropump technology is designed to extend and/or delay the absorption of drugs, which 
allows more controlled regulation of the drug’s PK profile. FT218 is intended to provide a 
formulation of sodium oxybate which is dosed once at bedtime rather than the twice nightly 
dosing regimen of Xyrem which is taken at bedtime and then again 2.5 to 4 hours later. It is 
proposed that the FT218 once nightly dosing regimen represents an improved therapeutic option 
for subjects.   
The FT218 drug product is composed of both immediate and modified release microparticles, 
where release is a function of time and pH. The formulation also contains a range of suspending 
agents and an acid buffer which impart both physical and chemical stability to the reconstituted 
aqueous suspension before administration. All FT218 formulation excipients are adequately 
qualified for use at the doses of the FT218 product.  
6.3 
Preclinical Experience and Animal Models 
No nonclinical studies have been conducted during FT218 development. The reason was 2-fold, 
firstly, animal species are not relevant to evaluate the PK profile of FT218 due to the specific 
nature of the product’s release mechanism and the differences between animal and human GI 
physiology. Secondly, the availability of nonclinical data on sodium oxybate, from the Xyrem 
nonclinical reviews by the FDA in 2002, the European Medicines Agency (EMA) in 2005, and 
by Health Canada in 2006 with later updates and assessment reports on intended extension of 
use.  
At pharmacological doses sodium oxybate acts as a CNS depressant. Sodium oxybate was found 
to have an affinity for 2 receptors in the brain, a GHB specific receptor and a GABA-B receptor. 
Sodium oxybate appears to have no affinity for the GABA-A receptor.  


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The submitted nonclinical data for Xyrem showed the safety of sodium oxybate in animal 
models, and it demonstrated transient drops in blood pressure (BP) as well as bradycardia. This 
was however limited to the species evaluated. Induced sleep from sodium oxybate, in both 
animal and man was found not to be accompanied by a decrease in oxygen consumption. The 
respiratory center remains sensitive to carbon dioxide although the slow-wave/delta sleep is 
enhanced. A slight drop in body temperature was observed in rats given sodium oxybate. Some 
animal studies report apparent epileptiform (epileptic/seizure-like) electroencephalography 
changes which have not been observed in human studies following sodium oxybate 
administration.  
Pharmacodynamic interaction during the concomitant administration of sodium oxybate with 
CNS depressants such as benzodiazepines, barbiturates, and alcohol may result in additive 
increases in sedation and respiratory adverse effects. They are thus contraindicated. 


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6.5 
Study Rationale 
Sodium oxybate has shown significant efficacy for EDS and cataplexy in the treatment of NT1 
and NT2. Flamel Technologies is proposing a new sodium oxybate drug product, FT218, which 
utilizes the company’s proprietary Micropump technology. The proposed innovation is clinically 
relevant as the current marketed product, Xyrem, has to be taken twice during the night, 2.5 to 4 
hours apart, which is a limitation. 
The FT218 Phase 1 study (study PKFT218-1301) confirmed the expected PK properties of the 
FT218 formulation i.e. a release of the drug over at least 6 hours, a lower Cmax and a residual 
plasma level at 8 hours after intake not significantly different than the reference. Overall, under 
the hypothesis of a PK exposure-clinical effect relationship, this study confirmed that FT218 will 
be as safe as the reference marketed product. The forced up-titration design of this study is 
expected to be particularly informative, allowing observations of efficacy and safety at 6.0, 7.5, 
and 9g doses. Three therapeutic doses will be tested under forced up-titration (6.0, 7.5, and 9.0 g) 
since no concentration/response relationship is known. The study allows for forced dose 
increments at fixed times from 4.5 g/night followed by 1.5 g/night increments until the final 9.0 
g dose is reached. Subjects will remain on the 4.5 g dose for 1 week, the 6.0 g dose for 2 weeks, 
the 7.5 g dose for 5 weeks and the 9.0 g dose for 5 weeks. Evaluations for efficacy and safety for 
6.0, 7.5, and 9.0 g will be done over a 12-week period (total of 13 weeks on study drug) relative 
to the placebo group.  
The up-titration is based on the dosage schedule recognized as safe with Xyrem. A full efficacy 
assessment will occur for the 6.0 g/night dose after 3 weeks on study drug (including a titration 
from 4.5 g/night for the first week followed by 2 weeks at 6.0 g/night). The 7.5 g full efficacy 


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assessment will occur after 8 weeks on study drug (including 1 week at 4.5 g and 2 weeks at 6.0 
g). A final titration occurs to maximum dose (i.e. 9.0 g). A full efficacy assessment will be done 
following 5 weeks on the final dose (that is following a total of 13 weeks on medication) relative 
to the placebo group. During both the 7.5 g and the 9.0 g 5-week treatment a partial efficacy 
assessment 
 will be carried out after 
2 weeks on the respective doses. 
The selected FT218 doses for the current study match the therapeutic dose range recognized as 
safe and effective for the reference drug product, Xyrem. All FT218 doses (6.0, 7.5, and 9.0 g) 
were selected for their safety and efficacy profile in treating subjects with narcolepsy based on 
previous studies with sodium oxybate. In addition, results from the Phase 1 PKFT218-1301 
study indicated that the study formulation is safe at 4.5, 6.0, and 7.5 g/night in healthy 
volunteers. Given the PK characteristics of the current formulation of FT218, the proposed doses 
are not anticipated to be associated with any safety concerns.  
Full safety and efficacy of FT218 will be evaluated in this clinical study. A double-blind, 
placebo-controlled randomized methodology has been identified as the optimal design to support 
efficacy and safety evaluation.  
This FT218 clinical study has been designed to ensure conduct and analysis according to sound 
scientific principles to achieve study objectives. Placebo has been selected as the choice for the 
control group, as this will optimize inferences drawn from the study. It will provide for an 
undiluted evaluation of total pharmacological and treatment effect (i.e., study drug versus 
disease). In addition, this approach lends itself to a smaller sample size requirement.   
Randomization will provide a means of assuring comparability of test groups in expectation and 
minimize selection bias, and the double-blind method will minimize risk of biased study 
outcomes. The set study enrollment criteria, screening and baseline assessment, washout 
requirements and on-treatment conduct and assessment will minimize variables that could 
influence outcome except for that of the study drug being evaluated. The proposed study 
population as defined by the enrollment criteria will ensure a consistent sample and one that is 
largely representative of the broader patient population with NT1 and NT2. Combined these will 
enhance the generalizability of the study results.   
The safety, dignity, and rights of study subjects predominate. It is thought that the proposed 
study design does not raise any ethical issues. The study is of appropriate duration for a chronic 
condition, there are no life-limiting effects from placebo, and study subjects can withdraw from 
the study at any time. This latter option will be made explicit during the informed consent 
process.  
6.6 
Potential Risks and Benefits 
Based on early studies of FT218, it is possible to predict some of the discomforts and risks. The 
data suggest that the potential risks of FT218 are likely to be manageable and will be monitored 
like Xyrem. Clinical studies with Xyrem have yielded detailed information of its safety profile. 
Xyrem is approved by the FDA in the US and EMA for the treatment of subjects with 
narcolepsy. The potential risks of FT218 from PK studies in humans have been discussed in the 


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summary from the Phase 1 safety study (discussed in Section 6.3) and to date are consistent with 
and similar to what has been previously reported with sodium oxybate.  
Clinical safety of Xyrem has been established and forms the basis for the FT218 safety plan. All 
causality and treatment-related events for Xyrem include: abdominal pain, diarrhoea, nausea, 
vomiting, fatigue, peripheral oedema, anorexia, dizziness, headache, abnormal dreams, confused 
state, nightmare, sleep walking and enuresis. The most commonly identified AEs for sodium 
oxybate are nausea, dizziness and headache. In terms of AEs where there was a dose response 
relationship, these AEs included nausea, vomiting, paraesthesia, disorientation, irritability, 
disturbance in attention, feeling drunk, sleepwalking and enuresis. These events are most 
pronounced at the higher, 9.0 g dose, and in some cases related to the 7.5 g dose. The up-titration 
methods, as used with Xyrem, to maximum dose, are thus appropriate to establish safety and 
tolerability in study subjects who will participate in this clinical study.  
The safety profile of Xyrem is thus well characterized. The safety profile, as described in the 
Xyrem approved labelling supports the safety of the FT218 study formulation. In addition, all 
necessary precautions and warnings related to subject self-care and self-monitoring for any signs 
and symptoms of respiratory or CNS depression, alcohol consumption, contraindicated 
medications, driving and use of heavy machinery apply to FT218. The proprietary extended-
release oral suspension technology used for FT218 is well established. The technology is the 
same as that used for the marketed product Coreg CR (carvedilol, NDA 022012) for the 
treatment of hypertension, left ventricular dysfunction and mild to severe heart failure. This has 
been marketed in the US since 2007. 
In addition to clinical safety and efficacy, consideration to the risk-benefit profile as it relates to 
abuse potential warrants careful consideration. Flamel Technologies has considered the wider 
risks of abuse potential. Data relating to drug abuse potential of illicit forms of GHB, sodium 
oxybate and related products with abuse potential, underwent extensive review by the World 
Health Organization (WHO) Expert Committee on drug dependence in 2012. At this meeting it 
was acknowledged that most GHB for abuse originates from clandestine manufacture and there 
was consensus on the associated narrow margin for safety. Outputs from Xyrem’s risk evaluation 
and mitigation strategies postmarketing data were also evaluated. The finding showed minimal 
abuse or diversion of Xyrem. Clinical study supply and distribution methods for FT218 will 
adhere to regulatory and current Good Clinical Practice (cGCP) requirements. Within the clinical 
study framework a “closed system” of supply and distribution will be employed. Enhancement of 
this approach will be facilitated through implementation of study specific strategies to augment 
safety and mitigate abuse potential. 
FT218 will provide a beneficial and alternative therapeutic strategy for subjects with narcolepsy. 
Sodium oxybate has a well characterized safety profile and is a known and established 
therapeutic choice among physicians for treating subjects with NT1 and NT2. Physicians are 
largely familiar with its use and application in clinical practice and the potential benefits of the 
sodium oxybate have been documented in the literature. The burden for the subject enrolled in 
this study is concentrated but not significantly greater than that which they experience during 
routine clinical practice for disease management.  


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This study will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and International Council for Harmonisation (ICH) guidelines. Cognizant of 
FT218’s designation as a Schedule I/Controlled Drug and associated safety risk profile and abuse 
potential, study specific risk mitigation strategies will underpin clinical roll-out of this clinical 
study. 


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7 
STUDY OBJECTIVES 
7.1 
Primary Objective 
The primary objective of the study is: 
• To compare the efficacy of 6.0, 7.5, and 9.0 g of FT218 to placebo in treating EDS in 
both NT1 and NT2 subjects as measured by mean sleep latency on the Maintenance of 
Wakefulness Test (MWT) and by the Clinical Global Impression (CGI) rating of 
sleepiness 
• To compare the efficacy of 6.0, 7.5, and 9.0 g of FT218 to placebo in treating cataplexy 
in NT1 subjects as measured by the number of cataplexy attacks (NCA) determined from 
the cataplexy frequency item in the Sleep and Symptom Daily Diary 
7.2 
Secondary/Exploratory Objectives 
The secondary/exploratory objectives of the study are to compare the efficacy of 6.0, 7.5, and 9.0 
g of FT218 to placebo for the following outcomes: 
7.3 
Safety Objective 
The safety objective of the study is: 
• To evaluate the relative safety of FT218 compared to placebo. 


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8 
INVESTIGATIONAL PLAN 
8.1 
Overall Study Design and Plan: Description 
This is a Phase 3 double-blind, randomized, placebo-controlled, 2-arm clinical study. The 
purpose of this study is to assess the efficacy and safety of a once nightly formulation of sodium 
oxybate for the treatment of EDS and cataplexy in subjects with narcolepsy. Two populations of 
narcoleptic subjects will be studied in a single parallel group design: 1) NT1, and 2) NT2. 
The study treatment period from screening to follow-up will last approximately 17 weeks. There 
is a 3-week screening period, followed by a central assessment of PSG and next-day MWT 
screening results (may take up to 3 days). If the subject is eligible, then randomization occurs. 
After randomization, dosing must start within 5 days (the window from randomization to dosing 
is to allow delivery of study drug to the site). There is a 13-week treatment period and a 1-week 
follow-up period. For subjects randomized to the active arm of the study the maximum duration 
of treatment with FT218 will be 13 weeks incorporating up-titration over a period of 8 weeks 
with 5 weeks on stable dosing at 9.0 g/night. For subjects randomized to placebo, there is no 
exposure to the study treatment.  
The follow-up study visit will occur at least 1 week after the last dose of FT218 or placebo i.e. 
Period 4 (Visit 9, Week 15, Day 1 [+4/-0 i.e. a minimum of 7 days after the last on study dose]). 
Additional follow-up for safety surveillance and management will be done for unresolved 
AE/residual effects of FT218 study drug following last dose as determined by the study 
investigator and/or sponsor.  
 


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8.1.1 
Study Design 
Screening and Baseline 
Rand 
Dose Titration 
Dose Titration 
Stable Dosing 
EOS 
FU 
 
 
 
 
 
 
 
 
 
 
 
 
9.0g 
9.0g 
9.0g 
9.0g 
9.0g 
 
 
 
 
 
 
 
 
 
7.5g 
7.5g 
7.5g 
7.5g 
7.5g 
 
 
 
 
 
 
 
 
 
 
 
 
6g 
6g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm 
1 
4.5g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm 
2 
Placeb
o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placeb
o 
Placeb
o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placeb
o 
Placeb
o 
Placeb
o 
Placeb
o 
Placeb
o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placeb
o 
Placeb
o 
Placeb
o 
Placeb
o 
Placeb
o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 1 
 
Visit 2* 
 
Visit 
3** 
 
Visit 4* 
 
 
Visit 5 
 
Visit 6* 
 
 
Visit 7 
 
 
Visit 8* 
Visit 9 
W-3 
D1 
 
W-1 D7 
W0 D1 
EOSc 
+2 D 
W1 D1 
 
W3 D7 
W4 D1 
 
W6 D1 
 
W8 D7 
W9 D1 
 
W11 
D1 
 
 
W13 D7 W14 
D1 
W15 
D1 
<------3-week washout-----> 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
W-3 
 
W0 
 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W12 
W13 
W14 
W15 
Period 1 
Period 
2 
 
Period 3a 
Period 3b(i) 
Period 3b(ii) 
Period 3c(i) 
Period 3c(ii) 
Period 3c(iii) 
Period 
4 
Abbreviations: D = day, EOS = End of Study, EOSc = End of Screening, FU = Follow-up, Rand = randomization, W = week, W/O = Washout 
*Study visits where baseline assessment or full efficacy assessment are done extend into the following day and are thus indicated 
**Up to 6 days is allowed between randomization (which occurs up to 2 days after the end of the screening period) and dosing to allow shipment of study drug to site. (Duration between end of 
screening period and dosing is no more than 7 days.) 
 


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8.2 
Discussion of Study Design 
The rationale for the study design can be found in Section 6.  
8.3 
Selection of Study Population 
8.3.1 
Number of Planned Subjects  
8.3.2 
Inclusion Criteria 
To be eligible for study entry subjects must satisfy all of the following criteria at the screening 
assessment visit: 
1. Male or female subjects 16 years of age or older 
2. Willing and able to give written informed consent for study participation. For young 
adults (16 and 17 years old) who have not reached the age of majority they must be 
capable of giving assent and consent from a legally authorized guardian must be 
obtained, as required by local laws and regulations 
3. Documented evidence of a diagnosis of NT1 or NT2 as, in part, determined by an 
overnight PSG and next-day MSLT with 2 or more SOREMPs with mean sleep latency in 
the pathological range i.e. < 8 minutes and meeting the NT1 and the NT2 as defined by 
the International Classification of Sleep Disorders -3 criteria11 
4. Current continuing presence of EDS as defined by subject report for the last 3 months 
and an ESS > 10 
5. For NT1 only, current continuing presence of cataplexy as defined by subject report for 
the last 3 months 
6. Subjects may use concomitant stimulants, but must comply with the following: 
a. They must be on a stable dose of stimulants for at least 3 weeks prior to starting 
the screening process for this study; AND 
b. They must use the same stimulant regimen throughout the entire study period, 
including during screening and posttreatment periods 
c. They must discontinue all anti cataplexy drugs 
7. Female subjects who: 
a. Are postmenopausal for at least 1 year before the screening visit 
b. Are surgically sterile, OR 


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c. If of childbearing potential agree to practice effective double barrier methods of 
contraception, from the time of the signing of informed consent through the last 
dose of study drug, or agree to completely abstain from heterosexual intercourse 
8. Willing and able to comply with all study mandated requirements and procedures for the 
duration of the clinical study 
9. Willing to adhere to all study restrictions including:   
a. Willingness to comply with the requirement to remain in bed for a minimum of 6 
hours after taking the study drug 
b. Adherence to concomitant drug washout requirements, as applicable, for the 
duration of the clinical study. Refer to Section 8.4.8.1 for a list of all prohibited 
medications 
c. Willing to refrain from operating a car or heavy machinery if determined 
necessary by the investigator or willingness to refrain from operating a car or 
heavy machinery for at least 6 hours after taking the nightly dose of FT218 
d. Willing to abstain from alcohol for the duration of the clinical study 
e. If a smoker, willing to abstain from smoking at night from approximately 9 pm to 
7 am for the duration of the clinical study 
10. Evidence of adequate support for the duration of the study, including transportation to 
and from the study site if needed 
To be eligible for randomization, subjects must satisfy all of the following criteria: 
1. Written informed consent obtained during the screening assessment visit 
2. Still eligible as per requirements in Section 8.3.2 
3. Compliance with drug washout requirements 
4. Compliance in completing the study screening/baseline Sleep and Symptom Daily Diary. 
Compliance is defined as completing the diary at least 4 times in each of the screening 
weeks 
5. Confirmation of EDS as defined by all of the following 
a. Baseline ESS score > 10 points; AND 
b. Baseline MWT mean sleep latency < 11 minutes following baseline PSG and as 
confirmed by the central scoring laboratory (Section 11.12) 
6. For NT1 only, current continuing presence of cataplexy as defined by an average of 8 
reported cataplexy attacks per week in the screening/baseline Sleep and Symptom Daily 
Diary 
7. Women of childbearing potential must have a negative serum pregnancy test at screening 
and a negative urine test within 7 days prior to treatment 
 
