Conditions: Narcolepsy With Cataplexy Narcolepsy Without Cataplexy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 110
Healthy volunteers: no

Brief summary:
The purpose of this multicenter double blind study is to assess efficacy and safety of Pitolisant versus placebo in paediatric Narcoleptic patients with or without cataplexy.

Detailed description:

Arms:
arm 1: tablet, oral, once a day. arm 2: tablet, oral, once a day.

Interventions: intervention 1: pitolisant intervention 2: Placebo
Intervention descriptions: intervention 1: Tablet intervention 2: Tablet

Protocol document:
Prot_000.pdf: 
 
NCT number: 
NCT02611687 
Protocol ID:  P11-06/BF2.649 
 
 
 
Title: 
Double blind, mulƟcentre, randomized, 
placebo-controlled trial to evaluate safety and 
eﬃcacy of pitolisant in children from 6 to less 
than 18 years with narcolepsy with/without 
cataplexy, followed by a prolonged open-label 
period. 
 
 
Document: Protocol, Version 3.0_30 September 2020 
 






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Signature Page 
 
PROTOCOL P11-06 / BF 2.649 
 
DOUBLE BLIND, MULTICENTRE, RANDOMIZED, PLACEBO-
CONTROLLED TRIAL TO EVALUATE SAFETY AND EFFICACY OF 
PITOLISANT IN CHILDREN FROM 6 TO LESS THAN 18 YEARS WITH 
NARCOLEPSY WITH/WITHOUT CATAPLEXY, FOLLOWED BY A 
PROLONGED OPEN-LABEL PERIOD 
 
 
The signature below constitutes the approval of this protocol P11-06/BF2.649 
and the attachments, and provides the necessary assurances that this trial will be 
conducted in accordance with all stipulations of the protocol, including all 
statements regarding confidentiality, and in accordance with local legal and GCP 
regulatory requirements and ICH guidelines. 
 
 
The site Investigator: 
 
Name: 
………………………………………………………………………… 
 
Hospital: ……………………………………………………………………… 
 
Address: ……………………………………………………………………… 
 
 
…………………………………………………………………….. 
 
 
 
 
Date:__________________ 
 
 
Signature:______________  
 
 
 




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3.7.1.2.2. 
Pediatric Daytime Sleepiness Scale scores (PDSS) ................................................. 57 
3.7.1.2.3. 
Clinical Global Impressions of Change ................................................................... 58 
3.7.1.2.4. 
Test of Everyday Attention for Children (TEA-Ch) .............................................. 58 
3.7.1.2.5. 
Maintenance of Wakefulness Test 30-minute version ............................................ 59 
3.7.1.2.6. 
Patient sleep diary ..................................................................................................... 59 
3.7.1.2.7. 
Patient’s Global Opinion on the effect of treatment ............................................... 60 
3.7.1.3. 
Compliance ......................................................................................................................... 60 
3.7.2. 
Safety criteria .................................................................................................................................60 
3.7.2.1. 
Cardiovascular safety: vital signs and ECG ...................................................................... 61 
3.7.2.2. 
Physical examination .......................................................................................................... 61 
3.7.2.3. 
Adverse events and Treatment Emergent Adverse Events ................................................. 61 
3.7.2.4. 
Blood Laboratory tests, urinalysis, urinary drug testing ................................................... 62 
3.7.2.5. 
Childhood Depression Inventory ........................................................................................ 63 
3.7.2.6. 
Columbia-Suicide Severity Rating Scale ............................................................................ 63 
3.7.2.7. 
Withdrawal symptoms ......................................................................................................... 63 
4. INVESTIGATIONAL TREATMENT ........................................................................................................65 
4.1. 
Description of study treatment: BF 2.649 .........................................................................................65 
4.1.1. 
Chemical structure .........................................................................................................................65 
4.1.2. 
Composition and form of investigational treatments .....................................................................65 
4.2. 
Dosage regimen ..................................................................................................................................66 
4.3. 
Packaging and labelling of treatment ...............................................................................................69 
4.4. 
Management and storage of therapeutic units ..................................................................................69 
4.5. 
Treatment Dispensation .....................................................................................................................70 
4.5.1. 
Patient Study Number.....................................................................................................................70 
4.5.2. 
Investigational treatment allocation ..............................................................................................71 
4.5.3. 
Procedure to open the individual randomization code in emergency ............................................71 
4.6. 
Treatment compliance and Accountability procedures .....................................................................71 
5. CONDUCT OF THE STUDY .....................................................................................................................71 
5.1. 
Expected duration of subject participation........................................................................................71 
5.2. 
study procedures at each visit ............................................................................................................72 
5.2.1. 
V0-screening visit and start of wash-out period: at D-28 ..............................................................72 
5.2.2. 
V1-screening visit and Baseline period: at D-14 ...........................................................................73 
5.2.3. 
V2- Randomization and start of escalating period: at D0 ..............................................................75 
5.2.4. 
V3 – Dose adjustment visit (Day 14 ± 2 days) ...............................................................................75 
5.2.5. 
V4 – Dose adjustment visit (Day 21 ± 2 days) ...............................................................................76 
5.2.6. 
V5 – Dose adjustment visit (Day 28 ± 2 days) ...............................................................................77 
5.2.7. 
V6 – Control treatment visit (Day 49 ± 2 days) .............................................................................77 
5.2.8. 
V7 – End of Double Blind period (Day 56 ± 2 days)......................................................................78 
5.2.9. 
T1 – Telephone contact (Day 59± 1 day) .......................................................................................79 
5.2.10. V8 – End of study visit or Start of Open-Label after 1 week of placebo wash out (Day 63 ± 2 days) 
/ Premature withdrawal visit (Double blind phase) .....................................................................................79 
5.2.11. V9- Dose adjustment visit (Day 77± 2 days) ..................................................................................80 


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5.2.12. T2- Telephone contact at D98 (± 1 day) ........................................................................................81 
5.2.13. V10- Dose adjustment visit (Day 84± 2 days) ................................................................................81 
5.2.14. V11- Dose adjustment visit (Day 112± 7 days) ..............................................................................81 
5.2.15. V12- Dose adjustment visit (Day 196± 7 days) ..............................................................................81 
5.2.16. V13- Dose adjustment visit (Day 364± 7 days) ..............................................................................82 
5.2.17. Early withdrawal visit (Open label phase) .....................................................................................82 
5.2.18. Phone visits during the COVID-19 pandemic ................................................................................82 
5.3. 
Patient Withdrawal criteria ................................................................................................................83 
5.3.1. 
Criteria to withdraw subject from the trial treatment ....................................................................83 
5.3.2. 
Type and timing of data to be collected from withdrawn patients..................................................83 
5.3.3. 
The follow -up for withdrawn patients ...........................................................................................83 
5.4. 
Study discontinuation criteria ............................................................................................................83 
5.4.1. 
Criteria for terminating the trial ....................................................................................................83 
5.4.2. 
Criteria for terminating site ...........................................................................................................84 
6. SAFETY ASSESSMENT AND REPORTING ...........................................................................................84 
6.1. 
Description of Safety Parameters ......................................................................................................84 
6.1.1. 
Vital signs .......................................................................................................................................84 
6.1.2. 
Physical examination .....................................................................................................................84 
6.1.3. 
Electrocardiogram (ECG) ..............................................................................................................85 
6.1.4. 
Blood Laboratory tests and Urinalysis...........................................................................................85 
6.1.5. 
Adverse Events ...............................................................................................................................86 
6.1.5.1. 
Definitions ........................................................................................................................... 86 
6.1.5.2. 
Monitoring and recording of adverse events ....................................................................... 89 
6.1.5.3. 
Analysis of adverse events ................................................................................................... 89 
6.1.5.4. 
Reporting Serious Adverse Event or Serious Adverse Drug Reaction ................................. 91 
7. STATISTICAL ANALYSIS .........................................................................................................................92 
7.1. 
Summary ............................................................................................................................................92 
7.2. 
Statistical methods ..............................................................................................................................92 
7.3. 
Main endpoint ....................................................................................................................................93 
7.4. 
Statistical Inference ...........................................................................................................................93 
7.5. 
Sample size determination .................................................................................................................93 
7.6. 
Handling of missing data ...................................................................................................................93 
7.7. 
Interim analysis ..................................................................................................................................94 
7.7.1. 
DSMB .............................................................................................................................................94 
7.7.2. 
Adaptive sample size to 96 patients ................................................................................................94 
 