8.3.3 
Exclusion Criteria 
Subjects will be excluded from the study if one or more of the following criteria are applicable:  
1. Prior use of sodium oxybate is allowed in the study but with the following exclusions: 
a. Previous dosing must have been limited to no more than 4.5g per night 
b. Patient should not have taken sodium oxybate for more than 2 weeks 


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c. All previous dosing must not have occurred within the last year prior to entry to 
the study  
2. Current use of sodium valproate 
3. Any use of the following prohibited medications for the duration of the clinical study: 
(Section 8.4.8.1)  
a. Anticonvulsants 
b. Clonidine 
c. SSRIs and serotonin and norepinephrine re-uptake inhibitors (SNRIs) 
d. MAOIs  
e. TCAs 
f. Hypnotics 
g. Anxiolytics 
h. Sedating antihistamines 
i. Antipsychotics 
j. Other experimental medications designed to treat narcolepsy, cataplexy or any 
other condition 
4. Treatment with any investigational products within 3 months before study enrollment 
5. Any drug known to affect sleep-wake function. Concomitant stimulant use is permitted 
(Section 8.4.8) 
6. A diagnosis of sleep apnea or any other sleep disorder known to cause EDS as 
determined by PSG and sleep history, including any PSG results indicating an apnea-
hypopnea index (AHI) ≥ 15 
7. The presence of any unstable or clinically significant medical and psychiatric disorders 
(as determined by medical or psychiatric history, physical examination, and/or clinical 
laboratory test) which in the opinion of the investigator may either put the subject at risk 
by participation in the study, or may influence the results of the study 
8. Subjects with a previous history or current ideation of suicide attempt 
9. Subjects who have a history of drug or alcohol use that, in the opinion of the investigator 
would interfere with study subject safety and adherence to study requirements 
10. Required commercial or equivalent driving during the study period 
11. An occupation that requires variable shift work or routine night shifts 
12. Any travel across more than 3 time zones during the course of the study 
13. Consuming more than 14 standard alcoholic drinks per week, on average, before 
participating in the clinical research study 
14.  Smoking during the night (approximately between 9 pm and 7 am) during the course of 
the study 
15. Female subjects who are lactating or have a positive pregnancy test. Females of 
reproductive potential not willing or able to employ effective methods of birth 
control/contraception to prevent pregnancy for the duration of the study and for up to 1 
week after completing study treatment 
16. Any current malignancy and/or any history of malignancy within last 3 years 
17. A history of seizure disorder, head trauma, or past invasive intracranial surgery 
18. Subjects with severe chronic obstructive pulmonary disease. Subjects with mild to 
moderate chronic obstructive pulmonary disease and assessed as stable by the principal 
investigator (PI) are eligible 


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19. Principal investigator judgement on other underlying respiratory and/or other underlying 
condition or disorder that would potentiate risk of respiratory or CNS depression with 
concomitant use of sodium oxybate 
20. Known hepatitis B surface antigen-positive status or known or suspected active hepatitis 
C infection 
21. Known human immunodeficiency virus infection or acquired immunodeficiency 
syndrome related illness 
22. Scheduled for procedures requiring general anesthesia during the study 
23. Known contraindication/allergy/sensitivity/intolerance to the study drug, sodium oxybate, 
or the inactive ingredients of FT218 or placebo 
24. Atrial fibrillation or an abnormal electrocardiogram (ECG) demonstrating clinically 
significant dysrhythmia(s) 
25. Recent myocardial infarction or coronary revascularization (less than 3 months) 
26. Uncontrolled hypertension 
27. Known succinic semi-aldehyde dehydrogenase deficiency  
28. Moderately or severely altered blood chemistry as defined by any one of the following: 
a. A Cockcroft-Gault calculated creatinine clearance < 60 mL/min; OR  
b. Liver function tests more than twice the upper limit of normal; OR 
c. Serum bilirubin more than 1.5 times the upper limit of normal 
8.3.4 
Removal of Subjects From Therapy or Assessments 
In accordance with the Declaration of Helsinki, subjects may withdraw consent to continued 
participation in the study at any time without giving a reason. This right will be respected 
without affecting the routine treatment or care of the subject. If the reason for withdrawal is 
volunteered by the study subject it will be recorded in the subject’s medical notes and in the 
electronic case report form (eCRF). The Principal Investigator (PI) will ensure the protection of 
the study subject’s interests is prioritized.  
Study subjects must discontinue study drug and be withdrawn from the study for any of the 
following reasons.  
• 
Withdrawal of consent by the subject 
• 
Withdrawal of assent and corroborated by parent(s)/legal guardian 
• 
Any medical condition that the PI or sponsor determines may compromise the study 
subjects safety by continuing to receive study drug 
• 
Pregnancy 
• 
An AE or SAE which requires discontinuation from study drug 
• 
Inability to remain under medical observation for the duration of the study 
• 
Clinical risk of emergent suicidal ideation 
• 
Noncompliance to: 
o Study schedule 
o Sleep and Symptom Daily Diary completion requirements 
o Major deviation from protocol mandated procedures 
o Concerns over subject study drug handling in terms of subject safety, abuse, 
and/or dependence potential as determined by the PI 


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• 
Any other situation where, in the opinion of the investigator or the sponsor, continuation of 
the study would not be in the interest of the subject 
• 
Lack of efficacy 
• 
Discontinuation of the study by the sponsor 
• 
Regulatory authority decision or change in Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB) opinion for drug safety problems 
Irrespective of reason for withdrawal or discontinuation the PI must record the reason for 
withdrawal (if subject initiated withdrawal, this information must be voluntarily given by the 
subject). All data available for the study subject at the time of withdrawal/discontinuation must 
be recorded in the eCRF, unless specified otherwise by the subject. The PI will request that the 
subject return all study drug and may request a follow-up visit especially if any adverse event(s) 
remain unresolved.  
In the event a subject does not return for a scheduled visit after withdrawal, every effort should 
be made to contact the subject. This should be documented. Every effort to document subject 
outcome should be made.  
PSG and MWT are at the discretion of the PI and consent of the subject. Early withdrawal study 
subjects will be followed for a week after the last dose of study drug. All SAEs and nonserious 
AEs assessed by the PI as related to the study drug should be followed to resolution or until the 
PI assesses them to be chronic or stable. 
It will be left to the investigator’s clinical judgement whether or not an AE is of nature, or 
severity to require the subject’s removal from treatment. A subject may also voluntarily 
withdraw from treatment due to what is perceived as an intolerable AE. If either of these occurs, 
the subjects must undergo an end-of-study assessment and receive appropriate care under 
medical supervision until symptoms cease or the condition becomes stable.  
Withdrawal due to an AE should be distinguished from withdrawal due to lack of efficacy. 
If the subject withdraws due to a SAE, the SAE must be reported in accordance with SAE 
reporting requirements. 
Randomized subjects who have received at least 1 dose of study drug, who withdraw from the 
study prematurely will not be replaced. 
8.3.4.1 
Pregnancy 
Study subjects may not be pregnant or nursing during the course of this study as indicated in the 
inclusion and exclusion criteria. Subjects of childbearing potential include all females who are 
not postmenopausal for at least 1 year before the screening visit and are not surgically sterile.  
All female subjects of childbearing potential must agree to practice 2 effective methods of 
contraception, from the time of the signing of informed consent through the last dose of study 
drug or agree to completely abstain from heterosexual intercourse.  


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For all women of childbearing potential a serum pregnancy test will be performed at screening 
and a urine pregnancy test will be performed at least 7 days before commencing FT218/placebo 
dosing. The results must be available, documented and negative before the first dose of study 
drug is administered.  
After study drug is dispensed at Visit 3, urine pregnancy tests will be repeated at each study visit 
throughout the remainder of the study, including the final study visit (Visit 9) or at the 
withdrawal visit if the subject withdraws from the study. 
The investigator must report to the sponsor any pregnancy occurring in a study subject, during 
the subject’s participation in this study. The study Pregnancy Reporting Form will be used. The 
report will be submitted within the same timelines as an SAE.  
For a study subject, the outcome of the pregnancy should be followed up carefully, and any 
abnormal outcome of the mother or the child should be reported. In some circumstances, it may 
be necessary to monitor the development of the newborn for an appropriate period after delivery. 
Although pregnancy is not an SAE, and an elective abortion is not an SAE, any spontaneous 
abortion and/or any pregnancy that meets any regulatory serious criterion, or any pregnancy with 
an outcome for the pregnant person or the infant that meets regulatory serious criterion will be 
captured as an SAE. 
8.4 
Investigational Product 
The active ingredient of FT218, sodium oxybate (GHB), is a CNS depressant. Drug product 
formulations containing GHB that have no marketing authorization are classified as Schedule I 
controlled substances within the US. For all non-US sites classification across regions can vary, 
local/regional classification will apply.  
This study has been developed to ensure all local legal and regulatory requirements for the safe 
handling of Schedule I/Controlled Drug for all participating regions in the CLFT218-1501 
clinical study are adhered to. 
8.4.1 
Investigational Products Administered 
8.4.1.1 
Definition of a Schedule I/Controlled Drug Substance 
A substance where there is no current accepted medical use in treatment, a lack of accepted 
safety for therapeutic use under medical supervision and a high potential for abuse.  
8.4.1.2 
FT218 Study Drug Risk Management  
The CLFT218-1501 operational framework will be structured to mitigate safety, abuse, misuse, 
and diversion risks associated with FT218. The framework will: 
1. Safeguard subject safety and mitigate abuse, misuse, and diversion risks, and minimize 
potential for public-health risk through the implementation of best practice handling and 
distribution processes and procedures 


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2. Allow for robust evaluation of emerging safety data and FT218 study drug management 
for detection of risk in terms of subject safety, abuse, and misuse potential  
8.4.1.3 
Specification for Managing Controlled Substances  
Systems and structures will be put in place to ensure compliance in the handling, distribution, 
prescription, and management of FT218. This will include:  
1. A “closed system” of FT218 distribution  
2. All study investigators and investigative site facilities will be assessed and qualified in 
advance of site set up. Only investigative sites meeting requirements will be qualified for 
participation in this clinical study. All qualified investigative sites will be monitored on 
an ongoing basis for the duration of the clinical study to ensure ongoing compliance with 
all legal and regulatory requirements as applicable to the FT218-1501 clinical study 
3. Subject education on FT218 handling 
4. Key investigator requirements include but are not limited to:  
a. Authorization to prescribe the FT218 controlled substance by the jurisdiction in 
which they are licensed to practice 
b. Evidence of current registration (Drug Enforcement Agency in the US, as per 
local/regional requirements for non-US sites) for the handling of the FT218 
controlled substance 
c. Complying with all FT218-1501 clinical study requirements and all legal and 
regulatory requirements specific to the safe handling and management of the 
FT218 drug product 
d. Awareness of ramifications of noncompliance with requirements 
All site specific approvals, registration forms and/or exemptions (if applicable for the latter) will 
be filed in the local study file at each site and a copy from each site will be provided for filing in 
the Trial Master File.  
8.4.1.4 
Drug Accountability 
Sites must have the appropriate registration and authorizations to manage Schedule I/Controlled 
Drugs according to regional legal and regulatory requirements. Documented evidence of this 
authorization will be provided to the sponsor/designated contract research organization (CRO) 
before study site initiation. 
Optimized study drug supply strategy is being applied to safeguard against loss, diversion, or 
theft of product.  
All clinical drug supplies shipped to study sites will have clear instruction on-site requirements 
for receipt of drug, inspection of the shipment, confirmation or receipt, and storage requirements, 
all of which will be compliant with all applicable regional/local legal and regulatory 
requirements.  
The FT218 pharmacy manual will be issued to each study site and will include detailed 
instruction as to applicable country and state level requirements including: inventory, storage, 
randomization, dispensing, dosing requirements, and returns processes to final disposition. 


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On receipt, clinical study material will be transferred to a secure location (appropriate for 
Schedule I/Controlled Drug). The PI/designee will inspect the shipment and enclosed 
temperature monitoring device to verify that clinical study materials were received in an 
acceptable condition and that the specified quantities have reached the study site. The 
PI/designee will complete and return all necessary paperwork as specified in the pharmacy 
manual.  
Any quality issue, i.e. deficient clinical study material condition, appearance, documentation, 
labelling etc. either on shipment receipt or at any stage during the study must be reported. 
Necessary corrective actions will be identified and implemented as determined by the 
CRO/sponsor.  
Upon receipt of FT218 study drug at site the PI/designee will check and document:  
• Consistency of the FT218 study drug received against the shipping records 
• Integrity of packages and seals 
• Temperature records and temperature recording devices 
• Receipt of associated documents as detailed in the study pharmacy manual 
The PI/designee will file all related documentation and receipts to enable the tracking of product 
batches, shipping conditions and accountability in the study pharmacy file.   
FT218 study drug must be stored as per protocol requirements and as per applicable legal, 
regulatory and labelling requirements. Details of storage requirements will be specified in the 
study pharmacy manual. Access to where study drug is stored must be restricted to preapproved 
personnel.  
The location of the FT218 study drug will be recorded. FT218 study drug should not be moved 
from one storage location to another without prior approval from the CRO/sponsor. Full 
traceability of study drug storage must at all times be in place.  
8.4.1.5 
FT218/Placebo  
FT218 study drug and placebo for each dosing period will be provided in a kit. Study drug will 
be provided as a powder in a sachet which will be of child proof quality. Each kit will contain the 
requisite number of study drug dose sachets. Sachet doses of 3.0 g and 4.5 g will be provided. 
Subjects will reconstitute to achieve the target dose levels, as necessary.   
Treatment Arm 1 
The treatment with FT218 is started with a gradual up-titration to stable dosing according to the 
following steps: 
 
Starting Dose 
× 1 week 
Titration Dose 
× 2 weeks 
Titration Dose  
× 5 weeks 
Stable Dosing Period 
× 5 weeks 
Arm 1 
FT218 4.5 g 
(1 × 4.5 g sachet) 
FT218 6.0 g 
(2 × 3 g sachets) 
FT218 7.5 g 
(1 × 3 g sachet, 
1 × 4.5 g sachet) 
FT218 9.0g 
(2 × 4.5 g sachet) 


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Treatment Arm 2 
The treatment with placebo is started with a sham gradual up-titration to sham stable dosing 
according to the following steps: 
 
Starting Dose 
× 1 week 
Titration Dose 
× 2 weeks 
Titration Dose  
× 5 weeks 
Stable Dosing Period 
× 5 weeks 
Arm 2 
Placebo 
(1 × 4.5 g match 
sachet) 
Placebo 
(2 × 3 g match 
sachets) 
Placebo 
(1 × 3 g, 1 × 4.5 g 
match sachet) 
Placebo 
(2 × 4.5 g match sachet) 
 
8.4.2 
Identity of Investigational Products 
Test medication: FT218: Sodium Oxybate for Extended-Release Oral Suspension 
Active substance  
 
 
 
Sodium Oxybate 
Strength 
3.0 and 4.5 g sachets (for dosing at 4.5, 6.0, 7.5, and 9.0 
g)  
Dosage form 
 
 
 
 
Powder for oral suspension 
Manufacturer 
 
 
 
 
Recipharm 
Batch release  
: 
 
 
 
FLAMEL TECHNOLOGIES  
Storage 
 
 
 
 
 
Room temperature 
Test Medication: Placebo 
Substance  
 
 
 
 
Inert constituents 
Strength and Dose 
Placebo; packaging and labelling will indicate doses as 
used in the active arm as per drug dosing schedule.  
Dosage form 
 
 
 
 
Powder for oral suspension 
Manufacturer 
 
 
 
 
Recipharm 
Batch release 
 
 
 
 
FLAMEL TECHNOLOGIES 
Storage 
 
 
 
 
 
Room temperature 
8.4.3 
Packaging and Labelling 
Study drug management, handling, packaging, and labelling will comply with all applicable 
regional/local legal, regulatory, GxP regulations and sponsor requirements.  
Active Drug: Arm 1:  
A study kit will be provided to study subjects with enough study drug supply for the assigned 
dosing weeks. Active drug dose will be supplied in sachets. Two strengths will be supplied; 3.0 
and 4.5 g, with the exception of the Week 1 dosing kit which will only contain a single dose 
strength of 4.5 g. Study subjects will be instructed on reconstitution methods according to their 
drug dosing regimen as predetermined by the drug randomization schedule. Each allocated drug 
kit will supply study subjects with enough drug until their next scheduled study visit for 
assessment and resupply. No oversupply will be provided.  


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Placebo Match: Arm 2:  
Placebo kits and sachets will be identical in presentation and content feel to that of active drug. It 
will be labelled using the same strength dosages i.e. 3.0 and 4.5 g doses, with the exception of 
the Week 1 dosing kit, which will only contain a single dose strength of 4.5 g. Study subjects 
will be instructed on the reconstitution method identical to that of active study drug. Each 
allocated drug kit will supply study subjects with enough drug until their next scheduled study 
visit for assessment and resupply. No oversupply will be provided.  
Specifications of Study Drug Quantities Supplied per Kit per Dosing Week.  
Each study kit will provide enough study drug supply for the assigned dosing weeks. For weeks 
that require overnight PSG and next-day MWT, as part of the full efficacy assessment 
requirement, study kit supplies will be modified to allow for study sites to dispense a single night 
time dose to subjects at the PSG laboratory. Kit supplies for such weeks will contain enough 
study drug for 6 nights of dosing in the home setting. Study drug dose for night 7 will be 
dispensed at the PSG laboratory.  
For all other weeks where there is no overnight PSG requirement study subjects will be supplied 
with the full quota of 7 nights drug supply for home dosing.  
Details of the specifications of study drug supply quantities for each week of dosing are 
presented in Appendix 17.2. 
Labelling 
FT218 and placebo will be dispensed to study subjects in a kit(s) containing study drug with 
sufficient drug supply to the next scheduled visit as detailed in Appendix 17.2.  
Labelling of both outer kit packaging and individual dosing sachets for both FT218 and placebo 
will meet with all legal and regulatory labelling requirements. 
8.4.4 
Method of Assigning Subjects to Treatment Groups 
The drug dispensing strategy will, where feasible, minimize quantities of study drug stored at site 
at any one time. This will be mediated thought a study specific interactive response technology 
(IRT) system (endpoint, San Francisco, US). 
Once the overnight PSG and next-day MWT has been completed, the results will be reviewed 
and scored by a central scoring laboratory (Section 11.12). The targeted turnaround time for 
results following completion of MWT is ≤ 2 days. Results will be transmitted to the study PI.  
Where possible, on the same day confirmation of subject PSG and MWT eligibility has been 
received from the central scoring laboratory and all other study entry criteria are met, the 
PI/designee will randomize the study subject.   