 
7.7.4. 
References ......................................................................................................................................95 
8. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ..........................................................................95 
9. QUALITY CONTROL AND QUALITY ASSURANCE .............................................................................96 
9.1. 
Mornitoring and Good clinical Practice............................................................................................96 
9.2. 
Quality Control and Audit .................................................................................................................97 
9.3. 
Monitoring ..........................................................................................................................................97 


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9.4. 
Investigator Qualifications/Responsibilities ......................................................................................98 
10. 
ETHICS .................................................................................................................................................98 
10.1. 
Declaration if Helsinki and Conformity with other International Standards ..................................98 
10.2. 
Ethics Committee/Institutional Review Board Approval ..................................................................99 
10.3. 
Emergency Actions ............................................................................................................................99 
10.4. 
Patient Informed Consent Procedure ................................................................................................99 
10.5. 
Amending the Protocol ....................................................................................................................100 
11. 
DATA HANDLING AND RECORD KEEPING ................................................................................101 
11.1. 
Identification of any data to be recorded on the CRF, considered as source data ........................101 
11.2. 
Data Handling and Record keeping ................................................................................................101 
11.3. 
Data Protection and Confidentiality ................................................................................................102 
12. 
REGULATORY ASPECTS .................................................................................................................103 
13. 
FINANCING AND STUDY INSURANCE ........................................................................................103 
14. 
PUBLICATION POLICY ...................................................................................................................104 
15. 
CALENDAR FORECAST...................................................................................................................104 
16. 
APPENDICES .....................................................................................................................................105 
17. 
REFERENCES ...................................................................................................................................114 
 
 




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of the sample size. At least 96 patients (64 patients being administrated 
pitolisant, and 32 patients receiving placebo) should be needed for a power 
of at least 0.75, given the observed values of SD and baseline correlation. 
 
A new sample size was calculated further the change of the main endpoint 
and adjustment of the corresponding variability (SD and baseline 
correlation): 
A difference of at least UNS=3 between the studied treatment and placebo 
with the observed values of SD and baseline correlation will be detected 
as significant with a power of 85%, once the sample size is at least 36+72 
patients for control and tested drug groups, respectively, thus a total of 108 
patients. 
Study duration for 
participants 
Inclusion period 4 weeks (including 2-week baseline period). Followed 
by,  
Double-blind period, treated by pitolisant or placebo for 8 weeks, 
Followed by,  
Single blind wash-out period, treated by placebo for 1 week and then 
Followed by a prolonged open-label period depending on patient wish. 
Main inclusion 
criteria 
1) Male and female children from 6 to less than 18 years of age (until V8) 
suffering from narcolepsy with or without cataplexy - meeting the 
International Classification of Sleep Disorders (ICSD-3) criteria 
(narcolepsy 
type 
1 
and 
2). 
Diagnosis 
confirmed 
with 
polysomnography and Multiple Sleep Latency Test for patients 
without cataplexy (if these examinations were not performed within 
the last 12 months) 
2) PDSS score ≥ 15 during baseline period (V1+V2) / 2. 
3) Patients should be free of non-authorized medication, in particular 
psychostimulant treatments as from the screening visit (V0) onwards. 
4) Parents – and patients old enough to understand who have expressed a 
willingness to participate in the study, who have signed and dated the 
informed consent form prior to beginning protocol required 
procedures. 
5) In the opinion of the investigator, the patient must have adequate 
support to comply with the entire study requirements as described in 
the protocol (e.g., transportation to and from trial site, self rating scales 
and diaries completion, drug compliance, scheduled visits, tests).  
6) Female pubescent patients shall use a birth control method, judged 
efficient by the investigator, throughout the study and during the 
month following treatment discontinuation. 
7) Patients should benefit from appropriate healthy insurance system 
(only applicable where mandatory e.g. in France). 
Main non-inclusion 
criteria 
1) Any other conditions that can be considered the primary causes of 
EDS: such as sleep related breathing disorders as defined by a sleep 
Apnea Index ≥ 5 per hour or/and an Apnea/Hypopnea Index ≥ 10 per 
hour, chronic sleep deprivation, circadian sleep wake rhythm disorder 
or any other medical or neurological causes that could account for 
narcolepsy symptoms associated with EDS. 


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2) Cataplectic patients treated by anticataplectics (SNRI, SSRI, sodium 
oxybate) which are not under a stable treatment since at least 4 weeks 
at the time of inclusion (V2).  
3) Patients treated for cataplexy or any other pathology, by tricyclic 
antidepressants 
(clomipramine, 
imipramine, 
mirtazapine, 
desmethylimipramine and protriptyline) are not authorized because 
they display histamine H1 receptor antagonist activity. 
4) The use of pitolisant within a 30-day period prior to initial screening 
visit (V0) for this trial. 
5) Current or recent (within one year) history of a substance abuse or 
dependence disorder including alcohol abuse as defined in Diagnostic 
and Statistical Manual of Mental Disorders (DSM-IV). 
6) Any significant abnormality of the electrocardiogram and particularly 
Fridericia’s QTc interval (QTcF = QT/3√ 60/HR) higher than 450ms.  
7) Patients with severe depression (CDI ≥ 16) 
8) Patient with suicidal risk (C-SSRS)  
9) Positive urinary drug testing (test applicable to patients from 12 years) 
10) Pregnancy (defined as positive β-HCG blood test), breast-feeding, or 
patients and unable to use an efficient method of birth control shall not 
be included in the study (for pubescent female only). 
11) Patients with severe hepatic Impairment (Child Pugh C) or with any 
other significant abnormality in the physical examination or clinical 
laboratory results. 
12) Psychiatric and neurological disorders, such as moderate or severe 
psychosis or dementia, depression, history of seizure disorder or other 
problem that, in the investigator’s opinion, would preclude the 
patient’s participation and completion of this trial or comprise reliable 
representation of subjective symptoms. 
13) Active clinically significant illness, including unstable cardiovascular, 
endocrine, neoplastic, gastrointestinal, haematological, hepatic, 
immunologic, 
metabolic, 
neurological 
(other 
than 
narcolepsy/cataplexy), pulmonary, and/or renal disease which could 
interfere with the study conduct or counter-indicate the study 
treatments or place the patient at risk during the trial or compromise 
the study objectives. 
14) Prior severe adverse reactions to CNS stimulants. 
15) Known hypersensitivity to the tested treatment including active 
substance and excipients. 
16) The inability to continue daily activities safely, without the use of 
treatment against EDS. 
17) Any patient presenting congenital galactosemia, glucose-galactose 
malabsorption or lactase deficiency due to the presence of lactose in 
investigational treatments. 
18) Patients participating in another study or being in a follow–up period 
for another study. 
19) Cannot be contacted in case of emergency. 
Dosage, treatment 
regimen, route of 
Starting dose of 5 mg, increasing to a maximum oral dose of 20 or 40 mg 
once daily, according to efficacy, tolerability and patient weight.  
Patients with a weight less than 40kg will be treated with a maximum daily 