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All screening and baseline assessments confirming eligibility must be documented in advance of 
subject randomization to the double-blind study period. The PI/designee enters the information 
into the IRT system, and the appropriate study drug is sent to the site. This process may take up 
to 6 days. 
The study site will notify all subjects of their eligibility status. Where a subject is eligible, the 
site will clarify requirements and arrange the first dispensing visit with the subject i.e., Visit 3.  
1. Within 5 days of randomization where it took 2 days for the Central Scoring Laboratory 
to respond with the PSG/MWT eligibility response  
2. Within 6 days of randomization where it took 1 day for the Central Scoring Laboratory to 
respond with the PSG/MWT eligibility response  
As no oversupply of study drug will be provided. Study subjects will be reminded to adhere to 
the dosing schedule and assigned schedule of visits to the hospital/clinic. Periodically, electronic 
alerts via the ePRO systems will be sent to study subjects to promote compliance with the visit 
schedule and all drug handling and management requirements. 
Following randomization, study subjects will be treated with their assigned study drug for a total 
of 13 weeks or until unacceptable AEs, withdrawal of consent or other treatment discontinuation 
criteria are met.  
8.4.5 
Selection of Doses in the Study 
A description of the selection of doses for the study is provided in Section 6.5. 
8.4.6 
Selection and Timing of Dose for Each Subject 
Subjects will be instructed on the safe management of study drug within their residential setting. 
All FT218 study drug must be kept out of reach from children and stored safely and securely to 
protect it from theft. It must be stored at 25°C with allowable excursions to 15°C to 30°C. 
As food significantly reduces the bioavailability of sodium oxybate, study subjects will be 
instructed to take their nightly dose at least 2 hours after eating.  
Study subjects will be instructed by study site staff on their nightly dosing regimen. 
Guidance for Unused or Missed Doses 
All doses of the study drug are intended to be taken as outlined in the protocol schedule. No 
doses should be missed or delayed due to subject visit scheduling and/or drug dispensing 
activities. 
Reconstituted product should be taken on the night it is reconstituted. In the event that 
reconstituted drug is not used it must be stored securely and returned to the study site at the next 
visit. Any reconstituted but unused study drug should not be substituted for the following nights 
dosing.  


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Any missed nightly doses of the study drug are not to be taken, and the study drug for that night 
returned to the study site staff at the next study visit. 
If there is a delay in taking the study drug or if the subject inadvertently falls asleep but wakes 
again prior to taking their study drug, a delayed start may be possible provided both the 
following criteria are met: 
1. Study subjects feel awake enough to prepare and take the study drug as directed; and 
2. Study subjects have a minimum of 6 hours left to sleep prior to waking up in the 
morning  
In the event that fewer than 6 hours of possible sleep remain, subjects will be instructed to forego 
taking the study drug that evening. Subjects will be advised on reporting requirements for any 
deviation to the protocol mandated dosing regimen. 
Study drug must be taken every night for the first week of study drug administration (Week 1) so 
that subjects are adequately prepared for the first up-titration at the end of that week. Thereafter, 
a maximum of 2 missed doses during each study period will be allowed. If, at any time, study 
subjects are not compliant with the study protocol dosing requirements, they may be withdrawn 
from further participation in the study. 
Should study subjects become ill during the study, they should contact the study coordinator to 
discuss the decision surrounding taking the study drug.  
If study subjects are too ill to take study drug on the night of PSG, the PSG will be scheduled for 
the following night. If this is not possible, or the subject remains ill the PSG for that period will 
not be done. In the event of a persistent AE and or where the study subject misses more than 2 
doses of study drug in a single dosing period the subject will be assessed for potential withdrawal 
in conjunction with the sponsor.  
8.4.7 
Study Blinding and Unblinding Procedures 
Provisions to ensure the integrity of the study blind include:  
1. Provisioned drug product and placebo being identical in color, texture, taste, and 
appearance 
2. All packaging being identical between groups (other than study randomization number 
allocation and kit number) 
3. Labelling of FT218 study drug will preserve the double-blind integrity for the study 
4. No biological tests being completed during the study risk inadvertent unblinding to study 
treatment allocation 
To maintain the overall quality and integrity of CLFT218-1501 clinical study data, a code break 
will only occur in exceptional circumstances. Knowledge of the study subject’s drug assignment 
would occur in circumstances where subject safety is at risk and knowledge of assignment is 
critical to the clinical management and safety of the subject.  


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In circumstances where unblinding is deemed to be necessary, the PI must first speak with the 
medical monitor. In case of emergency, or if the PI cannot reach the medical monitor, the PI will 
use his/her best clinical judgement, however, must notify the medical monitor as soon as 
possible. The PI will use the IRT system and/or the toll-free helpline for unblinding.  
After unblinding of an individual subject, every effort must be made by the PI to maintain the 
blind as far as possible. The PI will not reveal the treatment allocation to the study subject nor 
any other personnel involved in the conduct of this study as far as possible. This includes other 
study site personnel, study monitors, the study CRO/sponsor or associated external parties 
involved in the running of the FT218 clinical study.  
The PI will document in the subject’s source documents and eCRF that the blind was broken but 
will not disclose the subject’s drug assignment.  
Where the study blind is broken for emergency, the subject will be withdrawn from the study. 
The early withdrawal visit will be completed and the End of Study (EOS)/Withdrawal eCRF 
form will be completed. Reason for withdrawal will be detailed code break and reason for code 
break will be documented. 
8.4.8 
Prior and Concomitant Therapy 
All concomitant medications are to be taken as prescribed during the clinical study. All 
concomitant medications will be documented in both source documents and eCRF.  
All medications (narcolepsy and non-narcolepsy), including washout medications, taken within 
30 days of Visit 1 will be recorded in both source documents and eCRF at the screening and 
baseline visits. There will be ongoing recording of concomitant medications taken during the 
study. 
Permitted concomitant medications are: 
a. Modafinil or armodafinil 
b. Methylphenidate 
c. Dextroamphetamine 
d. Methamphetamine 
e. Mixed salts amphetamines (Adderall, Vyvanse, etc.) 
f. Medications used to treat other diseases/conditions with mechanisms of action that do not 
influence sleep-wake function (i.e., insulin for diabetes or levothyroxine for 
hypothyroidism) 
8.4.8.1 
Prohibited Medication/Therapy 
The following concomitant medications are prohibited during this study: 
a. Prior use of sodium oxybate s allowed in the study but with the following exclusions.  
• Previous dosing must be limited to no more than 4.5g per night 
• Patient should not have taken sodium oxybate for more than 2 weeks.  


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• All previous dosing must not have occurred within the last year prior to entry to 
the study 
b. Sodium valproate  
c. Anticonvulsants 
d. Clonidine 
e. SSRIs and SNRIs 
f. MAOIs  
g. TCAs 
h. Hypnotics 
i. Anxiolytics 
j. Sedating antihistamines 
k. Other experimental medications designed to treat narcolepsy, cataplexy or any other 
condition 
l. Antipsychotics 
8.4.9 
Treatment Compliance 
Study subjects will receive training from study site staff who will have received protocol and 
study specific training from the CRO/sponsor. Site training will occur in the study set up period 
(i.e. at the investigator meeting and/or at the site initiation visit). Additional site training will be 
facilitated at study monitoring visits where appropriate via study manuals and guides.  
Site staff will have documented training on the study protocol and will be aware of all 
requirements and advisory to give to study subjects and where applicable family members.  
Site staff will be both capable and competent in clinical care management of subjects with 
narcolepsy and will be responsible for monitoring and advising subjects on the key safety risks 
associated with the FT218 drug product.  
Study subjects will be informed on all requirements for the safe handling and self-administration 
of study drug. They will be both familiar and comfortable with its presentation, handling, and 
reconstitution. All training provided to study subjects must be documented.  
Subject training will include:  
1. Subject family members, where appropriate, will engage in the training process to allow 
for additional subject support in the home setting in both the drug reconstitution process 
and all of the safety, procedural and visit scheduling requirements for this study. The 
parent(s)/legal guardian of study subjects who have not reached the age of majority will 
be included in the study training process 
2. Study subjects will be advised on the food requirement i.e. dosing at least 2 hours after 
the evening meal, and dietary salt restrictions, if applicable 
3. Study subjects will be advised on best practice for study drug storage relative to their 
specific living arrangements. Site staff must be satisfied that study subjects have the 
necessary comprehension of what is required for study drug storage (both pre and post 


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reconstitution) and the necessary facilities, and contingency if away from their usual 
residence to store study drug safely 
4. Study subjects will be advised on the potential side effects of study drug and will receive 
instruction on what to do in the event of a health-related emergency. Additionally, they 
will be advised on how and when to report such events to the site 
5. Study subjects will be provided with emergency site contact numbers in the event of an 
emergency. To circumvent risk in the case of a health-related emergency all study 
subjects will be provided with an alert card with details of subject study participation 
with the FT218 sodium oxybate for extended-release oral suspension product. This card 
will flag that they are on a clinical study with a 1:1 chance that they are receiving a new 
extended-release oral suspension formulation of sodium oxybate. The contact details of 
the PI will be provided 
6. Study subjects will be advised on rationale and importance of adhering to study 
restrictions  
7. Subjects will be advised of what to do in the event of suspected loss or theft of drug 
product 
8. Study subjects will be advised on study drug returns requirements. This will include 
detail on what to do with: 1) unused and unopened study drug, 2) what to do with 
reconstituted and unused study drug, 3) requirement for the return to site of all empty 
study drug sachets 
9. Study subjects will be trained on using the ePRO device.  
The site staff will assess subjects to determine the need for additional training at each study visit.  
On return visit, the PI or designee will assess study subject compliance both verbally and by 
inventory of returns. All returns i.e. used, reconstituted and unused, and unopened study drug 
will be inventoried. Any deviation from dosing schedule will be documented and assessed for 
criteria for withdrawal. 
9 
TIMING OF STUDY PROCEDURES 
Study subjects will receive study drug (FT218 or placebo) as outpatients. The study is divided 
into 4 sequential periods with a total of 9 required study visits. One in Period 1, one in Period 2, 
six in Period 3 (the double-blind period) concluding with a single follow-up visit in Period 4.  
Where additional study visits are clinically required an unscheduled visit will be performed. A 
separate unscheduled eCRF visit module will be completed to record these visits. A set minimum 
of procedures to capture subject safety and progress will be done at the unscheduled visit, 
requirements for additional procedures will be determined by the PI/designee.  
For early withdrawal, the EOS/Withdrawal eCRF module will be completed. In addition the 
EOS/Withdrawal eCRF page must be completed detailing the reason for subject withdrawal. The 
reason for withdrawal must also be recorded in the source documents.  
Subjects will provide written informed consent as appropriate and according to local laws and 
regulations, before any study-related procedures are performed. 
 


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9.1 
Pre-treatment – Periods 1 and 2 
9.1.1 
Period 1: Visit 1 (Week -3, Day 1) Screening and Assessment 
Period 1 of the study commences with Visit 1. The purpose of this visit is to include subjects 
who meet the primary enrollment criteria for the study. All information collected will be clearly 
documented in the subject’s medical notes. The following assessments will be performed: 
• 
Complete informed consent procedures. Two originals of the subject information 
leaflet/informed consent and assent form, where applicable, must be collected. One will be 
given to the subject, one will be filed in the study site file, and a copy will be made and 
filed in the subject's medical note 
• 
Record demographic data 
• 
Assess for subject eligibility  
• 
Collect full medical and surgical history. All baseline conditions will be recorded in the 
subject's medical notes 
• 
Written confirmation of narcolepsy diagnosis by type i.e. NT1/NT2. A copy of all 
diagnostic records for narcolepsy, including, overnight PSG and next-day MSLT must be 
filed, and accessible to study monitors in the subject's medical notes. 
In addition, from historical PSG it must be confirmed that the subject did not have an AHI 
of ≥ 15 
• 
Collect full psychiatric history 
• 
Assess subjects for any prior or current drug abuse and dependence (which will exclude 
study subjects) 
• 
Collect concomitant medications taken within 30 days of Visit 1. Specifically the following 
will be documented:  
o Confirmation that the subjects prior to sodium oxybate, if any, meets with the 
inclusion/exclusion criteria i.e. Prior use of sodium oxybate is allowed in the study but 
with the following exclusions: 
a) Previous dosing must have been limited to no more than 4.5g per night 
b) Patient should not have taken sodium oxybate for more than 2 weeks 
c) All previous dosing must not have occurred within the last year prior to 
entry to the study  
o Confirmation that the subject has no current exposure to sodium valproate 
o Details of use of protocol prohibited concomitant medications: anticonvulsants, 
clonidine, SSRIs and SNRIs, MAOIs, TCAs, hypnotics, anxiolytics, sedating 
antihistamines, and antipsychotics within the last 30 days 
o Confirmation that the subject has not been exposed to any experimental 
medications designed to treat narcolepsy, cataplexy or any other condition within 
the last 3 months 
• 
Obtain confirmation of subject's agreement to comply with the study washout requirements 
for prohibited medications for the duration of the clinical study 
• 
Record subject alcohol, caffeine, and nicotine consumption (study restriction questions) 
o Obtaining confirmation of subject’s agreement to abstain from alcohol for the 
duration of the study 


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o For smokers, obtain confirmation of subject's agreement to adhere to study 
mandated smoking restrictions for the duration of the clinical study 
• 
Conduct screening C-SSRS (any current suicidal ideation or attempt will exclude subject) 
• 
Conduct obstructive sleep apnea assessment, including measurement of subject’s neck 
circumference and documentation of snoring patterns 
• 
Perform complete physical examination  
• 
Collect height (cm), weight (kg) and calculate body mass index (kg/m²) 
• 
Record vital signs (systolic and diastolic BP, heart rate) 
• 
Perform a 12-lead ECG after subject has been supine for 5 minutes 
• 
Collect samples for hematology, biochemistry, hepatitis B surface antigen (HBsAg) and 
anti-hepatitis C virus HCV antibody (HCVAb) 
• 
Collect sample for serum pregnancy test (female subjects) 
• 
Collect sample for urinalysis, and urine drug screen (includes benzodiazepines, cannabis, 
cocaine, opiates, and barbiturates) 
• 
Administer ESS 
• 
Provide ePRO device, and training and education on its use as it relates to study protocol 
diary records, drug adherence record and notifications and all other subject facing 
applications 
• 
Explain Sleep and Symptoms Daily Diary completion. Inform subjects that for ongoing 
eligibility they must complete the Sleep and Symptom Daily Diary every day during Period 
1 (every day for the 3-week period) 
• 
Provide all necessary materials for participation including emergency site contact numbers 
advising subjects that they can contact the site at any time should they have any concerns 
or questions 
• 
Schedule Visit 2 with overnight PSG and next-day MWT with the subject 
• 
Update the IRT system with subject details and planned Visit 2 date 
This visit marks the beginning of the washout period when prohibited concomitant medications 
are no longer permitted. 
9.1.2 
Period 2: Visit 2 (Week -1, Day 7) Baseline Visit  
Following the screening visit, the second stage of subject assessment for continued eligibility 
will occur at the baseline visit i.e. Visit 2.  
At this visit the PI/designee will firstly assess for: 
• 
Confirmation of continued eligibility 
• 
Compliance with drug washout requirements 
• 
Assess compliance with alcohol consumption, abstinence from alcohol, and all other study 
restrictions (study restriction questions) 
• 
Assess drug abuse and dependence. Clinical judgement to be exercised in determining need 
for performing additional urine drug screen for benzodiazepines, cannabis, cocaine, opiates 
and barbiturates at this visit 


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• 
Compliance in completing the screening/baseline Sleep and Symptom Daily Diary.  
Compliance is defined as completing the diary at least 4 times in each of the screening 
weeks. 
o Confirmation of continued presence of cataplexy (NT1 subjects only) as defined 
by an average of 8 reported cataplexy attacks per week as reported in the Sleep 
and Symptom Daily Diary 
• 
EDS as defined by a baseline ESS score > 10 points 
If these criteria are met the following assessments and procedures will occur:  
• 
Review and record all concomitant medication 
o Assess for adherence to prohibited medication requirements 
• 
Document any AEs 
• 
Complete baseline CGI assessment of severity of sleepiness (by investigator) 
• 
Administer baseline C-SSRS questionnaire 
• 
Perform complete physical exam if determined clinically indicated by the PI 
• 
Record vital signs (systolic and diastolic BP, heart rate) 
• 
Collect samples for hematology and biochemistry  
• 
Collect sample for urinalysis 
• 
Perform urine pregnancy test (female subjects) 
• 
Update the IRT system with planned Visit 3 date 
If all assessments are satisfactory the study subject will then progress to having overnight 8-hour 
PSG with next-day 5 hour nap MWT. Results will be reported from the central scoring 
laboratory (Section 11.12).  
9.1.2.1 
Central Scoring Laboratory: PSG and MWT (+ 2 Days for results) 
Once the overnight PSG and next-day MWT has been completed, the results will be reviewed 
and scored by a central scoring laboratory (Section 11.12). The targeted turnaround time for 
results following completion of MWT is ≤ 2 days. Results will be transmitted to the study PI.  
Once confirmation of subject PSG and MWT eligibility has been received from the central 
scoring laboratory and all other study entry criteria are met, the PI/designee can randomize the 
study subject.  
9.1.2.2 
Randomization 
Where possible, on the same day confirmation of subject PSG and MWT eligibility has been 
received from the central scoring laboratory and all other study entry criteria are met, the 
PI/designee will randomize the study subject. There is no clinic visit for randomization, i.e., 
the subject is not present at site. 
All screening and baseline assessments confirming eligibility must be documented in advance of 
subject randomization to the double-blind study period. The PI/designee enters the information 
into the IRT system, and the appropriate study drug is sent to the site. This process may take up 
to 6 days.  