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administration 
dose of to 20mg. 
Treatment taken the morning before breakfast. 
Control(s) 
Placebo 
Primary 
efficacy 
endpoint 
Change in the intensity and frequency of symptoms of narcolepsy (EDS 
and cataplexy) as measured by the Ullanlinna Narcolepsy Scale (UNS) 
between baseline: [V1 score (D-14) + V2 score (D0)]/2 and the end of 
treatment: [V6 score (D49) + V7 score (D56)]/2. We will compare the 
results between pitolisant and placebo groups. 
Main 
secondary 
endpoint(s) 
with 
time(s) of assessment 
- Changes in EDS as measured by the maintenance of wakefulness test 
(MWT) between baseline and V7, in pitolisant and placebo groups. 
- Change in EDS measured by the Paediatric Daytime Sleepiness Scale 
(PDSS) between baseline: [V1 score (D-14) + V2 score (D0)]/2 and the 
end of treatment: [V6 score (D49) + V7 score (D56)]/2. We will compare 
the results between pitolisant and placebo groups. 
- Changes in EDS as measured by the Child and Adolescent Sleepiness 
Scale (CASS) between baseline and the end of treatment, in pitolisant 
and placebo groups. 
- Changes in the average number of cataplexy episodes per weeks 
(recorded in sleep diary by patient and/or parent/teacher) between the 2 
weeks of baseline and the 2 weeks of end study treatment period (V6, 
V7), in pitolisant and placebo groups. 
- Differences in weekly frequency of cataplexy episodes (recorded in 
sleep diary by patient and/or parent/teacher) between baseline and the 4 
weeks of stable treatment period (V4 to V7), in pitolisant and placebo 
groups. 
- Severity of EDS measured by the Clinical Global Impression of severity 
and change. Changes between baseline and V6, V7, in pitolisant and 
placebo groups. 
- Severity of cataplexy measured by the Clinical Global Impression of 
severity and change. Changes between baseline and V6, V7, in pitolisant 
and placebo groups. 
- Changes between baseline and V6 will be compared for the TEA-Ch 
test, in pitolisant and placebo groups. 
- Comparison between placebo and pitolisant groups on: 
- Withdrawal symptoms questionnaire (DSM IV) 
- Patients’ Global Opinion on treatment effect at the end of 
treatment if able to express himself. If not will be reported either 
by parents or teachers. 
- Changes between baseline and at each visit of the open-label period in 
EDS. 
- Safety assessment will be done on monitoring of adverse events, 
physical examination, vital signs, ECG and Blood Laboratory tests 
modifications and the mood appraisal throughout the study. 
Authorized 
treatments 
Double-blind period: 
 If Patients are treated with sodium oxybate, a stable dosage is required 
for a minimum period of 4 weeks prior to inclusion (V2), and this 
dosage should be maintained stable throughout the study. 


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 Other purported anticataplectic treatments e.g. SSRI (fluoxetine, 
fluvoxamine, 
citalopram, 
sertraline, 
paroxetine) 
or 
norepinephrine/serotoninergic 
uptake 
inhibitor 
(venlafaxine), 
norepinephrine uptake inhibitors (viloxazine, duloxetine, reboxetine, 
atomoxetine) are authorized only if they are maintained at stable dose 
for a minimum period of 4 weeks prior to inclusion (V2), and their 
dose should not be changed throughout the trial. 
 Antihistamic H1 which do not cross blood brain barrier (BBB) (2nd and 
3rd generation) 
 Any change in the dosage of the other authorized concomitant 
treatments should be recorded in the CRF.  
 
Open label period:  
Concomitant treatments against EDS and cataplexy such as modafinil, 
sodium oxybate, methylphenidate or antidepressants (except tricyclics) 
are authorized. The investigator will be free to adapt posology.  
Non-authorized 
treatments 
Double blind period: 
At V0, all ongoing prohibited treatments are discontinued. At V1, first 
visit with baseline assessment, all prohibited treatments should have been 
stopped for at least 2 weeks.   
 
 From screening visit (V0) throughout V8, subjects should be free of 
all other drugs or substances, namely; 
- with a psychotropic effect, including psychostimulants for the 
treatment of EDS (amphetamine and amphetamine-like CNS stimulants, 
methylphenidate or others, such as modafinil);  
- medication with sedating properties (e.g. benzodiazepines, non-
benzodiazepine anxiolytics, hypnotics sedatives, neuroleptics, opioids, 
antihistaminic products (1st generation), and anticonvulsants). 
 Tricyclic antidepressants such as clomipramine, imipramine, 
Mirtazapine, desmethylimipramine and protriptyline are not 
authorized because they display histamine H1 receptor antagonist 
activity and possibly interfere with the effect of pitolisant by 
abrogating the effect of endogenous histamine released in brain by 
pitolisant. 
 
Open label period:  
Medication with sedating properties (e.g. benzodiazepines, non-
benzodiazepine anxiolytics, hypnotics sedatives, neuroleptics, opioids, 
antihistaminic products (1st generation), and anticonvulsants) are 
prohibited. 
Tricyclic antidepressants such as clomipramine, imipramine, mirtazapine, 
desmethylimipramine and protriptyline are not authorized because they 
display histamine H1 receptor antagonist activity and possibly interfere 
with the effect of pitolisant by abrogating the effect of endogenous 
histamine released in brain by pitolisant. 
Statistical Analysis 
The primary selection will be the Full Analysis Set (FAS), defined as all 
the randomized patients irrespective of their outcome, this analysis with 
the best conformity with Intent To Treat principle. 


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The main endpoint is the UNS measuring the quantity and intensity of 
symptoms of narcolepsy in particular of EDS and cataplexies. 
Metric properties of this scale are summarized as follows: Total scores 
range from 0 to 44 with higher scores denoting greater narcoleptic 
tendencies. 
The significance of the active tested drug compared with placebo on the 
change of UNS will be assessed by Analysis of Covariance on Final UNS 
estimate (the summary mean of the two Final UNS measures V6 and V7) 
adjusted for baseline (summary mean of the two pre-treatment UNS values 
V1 and V2). ANCOVA will be conducted with a Mixed Linear Model 
taking into account centre heterogeneity. 
A standardized mean difference of at least 0.5 on the UNS (considered as 
the minimum clinically significant difference) will be detected at a two-
sided 0.05 confidence level with a type 2 risk of 0.15 (power ≥ 0.85), 
assuming a baseline-final correlation R=0.4, and a sample size ratio 1:2 
when the sample size/group is at least 36+72 patients for control and tested 
drug groups, respectively, thus a total of 108 patients. 
For patients terminating the trial before completion, the final value will be 
calculated as the mean of the two last known values (baseline if needed).  
The independent Data Safety Monitoring Board (DSMB) will regularly 
follow the progress of the clinical trial, monitor safety data and critical 
efficacy variables and be consulted concerning the opportunity of 
modifying the sample size (see next point), or terminate a trial for futility 
(see next point). 
- A one–stage Futility stopping will be based on Conditional Power (CP), 
(probability to detect a significant result at the end of the study), given the 
results observed at an intermediate time. CP will be estimated through B-
values and (Lan & Wittes, 1988, Lan & Zucker, 93). This analysis was 
planned when at least 20 patients are available, and futility threshold will 
be CPmin=.10 involving a slight increase of type 2 error (β=0.1/.9=.111-
.10≅.01) (Proschan, 1999). This intermediate futility analysis does not 
require any type-I adjustment, this trial does not plan g rejection of the null 
hypothesis before its end. 
This analysis was delayed sine die due to necessity of reconsideration of 
the sample size and a proposal of change of the main endpoint. This 
analysis will be conducted as soon as the sample size is definitely fixed 
and the main endpoint endorsed by the European regulatory authority. 
Safety 
Adverse events and drug safety: 
• Monitoring of adverse events at each visit: investigators will assess, 
among other things, the severity and the relationship of each adverse 
event to study medication. 
N.B.: hallucinations, sleep paralysis, dyssomnia and automatic behaviour, 
which are part of the usual associated symptoms of narcolepsy will only 
be considered as adverse events if the number of occurrences, or severity, 
is increased during the study treatment period. 
• Cardiovascular safety:  
1. Vital sign checking at each visit including blood pressure, heart 
rate and body weight. 
2. ECG at each visit and calculation of Fridericia’s corrected QTc 
interval  


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(QTcF = QT/3√ (60/HR)). If the QTcF is ≥ 500 ms or if the 
difference between the QTcF on treatment and the QTcF at 
baseline is ≥ 60 ms, (observed on two consecutive occasions, i.e. 
after performing a recheck a few hours later) the treatment shall be 
discontinued and the corresponding ECG forwarded to Bioprojet. 
• Mood appraisal adapted to children (CDI<16) at visits: V1, V4, V6, 
and V8 
• Columbia-Suicide Severity Rating Scale (C-SSRS) from V1 to V8. 
• Blood laboratory tests (haematology, blood chemistry), at the initial 
screening visit (V1), at the final treatment phase evaluation visit (V7), 
and for any subject who withdraws prior to treatment phase 
completion, within five days after the last treatment intake.  
• Withdrawal symptom questionnaire (DSM-IV) at T1 (D59 ± 1) and at 
V8. 
The independent Data Safety Monitoring Board (DSMB) will regularly 
follow the progress of the clinical trial, monitor safety data and critical 
efficacy variables and be consulted concerning the opportunity of 
modifying the sample size, or terminate a trial for futility. 
Study design and 
conduct 
V0 – Screening visit and start of wash out period (Day-28 = only for 
patients under prohibited medications and cataplectic patients under 
anti-cataplectic treatment) 
The investigator will provide the patient and parents with the necessary 
information regarding the study objectives, the investigational product 
(pitolisant), the expected benefit, the potential risks and the study 
procedures.  
The informed consent will be signed by patient and parents prior to the 
study entry for each patient.  
Prohibited treatments will be discontinued at V0. 
A complete medical examination, detailed questionnaires on his/her 
medical history and narcolepsy history will be recorded. 
A complete physical examination including, weight, height and BMI. 
Vital signs (blood pressure, heart rate) 
Questioning on previous and concomitant medication used and possible 
occurrence of adverse events. 
Delivery of two sleep diaries (one per week) which has to be completed 
by the patient (if old enough to understand) and/or parents every evening. 
(Hour of bedtime in the evening, wake-up time in the morning, and 
number of sleepiness periods during the day, number of (total or partial) 
cataplexy attacks, number of hallucinations and sleep paralysis). 
 
V1 – Screening visit and Baseline period (Day -14) 
If no V0 visit is required, the investigator will provide the patient and 
parents with the necessary information regarding the study objectives, the 
investigational product (pitolisant), the expected benefit, the potential 
risks and the study procedures.  
The informed consents will be signed by patient and parents prior to the 
study entry for each patient. 
Patients who fulfil all inclusion and exclusion criteria and after providing 
informed consent, could be enrolled in the study and complete the 
procedures:  
Complete physical examination (including height and weight),  
Detailed questioning on medical history and narcolepsy history, 


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Questioning on previous and concomitant medication used and possible 
occurrence of adverse events, 
Vital signs (blood pressure, heart rate), 
12-lead ECG (QTcF control),  
A blood sample will be taken for routine haematological and biochemical 
test (including β-HCG pregnancy test for pubescent female) and semi-
quantitative urinalysis (dipstick), 
A urine drug testing (for patients from 12 years),  
The following questionnaires should be performed:  
- Pediatric Daytime Sleepiness Scale (PDSS), 
- Child and Adolescent Sleepiness Scale (CASS) 
- Ullanlinna Narcolepsy Scale (UNS), 
- Test of Everyday Attention for Children (TEA-Ch), 
- Clinical Global Impression of Severity (CGI-S) on EDS and on 
cataplexy, 
- Childhood Depression Inventory (CDI), 
- Columbia-Suicide Severity Rating Scale (C-SSRS), 
- Retrieval of the 2 first sleep diaries (when applicable) and check by 
the investigator. Delivery of two sleep diaries (one per week) which 
has to be daily completed by the patient (if old enough to understand) 
and/or parents every evening. (Hour of bedtime in the evening, wake-
up time in the morning, and number of sleepiness periods during the 
day, number of (total or partial) cataplexy attacks, number of 
hallucinations and sleep paralysis). 
 
V2 – Randomization and start of escalating period (Day 0) 
- A physical examination including vital signs shall be carried out. 
- Adverse events and concomitant medication recording 
- 12-lead ECG (QTcF value),  
- Maintenance of Wakefulness Test (MWT) (four sessions of 30-minute 
tests), 
- Polysomnography with Multiple Sleep Latency Test will be performed 
the day preceding V2, unless performed during the previous year, 
- The following questionnaires should be performed:  
- PDSS,  
- CASS, 
- UNS, 
- CGI-S on EDS and on cataplexy, 
- C-SSRS, 
- Retrieval of the 2 first sleep diaries and delivery of two other sleep 
diaries which have to be completed every day throughout the baseline 
period, 
- Treatment dispensation for the next two weeks 
- First week with 5mg of pitolisant (or placebo) per day in the 
morning, before breakfast, 
- Second week with a 10mg of pitolisant (or placebo) per day in the 
morning before breakfast. 
 