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Study treatment must begin: 
1. Within 5 days of randomization where it took 2 days for the Central Scoring Laboratory 
to respond with the PSG/MWT eligibility response  
2. Within 6 days of randomization where it took 1 day for the Central Scoring Laboratory to 
respond with the PSG/MWT eligibility response  
The study site will notify all subjects of their eligibility status. Where a subject is eligible, the 
site will clarify requirements and arrange the first dispensing visit with the subject i.e., Visit 3.  
The CRO/sponsor must be notified of any deviations to this. Deviations are to be documented.  
9.2 
Treatment Period – Period 3 (Dose Titration and Stabilization) 
9.2.1 
Period 3a: Visit 3 (Week 1, Day 1) Dose Titration to 6.0 g/Night 
Period 3a will commence at Visit 3 with provision of the study drug to the subject. This marks 
the start of the double-blind period. 
Dose titration steps for this period:  
• 
Week 1: 1st week on study drug in this period: 4.5 g/night of FT218 or placebo  
• 
Week 2: 2nd week on study drug: Increase dose by 1.5 g/night for a dosing regimen of 
6g/night of FT218 or placebo 
• 
Week 3: 3rd week on study drug: No dose increment - dosing regimen remains at 
6.0 g/night of FT218 or placebo 
The following assessments and procedures will be performed at Visit 3:  
• 
Compliance with drug washout requirements 
• 
Confirmation of continued eligibility 
• 
Assess study restrictions compliance: (i)  abstinence from alcohol, (ii) smoking restrictions, 
and (iii) all other study restrictions 
• 
Assess drug abuse and dependence. Clinical judgement to be exercised in determining need 
for performing urine drug screen for benzodiazepines, cannabis, cocaine, opiates, and 
barbiturates 
• 
Review and record all concomitant medication 
o Assess for adherence to prohibited medication requirements 
• 
Document any AEs 
• 
Administer “since last visit” C-SSRS questionnaire 
• 
Perform physical examination if determined clinically necessary by the PI 
• 
Perform urine pregnancy test (female subjects) 
• 
Record vital signs (systolic and diastolic BP and heart rate) 
• 
Collect weight 
• 
Education & training and assessment of study subject on-study requirements and study 
drug reconstitution, compliance, management, prohibited medications, subject self-care 
and safety 


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• 
Dispense study drug 
• 
Remind subject about instructions on Sleep and Symptom Daily Diary completion using 
the ePRO device 
If the PI is concerned that the study subject will be unable to comply with FT218 study drug and 
study requirements following the training and education session the subject will be informed and 
withdrawn from study.  
• 
Schedule Visit 4 with the study subject 
• 
Update IRT system with subject’s details for next visit 
9.2.2 
Period 3b(i): Visit 4 (Week 3, Day 7) Dose Titration to 7.5 g /Night 
Dose titration steps for this period:  
• 
Week 4: 1st week on study drug in this period: Increase dose by 1.5 g/night for a dosing 
regimen of 7.5 g/night of FT218 or placebo 
• 
Week 5: 2nd week on study drug: 7.5 g/night of FT218 or placebo.  
Visit 4 includes a full efficacy assessment (evaluation of the 6.0 g efficacy). Procedures at this 
visit include:  
• 
Compliance with drug washout requirements 
• 
Confirmation of continued eligibility  
• 
Assess study restrictions compliance: (i)  abstinence from alcohol, (ii) smoking restrictions, 
and (iii) all other study restrictions 
• 
Assess for drug abuse and dependence. Clinical judgement to be exercised in determining 
need for performing urine drug screen for benzodiazepines, cannabis, cocaine, opiates, and 
barbiturates 
• 
Assess compliance with drug handling, management, and safety requirements 
o Confirm subject is adhering to requirement to eat at least 2 hours before taking 
study drug 
o Subject re-education on study drug safety and handling and study-related 
procedures if deemed necessary by PI 
• 
Review and record of concomitant medication 
o Assess for adherence to prohibited medication requirements.  
• 
Document any AEs 
• 
Collect CGI assessment of improvement in sleepiness (investigator blinded to MWT 
results) 
• 
Administer “since last visit” C-SSRS questionnaire 
• 
Perform physical examination if determined clinically indicated by the PI 
• 
Record vital signs (systolic and diastolic BP and heart rate) 
• 
Perform urine pregnancy test (female subjects) 
• 
Review and confirmation of ePRO diary and questionnaire completion (on subject 
questioning and ePRO check).  
o Self-recorded study drug compliance record (with returns check) 


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o Compliance with Sleep and Symptom Daily Diary completion requirements for 
the past 3-week period. Completion of ESS (subject questionnaire) 
• 
Overnight PSG 
o Next-day 5 hour nap MWT 
• 
Dispense drug and perform accountability 
• 
ePRO device handling and ePRO completion requirements and consequences of poor 
compliance will be discussed again with the study subject 
o Study subjects will be instructed to complete their Sleep and Symptom Daily 
Diary on a daily basis for the next 2 weeks 
If the PI is concerned that the study subject will be unable to comply with FT218 study drug and 
study requirements following training and education session the subject will be informed and 
withdrawn from study.  
• 
Schedule Visit 5 with the study subject 
• 
Update IRT system with subject’s details for next visit and study drug returns 
9.2.3 
Period 3b(ii): Visit 5 (Week 6, Day 1) 7.5 g/Night 
There are no dose titration steps for this period:  
• 
Week 6: 1st week on study drug: 7.5 g/night of FT218 or placebo 
• 
Week 7: 2nd week on study drug: 7.5 g/night of FT218 or placebo 
• 
Week 8: 3rd week on study drug: 7.5 g/night of FT218 or placebo 
Visit 5 includes a partial efficacy assessment. Procedures at this visit include:  
• 
Compliance with drug washout requirements 
• 
Confirmation of continued eligibility  
• 
Assess study restrictions compliance: (i)  abstinence from alcohol, (ii) smoking restrictions, 
and (iii) all other study restrictions 
• 
Assess drug abuse and dependence. Clinical judgement to be exercised in determining need 
for performing urine drug screen for benzodiazepines, cannabis, cocaine, opiates and 
barbiturates 
• 
Assess compliance with drug handling, management, and safety requirements 
o Confirm subject is adhering to requirement to eat at least 2 hours before taking 
study drug 
o Subject re-education on study drug safety and handling and study-related 
procedures if deemed necessary by site PI 
• 
Review and record of concomitant medication 
o Assess for adherence to prohibited medication requirements 
• 
Document any AEs 
• 
Complete CGI assessment of improvement in sleepiness (investigator blinded to MWT 
results) 
• 
Administer “since last visit” C-SSRS questionnaire 
• 
Perform physical examination if determined clinically indicated by the PI 


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• 
Record vital signs (systolic and diastolic BP and heart rate) 
• 
Perform urine pregnancy test (female subjects) 
• 
Review and confirmation of ePRO diary and questionnaire completion: (on subject 
questioning and ePRO check) 
o Self-recorded study drug compliance record (with returns check) 
o Compliance with Sleep and Symptom Daily Diary completion requirements for 
the past 2-week period. Completion of ESS (subject questionnaire) 
• 
Dispense drug and perform accountability 
• 
ePRO device handling and ePRO completion requirements and consequences of poor 
compliance will be discussed again with the study subject 
o Study subjects will be instructed to complete their Sleep and Symptom Daily 
Diary on a daily basis for the next 3 weeks.  
If the PI is concerned that the study subject will be unable to comply with FT218 study drug and 
study requirements following training and education session the subject will be informed and 
withdrawn from study.  
• 
Schedule Visit 6 with the study subject 
• 
Update IRT system with subject’s details for next visit and study drug returns 
9.2.4 
Period 3c(i): Visit 6 (Week 8, Day 7) Dose Titration to 9.0 g/Night, Stabilization 
Dose titration and stabilization steps for this period:  
• 
Week 9: 1st week on study drug in this period: Increase dose by 1.5 g/night for a dosing 
regimen of 9.0 g/night of FT218 or placebo  
• 
Week 10: 2nd week on study drug: 9.0 g/night of FT218 or placebo.  
This visit includes a full efficacy assessment (evaluation of the 7.5 g efficacy). Procedures at this 
visit include:  
• 
Compliance with drug washout requirements 
• 
Confirmation of continued eligibility  
• 
Assess study restrictions compliance: (i)  abstinence from alcohol, (ii) smoking restrictions, 
and (iii) all other study restrictions 
• 
Assess drug abuse and dependence. Clinical judgement to be exercised in determining need 
for performing urine drug screen for benzodiazepines, cannabis, cocaine, opiates and 
barbiturates 
• 
Assess compliance with drug handling, management and safety requirements 
o Confirm subject is adhering to requirement to eat at least 2 hours before taking 
study drug 
o Subject re-education on study drug safety and handling and study-related 
procedures if deemed necessary by site PI 
• 
Review and record of concomitant medication 
o Assess for adherence to prohibited medication requirements 
• 
Document AEs 


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• 
Complete CGI assessment of improvement in sleepiness (investigator blinded to MWT 
results) 
• 
Administer “since last visit” C-SSRS questionnaire 
• 
Perform physical examination if determined clinically indicated by the PI 
• 
Collect vital signs (systolic and diastolic BP and heart rate) 
• 
Perform urine pregnancy test (female subjects) 
• 
Review and confirmation of ePRO diary and questionnaire completion: (on subject 
questioning and ePRO check) 
o Self-recorded study drug compliance record (with returns check) 
o Compliance with Sleep and Symptom Daily Diary completion requirements for 
the past 3-week period. Completion of ESS (subject questionnaire) 
• 
Overnight PSG 
o Next-day 5 hour nap MWT 
• 
Dispense drug and perform accountability 
• 
ePRO device handling and ePRO completion requirements and consequences of poor 
compliance will be discussed again with the study subject 
o Study subjects will be instructed to complete their Sleep and Symptom Daily 
Diary on a daily basis for the next 2 weeks 
If the PI is concerned that the study subject will be unable to comply with FT218 study drug and 
study requirements following training and education session the subject will be informed and 
withdrawn from study.  
• 
Schedule Visit 7 with the study subject 
• 
Update IRT system with subject’s details for next visit and study drug returns 
9.2.5 
Period 3c(ii): Visit 7 (Week 11, Day 1) Stabilization 
Stable dosing: 
• 
Week 11: 1st week on study drug in this period: 9.0 g/night of FT218 or placebo 
• 
Week 12: 2nd week on study drug: 9.0 g/night of FT218 or placebo 
• 
Week 13: 3rd week on study drug: 9.0 g/night of FT218 or placebo 
Visit 7 includes a partial efficacy assessment. Procedures at this study visit include:  
• 
Compliance with drug washout requirements 
• 
Confirmation of continued eligibility  
• 
Assess study restrictions compliance: (i)  abstinence from alcohol, (ii) smoking restrictions, 
and (iii) all other study restrictions 
• 
Assess drug abuse and dependence. Clinical judgement to be exercised in determining need 
for performing urine drug screen for benzodiazepines, cannabis, cocaine, opiates and 
barbiturates 
• 
Assess compliance with drug handling, management, and safety requirements 
o Confirm subject is adhering to requirement to eat at least 2 hours before taking 
study drug 


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o Subject re-education on study drug safety and handling and study-related 
procedures if deemed necessary by site PI 
• 
Review and record of concomitant medication 
o Assess for adherence to prohibited medication requirements.  
• 
Document any AEs 
• 
Collect CGI assessment of improvement in sleepiness (investigator blinded to MWT 
results) 
• 
Administer “since last visit” C-SSRS questionnaire  
• 
Perform physical examination if determined clinically indicated by the PI 
• 
Collect vital signs (systolic and diastolic BP and heart rate) 
• 
Perform urine pregnancy test (female subjects) 
• 
Review and confirmation of ePRO diary and questionnaire completion: (on subject 
questioning and ePRO check) 
o Self-recorded study drug compliance record (with returns check) 
o Compliance with Sleep and Symptom Daily Diary completion requirements for 
the past 2-week period. Completion of ESS (subject questionnaire) 
• 
Dispense drug and perform accountability 
• 
ePRO device handling and ePRO completion requirements and consequences of poor 
compliance will be discussed again with the study subject 
o Study subjects will be instructed to complete their Sleep and Symptom Daily 
Diary on a daily basis for the next 3 weeks.  
If the PI is concerned that the study subject will be unable to comply with FT218 study drug and 
study requirements following training and education session the subject will be informed and 
withdrawn from study.  
• 
Schedule Visit 8 with the study subject 
• 
Update IRT system with subject’s details for next visit and study drug returns 
9.2.6 
Period 3c(iii) Visit 8 (Week 13, Day 7) End of Study (EOS) 
This visit includes a full efficacy assessment (evaluation of the 9.0 g efficacy). 
• 
Compliance with drug washout requirements 
• 
Confirmation of continued eligibility  
• 
Assess study restrictions compliance: (i)  abstinence from alcohol, (ii) smoking restrictions, 
and (iii) all other study restrictions 
• 
Assess drug abuse and dependence. Clinical judgement to be exercised in determining need 
for performing urine drug screen for benzodiazepines, cannabis, cocaine, opiates and 
barbiturates 
• 
Assess compliance with drug handling, management and safety requirements 
o Confirm subject is adhering to requirement to eat at least 2 hours before taking 
study drug 
• 
Review and record of concomitant medication 
o Assess for adherence to prohibited medication requirements 
• 
Document any AEs 


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• 
Complete CGI assessment of improvement in sleepiness (investigator blinded to MWT 
results) 
• 
Administer “since last visit” C-SSRS questionnaire  
• 
Perform full physical examination 
• 
Collect weight  
• 
Collect vital signs (systolic and diastolic BP and heart rate) 
• 
Collect samples for hematology, biochemistry, and perform urine pregnancy test (female 
subjects) 
• 
Collect sample for urinalysis 
• 
Perform 12-lead ECG after subject is supine for 5 minutes 
• 
Review and confirmation of ePRO diary and questionnaire completion: (on subject 
questioning and ePRO check) 
o Self-recorded study drug compliance record (with returns check) 
o Compliance with Sleep and Symptom Daily Diary completion requirements for 
the past 3-week period. Completion of ESS (subject questionnaire) 
• 
Overnight PSG 
o Next-day 5 hour nap MWT 
• 
Perform drug accountability and reconciliation 
• 
Update IRT system with EOS details and final subject drug accountability 
• 
Obtain ePRO device from subject and place in on-site safe storage 
• 
Schedule follow-up visit with study subject 
9.3 
Follow-up Period – Period 4 
9.3.1 
Period 4: Visit 9 (Week 15, Day 1) Follow-up 
A safety follow-up visit will take place at Week 15 Day 1 (+4/-0) when subjects have been off 
study drug for ≥ 1 week. Study procedures include:  
• 
Review and record all concomitant medication 
• 
Safety assessment: To include assessment for residual effects of study drug and all AE 
review. 
o All AEs including residual effects of study drug to be reported as per study 
protocol requirements. The outcome of any AEs with a date of onset during the 
double-blind period should be reevaluated and any new AEs should be recorded. 
All SAEs and nonserious AEs assessed by the PI as related to the study drug 
should be followed to resolution or until the PI assesses them to be chronic or 
stable 
o In the event that a study subject is unable to return to clinic for the follow-up visit, 
telephone contact with the study subject to assess for AEs and or residual effects 
of study drug and concomitant medications is expected. 
• 
Perform physical examination if determined clinically indicated by the PI 
• 
Collect weight  
• 
Collect vital signs (systolic and diastolic BP and heart rate) if clinically indicated 
• 
Collect samples for hematology or biochemistry if clinically indicated, and perform urine 
pregnancy test (female subjects) 


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• 
Discuss off-study narcolepsy therapeutic pathway with study subject 
9.4 
Unscheduled Visits 
Where additional study visits are clinically required an unscheduled visit will be performed. 
Where an unscheduled visit leads to the subject’s withdrawal, the procedures to be performed are 
those planned for the EOS visit as detailed in Section 9.2.6. 
Study procedures include:  
• 
Compliance with drug washout requirements 
• 
Confirmation of continued eligibility 
• 
Assess study restrictions compliance: (i)  abstinence from alcohol, (ii) smoking restrictions, 
and (iii) all other study restrictions 
• 
Assess drug abuse and dependence. Clinical judgement to be exercised in determining need 
for performing urine drug screen for benzodiazepines, cannabis, cocaine, opiates and 
barbiturates 
• 
Assess compliance with drug handling, management and safety requirements. 
o Confirm subject is adhering to requirement to eat at least 2 hours before taking 
study drug 
o Subject re-education on study drug safety and handling and study-related 
procedures if deemed necessary by site PI 
• 
Review and record of concomitant medication 
o Assess for adherence to prohibited medication requirements 
• 
Document any AEs 
• 
Collect CGI assessment of improvement (investigator blinded to MWT results as 
applicable) 
• 
Administer “since last visit” C-SSRS questionnaire 
• 
Perform physical examination*  
• 
Collect weight* 
• 
Record vital signs (systolic and diastolic BP and heart rate)* 
• 
Collect samples for hematology*, biochemistry*, and perform urine pregnancy test (female 
subjects) 
• 
Perform 12-lead ECG after subject is supine for 5 minutes* 
• 
Review and confirmation of ePRO diary and questionnaire completion: (on subject 
questioning and ePRO check) 
o Self-recorded study drug compliance record (with returns check) as applicable 
o Compliance with Sleep and Symptom Daily Diary completion requirements for 
the past period. Completion of ESS (subject questionnaire) 
• 
Overnight PSG* 
o Next-day 5 hour nap MWT* 
• 
Schedule next or follow-up visit with study subject if not withdrawing at this visit.  
* At the PI’s discretion 


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9.5 
Duration of Treatment 
The duration of treatment will be approximately 17 weeks. There will be a 3-week screening 
period, a 13-week treatment period, and a 1-week follow-up period. 
Following the end of the subject’s participation in the clinical study, no further study drug will 
be dispensed. The study PI will determine the most suitable medical care for the subject. 
10 EFFICACY AND SAFETY VARIABLES  
 
10.1 
Efficacy and Safety Measurements Assessed  
10.1.1.1 Maintenance of Wakefulness Test 
The MWT is an evaluation used as a quantitative PSG measurement of daytime 
wakefulness/somnolence.24 It shows whether or not a subject is able to stay awake for a defined 
period of time (90-minutes between one nap ending and the next one starting, spaced at 2-hour 
intervals throughout the day). Sleep latency is assessed by the amount of time it takes for 
subjects to fall asleep during the test. The MWT is an indicator of how well subjects may be able 
to function and remain alert during quiet times of inactivity. 
10.1.1.2 Clinical Global Impression of Sleepiness 
At Visit 2, the CGI assessment of severity of sleepiness scale will be conducted. At subsequent 
assessments, the CGI is evaluated on a 7-point scale, centered at No Change, and ranging from 
Very Much Worse to Very Much Improved. Subjects are rated by the qualified and approved 
evaluators who based their assessments on the severity of sleepiness at baseline. 
10.1.1.3 Sleep and Symptoms Daily Diary 


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10.1.1.5 Epworth Sleepiness Scale 
The ESS is intended to evaluate the extent of sleepiness in everyday situations by asking the 
subject a series of questions. In these questions, subjects are asked to rate their chances of dozing 
during each of 8 activities on a scale from 0 through 3 (0=never; 1=slight; 2=moderate; 3=high). 
Higher total scores indicate a greater tendency to sleepiness. 
10.1.2 Safety Assessments 
10.1.2.1 Adverse Events 
Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a clinical study subject administered a 
medicinal product which does not necessarily have a causal relationship with this treatment. 
Adverse events may include, but are not limited to the following: abnormal test findings, 
clinically significant signs and symptoms, hypersensitivity, any signs and/or symptoms from: 
drug overdose, drug administration/reconstitution error, any drug misuse, accidental exposure 
withdrawal, and or interactions, and exposure in utero.  
Symptoms and signs of clinical and functional deterioration as defined in study efficacy 
assessment criteria for subjects with NT1 and NT2 will be not be captured as AEs. These signs 
and symptoms will be captured in the context of efficacy assessments via the ePRO enabled 
Sleep and Symptom Daily Diary, CGI rating of sleepiness, and on overnight PSG and next-day 5 
hour nap MWT and will be reported as part of the efficacy analysis.  
They include:  
• 
Excessive daytime sleepiness 
• 
Number of cataplexy attacks 
• 
Disturbed nocturnal sleep 
• 
Nightly arousals 
• 
Sleep quality 
• 
Refreshing nature of sleep 
• 
Sleep paralysis 
All other signs and symptoms of clinical and functional deterioration as they relate to the 
underlying diagnosis of narcolepsy (NT1 and NT2), study drug, and concomitant medications, or 
other will be recorded as AEs. 