V3 - Dose adjustment visit (D 14 ± 2 days) 
- A complete interrogation including control of the treatment compliance, 
count of remaining tablets and verification of the forgotten treatment 
intake, 
- Adverse events and concomitant medication recording, 
- A physical examination including vital signs shall be carried out, 


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- 12-lead ECG (QTcF value),  
- The following questionnaires should be performed:  
- PDSS, 
- CASS, 
- C-SSRS, 
- Retrieval of sleep diary of the previous visit and delivery of one 
other sleep diary which have to be completed every evening until the 
next visit, 
- Investigational treatment allocation: the dose of pitolisant will be 
individually adjusted according to the assessment of investigators on the 
basis of efficacy and tolerance,  
Patients taking pitolisant 10 mg/d (or placebo) continue the same dose or 
could reduce to pitolisant 5 mg/d (or placebo) or increase to 20 mg (or 
placebo).  
 
V4 - Dose adjustment visit (D21 ± 2 days) 
- A complete interrogation including control of the treatment compliance, 
count of remaining tablets and verification of the forgotten treatment 
intake, 
- Adverse events and concomitant medication recording, 
- A physical examination including vital signs shall be carried out, 
- 12-lead ECG (QTcF value),  
- The following questionnaires should be performed:  
- PDSS, 
- CASS, 
- CDI, 
- C-SSRS, 
- Retrieval of sleep diary of the previous visit and delivery of one 
other sleep diary which have to be completed every evening until the 
next visit, 
- Investigational treatment allocation: the dose of pitolisant will be 
individually adjusted according to the assessment of investigators on the 
basis of efficacy, tolerance and weight,  
Patients taking pitolisant 5 mg/d (or placebo) continue the same dose or 
could increase to 10 mg (or placebo),  
Patients taking pitolisant 10 mg/d (or placebo) continue the same dose or 
could reduce to pitolisant 5 mg/d (or placebo) or increase to 20 mg (or 
placebo),  
Patients taking pitolisant 20 mg/d (or placebo) continue the same dose or 
could reduce to pitolisant 10 mg/d (or placebo) or increase to 40 mg (or 
placebo). Patients with a weight less than 40kg could be treated with a 
maximum daily dose of 20 mg. 
 
V5 – Dose adjustment visit (D28 ± 2 days) 
- A complete interrogation including control of the treatment compliance, 
count of remaining tablets and verification of the forgotten treatment 
intake, 
- Adverse events and concomitant medication recording, 
- A physical examination including vital signs shall be carried out, 
- 12-lead ECG (QTcF value),  
- The following questionnaires should be performed:  
- PDSS, 
- CASS, 
- C-SSRS, 


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- Retrieval of sleep diary of the previous visit and delivery of one 
other sleep diary which have to be completed every evening until the 
next visit, 
- Investigational treatment allocation: No increase of pitolisant dosage 
will be authorized, the dose of pitolisant will be individually adjusted 
according to the assessment of investigators on the basis of efficacy, 
tolerance and weight,  
Patients taking pitolisant 5 mg/d (or placebo) continue the same dose, 
Patients taking pitolisant 10 mg/d (or placebo) continue the same dose or 
could reduce to pitolisant 5 mg/d (or placebo),  
Patients taking pitolisant 20 mg/d (or placebo) continue the same dose or 
could reduce to pitolisant 10 mg/d (or placebo),  
Patients taking pitolisant 40 mg/d (or placebo) continue the same dose or 
could reduce to pitolisant 20 mg/d (or placebo), 
From this date onwards, no dosage change will be allowed. Beginning of 
the 4-week stable dose period. 
 
V6 – Control treatment visit (D49 ± 2 days) 
- A complete interrogation including control of the treatment compliance, 
count of remaining tablet and verification of the forgotten treatment 
intake, 
- Adverse events and concomitant medication recording, 
- A physical examination including vital signs shall be carried out, 
- 12-lead ECG (QTcF value),  
- The following questionnaires should be performed:  
- PDSS,  
- CASS, 
- CDI, 
- C-SSRS, 
- UNS,  
- TEA-Ch, 
- Clinical Global Impression of Change (CGI-C) on EDS and on 
cataplexy, 
- Retrieval of sleep diary of the previous visit and delivery of one 
other sleep diary which have to be completed every evening until the 
next visit. 
- No dispensation performed at V6. 
 
V7 – End of Double Blind Period (D56 ± 2 days) 
- A complete interrogation including control of the treatment compliance, 
count of remaining tablets and verification of the forgotten treatment 
intake, 
- Adverse events and concomitant medication recording, 
- A physical examination including vital signs shall be carried out, 
- 12-lead ECG (QTcF value),  
- A blood sample will be taken for routine haematological and 
biochemical test (including β-HCG pregnancy test for pubescent female) 
and semi-quantitative urinalysis (dipstick), 
A urine drug testing (for patients from 12 years),  
- Maintenance of Wakefulness Test (MWT) (four sessions of 30-minute 
tests), 
- The following questionnaires should be performed:  
- PDSS,  
- CASS, 


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- C-SSRS, 
- UNS,  
- CGI-C on EDS and on cataplexy, 
- Retrieval of sleep diary of the previous visit and delivery of one 
other sleep diary which have to be completed every evening until the 
next visit, 
- Global opinion on the effect of investigational treatment will be 
reported by patient if able to express himself. If not will be reported 
either by parents or teachers. 
- Investigational treatment allocation: start 1-week wash-out period. 
 
T1 - Telephone contact at D59 (± 1 day) 
During this telephone contact, the investigator should: 
- Ascertain that the treatment discontinuation is well tolerated 
- Record all adverse events that have occurred 
- Withdrawal symptoms questionnaire 
 
V8 - End of study visit after 1 week of placebo wash out or (D63 ± 2 
days) / Start of Open label or Premature withdrawal visit (within 5 
days after last treatment intake) 
The premature withdrawal patients should be followed by a visit 
performed within a maximum of 5 days after the last dose of study drug.  
- A complete interrogation including control of the treatment compliance, 
count of remaining tablets and verification of the forgotten treatment 
intake, 
- Adverse events and concomitant medication recording, 
- A physical examination including vital signs shall be carried out, 
- 12-lead ECG (QTcF value),  
- A blood sample will be taken for routine haematological and 
biochemical test (including β-HCG pregnancy test for pubescent female) 
and semi-quantitative urinalysis (dipstick). (only for premature 
withdrawal patients), 
- The following questionnaires should be performed:  
- PDSS,  
- CASS, 
- UNS (only for premature withdrawal patients),  
- CGI-C on EDS and on cataplexy, 
- CDI, 
- C-SSRS, 
-Global opinion on the effect of investigational treatment will be 
reported by patient if able to express himself. If not will be reported 
either by parents or teachers. (only for premature withdrawal 
patients), 
- Retrieval of sleep diary.  
-Withdrawal symptoms questionnaires. 
Patients willing to continue the study in the prolonged open label period 
will receive a new pack of investigational treatment and will start an 
escalating dose treatment. Those patients will receive one sleep diary 
which have to be filled out daily during the 7 days prior to the next visit. 
Patients not willing to continue in the study will be followed under usual 
practice. 
 


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Patients completing V8 will have the possibility to continue the treatment 
with pitolisant in open conditions until BF2.649 (pitolisant) is available on 
the market for children/adolescent from 6 to 17 years included or as soon 
as the patient becomes older than 18 years. Then he will have access to the 
treatment already on the market for adults. 
--------- 
 
V9 - Dose adjustment visit (D77 ± 2 days) 
- A complete interrogation including control of the treatment compliance, 
count of remaining tablets and verification of the forgotten treatment 
intake, 
- Adverse events and concomitant medication recording, 
- A physical examination including vital signs shall be carried out, 
- 12-lead ECG (QTcF value),  
- The following questionnaires should be performed:  
- PDSS,  
- CGI-C on EDS and on cataplexy, 
- CDI, 
- C-SSRS, 
- Global opinion on the effect of investigational treatment will be 
reported by patient if able to express himself. If not will be reported 
either by parents or teachers, 
- Retrieval of sleep diary. (Sleep diary will be filled out daily during the 
7 days prior to the next visit) and delivery of one other.  
- Investigational treatment allocation: the dose of pitolisant will be 
individually adjusted according to the assessment of investigators on the 
basis of efficacy and tolerance,  
 
V10 - Dose adjustment visit (D84 ± 2 days) 
- A complete interrogation including control of the treatment compliance, 
count of remaining tablets and verification of the forgotten treatment 
intake, 
- Adverse events and concomitant medication recording, 
- A physical examination including vital signs shall be carried out, 
- 12-lead ECG (QTcF value),  
- A blood sample will be taken for routine haematological and 
biochemical test (including β-HCG pregnancy test for pubescent female) 
and semi-quantitative urinalysis (dipstick),  
- The following questionnaires should be performed:  
- PDSS,  
- CGI-C on EDS and on cataplexy, 
- CDI, 
- C-SSRS, 
- Global opinion on the effect of investigational treatment will be 
reported by patient if able to express himself. If not will be reported 
either by parents or teachers, 
- Retrieval of sleep diary. (Sleep diary will be filled out daily during 
the 7 days prior to the next visit) and delivery of one other.  
- Investigational treatment allocation: the dose of pitolisant will be 
individually adjusted according to the assessment of investigators on the 
basis of efficacy, tolerance and weight. 
 
 


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6 treatment daily dose regimens are available: 5mg, 10mg, 15mg, 
20mg, 30mg and 40mg/d from the visit 10 until the end of study. 
 
T2 - Telephone contact at D91 (± 1 day) 
During this telephone contact: 
- The investigator should assess the efficacy and tolerance.  
In opinion of investigator, if patient needs a dose adjustment, the dose 
could be re-adjusted according the effectiveness/tolerability of treatment 
to patient.  
In case of need, it is possible to plan a visit on site within the week 
following phone contact for obtaining new bottles of treatment with the 
corresponding dose.  
- Record all adverse events that have occurred. 
 
V11 - Dose adjustment visit (D112 ± 7 days) 
Idem to the visit V9 
 
V12 - Dose adjustment visit (D196 ± 7 days) 
Idem to the visit V11 
 
V13 - Dose adjustment visit (D364 ± 7 days) 
Idem to the visit V12 + a blood sample will be taken for routine 
haematological and biochemical test (including β-HCG pregnancy test for 
pubescent female) and semi-quantitative urinalysis (dipstick). 
 
All subsequent visits are performed each 6 months. 
Idem to the visit V13 
 
Phone visits during the COVID-19 pandemic 
In order to limit the risk for the patient to spread/acquire the infection, 
special measures are put in place to maintain the participants in the study. 
The investigator should assess during these calls the efficacy and tolerance 
and the dose of treatment should be adjusted accordingly, when 
applicable. 
Direct shipment of study treatment from the site, or hospital pharmacy, to 
the patient’s home is allowed via a courier with the full documentation of 
shipment and receipt by the patient/parents. Patients will return all 
medication at his/her subsequent site visit. Diaries to be documented daily 
are sent to the patient with the study treatment. 
Study Duration and 
planned dates 
The actual overall study duration or patients recruitment period may vary 
according to the number of screened patients presenting the main inclusion 
and exclusion criteria. 
Study duration for each patient: 13 weeks (2 week of wash-out + 2 weeks 
for baseline + 8 weeks under double blind study treatment + 1 week for 
study treatment wash-out). Followed by a prolonged open-label period. 
Planned dates for the Clinical Study: Start Q1 2016 
 


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1 The 4-week escalating dosage phase is followed by a 4-week stable-dose period during which the dose will be 5-, 10-, 20, or 40 mg/d of pitolisant or placebo 
2 Complete biological examination including: Red Blood Cells, White Blood Cells (differential count, absolute value), Hemoglobin, haematocrit, Mean corpuscular volume (MCV), 
platelet count, quick time, sodium, potassium, chloride, creatinine, alkaline phosphatases, urea, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), gamma 
glutamyl transpeptidase (GGT), total bilirubin, glucose, triglycerides, total cholesterol, βHCG (only for pubescent female). Dipstick urinalysis. A urinary drug testing (test 
applicable to patients from 12 years). 
3 The premature withdrawal from the study should be followed by a visit performed within a maximum of 5 days after the last dose of study drug.  
   4  The sleep diary has to be completed every evening from V0 to V8. 
   5  The global opinion will be reported by patient if able to express himself. If not will be reported either by parents or teachers.  
   6  ECG: calculation of the QTcF value and delta of QTcF values between baseline ECG and ECGs performed at each subsequent visits. 
   7  Polysomnography-MSLT will be performed the day preceding V2, unless performed during the previous year.   
   8  V0 is required to ensure proper selection of patients under prohibited medications. For patients not using any prohibited medication study or patients cataplectic not using anti-
cataplectic treatments may start at V1.  
* Inform consent will be signed once either at V0 or V1 when applicable. 






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1 Treatment administration of open label period will start by an escalating dose phase for all patients. 
2 Complete biological examination including: Red Blood Cells, White Blood Cells (differential count, absolute value), Hemoglobin, haematocrit, Mean corpuscular volume (MCV), 
platelet count, quick time, sodium, potassium, chloride, creatinine, alkaline phosphatases, urea, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), gamma 
glutamyl transpeptidase (GGT), total bilirubin, glucose, triglycerides, total cholesterol, βHCG (only for pubescent female). Dipstick urinalysis. A urinary drug testing (test 
applicable to patients from 12 years). 
3 The premature withdrawal from the study should be followed by a visit performed within a maximum of 5 days after the last dose of study drug. 
4  The sleep diary has to be completed daily the 7 days prior to the next visit. 
5  The global opinion will be reported by patient if able to express himself. If not will be reported either by parents or teachers. 
6  ECG: calculation of the QTcF value and delta of QTcF values between baseline ECG and ECGs performed at each subsequent visits. 
7  In case of dose decrease, an unscheduled visit should be planned within the week following the phone contact in order to decrease the dose from 20 to 10 mg. The other doses 
decrease, from 40 to 20 and 10 to 5 mg, don't require a visit. 
 