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It is the responsibility of the investigator to document all AEs that occur during the study. AEs 
should be reported on the appropriate page of the eCRF. 
Assessment of Severity 
Each AE will be assigned a category by the investigator as follows: 
Mild: 
An AE that is easily tolerated by the subject, causes minimal discomfort, 
and does not interfere with everyday activities 
Moderate: 
An AE that is sufficiently discomforting to interfere with normal 
everyday activities; intervention may be needed 
Severe: 
An AE that prevents normal everyday activities; treatment or other 
intervention usually needed 
If there is a change in severity of an AE, it must be recorded as a separate event. 
Assessment of Causality 
For each recorded AE or SAE, the investigator or designee must make an assessment of causality 
based on the following criteria to determine the relationship between the AE and study drug: 
 
Classification 
Investigator’s 
Judgement 
Definition 
Not Related: 
assigned when: 
Not related 
Where an AE or SAE is judged to be clearly and incontrovertibly due only to 
extraneous causes (e.g. disease, environment) and does not meet the criteria for 
study drug relationship listed under likely, possibly, or unlikely 
Unlikely 
The AE or SAE is unlikely related to the study drug, when the AE or SAE (the 
first 2 criteria must be met): 
• 
Does not follow a reasonable temporal sequence from administration 
of the study drug 
• 
May readily have been produced by the subject’s clinical state, 
environmental, or toxic factors, or other modes of therapy 
administered to the subject 
• 
Does not follow a known pattern of response to the study drug  
• 
Does not reappear or worsen when the study drug is readministered 
Related: 
assigned in any 
other cases when:  
Possibly 
The AE or SAE is possibly related to the study drug, when the connection to 
the study drug appears unlikely but cannot be ruled out with certainty. This 
causal relationship is assigned when the AE or SAE (the first 2 criteria must be 
met): 
• 
Follows a reasonable temporal sequence from administration of the 
study drug 
• 
May have been produced by the subject’s clinical state, environmental, 
or toxic factors or other modes of therapy administered to the subject.  
• 
Follows a pattern of response to the suspected study drug. 


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Related: 
assigned in any 
other cases when: 
Related 
The AE or SAE is considered related to the study drug, when the connection to 
study drug can be made with a high degree of certainty. This causal relationship 
is assigned when the AE or SAE (the first 3 criteria must be met): 
• 
Follows a reasonable temporal sequence from administration of the 
study drug 
• 
Cannot be reasonably explained by the known characteristics of the 
subject’s clinical state, environmental, or toxic factors, or other modes 
of therapy administered to the subject 
• 
Disappears or decreases upon cessation or reduction in dose (note that 
there are important exceptions when an AE or SAE does not disappear 
upon discontinuation of the study drug, yet drug relatedness clearly 
exists [e.g. bone marrow depression or tardive dyskinesia]) 
• 
Follows a known pattern of response to the suspect study drug 
• 
Reappears upon rechallenge 
 
If the investigator determines that the causality is unknown, the PI must then assign a causality 
of “Possibly” for the purposes of reporting. The causality must be clearly documented in the 
subject’s medical notes and eCRF and report in accordance with the SAE reporting requirements 
if applicable. 
Action Taken 
The investigator will describe the action taken in the appropriate section of the eCRF, as follows: 
• None 
• Study drug stopped 
• Study drug temporarily interrupted 
• Concomitant medication 
• Other, specify. 
Adverse Event Outcome 
The investigator will assess the outcome of the AE or SAE as follows: 
• Fatal (the subject has died) 
• Resolved (the AE or SAE has ended) 
• Ongoing (the AE has not ended)* 
• Unknown (lost to follow-up after repeated unsuccessful attempts to contact the subject) 
* An AE outcome can only be categorized as ongoing if the AE is: 
• 
Ongoing at the end of the reporting period: improved, stable or worsening  
• 
Ongoing: improved, stable, or worsening, and referred to the subject’s physician or a 
specialist. 


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Follow-up of Adverse Events 
All investigators should follow up subjects with AEs until the event is resolved or until, in the 
opinion of the investigator, the event is stabilized or determined to be chronic. Details of AE 
resolution must be documented in the eCRF. 
Subjects should be followed for 7 days after receiving the last dose of study drug, and any AEs 
that occur during this time should be reported according to the procedures outlined above. 
Documentation and Reporting of Adverse Events 
Attention will be paid to the occurrence of AEs at all stages of the clinical study starting from 
signing of the informed consent to the follow-up visit which takes place 1 week after study 
completion or 1 week after premature withdrawal. Baseline events (i.e. medical history events 
that are ongoing) captured at the first study visit will only be recorded as AEs if during the 
screening and assessment period or double-blind period there is deterioration.  
Information regarding all AEs, including SAEs, will be collected at each visit. All AE/SAEs that 
are encountered during the protocol specified AE/SAE reporting period will be followed to their 
resolutions, until the investigator assesses them as stable, or the subject is lost to follow-up.  
Adverse events will be identified as treatment-emergent (TEAE) if the event occurs or increases 
in severity after the first dose of study drug is taken.  
Adverse events considered related to study drug at the EOS or Early Withdrawal Visit (if 
applicable) will be followed until the subject is stable or the AE is resolved or the subject is lost 
to follow-up. 
Adverse event data will be obtained at all study visits scheduled or unscheduled. Reporting will 
be based on information provided spontaneously by the subject and/or through questioning of the 
subject.  
To elicit AEs, questioning at each study visit should begin with simple nonleading questions.  
For example:  
• 
How have you felt since your last visit? 
• 
Have you had any health problems since you were here last? 
Complete and appropriate data on all AEs experience (observed, volunteered or elicited) during 
the reporting period will be reported on an ongoing basis in the Adverse Event Form pages of the 
eCRF.  
The following information regarding any AEs will be determined and documented by the 
investigator.  
• 
Subject number 
• 
The event (diagnosis preferred) 
• 
The relationship of the AE to the study drug (causal relationship) 


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• 
Study drug information 
• 
Seriousness (serious or not serious) 
As the quality and precision of acquired AE data are critical, investigators will use the AE 
definitions provided in the protocol and will observe the following guidelines when describing 
adverse events in the Adverse Event Form pages of the eCRF.  
• 
Whenever possible recognized medical terms will be used to describe AEs rather than 
colloquialisms (for example, “influenza” rather than “flu”) and abbreviations will be 
avoided 
• 
Adverse events occurring secondary to other AEs (e.g. sequela or complications) will be 
identified by the primary cause. A primary AE, if clearly identifiable, generally represents 
the most accurate clinical term to record in the eCRF. The investigator will provide his/her 
opinion of which is the primary AE 
10.1.2.1.1 
Serious Adverse Events 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence or effect that, at any dose, 
• 
Results in death 
• 
Is life-threatening (an AE is life-threatening if the subject was at immediate risk of death 
from the event as it occurred, i.e. it does not include a reaction that might have caused 
death if it had occurred in a more serious form) 
• 
Requires or prolongs inpatient hospitalization. (Complications occurring during 
hospitalization are AEs and are SAEs if they cause prolongation of the current 
hospitalization. Hospitalization for elective treatment of a preexisting nonworsening 
condition is not, however, considered an AE. The details of such hospitalizations must be 
recorded on the medical history or physical examination page of the eCRF) 
• 
Results in persistent or significant disability/incapacity. (An AE is incapacitating or 
disabling if it results in a substantial and/or permanent disruption of the subject’s ability to 
carry out normal life functions) 
• 
Results in a congenital anomaly/birth defect 
In addition, medical and scientific judgement is required to decide if prompt notification is 
required in situations other than those defined for SAEs above. This may include any event that 
the investigator regards as serious that did not strictly meet the criteria above but may have 
jeopardized the subject or required intervention to prevent one of the outcomes listed above, or 
that would suggest any significant hazard, contraindication, side effect, or precaution that may be 
associated with the use of the investigational product. 
Reporting of Serious Adverse Events 
If a SAE occurs, the CRO/sponsor is to be notified within 24 hours of awareness of the event by 
the investigator. If the SAE is fatal or life-threatening, notification to the CRO/sponsor must be 
made immediately, irrespective of the extent of available AE information. This timeframe also 


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applies to additional new information (follow-up) on previously forwarded SAE reports as well 
as to the initial and follow-up reporting of exposure in utero cases.  
In the rare event that the investigator does not become aware of the occurrence of a SAE 
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere) the 
investigator is to report the event within 24 hours after learning of it and document the time of 
his/her first awareness of the AE.  
For all SAEs, the investigator is obligated to pursue and provide information to the CRO/sponsor 
in accordance with the timeframes for reporting specified above. In addition, an investigator may 
be requested by the CRO/sponsor to obtain specific additional follow-up information in an 
expedited fashion. This information may be more detailed than that captured on the SAE form. It 
will describe the SAE in enough detail to allow for a complete medical assessment of the case. 
Additional information concomitant medications and illnesses must be provided. In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible to 
the CRO/sponsor. 
The SAE forms must be faxed within 24 hours for the attention of 
INC Research Drug Safety 
Fax No. +1 877-464-7787 
e-mail: INCdrugSafety@INCResearch.com 
The immediate SAE report will be made by the investigator within a very short period of time 
and under no circumstances should this exceed 24 hours following knowledge of the SAE. 
Although the information required for completion of a SAE report form may not be available 
within the specified time period, an initial report should be submitted with the following 
information available.  
• 
Subject ID (screening/randomization number) 
• 
The suspect product/formulation – as blinded only the dose strength will be detailed 
• 
An event or outcome that can be identified as serious 
• 
The seriousness criterion 
• 
The causal assessment (note: this may changes as more information is learned, however, an 
assessment MUST accompany the original report) 
All SAE information must be recorded on an SAE form and sent within 24 hours or 1 business 
day of learning of the report to INC Drug Safety. Additional information received for a case 
(follow-up or corrections to the original case) need to be detailed on an SAE form and sent to 
INC Drug Safety. The SAE will be followed up until a final outcome and date are available. 
Instances of death, congenital abnormality, or an event that is of such clinical concern as to 
influence the overall assessment of safety, if brought to the attention of the investigator at any 
time after cessation of study drug administration and linked by the investigator to this study, 
should be reported to the study monitor. 


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The sponsor/CRO will promptly notify all relevant investigators and the regulatory authorities of 
findings that could adversely affect the safety of subjects, impact on the conduct of the study or 
alter the IEC/IRB approval/favorable opinion of the study. In addition, CRO/sponsor will 
expedite the reporting to all concerned investigators, to the IECs/IRBs, where required, and to 
the regulatory authorities of all adverse reactions that are both serious and unexpected. 
Details of the procedures to be followed if a pregnancy occurs are provided in Section 8.3.4. 
Although pregnancy is not an SAE, and an elective abortion is not an SAE, any spontaneous 
abortion and/or any pregnancy that meets any regulatory serious criterion, or any pregnancy with 
an outcome for the pregnant person or the infant that meets regulatory serious criterion will be 
captured as an SAE. 
10.1.2.1.2 
Unexpected Adverse Reactions 
Unexpected Adverse Reaction Definition 
An unexpected adverse reaction is any untoward and unintended response that is related to the 
administration of the study drug at any dose that is not consistent with the applicable product 
information (e.g. investigators brochure for an unauthorized investigational medicinal product or 
summary of product characteristics for an authorized product). 
All suspected unexpected serious adverse reactions (SUSARs) will be the subject of expedited 
reporting. The sponsor/CRO shall ensure that all relevant information about a SUSAR that is 
fatal or life-threatening is reported to the relevant competent authorities and IEC/IRB within 7 
days after knowledge by the sponsor of such a case and that relevant follow up information is 
communicated within an additional 8 days. All other SUSARs will be reported to the relevant 
competent authorities and IEC/IRB within 15 days after knowledge by the sponsor of such a 
case. All investigators should follow up SUSARs until the event is resolved or until, in the 
opinion of the investigator, the event is stabilized or determined to be chronic. Post study 
SUSARs that occur after the subject has completed the clinical study must be reported by the 
investigator to the sponsor. 
Warnings and Precautions  
Safety Assessment to Exclude Obstructive Sleep Apnea  
Sodium oxybate, when given to subjects with obstructive sleep apnea (OSA) will increase the 
risk of advancing sedation and respiratory depression. To support screening activities in ensuring 
subjects with OSA are detected and excluded as early as possible from the FT218 clinical study, 
a number of primary criteria will be assessed at Visit 1 to rule out OSA. Specifically, this will 
include taking the subject’s neck circumference and documenting snoring patterns. These criteria 
will be assessed relative to ESS score, BMI, BP, age, and gender. A determination on eligibility 
to proceed through the screening period will be made relative to OSA risk. PIs will be trained on 
this at Site Initiation. In the event that following completion of the assessment the risk of OSA 
goes undetected, confirmation of the presence of OSA will be detected on overnight PSG (AHI ≥ 
15) at Week 3 in the screening and baseline period of the study. Where OSA is detected, the 


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subject will be withdrawn from study. Include any information relevant to safety (i.e., known 
side effects or treatment of potential side effects). 
Safety Assessment of Suicidality 
Study subjects will be assessed at study screening for suicidality using the C-SSRS. At risk 
subjects will be withdrawn. Risk for the emergence of suicidality, using the C-SSRS, will be 
assessed at each study visit for the duration of the clinical study. Where risk is identified, study 
subjects will immediately be withdrawn from study. The PI will implement the most appropriate 
medical and psychological care pathway to ensure subject safety and recover. Where a subject is 
withdrawn for suicidality this will be clearly indicated as the reason for withdrawal on the 
withdrawal form and in source data. 
Safety Assessment for Abuse and Dependence 
Subjects with a history of drug abuse and/or dependence will be assessed at the screening visit by 
the PI/designee. Subjects with a known and discernable history of abuse and/or dependence will 
be excluded.  
Subjects will be assessed by the PI/designee for any signs and symptoms which may indicate an 
emergent abuse and dependence i.e. positive urine drug screen indicating concomitant use of 
contraindicated prescription drugs and/or illicit drug use, evidence or family report of 
concomitant use of alcohol with study drug product, suspicious claim(s) of lost product and 
looking for replacement study drug 
10.1.2.2 Clinical Laboratory Evaluation 
The hematology and biochemistry laboratory analyses will be performed at a central laboratory 
(ACM Global Central Laboratory, Rochester, US). Reference ranges will be supplied and used 
by the investigator to assess the laboratory data for clinical significance and pathological 
changes. The following laboratory safety tests will be performed: 
Hematology 
Hemoglobin, hematocrit, white blood cell count (total and differential), red blood cell count, 
platelet count, mean cell volume, mean cell hemoglobin, and mean cell hemoglobin 
concentration 
Biochemistry 
Creatinine, blood urea nitrogen, aspartate transferase, alanine transferase, gamma 
glutamyltransferase, alkaline phosphatase, total bilirubin, albumin, globulin, total protein, 
sodium, potassium, chloride, bicarbonate, estimated glomerular filtration rate, carbon dioxide, 
glucose, total cholesterol, triglycerides, and creatine phosphokinase. 


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Urinalysis 
pH, glucose, ketones, blood, and protein by dipstick test at the central laboratory. If any of these 
parameters gives a positive result, a quantitative result will be transmitted. 
10.1.2.2.1 
Other Laboratory Variables 
Drugs of Abuse Screening: Urine drug screen will comprise cocaine, benzodiazepines, 
cannabis, opiates, and barbiturates. 
Serology: Hepatitis B surface antigen, and hepatitis C antibody 
Pregnancy: serum β-human chorionic gonadotropin test will be performed at screening (Visit 1), 
urine β- human chorionic gonadotropin test at all other visits.  
10.1.2.3 Vital Signs 
Vital signs consisting of systolic and diastolic BP and heart rate will be recorded after at least 
5 minutes in the sitting position. 
10.1.2.4 Physical Examination 
A complete physical examination including weight and evaluation of main body systems/regions, 
including: skin and mucous, ears/nose/throat, pulmonary, cardiac, GI, and neurological systems. 
In case of abnormality, a comment will be recorded in the eCRF and subjects medical notes. Any 
deterioration in condition will be reported as an AE. 
10.1.2.5 Electrocardiogram 
Twelve-lead ECGs will be recorded after at least 5 minutes in the supine position.  
Each ECG consists of a 10 second recording of the 12 leads simultaneously, leading to a 12-lead 
ECG (25 mm/s, 10mm/mV) printout with HR, PR, QRS, QT, QTc automatic correction 
evaluation, including date, time, initials and number of the subject, signature of the research 
physician, and at least 3 complexes for each lead. The ECG interpretation and values will be 
recorded in the eCRF. 
10.1.3 Appropriateness of Measurements 
The efficacy and safety assessments planned for this study are widely used and generally 
recognized as reliable, accurate, and relevant to the disease condition. 
 


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11 STATISTICAL METHODS 
Two subject populations, one with both narcolepsy symptoms and one with EDS will be studied 
in a single parallel group dose-escalation design. The treatments are placebo and increasing 
doses of the test drug, FT218. Two primary outcome measures, MWT and CGI quantify the 
treatment effect on EDS and the NCA is the primary outcome measure for cataplexy.  
11.1 
Statistical and Analytical Plans 
The material in this section provides the basis of the statistical analysis plan (SAP) for this study. 
A complete SAP has been prepared to accompany this protocol for submission to the FDA for 
the Special Protocol Assessment. Details are provided therein.  
11.2 
Definition of the Analysis Populations 
The target population is individuals in need of treatment of EDS and cataplexy in subjects with 
narcolepsy. The full analysis population for efficacy is the intent-to-treat (ITT) population 
including all randomized subjects with at least one efficacy measurement after receiving the 6.0 
g dose (whether FT218 or placebo). 
11.2.1 Determination of Sample Size 
Estimation of sample size to achieve a desired power depends on the number and nature of the 
hypothesis testing paradigm and assumptions about the magnitude of the underlying effects. In 
this study, hypothesis testing will proceed in the following order. First MWT and CGI will be 
examined for statistical significance in the full sample including both NT1 and NT2 subjects for 
the 9 g dose. If significant, NCA for the same dose will be tested in NT1 subjects. If the first test 
fails, the data from this dose is not able to reject the null hypothesis of equality to placebo. If the 
first test is significant, but the second fails, the dose has been demonstrated to be superior to 
placebo for EDS treatment, but not for cataplexy. If both tests are statistically significant, the 
dose has been shown to be effective for both EDS and cataplexy treatment. The same sequence 
of testing will be followed for the 7.5 g and then the 6.0 g  dose in a hierarchical manner.  
Each outcome measure for the 9.0 g, 7.5 g and 6.0 g dose  will be tested at the 2-sided α level of 
0.05. 
11.2.2 Randomization and Blinding 


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11.2.3 Interim Analysis and Unblinding 
There are no planned interim analyses. Other than individual subjects being unblinded for safety 
issues, the database will remain blinded until after the database is locked. 
11.2.4 Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will be appointed to review and 
assess study conduct and safety for the duration of the clinical study. 
11.3 
Analysis Sets 
The ITT and per protocol (PP) populations form the bases for the evaluation of efficacy. The 
safety (S) population forms the basis for the evaluation of safety 
11.3.1 Intent-to-Treat (ITT) Population 
The ITT population includes all randomized subjects with at least one efficacy measurement 
after receiving the 6.0 g dose (whether FT218 or placebo). A valid diary measurement is defined 
to include at least 3 days of entries per week. Diary measurements with fewer days will be 
treated as missing, and if there are no other measurements, will not qualify the subject for the 
ITT population. Subjects will be assigned to treatment arms in the analysis as randomized.  
11.3.2 Per Protocol (PP) Population 
The PP population includes all subjects in the ITT population reduced by those who failed to 
follow the protocol with respect to protocol deviations. These are, inclusion or exclusion criteria 
not satisfied (Section 8.3.2 and Section 8.3.3); deviations related to study drug administration, 
deviations to the schedule of visits and procedures, or deviations related to non-permitted 
concomitant medications (Section 8.4.8.1). Subjects will be assigned to treatment arms as 
randomized. 
11.3.2.1 Safety (S) Population 
The S population includes all subjects that receive at least one dose of study drug. Subjects will 
be assigned to treatment arms based on the treatment actually administered (FT218 if active drug 
was administered at any time, placebo otherwise). 
11.4 
Description of Statistical Analysis 
The formal statistical analysis and specific dose/placebo contrasts will be based on a mixed-
effects repeated measures model. Descriptive statistics characterizing the study population and 
the observed outcomes will be produced. 


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11.4.1 General Considerations 
All statistical tests will be performed using a 2-tailed 5% overall significance level, unless 
otherwise specified. Descriptive statistics will be provided by treatment arm and as a summary 
across both treatment arms. 
11.4.2 Use of Analysis Sets 
For the primary statistical analysis of efficacy endpoints, the ITT will be used; a supportive 
analysis will be carried out on the PP population unless it is essentially the same as the ITT 
population, if the difference in sample sizes is less than 10%. All safety endpoints analysis will 
be conducted on the S population. 
11.4.3 Analysis of Subgroups 
The primary efficacy analyses of EDS will be performed on the ITT population. The primary 
efficacy analyses for cataplexy will be performed on the NT1 subgroup of the ITT population. 
11.5 
Subject Disposition 
The number of subjects within each treatment arm of each analysis population will be 
summarized. The number of subjects entering each period of the study will be tabulated along 
with the number of subjects who withdraw. The timing of withdrawal and reasons for withdrawal 
(Section 8.3.4) will be summarized by treatment arm for each period of the study and 
summarized over all periods in the randomized stage. 
11.6 
Demographic and Other Baseline Characteristics 
Subject demographics will be presented by treatment arm and for the total study. Baseline will be 
defined as the last measurement before randomization. Initial data at screening will also be 
reported for all screened subjects.  
Cases for which the entry criteria or other protocol requirements were violated will be identified 
and their baseline characteristics will be summarized. 
11.7 
Medical History 
Medical history data will consist of significant conditions or diseases recorded during the 
screening process. Data will be tabulated using the Medical Dictionary for Regulatory Activities 
(MedDRA) primary system organ class (SOC) and preferred term for subjects in the S 
population.  




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hypotheses for EDS, both MWT and CGI will be examined for statistical significance for the 9.0 
g dose using the data collected during Period 3c(i), and 3c(ii). If both tests are significant, NCA 
for the same dose will be tested. If the first test fails (either MWT or CGI not significant), the 
data for the 9.0 g dose was not able to reject the null hypothesis of equality to placebo for either 
symptom. If the first test is significant (both MWT and CGI significant) but the second test 
(NCA) fails, the dose has been demonstrated to exceed placebo for EDS treatment but not for 
cataplexy. If both tests are statistically significant, the dose has been shown to be effective for 
EDS and cataplexy.  
If the 9.0 g dose demonstrates efficacy for both EDS and cataplexy, the same sequence of testing 
will be followed for the 7.5 g dose using the data collected during Period 3b(i) and 3b(ii). If the 
7.5 g dose demonstrates efficacy for both EDS and cataplexy, the same sequence of testing will 
be followed for the 6 g dose using the data collected during Period 3a.  
 Each dose will be tested at the 2-sided alpha level of 0.05. Efficacy tests for MWT and for CGI 
within a dose need not be adjusted, since both are required for demonstrating efficacy for EDS at 
that dose. Efficacy tests for NCA within a dose for demonstrating efficacy for cataplexy also 
need not be adjusted because the test is reached via a step down procedure. At each step, 
rejection terminates all subsequent hypothesis tests, which will be deemed to be non-significant. 
A strictly exploratory analysis examining secondary/exploratory endpoints is also proposed to 
provide evidence of consistency. The type I error rate for these endpoints will all be tested at the 
α level of 0.05. 
Note: the testing of the efficacy of the 6.0 g dose is intended to address the question of 
identifying the minimally effective dose. If the 9.0 g dose and then  the 7.5 g dose is effective on 
the primary outcome variables, hypothesis tests on the efficacy of the 6.0 g dose will be carried 
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11.10 
Safety Analysis 
Safety evaluation will be conducted on the S population and using the same evaluation period as 
for efficacy analysis.  
Safety will be evaluated based on reports of AEs either spontaneously reported or observed in 
clinical laboratory analyses. They will be coded according to the MedDRA. 
Adverse events will be summarized based on number and percentages of subjects with any AEs, 
SAEs, and permanent withdrawal from the study. Adverse events will also be tabulated by SOC 
and preferred term. 
11.10.1.1 Laboratory Data 
Laboratory data will be summarized in terms of the proportions of subjects with clinically 
relevant abnormalities using normal ranges. Shift tables will tabulate baseline to most extreme 
post baseline value. Summary statistics of raw data and change from baseline values, including 
means, medians, standard deviations, and ranges will be produced. Analyses will include all 
subjects in the S population who have had at least one laboratory test performed after the first 
study drug administration with an available baseline laboratory value. Baseline values will be 
measured as the last available measure before taking study drug. 
11.11 
Data and Safety Monitoring Board 
An independent DSMB will be appointed to review and assess study conduct and safety for the 
duration of the clinical study. 
This clinical study will be conducted in a double-blind manner. The DSMB comprises 
independent experts who will advise the sponsor and study investigator on matters relating to the 
safety and conduct of the clinical study. The DSMB will make recommendations to the sponsor 
and clinical study investigators about the continuation, modification or termination of the clinical 
study. To achieve this aim the appointed independent DSMB will periodically review and 
evaluate accumulated study data as they relate to study subject safety, study progress and 
conduct. 
The DSMB will be governed by a charter which will define the deliberative processes of the 
group, including event triggers which would necessitate an unscheduled review, stopping rules, 
unblinding, and any voting procedures to initiate any data review. Confidentiality of internal 
discussions and activities will be upheld with a systematic reporting process to sponsor and 
dissemination process to all study investigators, IEC/IRBs and regulatory authorities as 
appropriate. The membership of the DSMB will reflect necessary clinical, scientific, and related 
disciplines necessary to interpret data from the clinical study to allow for full evaluation of study 


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subject safety. The DSMB will be blinded to treatment assignment with the exception of the 
unblinded biostatistician. 
The composition of the DSMB will be laid out in the charter. No member of the DSMB should 
have direct involvement in the conduct of the study. In addition, no member will have financial, 
proprietary, professional, or other interests in Flamel Technologies that may affect impartial, 
independent decision-making by the DSMB. 
11.12 
Central Scoring Laboratory 
At Visit 2 (Week -1, Day 7) a complete assessment for baseline efficacy parameters including an 
overnight baseline PSG and next-day MWT will be performed, after which a central scoring 
laboratory (Clinilabs, Inc New York, US) will confirm the eligibility of each subject. The central 
scoring lab will respond with its assessment within 2 days of receipt of PSG and MWT 
assessments.  
The central scoring laboratory will have the necessary expertise and qualification to conduct 
PSG and MWT scoring.  
11.13 
Protocol Deviations 
Protocol deviations will consist of: inclusion or exclusion criteria not satisfied (Section 8.3.2 and 
Section 8.3.3); deviations related to study drug administration, deviations to the schedule of 
visits and procedures, or deviations related to nonpermitted concomitant medications (Section 
8.4.8.1).  
12 QUALITY ASSURANCE AND QUALITY CONTROL 
12.1 
Audit and Inspection 
Study centers and study documentation may be subject to quality assurance audit during the 
course of the study by the sponsor or its nominated representative. In addition, inspections may 
be conducted by regulatory authorities at their discretion. 
12.2 
Monitoring 
Data for each subject will be recorded on an eCRF. Data collection must be completed for each 
subject who signs an informed consent form (ICF) and is administered study drug. 
In accordance with cGCP and ICH guidelines, the study monitor will carry out source document 
verification at regular intervals to ensure that the data collected in the eCRF are accurate and 
reliable.  
The investigator must permit the monitor, the IEC/IRB, the sponsor’s internal auditors, and 
representatives from regulatory authorities direct access to all study-related documents and 
pertinent hospital or medical records for confirmation of data contained within the eCRFs. 


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12.3 
Data Management and Coding 
The CRO will be responsible for activities associated with the data management of this study. 
This will include setting up a relevant database and data transfer mechanisms, along with 
appropriate validation of data and resolution of queries. Data generated within this clinical study 
will be handled according to the relevant standard operating procedures of the data management 
and biostatistics departments of the CRO. 
Study centers will enter data directly into an electronic data capture (EDC) system by completing 
the eCRF via a secure internet connection. Data entered into the eCRF must be verifiable against 
source documents at the study center. Data to be recorded directly on the eCRF will be identified 
and the eCRF will be considered the source document. Any changes to the data entered into the 
EDC system will be recorded in the audit trail and will be FDA CFR 21 Part 11 compliant. 
Medical coding will use MedDRA for concomitant diseases and AEs and WHO Drug Dictionary 
for medications. 
Missing or inconsistent data will be queried in writing to the investigator for clarification. 
Subsequent modifications to the database will be documented. 


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13 RECORDS AND SUPPLIES 
13.1 
Financing and Insurance 
Financing and insurance of this study will be outlined in a separate agreement between the CRO 
and the sponsor. 


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14 ETHICS 
14.1 
Independent Ethics Committee or Institutional Review Board 
Before initiation of the study at each study center, the protocol, the ICF, other written material 
given to the subjects, and any other relevant study documentation will be submitted to the 
appropriate IEC/IRB. Written approval of the study and all relevant study information must be 
obtained before the study center can be initiated or the study drug is released to the investigator. 
Any necessary extensions or renewals of IEC/IRB approval must be obtained for changes to the 
study such as amendments to the protocol, the ICF or other study documentation. The written 
approval of the IEC/IRB together with the approved ICF must be filed in the study files. 
The investigator will report promptly to the IEC/IRB any new information that may adversely 
affect the safety of the subjects or the conduct of the study. The investigator will submit written 
summaries of the study status to the IEC/IRB as required. On completion of the study, the 
IEC/IRB will be notified that the study has ended. 
14.2 
Regulatory Authorities 
Relevant study documentation will be submitted to the regulatory authorities of the participating 
countries, according to local/national requirements, for review and approval before the beginning 
of the study. On completion of the study, the regulatory authorities will be notified that the study 
has ended. 
14.3 
Ethical Conduct of the Study 
The investigator(s) and all parties involved in this study should conduct the study in adherence to 
the ethical principles based on the Declaration of Helsinki, GCP, ICH guidelines, and the 
applicable national and local laws and regulatory requirements. 
14.4 
Informed Consent and Assent 
The process of obtaining informed consent must be in accordance with applicable regulatory 
requirement(s) and must adhere to GCP. 
Young adults who have not reached the age of majority i.e. those who are 16 or 17 years of age, 
who meet the enrollment criteria are eligible to participate in this clinical study. The basic 
requirement of 21 Code of Federal Regulations (CFR) 50.20 applies, that is, 1) consent from 
their legally authorized representative must be obtained and 2) the assent of the young adult must 
be obtained. In obtaining assent, it must be determined by the PI that the young adult is of both 
intellectual and emotional ability to comprehend study requirements and implications. 
The investigator is responsible for ensuring that no subject undergoes any study-related 
examination or activity before that subject has given written informed consent to participate in 
the study. 
The investigator or designated personnel will inform the subject of the objectives, methods, 
anticipated benefits and potential risks and inconveniences of the study. The subject should be 


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given every opportunity to ask for clarification of any points s/he does not understand and, if 
necessary, ask for more information. At the end of the interview, the subject will be given ample 
time to consider the study. Subjects will be required to sign and date the ICF. After signatures 
are obtained, the ICF will be kept and archived by the investigator in the investigator’s study file. 
A signed and dated copy of the subject ICF will be provided to the subject or their authorized 
representative. 
It should be emphasized that the subject may refuse to enter the study or to withdraw from the 
study at any time, without consequences for their further care or penalty or loss of benefits to 
which the subject is otherwise entitled. Subjects who refuse to give or who withdraw written 
informed consent should not be included or continue in the study. 
If new information becomes available that may be relevant to the subject’s willingness to 
continue participation in the study, a new ICF will be approved by the IEC(s)/IRB(s) (and 
regulatory authorities, if required). The study subjects will be informed about this new 
information and reconsent will be obtained. 
14.5 
Subject Confidentiality 
Monitors, auditors, and other authorized agents of the sponsor and/or its designee, the 
IEC(s)/IRB(s) approving this research, and the US FDA, as well as that of any other applicable 
agency(ies), will be granted direct access to the study subjects’ original medical records for 
verification of clinical study procedures and/or data, without violating the confidentiality of the 
subjects to the extent permitted by the law and regulations. In any presentations of the results of 
this study or in publications, the subjects’ identity will remain confidential. 
All personal data collected and processed for the purposes of this study should be managed by 
the investigator and his/her staff with adequate precautions to ensure confidentiality of those 
data, and in accordance with the Health Insurance Portability and Accountability Act, applicable 
to national and/or local laws and regulations on personal data protection. 


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15 REPORTING AND PUBLICATION, INCLUDING ARCHIVING 
Essential documents are those documents that individually and collectively permit evaluation of 
the study and quality of the data produced. After completion of the study (end of study defined as 
the date of the last visit of the last subject), all documents and data relating to the study will be 
kept in an orderly manner by the investigator in a secure study file. This file will be available for 
inspection by the sponsor or its representatives. Essential documents should be retained for 2 
years after the final marketing approval in an ICH region or for at least 2 years since the 
discontinuation of clinical development of the investigational product. It is the responsibility of 
the sponsor to inform the study center when these documents no longer need to be retained. The 
investigator must contact the sponsor before destroying any study-related documentation. In 
addition, all subject medical records and other source documentation will be kept for the 
maximum time permitted by the hospital, institution, or medical practice. 
The sponsor must review and approve any results of the study or abstracts for professional 
meetings prepared by the investigator(s). Published data must not compromise the objectives of 
the study. Data from individual study centers in multicenter studies must not be published 
separately. 


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16 REFERENCES 
 
Wake Up Narcolepsy Inc. Patient-focused Narcolepsy Survey: Interim Analysis as of September 16, 
2013; 
http://www.unitenarcolepsy.org/wp-content/uploads/Interim-Survey-Analysis-v1.pdf. 
Accessed May 10, 2015. 
 
Jennum P, Ibsen R, Knudsen S, Kjellberg J. Comorbidity and mortality of narcolepsy: a controlled 
retro- and prospective national study. Sleep. 2013;36:835-840. 
 
Ohayon MM. Narcolepsy is complicated by high medical and psychiatric comorbidities: a 
comparison with the general population. Sleep Med. 2013;14:488-492. 
 
Ohayon MM, Black J, Lai C, Eller M, Guinta D, Bhattacharyya A. Increased mortality in narcolepsy. 
Sleep. 2014;37:439-444. 
 
Ervik S, Abdelnoor M, Heier MS, Ramberg M, Strand G. Health-related quality of life in narcolepsy. 
Acta Neurol Scand. 2006;114:198-204. 
 
Broughton RJ, Guberman A, Roberts J. Comparison of the psychosocial effects of epilepsy and 
narcolepsy/cataplexy: a controlled study. Epilepsia. 1984;25:423-433. 
 
Jennum P, Ibsen R, Petersen ER, Knudsen S, Kjellberg J. Health, social, and economic consequences 
of narcolepsy: a controlled national study evaluating the societal effect on patients and their partners. 
Sleep Med. 2012;13:1086-1093. 
 
Dodel R, Peter H, Walbert T, et al. The socioeconomic impact of narcolepsy. Sleep. 2004;27:1123-
1128. 
 
Jennum P, Knudsen S, Kjellberg J. The economic consequences of narcolepsy. J Clin Sleep Med. 
2009;5:240-245. 
 
Black J, Reaven NL, Funk SE, et al. The Burden of Narcolepsy Disease (BOND) study: health-care 
utilization and cost findings. Sleep Med. 2014;15:522-529.  
 
American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed. 
Darien, Ill: American Academy of Sleep Medicine; 2014. 
 