 
 


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ABBREVATIONS USED IN THE PROTOCOL 
AEs 
 
 
Adverse events  
ALAT 
 
 
Alanine aminotransferase 
ANCOVA   
 
Analysis of Covariance test 
ASAT 
 
 
Aspartate aminotransferase 
AUC 
 
 
Area under the concentration-time curve 
BMI 
 
 
Body mass index 
CASS 
 
 
Child and Adolescent Sleepiness Scale 
CDI 
 
 
Childhood Depression Inventory 
CGI-C 
 
 
Clinical Global Impression of Change 
CGI-S 
 
 
Clinical Global Impression of Severity 
Cmax 
 
 
Maximum observed concentration 
CNIL  
 
 
Commission Nationale de l’Informatique et des Libertés 
CNS  
 
 
Central nervous system 
CRF 
 
 
Case report form  
CRO 
 
 
Contract Research Organization 
CSF 
 
 
Cerebral Spinal Fluid 
CSR 
 
 
Clinical Study Report 
C-SSRS 
 
 
Columbia-Suicide Severity Rating Scale 
DMB  
 
 
Data Management Book 
DSM-IV 
 
 
Diagnostic System Medical, fourth version 
DSMB 
 
 
Data Safety Monitoring Board 
ECG 
 
 
Electrocardiogram 
EDS 
 
 
Excessive Daytime Sleepiness 
FAS 
 
 
Full Analysis Set 
GCP 
 
 
Good Clinical Practice 
GGT 
 
 
Gamma glutamyltransferase 
GMP 
 
 
Good Manufacturing Practice 
H3R 
 
 
Histamine H3 receptor  
ICH 
International 
conference 
on 
harmonization 
of 
technical 
requirements for registration of pharmaceuticals for human use 
ICSD  
 
 
International Classification of Sleep Disorders  
IEC  
 
 
Independent Ethics Committee 
IRB  
 
 
Institutional Review Board  


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KO  
 
 
Knock-out 
MSLT 
 
 
Multiple Sleep Latency Test 
MWT 
 
 
Maintenance of Wakefulness Test 
NOAEL  
 
 
No observable adverse effect levels 
OSA  
 
 
Obstructive Sleep Apnoea syndrome 
PDSS 
 
 
Pediatric Daytime Sleepiness Scale 
PS  
 
 
Paradoxical sleep 
PSG 
 
 
Polysomnography 
REM 
 
 
Rapid Eye Movement 
SAE 
 
 
Serious Adverse Event 
SD  
Standard Deviation 
TEA-Ch 
Test of Everyday Attention for Children 
ß-hCG 
 
 
Human chorionic gonadotropin 
SWS 
 
 
Slow Wave Sleep 
Tmax 
 
 
Time to Cmax  
 
 


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1. 
INTRODUCTION 
 
Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness (EDS). The age-
at-onset may be childhood, and even more disabling symptoms such as cataplexy attacks can 
very often occur (80 % of cases approximately, according to renowned European neurologists). 
Cataplexy attacks facilitate the Δg since, in young children, sleepiness may take on the form of 
an increased rather than a decreased activity, including irritability, aggressiveness, and 
inattentiveness (resembling the attention-deficit/hyperactivity disorder). 
Pharmacological treatments consist of psychostimulants (modafinil, methylphenidate), whereas 
sodium oxybate is used to reduce the frequency and intensity of cataplexy attacks. 
However, a great number of adverse events (more particularly, confusion, dizziness, suicidal 
ideation, high blood pressure…) together with its administration rhythm requiring a nocturnal 
intake (not easily followed by patients) restrict its use. 
Pitolisant, an inverse agonist of H3 receptor, has been developed in adult, narcoleptic patients 
with or without cataplexy, during several phase II (P04-03, P05-03, P06-06) and phase III (P07-
03, P07-07, P09-15) clinical studies, with a good tolerance followed by favorable efficacy 
results, since it significantly reduced the diurnal sleepiness, as well as the number of cataplexy 
attacks. 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 


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1.1. 
SUMMARY OF RELEVANT NONCLINICAL STUDIES 
1.1.1. 
Pharmacological Profile 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 






























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1.3. 
SUMMARY OF THE KNOWN AND POTENTIAL RISKS AND 
BENEFITS TO HUMAN SUBJECTS 
The exposure to pitolisant in healthy volunteers was assessed in six pharmacokinetic studies in 
66 subjects that received doses of pitolisant in single administration up to 120 mg and during 
28 days with 50 mg once daily. The compound was well tolerated up to 90 mg by single dose; 
however the single dose at 120 mg led to irritability. The repeated administration (28 days up 
to 50 mg/day) was well tolerated. 


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Phase II studies demonstrated the positive effect of pitolisant in Excessive Daytime Sleepiness 
reduction in the indications intended for clinical trials. 
The tolerance was good and the most common adverse events with pitolisant were headache 
(9.5%), insomnia (9.3%) and middle insomnia (0.9%), nausea (4.3%) and irritability (3.2%). 
These adverse events were most of the time of mild to moderate intensity. 
 
Both phase III pivotal studies performed in 94 and 165 narcoleptic patients with or without 
cataplexy, respectively, all of them being treated by pitolisant, modafinil, or placebo during 
8 weeks and analyzed, confirmed the efficacy of pitolisant on excessive daytime sleepiness with 
effects statistically superior to those of the placebo at the level of the main efficacy endpoint 
(ESS score), but also at the level of secondary criteria such as MWT, SART, CGI (on EDS), 
and above all the “ESS responder” criterion (ESS ≤ 10, or ESS Final – ESS Baseline ≥ 3).  
The analysis of sleep diaries completed by the patients during 7 days prior to each visit showed 
a possible reduction of the risks of cataplexy, which remains to be confirmed by a new clinical 
study in this indication. 
Tolerance was checked in more than 50 patients treated during 12 months by pitolisant only, or 
in association with other products (P09-10). It was found to be excellent in both groups. 
 
 
2. 
RATIONALE FOR THE STUDY 
 
 
 
 
  
 
 


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3. 
TRIAL DESCRIPTION 
 
3.1. 
TRIAL OBJECTIVES 
During this trial, pitolisant will be compared to placebo, with regard to EDS on the one hand, 
and to the number of cataplexy episodes, if any, on the other hand. 
The clinical and biological tolerance of pitolisant will also be checked. 
 
This trial will characterize the efficacy of pitolisant (5-, 10-, 20-, 40 mg/d in Double Blind 
Period and 5-, 10-, 15-, 20-, 30-, 40 mg/d in Open Label Period) compared to placebo in 
showing an incremental improvement to the situation particularly in terms of a reduction of 
EDS as measured by the UNS, and also on the number of cataplexy episodes, if any. 
 