Longstreth WT Jr, Koepsell TD, Ton TG, Hendrickson AF, van Belle G. The epidemiology of 
narcolepsy. Sleep 2007; 30:13-26. 
 
Nohynek H, Jokinen J, Partinen M, et al. AS03 adjuvant AH1N1 vaccine associated with an abrupt 
increase in the incidence of childhood narcolepsy in Finland. PLoS One. 2012; 7:e33536. 
 
Partinen M, Saarenpää-Heikkilä O, Ilveskoski I, et al. Increased incidence and clinical picture of 
childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PLoS 
One. 2012;7:e33723. 
 
Mignot E, Lin L, Rogers W, et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-
cataplexy in three ethnic groups. Am J Hum Genet. 2001;68: 686-699. 


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Hor H, Kutalik Z, Dauvilliers Y, et al. Genome-wide association study identifies new HLA class II 
haplotypes strongly protective against narcolepsy. Nat Genet. 2010;42:786 789. 
 
Kornum BR, Kawashima M, Faraco J et al. Common variants in P2RY11 are associated with 
narcolepsy. Nat Genet. 2011;43:66-71. 
 
Aran A, Lin L, Nevsimalova S, et al. Elevated anti-streptococcal antibodies in patients with recent 
narcolepsy onset. Sleep. 2009;32:979-983. 
 
Cvetkovic-Lopes V, Bayer L, Dorsaz S, et al. Elevated Tribbles homolog 2-specific antibody levels 
in narcolepsy patients. J Clin Invest. 2010;120:713-719. 
 
Mitler MM. Evaluation of treatment with stimulants in narcolepsy. Sleep. 1994;17(8 Suppl):S103-
S106. 
 
Roth T, Dauvilliers Y, Mignot E, et al. Disrupted nighttime sleep in narcolepsy. J Clin Sleep Med. 
2013;9:955-65. 
 
Sangal RB, Thomas L, Mitler MM. Disorders of excessive sleepiness. Treatment improves ability to 
stay awake but does not reduce sleepiness. Chest. 1992;102:699-703. 
 
Nishino S. Clinical and neurobiological aspects of narcolepsy. Sleep Med. 2007;8:373-399.  
 
Doghramji K, Mitler MM, Sangal RB, et al. A normative study of the maintenance of wakefulness 
test (MWT). Electroencephalogr Clin Neurophysiol. 1997;103:554-562. 
 


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17 APPENDICES 


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17.1 
Investigator Signature Page 
Protocol Title: 
A Double-blind, Randomized, Placebo Controlled, Two Arm Multi-center 
Study to Assess the Efficacy and Safety of a Once Nightly Formulation of 
Sodium Oxybate for Extended-Release Oral Suspension (FT218) for the 
Treatment of Excessive Daytime Sleepiness and Cataplexy in Subjects 
with Narcolepsy 
Protocol Number: 
CLFT218-1501 
Confidentiality and cGCP Compliance Statement 
I, the undersigned, have reviewed this protocol (and amendments), including appendices, and I 
will conduct the study as described in compliance with this protocol (and amendments), GCP, 
and relevant ICH guidelines. 
Once the protocol has been approved by the IEC/IRB, I will not modify this protocol without 
obtaining prior approval of Flamel Technologies and of the IEC/IRB. I will submit the protocol 
amendments and/or any ICF modifications to Flamel Technologies and IEC/IRB, and approval 
will be obtained before any amendments are implemented. 
I understand that all information obtained during the conduct of the study with regard to the 
subjects’ state of health will be regarded as confidential. No subjects’ names will be disclosed. 
All subjects will be identified by assigned numbers on all eCRFs, laboratory samples, or source 
documents forwarded to the sponsor. Clinical information may be reviewed by the sponsor or its 
agents or regulatory agencies. Agreement must be obtained from the subject before disclosure of 
subject information to a third party. 
Information developed in this clinical study may be disclosed by Flamel Technologies, to other 
clinical investigators, regulatory agencies, or other health authority or government agencies as 
required. 
Investigator Signature 
Date 
Printed Name 
Institution 


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17.2 
Study Drug Kit Dispensing 
The table below details the specifications of drug supply quantities for each week of dosing for 
the duration of the study. 
Dosing Week 
& Type 
Dose 
Strength 
Sachet Strength 
Dispensing 
Efficacy Assessment Requirement 
Drug Administration 
Specifications 
Study Period 3a – Dose Titration 
Week 1 
 
4.5 g 
4.5 g 
(1× 4.5 g/night) 
+ dosing cup 
Not for this week  
Subject self- administration × 
7 nights 
Week 2 
 
6 g 
6 g  
(2 × 3.0 g/night) 
Not for this week 
Subject self-administration × 
7 nights 
Week 3 
 
6 g 
6 g  
(2 × 3.0 g/night) 
Yes: on night 7 of Week 3 
Full efficacy assessment – 
overnight PSG and next-day 
MWT 
Subject self-administration × 
6 nights.  
Night 7 Drug dispensed at clinic in 
advance of overnight PSG. 
Study Period 3b(i) - Dose Titration  
Week 4 
7.5 g 
7.5 g  
(1 × 3 g/night,  
1 × 4.5 g/night) 
Not for this week  
Subject self-administration × 
7 nights 
Week 5 
 
7.5 g 
7.5 g  
(1 × 3 g/night,  
1 × 4.5 g/night) 
Partial Efficacy Assessment  
Subject self -administration × 
7 nights 
Study Period 3b(ii) – Dose Titration 
Week 6 
7.5 g 
7.5 g  
(1 × 3 g/night, 
1 × 4.5 g/night) 
Not for this week  
Subject self -administration × 
7 nights 
Week 7 
 
7.5 g 
7.5 g  
(1 × 3 g/night,  
1 × 4.5 g/night) 
Not for this week 
Subject self -administration × 
7 nights 
Week 8 
 
7.5 g 
7.5 g  
(1 × 3 g/night,  
1 × 4.5 g/night) 
Yes: on night 7 of Week 8 
Full efficacy assessment -overnight 
PSG and next-day MWT 
Subject self -administration × 
6 nights.  
Night 7 Drug dispensed at clinic in 
advance of overnight PSG. 
Study Period 3c(i) – Stabilization 
Week 9 
 
9.0 g 
9.0 g  
(2 × 4.5 g/night) 
Not for this week  
Subject self -administration × 
7 nights 
Week 10 
 
9.0 g 
9.0 g  
(2 × 4.5 g/night) 
Partial Efficacy Assessment  
Subject self -administration × 
7 nights 
Study Period 3c(ii) – Stabilization 
Week 11  
 
9.0 g 
9.0 g  
(2 × 4.5 g/night) 
Not for this week  
Subject self -administration × 
7 nights 
Week 12 
 
9.0 g 
9.0 g  
(2 × 4.5 g/night) 
Not for this week 
Subject self -administration × 
7 nights 
Week 13 
 
9.0 g 
9.0 g  
(2 × 4.5 g/night) 
Yes: on night 7 of Week 13 
Full efficacy assessment - overnight 
PSG and next-day MWT 
Subject self -administration × 
6 nights.  
Night 7 Drug dispensed at clinic in 
advance of overnight PSG. 
 


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17.4 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Since Last Visit Version 


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17.5 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Baseline/Screening Version 
 


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17.6 
CGI-Severity (CGI-S) / CGI-Improvement (CGI-I)  
 
CGI-Severity (CGI-S) 
Considering your total clinical experience with this patient population, how sleepy is the patient at 
this time? 
 
☐ 1. Normal, not at all sleepy 
 
☐ 2. Borderline sleepy 
 
☐ 3. Mildly sleepy 
 
☐ 4. Moderately sleepy 
 
☐ 5. Markedly sleepy  
 
☐ 6. Severely sleepy  
 
☐ 7. Among the most extremely sleepy patients 
 
 
CGI-Improvement (CGI-I) 
 
Compared to the patient’s condition at BASELINE, this patient’s condition is: 
 
☐ 1. Very much improved 
 
☐ 2. Much improved 
 
☐ 3. Minimally improved 
 
☐ 4. No change from baseline 
 
☐ 5. Minimally worse 
 
☐ 6. Much worse 
 
☐ 7. Very much worse  
 
 
 
 
 
 
 


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17.7 
Epworth Sleepiness Scale 
 

SAP_001.pdf: 
Protocol CLFT218-1501: SAP Final Version 4    31 July 2019 
 
 
1
STATISTICAL ANALYSIS PLAN (SAP) 
Treatment: Once Nightly Formulation of Sodium Oxybate for Extended Release Oral 
Suspension (FT218) for Excessive Daytime Sleepiness and Cataplexy 
 
Study Title: A Double-blind, Randomized, Placebo Controlled, Two Arm Multi-center Study to 
Assess the Efficacy and Safety of a Once Nightly Formulation of Sodium Oxybate for Extended-
Release Oral Suspension (FT218) for the Treatment of Excessive Daytime Sleepiness and 
Cataplexy in Subjects with Narcolepsy 
Randomized study Evaluating the efficacy and SafeTy of a ONce nightly formulation of sodium 
oxybate (REST-ON Study) 
SAP Version:  
Version 4: Final: 31 July 2019 
Protocol Number: 
CLFT218-1501 
EudraCT Number: 
2016-000359-29 
IND Number: 
126321 
Investigational Product: 
Sodium 
Oxybate 
for 
Extended-Release 
Oral 
Suspension (FT218) 
Phase: 
3 
Sponsor: 
Flamel Ireland Limited 
Blanchardstown Corporate Park 
Block 10-1, Ballycoolin 
Dublin 15 
Ireland 
Flamel Ireland Limited, a wholly owned subsidiary of 
Flamel Technologies 


Protocol CLFT218-1501: SAP Final Version 4    31 July 2019 
 
 
2
 
 
 
Prepared by: 
 
 
 
  
Reviewed by: 
  
 
  
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 




Protocol CLFT218-1501: SAP Final Version 4    31 July 2019 
 
 
4
TABLE OF CONTENTS  
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................................................................... 6 
1 INTRODUCTION........................................................................................................................................................... 8 
1.1 Study Rationale ................................................................................................................................................ 8 
1.2 Changes from Protocol .................................................................................................................................... 8 
1.3 Definition of Analysis Population ..................................................................................................................... 8 
2 Study Summary ........................................................................................................................................................... 9 
2.1 Objectives ........................................................................................................................................................ 9 
2.1.1 Primary Objectives ................................................................................................................................ 9 
2.1.2 Secondary/Exploratory Objectives ....................................................................................................... 9 
2.1.3 Safety Objective .................................................................................................................................. 10 
2.2 Study Design .................................................................................................................................................. 10 
2.3 Schedule of Events ......................................................................................................................................... 10 
2.4 Sample Size Determination............................................................................................................................ 13 
2.5 Randomization and Blinding .......................................................................................................................... 14 
2.5.1 Interim Analysis and Unblinding. ........................................................................................................ 14 
2.5.2 Data and Safety Monitoring Board (DSMB) ........................................................................................ 14 
2.6 Study Endpoints ............................................................................................................................................. 14 
2.6.1 Primary endpoints for efficacy ............................................................................................................ 14 
2.6.1.1 Primary endpoints for EDS ............................................................................................................... 14 
2.6.1.2 Primary endpoint for Cataplexy ....................................................................................................... 14 
2.6.2 Secondary/Exploratory endpoints ...................................................................................................... 15 
2.6.3 Endpoints for safety ............................................................................................................................ 15 
3. Analysis Sets ............................................................................................................................................................ 15 
3.1 The Intent to Treat (ITT) Population .............................................................................................................. 15 
3.2 The Per Protocol (PP) Population .................................................................................................................. 16 


Protocol CLFT218-1501: SAP Final Version 4    31 July 2019 
 
 
5
3.3 The Safety (S) Population ............................................................................................................................... 16 
4. Description of Statistical Analysis ............................................................................................................................ 16 
4.1 General Considerations ................................................................................................................................. 16 
4.1.1 Standard descriptive statistics ............................................................................................................ 16 
4.1.2 Definition of study visits ..................................................................................................................... 17 
4.1.3 Analysis assessment windows ............................................................................................................ 17 
4.1.4 Treatment start/stop dates ................................................................................................................ 17 
4.1.5 Tables, listings and figure presentation .............................................................................................. 17 
4.1.6 Use of Analysis Sets ............................................................................................................................ 18 
4.1.7 Analysis of subgroups ......................................................................................................................... 19 
 ................................................................................................................... 19 
4.2 Subject disposition ......................................................................................................................................... 19 
4.3 Demographics and baseline subject characteristics ...................................................................................... 19 
4.4 Medical history .............................................................................................................................................. 19 
4.5 Study drug exposure and compliance............................................................................................................ 19 
4.6 Efficacy Analysis ............................................................................................................................................. 19 
4.6.1: Primary Analysis:................................................................................................................................ 20 
4.6.2 Sequential testing approach for comparing SOCR and placebo ......................................................... 21 
 ............................................................................................................................. 21 
 ...................................................................................................... 23 
4.7 Safety Analyses .............................................................................................................................................. 23 
 ........................................................................................................................... 24 
 ........................................................................................................................................... 25 
 ............................................................................................................................................... 28 


Protocol CLFT218-1501: SAP Final Version 4    31 July 2019 
 
 
6
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
%  
Percentage 
ADR 
Adverse Drug Reaction 
AE  
Adverse Event 
CGI 
Clinical Global Impression  
CR  
Controlled Release 
 
 
eCRF  Electronic Case Report Form 
EDS 
Excessive Daytime Sleepiness 
 
 
FAS 
Full Analysis Set 
FWER Family-Wide Error Rate 
FT218 Sodium oxybate for extended-release oral suspension 
  
 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
ITT  
Intent To Treat 
MMRM Mixed-effects Model for Repeated Measures 
MWT 
Maintenance of Wakefulness Test 
NCA 
Number of Cataplexy Attacks 
NT1 
Narcolepsy Type 1 
NT2 
Narcolepsy Type 2 
PGI  
Patient Global Impression 
PPS 
Per Protocol Set 
PSG   Polysomnogram 


Protocol CLFT218-1501: SAP Final Version 4    31 July 2019 
 
 
7
PT  
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SSDD  Sleep and Symptom Daily Diary 
SOC 
System Organ Class 
  
 
SS  
Safety Set 
TEAE Treatment Emergent Adverse Event 
TESAE Treatment Emergent Serious Adverse Event 
TFL 
Tables, Listings and Figures 
VAS 
Visual Analog Scale 


Protocol CLFT218-1501: SAP Final Version 4    31 July 2019 
 
 
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1 INTRODUCTION 
Sodium Oxybate is indicated for the treatment of excessive daytime sleepiness (EDS) and 
cataplexy in adults with narcolepsy. Flamel proposes a new sodium oxybate drug product based 
on its Micropump® technology, Sodium oxybate for extended-release oral suspension (FT218), to 
be taken once at bedtime. Sodium Oxybate has shown significant efficacy for treating EDS and 
cataplexy in narcolepsy.  
1.1 STUDY RATIONALE 
This study was designed as a pivotal efficacy study. The background data used to design the trial 
was obtained from a Phase I (PKFT218-1301) pharmacokinetic study in healthy volunteers. In that 
study the 4.5 g FT218 formulation was associated with a safety profile and total exposure similar 
to the reference marketed drug product, Xyrem®. Also, no safety concerns emerged with the 
FT218 formulation at 6 g and 7.5 g. The study confirmed the expected PK properties of the FT218 
formulation, i.e. a drug release over 6 hours, a lower Cmax and a residual plasma level at 8 hours 
after intake that was not significantly different from Xyrem®. These results indicate that the FT218 
formulation should be as safe as Xyrem®. Overall, the PK profile of FT218 at 4.5 g, 6 g, and at 
7.5 g supports the hypothesis that the IMP is as safe as the reference, Xyrem®. 
The forced up-titration design is intended to inform an appraisal of the benefits and risks of 
increasing doses. Three target therapeutic dose levels will be tested since a concentration/response 
relationship has not been established. The 6 g, 7.5 g and 9 g doses were selected for their safety 
and efficacy profile in treating patients with EDS and cataplexy; the study formulation has been 
found to be safe at 4.5 g, 6 g and 7.5 g in healthy volunteers. The up-titration schedule from 4.5 
g/night to 6 g/night is based on the dosage schedule recognized as safe with the reference product. 
Further 1.5 g increments commence after a period sufficiently long to permit evaluation of 
efficacy. Subjects remain on the 6 g dose for two weeks, on the 7.5 g dose for five weeks and on 
the 9 g dose for five weeks.  
1.2 CHANGES FROM PROTOCOL 
N.A. This is a Special Protocol Review. 
1.3 DEFINITION OF ANALYSIS POPULATION 
The target population is individuals in need of treatment of EDS and cataplexy in patients with 
narcolepsy. The full analysis population for efficacy is the intent to treat population including all 
randomized subjects with at least one efficacy measurement at the time of the 6 g dose (whether 
FT218 or placebo.)  
 


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9
2 STUDY SUMMARY 
This is a double-blind, randomized, placebo controlled, two arm multi-center forced up-titration 
study to assess the efficacy and safety of a once nightly formulation of Sodium Oxybate (FT218) 
for the treatment of EDS and cataplexy in patients with narcolepsy. The active arm will have forced 
dose increments at fixed times from 4.5 g/night followed by 1.5 g/night increments until the final 
9 g dose is reached. Subjects will remain on the 4.5 g dose for one week, the 6 g for two weeks, 
the 7.5 g for five weeks and the 9 g dose for five weeks. The primary contrasts are between the 9 
g dose and the corresponding placebo outcomes. If the 9 g dose is statistically significant, the 7.5 
g dose and the corresponding placebo outcomes will be compared. If the 7.5 g dose is statistically 
significant, the 6 g dose and the corresponding placebo outcomes will be compared. 
There are two types of narcolepsy patients to be studied. Patients with Narcolepsy Type 1 (NT1) 
who present with excessive daytime sleepiness (EDS) and cataplexy and patients with Narcolepsy 
Type 2 (NT2) who present with EDS (without cataplexy). For both NT1 and NT2, the historical 
Multiple Sleep Latency Test (MSLT) must indicate 2 or more sleep-onset REM periods 
(SOREMPs), the mean sleep latency on MSLT must be in the pathological range (i.e. <8 minutes) 
and no other sleep disorder better explains the EDS. 
The endpoints for evaluating EDS in both NT1 and NT2 narcolepsy patients are the mean sleep 
latency on the Maintenance of Wakefulness Test (MWT), and the Clinician Global Impression 
(CGI) for sleepiness. The endpoint for evaluating cataplexy in NT1 narcolepsy patients is the 
number of cataplexy attacks (NCA) obtained from the Sleep and Symptom Daily Diary.  
2.1 OBJECTIVES 
To compare the safety and efficacy of 6 g, 7.5 g and 9 g doses of FT218 to placebo in the treatment 
of symptoms in patients with Narcolepsy. 
2.1.1 PRIMARY OBJECTIVES  
• To compare the efficacy of 6.0, 7.5, and 9.0 g of FT218 to placebo in treating EDS in both 
NT1 and NT2 subjects as measured by mean sleep latency on the Maintenance of 
Wakefulness Test (MWT) and by the Clinical Global Impression (CGI) rating of sleepiness 
• 
To compare the efficacy of 6.0, 7.5, and 9.0 g of FT218 to placebo in treating cataplexy in 
NT1 subjects as measured by the number of cataplexy attacks (NCA) determined from the 
cataplexy frequency item in the Sleep and Symptom Daily Diary 
2.1.2 SECONDARY/EXPLORATORY OBJECTIVES 
The secondary/exploratory objectives of the study are to compare the efficacy of 6.0, 7.5, and 9.0 
g of FT218 to placebo for 
 






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Table 2: Study Design 
Screening and Baseline 
Rand 
Dose Titration 
Dose Titration 
Stable Dosing 
EOS 
FU 
 
 
 
 
 
 
 
 
 
 
 
 
9.0g 
9.0g 
9.0g 
9.0g 
9.0g 
 
 
 
 
 
 
 
 
 
7.5g 
7.5g 
7.5g 
7.5g 
7.5g 
 
 
 
 
 
 
 
 
 
 
 
 
6g 
6g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm 
1 
4.5g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm 
2 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placeb
o 
Placeb
o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placeb
o 
Placeb
o 
Placeb
o 
Placeb
o 
Placeb
o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placeb
o 
Placeb
o 
Placeb
o 
Placebo 
Placeb
o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 1 
 
Visit 2* 
 
Visit 
3*** 
 
Visit 4* 
 
 
Visit 
5** 
 
Visit 6* 
 
 
Visit 
7** 
 
 
Visit 8* 
Visit 
9 
W-3 D1 
 
W-1 
D7 
W0 D1 
EOSc 
+2 D 
W1 D1 
 
W3 D7 
W4 D1 
 
W6 D1 
 
W8 D7 
W9 D1 
 
W11 
D1 
 
 
W13 D7 W14 
D1 
W15 
D1 
<------3-week washout-----> 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
W-3 
 
W0 
 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W1
1 
W12 
W13 
W14 
W15 
Period 1 
Period 
2 
 
Period 3a 
Period 3b(i) 
Period 3b(ii) 
Period 3c(i) 
Period 3c(ii) 
Period 3c(iii) 
Period 4 
Abbreviations: D = day, EOS = End of Study, EOSc = End of Screening, FU = Follow-up, Rand = randomization, W = week, W/O = Washout




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2.5 RANDOMIZATION AND BLINDING 
 
 
 
2.5.1 INTERIM ANALYSIS AND UNBLINDING. 
There are no planned interim analyses. Other than individuals unblinded for safety issues, 
the data will remain blinded until after the database is locked.  
2.5.2 DATA AND SAFETY MONITORING BOARD (DSMB) 
An independent DSMB will be appointed to review and assess study conduct and safety 
for the duration of the clinical trial. 
2.6 STUDY ENDPOINTS 
The endpoints for evaluating EDS in both NT1 and NT2 narcolepsy patients are the 
Maintenance of Wakefulness Test (MWT), Clinician Global Impression (CGI) and 
secondarily the Epworth Sleepiness Scale (ESS). 
The endpoint for evaluating cataplexy in NT1 narcolepsy patients is the mean number of 
daily cataplexy attacks (NCA) as determined from the Sleep and Symptom Daily Diary 
during the Period 
 
 
 
2.6.1 PRIMARY ENDPOINTS FOR EFFICACY  
2.6.1.1 PRIMARY ENDPOINTS FOR EDS  
The co-primary endpoints for evaluating EDS in both NT1 and NT2 narcolepsy patients is 
mean sleep latency on the Maintenance of Wakefulness Test and the Clinician Global 
Impression for sleepiness. The MWT is the mean latency across 5 naps, averaged over the 
test day and the CGI is the clinician’s global impression of improvement in daytime 
sleepiness.  
2.6.1.2 PRIMARY ENDPOINT FOR CATAPLEXY  
The primary endpoint for evaluating cataplexy is the number of cataplexy attacks, which 
will be evaluated only on the narcolepsy NT1 subpopulation. The NCA is the mean number 
of cataplexy events recorded on the Sleep and Symptom Daily Diary (SSDD) during the 
Period. Because of concern about the variability of this measure, a minimum number of 
diary entries of 3 per week is required for the average to be considered an observation. If 


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the number of days with entries is less than three, the mean NCA for that week will be 
considered missing. 
2.6.2 SECONDARY/EXPLORATORY ENDPOINTS   
The secondary/exploratory efficacy endpoints are 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
2.6.3 ENDPOINTS FOR SAFETY 
Safety will be evaluated based on reports of adverse events either spontaneously reported 
or observed in clinical laboratory analyses. All adverse events and all serious adverse 
events will be tabulated by system organ class and preferred term. 
3. ANALYSIS SETS 
The intent to treat and per protocol populations form the bases for the evaluation of 
efficacy. The safety population forms the basis for the evaluation of safety. 
3.1 THE INTENT TO TREAT (ITT) POPULATION 
The ITT population includes all randomized subjects with at least one efficacy 
measurement after receiving the 6 g dose (whether FT218 or placebo.) A valid diary 
measurement is defined to include at least 3 days of entries per week. Diary measurements 
with fewer days will be treated as missing, and if there are no other measurements will not 


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qualify the subject for the ITT population. Patients will be assigned to treatment groups in 
the analysis as randomized.  
3.2 THE PER PROTOCOL (PP) POPULATION 
The PP population includes all subjects in the ITT population reduced by those who failed 
to follow the protocol with respect to protocol deviations. These are inclusion or exclusion 
criteria not satisfied (protocol chapter 8, sub-sections 8.3.2 and 8.3.3), deviations related to 
study drug administration, deviations to the schedule of visits and procedures (protocol 
chapter 9) or deviations related to concomitant medications not permitted (protocol chapter 
8, sub-section 8.4.8.1). Subjects will be assigned to treatment groups as randomized.  
3.3 THE SAFETY (S) POPULATION 
The S population includes all subjects that receive at least one dose of study medication. 
Subjects will be assigned to treatment group based on the treatment actually administered. 
4. DESCRIPTION OF STATISTICAL ANALYSIS 
The formal statistical analysis and specific dose/placebo contrasts will be based on a mixed-
effects repeated measures (MMRM) means model or a corresponding generalized mixed-
effects model (GLIMMIX) in case of categorical data. Descriptive statistics characterizing 
the study population and the observed outcomes will be produced. 
4.1 GENERAL CONSIDERATIONS 
All statistical tests will be performed using a two-tailed 5% overall significance level, 
unless otherwise specified. The null hypothesis for all tests is that FT218 and placebo 
have equal means. All sample mean outcome differences between the study 
treatments/doses will be reported with 95% confidence intervals. The p-value will be 
presented for each statistical test; if the value is less than 0.05, 0.01 or 0.001, the result 
will be highlighted by the respective annotation *, ** or ***. 
Descriptive statistics will be provided by dose group and as a summary across all dose 
groups. 
4.1.1 STANDARD DESCRIPTIVE STATISTICS 
CONTINUOUS VARIABLES 
Standard descriptive statistics will be reported for continuous variables including number 
of non-missing observations, mean, median, standard deviation, 95% confidence interval 
for the mean, median, inter-quartile range, minimum, and maximum value.   
CATEGORICAL VARIABLES 


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Standard descriptive statistics will be provided for categorical variables in contingency 
tables with cell frequencies and percentages for the number of non-missing observations. 
Entries will include total number, number missing, number available, number for each 
category, and the corresponding percentage of the total number of values available for each 
category. 
4.1.2 DEFINITION OF STUDY VISITS 
Study visits are identified by the week of the visit.  
At Week -1 (Baseline) a full baseline evaluation will take place. Thereafter with full 
efficacy assessments occurring at week 3 for the 6 g dose, week 8 for the 7.5 g dose and 
week 13 for the 9 g dose. Visits with partial efficacy assessments (MWT and PSG are 
excluded) occur following the first two weeks on the 7.5 g dose (week 6 day 1) and 
following the first two weeks on the 9 g (week 11 day 1).  
4.1.3 ANALYSIS ASSESSMENT WINDOWS 
Comparison between specific doses and placebo utilize measurements from comparable 
periods in the study. Thus, there will be 3 sets of placebo measurements; one corresponding 
to the 6 g dose (weeks 2 and 3), one corresponding to the 7.5 g dose (weeks 4 through 8) 
and one corresponding to the 9 g dose (weeks 9 through 13.) 
4.1.4 TREATMENT START/STOP DATES 
Treatment in the FT218 arm will begin on Day 1, Week 1 at 4.5 g dose. The dose will be 
increased to 6 g on Day 1, Week 2 and to 7.5 g on Day 1, Week 4. The dose will increase 
to 9 g on Day 1, Week 9 and continue at that dosage until Day 7, Week 13. 
4.1.5 TABLES, LISTINGS AND FIGURE PRESENTATION 
 
The treatment groups will be displayed in the tables, listings and figures as 
 
Group 1: 
9 g      
(Period 3c (i) and 3c (ii), weeks 9-13) 
Group 2: 
Placebo  
(Period 3c (i) and 3c (ii), weeks 9-13)  
Group 3: 
7.5 g    
(Period 3b (i) and 3b (ii), weeks 4-8) 
Group 4: 
Placebo  
(Period 3b (i) and 3b (ii), weeks 4-8) 
Group 5: 
6 g      
(Period 3a, weeks 2-3) 
Group 6: 
Placebo  
(Period 3a, weeks 2-3)  


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The listings will display all of the data contained in the eCRF. The listings will be ordered 
by the treatment groups shown above. 
Summaries of continuous variables will use the following descriptive statistics: n, mean, 
standard deviation, 95% confidence interval of the mean, median, interquartile range, 
minimum and maximum. 
The number of decimal places to be displayed for each statistic will be as follows: 
- Mean, 95% confidence intervals, median and interquartile range: one more decimal 
place than data. 
- Standard deviation: two more decimal places than the data. 
- Minimum and maximum: same number of decimal places as the data. 
- P-value: 3 decimal places, if less than 0.001 then display as “<0.001”. 
Categorical variables will be presented as frequency counts and percentages.  Percentages 
will be displayed to one decimal place throughout. 
All dates will be displayed in the format DDMMMYYYY 
Calculations using dates will follow these conventions: 
The relative study day of the event (DAY) is calculated as the difference between the 
date of the event of interest (EVENT DAY) and the date of first dose of study medication 
(FIRST DOSE), i.e. 
DAY = EVENT DATE - FIRST DOSE + 1 for EVENT DATE ≥ FIRST DOSE 
DAY = EVENT DATE - FIRST DOSE 
 for EVENT DATE < FIRST DOSE 
Durations will be calculated by: DURATION = (STOP DATE - START DATE) + 1 
4.1.6 USE OF ANALYSIS SETS 
For the primary statistical analyses of efficacy endpoints, the ITT will be used; a supportive 
analysis will be carried out on the PP population unless it is essentially the same as the ITT 
population, if the difference in sample sizes is less than 10%. All safety endpoints analysis 
will be conducted on the Safety population. 


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4.1.7 ANALYSIS OF SUBGROUPS 
The primary efficacy analyses for EDS will be performed on the full ITT population. The 
primary efficacy analyses for cataplexy will be performed on the NT1 subgroup of the ITT 
population.  
 
 
 
4.2 SUBJECT DISPOSITION 
The number of subjects within each dose of each analysis population will be summarized. 
The number of subjects entering each Period of the study will be tabulated along with 
number of subjects who withdraw. The timing of withdrawal and reasons for withdrawal 
(adverse event, lost to follow-up, withdrawal by subject, withdrawn due to physician 
decision, non-compliance with study drug, due to pregnancy, lack of efficacy, death, 
other reasons) will be summarized by treatment for each Period of the study and 
summarized over all Periods in the randomization stage. 
4.3 DEMOGRAPHICS AND BASELINE SUBJECT CHARACTERISTICS 
Subject demographics will be presented by treatment arm and for the total study. Baseline 
will be defined as the measurement in Period 2, prior to randomization. Initial data at 
screening will also be reported for all screened subjects. 
Cases for which the entry criteria or other protocol requirements were violated will be 
identified and their baseline characteristics will be summarized. 
4.4 MEDICAL HISTORY 
Medical history data will consist of significant conditions or diseases recorded during the 
screening process. Data will be tabulated using the MedDRA primary system organ class 
(SOC) and preferred term for subjects in the safety population.   
4.5 STUDY DRUG EXPOSURE AND COMPLIANCE 
Study drug exposure and duration in the study will be derived based on first and last dose 
taken. Compliance will be computed as percentage of medication taken. 
4.6 EFFICACY ANALYSIS 
Two patient populations, one with both narcolepsy symptoms (EDS and cataplexy) and one 
with only EDS will be studied in a single parallel groups, dose-escalation design. The 
treatments are placebo and increasing doses of the test drug, FT218. Two primary outcome 
measures, MWT and CGI quantify the treatment effect on EDS and the NCA is the primary 


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outcome measure for cataplexy. All ITT or PP subjects will be included in the evaluation 
of EDS and all ITT or PP subjects with both conditions will be used in the evaluation of 
cataplexy.  
Subject demographics and baseline characteristics will be tabulated for all randomized 
subjects. The baseline comparability of treatment groups with respect to subject 
demographics and baseline characteristics will be described, but formal statistical tests will 
not be performed. 
4.6.1: PRIMARY ANALYSIS:  
A mixed effect repeated measures (MMRM) means model will be used to analyze change 
from baseline for MWT and cataplexy. Each model will include treatment, time (at which 
the measurement was taken), treatment-by-time interaction, site and baseline score as fixed 
effects and subjects as random effects. In fitting the model, time will range over the entire 
period of observations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For CGI, a GLIMMIX model for binomial data with logit link will be used instead of a 
MMRM to analyze the categorized CGI response, i.e., proportion of patients who were 
very much or much improved. The observed values for the categorized response (very 
much or much improved versus other category) will be used as responses in the model. 
Each model will include treatment, time (at which the measurement was taken), treatment-
by-time interaction and site as fixed effects and subjects as random effects. In fitting the 
model, time will range over the entire period of observations. The odds ratio, 95% 
confidence intervals for the odds ratio and p-value will be provided. 


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4.6.2 SEQUENTIAL TESTING APPROACH FOR COMPARING SOCR AND PLACEBO  
The primary hypothesis tests of the efficacy of individual doses will be performed as 
contrasts within the mixed models. The hypothesis testing will proceed in the following 
order, which is represented pictorially in Figure 1. First to test hypotheses for EDS, both 
MWT and CGI will be examined, in parallel for statistically significant differences from 
placebo for the 9 g dose. The order of hypothesis testing and the tests to be performed are 
displayed in Figure 1. For the 9 g dose, if both tests are significant, NCA for the same dose 
will be tested. If the first test fails (either MWT or CGI not significant), the data for the 9 
g dose was not able to reject the null hypothesis of equality to placebo for either symptom. 
If the first test is significant (both MWT and CGI significant,) but the second test (NCA) 
fails, the 9 g dose has been demonstrated to exceed placebo for EDS treatment but not for 
cataplexy. If both tests are statistically significant, the 9 g dose has been shown to be 
effective for EDS and for cataplexy. Although all data are included in the full model, the 
tests for the 9 g dose are contrasts over the Periods 3c(i) and 3c(ii). 
If the 9 g dose demonstrates efficacy for both EDS and cataplexy, the same sequence of 
testing will be followed for the 7.5 g dose using contrasts over the Periods 3b(i) and 3b(ii). 
If the 7.5 g dose demonstrates efficacy for both EDS and cataplexy, the same sequence of 
testing will be followed for the 6 g dose using contrasts over Period 3a.  
Each dose will be tested at the two-sided alpha level of .05. Efficacy tests for MWT and 
for CGI within a dose need not be adjusted, since both are required for demonstrating 
efficacy for EDS at that dose. Efficacy tests for NCA within a dose for demonstrating 
efficacy for cataplexy also need not be adjusted because the test is reached via a step down 
procedure. Within each arm, rejection terminates all subsequent hypothesis tests, which 
will be deemed to be non-significant. A strictly exploratory analysis examining 
secondary/exploratory endpoints is also proposed to provide evidence of consistency. The 
Type I error rate for these endpoints will all be tested at the alpha level of .05. 
N.B. The testing of the efficacy of the 6 g dose is intended to address the question of 
identifying the minimally effective dose. If the 9 g dose and then the 7.5 g dose is effective 
on the primary outcome variables, hypothesis tests on the efficacy of the 6 g dose will be 
carried out.   
 
 
 
 
 
 




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4.7 SAFETY ANALYSES 
Safety evaluations will be performed on the safety population using the actual treatment 
administered. 
Adverse events will be identified as treatment-emergent (TEAE) if the event occurs or 
increases in severity after the first dose of study medication is taken. Adverse events will 
be identified as mild, moderate or severe and related to the treatment as reported on the 
CRF. The adverse events will be assigned a preferred term (PT) and a system organ class 
(SOC) according to the Medical Dictionary for Regulatory Activities (MedDRA), latest 
version .In counting the number of events reported, a continuous event, i.e., an event 
reported more than once and which did not cease, will be counted only once with the worst 
recorded severity. Non-continuous AEs reported multiple times by the same subject will 
be counted as multiple events. AEs will be assigned to the period of the study 
corresponding to the time of onset. Events presenting immediately prior to the first dose of 
study medication that do not worsen in severity, will not be included. In deriving the 
tabulation relating to preferred term reporting, the severity of a recurrent AE will be taken 
to be the most severe and the relationship to study medication as the most probable within 
the relevant period of the study. Total exposure to FT218 will be determined in terms of 
number of days and dose. 
Laboratory data will be summarized in terms of the proportions of patients with clinically 
notable abnormalities using normal ranges. Shift tables will tabulate baseline to most 
extreme post baseline values. Summary statistics of raw data and change from baseline 
values will be obtained including means, medians, standard deviations and ranges will be 
produced. 
The summaries will include subjects in the safety population who have had at least one 
laboratory test performed after the first study drug administration with an available baseline 
laboratory value. Baseline values will be measured as the last available measure before 
taking study drug. 
 


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