3.2. 
TRIAL DESIGN 
Randomized, double blind, placebo-controlled, parallel group, multicentre trial comparing the 
effects of pitolisant or placebo for the treatment during 8 weeks (double-blind period) of 
narcoleptic patients with or without cataplexy. After 4-week of individual up-titration scheme 
from 5 to a maximum of 40 mg/d pitolisant or placebo, the treatment will be administered at a 
stable dose during 4 weeks, followed by 1 week placebo period. 
Then, patients willing to continue will receive the study treatment during a prolonged open-
label period. 


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3.3. 
STUDY ENDPOINTS 
3.3.1. 
Primary Endpoint 
The primary endpoint of efficacy will be the changes in UNS (Ullanlinna Narcolepsy Scale) 
measuring the intensity and frequency of symptoms of narcolepsy (Excessive Daytime 
Sleepiness (EDS) and cataplexies), based on the change from baseline (mean of two pre-
treatment measures at [(V1 + V2)/2]) of the UNS score and at the end of double-blind phase 
(mean of the last two measures [(V6 + V7)/2]).  
 
. 
 
3.3.2. 
Secondary endpoints 
As secondary endpoints the study will assess efficacy and safety endpoints in pitolisant and 
placebo groups: 
- Changes in EDS as measured by the maintenance of wakefulness test (MWT) between 
baseline and V7, 
- Changes in EDS measured by the Paediatric Daytime Sleepiness Scale (PDSS) between 
baseline: [V1 score (D-14) + V2 score (D0)]/2 and the end of treatment: [V6 score (D49) + 
V7 score (D56)]/2, 
- Changes in EDS as measured by the Child and Adolescent Sleepiness Scale (CASS) between 
baseline and the end of treatment, 
- Changes in the average number of cataplexy episodes per weeks: (recorded in sleep diary by 
patient and/or parent/teacher) between the 2 weeks of baseline and the 2 weeks of end study 
treatment period (V6, V7), 
- Differences in weekly frequency of cataplexy episodes (recorded in sleep diary by patient 
and/or parent/teacher) between baseline and the 4 weeks of stable treatment period (V4 to V7), 
- Severity of EDS measured by the clinical Global Impression of severity and change. Changes 
between baseline and V6, V7, 
- Severity of cataplexy measured by the clinical Global Impression of severity and change. 
Changes between baseline and V6, V7, 
- Changes between baseline and V6 will be compared for the TEA-Ch test, 
- Comparison between placebo and pitolisant groups on: 
- Withdrawal symptoms questionnaire (DSM IV) on D59 during a phone call (T1) and 
at the end-of-study visit on D63 (V8) after a one-week period on placebo, 
- Patients’ Global Opinion on treatment effect at the end of treatment if able to express 


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himself. If not will be reported either by parents or teachers. 
- ,Tolerability as measured by Treatment Emergent Adverse Events (TEAE),  
- Changes in Physical examination and Vital signs,  
- ECG and calculation of Fridericia’s corrected QTc interval (QTcF = QT/3√ 60/HR), 
-  Blood laboratory tests (haematology, blood chemistry),  
-  Mood appraisal adapted to children (CDI and C-SSRS). 
- Changes between baseline and at each visit of the open-label period in EDS, 
- Safety assessment will be done on monitoring of adverse events, physical examination, vital 
signs, ECG and Blood Laboratory tests modifications and the mood appraisal throughout the 
study. 
 
3.4. 
STUDY POPULATION 
The study will be performed on 108 narcoleptic children to assess the effects of pitolisant 
compared with placebo in the relief of Excessive Daytime Sleepiness (EDS): children from 6 
to less than 12 years of age and adolescents from 12 to less than 18 years of age more or less 
equally balance between age groups (at least 40%). Each age groups should be also more or 
less equally balance between genders (at least 40%), all of them suffering from narcolepsy with 
or without cataplexy. 
 
Patients are allowed to continue their anticataplectic drugs, if they are at stable dosage for at 
least 4 weeks before the inclusion (V2), and this dosage should be maintained stable throughout 
the study (from V2 to V8).  
The previous use of drug with a psychotropic effect, including psychostimulants for the 
treatment of EDS should be discontinued at V0 (D-28).  
At V1 (D-14), all prohibited treatments should be stopped for at least 14 days. 
 
3.4.1. 
Inclusion criteria 
1) Male and female children from 6 to less than 18 years of age (at V8) suffering from 
narcolepsy with or without cataplexy - meeting the International Classification of Sleep 
Disorders (ICSD-3) criteria (Narcolepsy type 1 and 2). Diagnosis confirmed with 
polysomnography and Multiple Sleep Latency Test for patients without cataplexy (if these 
examinations were not performed within the last 12 months) 
2) PDSS score ≥ 15 during baseline period (V1+V2) / 2.  


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3) Patients should be free of non-authorized medication, in particular psychostimulant 
treatments as from the screening visit (V0) onwards.  
4) Parents – and patients old enough to understand who have expressed a willingness to 
participate in the study, who have signed and dated the informed consent form prior to 
beginning protocol required procedures. 
5) In the opinion of the investigator, the patient must have adequate support to comply with 
the entire study requirements as described in the protocol (e.g., transportation to and from 
trial site, self rating scales and diaries completion, drug compliance, scheduled visits, tests).  
6) Female pubescent patients shall use a birth control method, judged efficient by the 
investigator, throughout the study and during the month following treatment 
discontinuation. 
7) Patients should benefit from appropriate healthy insurance system (only applicable where 
mandatory e.g. in France). 
 
3.4.2. 
Non inclusion criteria 
1) Any other conditions that can be considered the primary causes of EDS: such as sleep 
related breathing disorders as defined by a sleep Apnea Index ≥ 5 per hour or/and an 
Apnea/Hypopnea Index ≥ 10 per hour, chronic sleep deprivation, circadian sleep wake 
rhythm disorder or any other medical or neurological causes that could account for 
narcolepsy symptoms associated with EDS. 
2) Cataplectic patients treated by anticataplectics (SNRI, SSRI, sodium oxybate) which are 
not under a stable treatment since at least 4 weeks at the time of inclusion (V2).  
3) Patients treated for cataplexy or any other pathology, by tricyclic antidepressants 
(clomipramine, imipramine, mirtazapine, desmethylimipramine and protriptyline) are not 
authorized because they display histamine H1 receptor antagonist activity. 
4) The use of pitolisant within a 30-day period prior to initial screening visit (V0) for this trial. 
5) Current or recent (within one year) history of a substance abuse or dependence disorder 
including alcohol abuse as defined in Diagnostic and Statistical Manual of Mental Disorders 
(DSM-IV). 
6) Any significant abnormality of the electrocardiogram and particularly Fridericia’s QTc 
interval (QTcF = QT/3√ 60/HR) higher than 450 ms.  
7) Patients with severe depression (CDI ≥ 16). 
8) Patient with suicidal risk (C-SSRS).  
9) Positive urinary drug testing (test applicable to patients from 12 years) 


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10) Pregnancy (defined as positive β-HCG blood test), breast-feeding, or patients and unable to 
use an efficient method of birth control shall not be included in the study (for pubescent 
female only). 
11) Patients with severe hepatic Impairment (Child Pugh C) or with any other significant 
abnormality in the physical examination or clinical laboratory results. 
12) Psychiatric and neurological disorders, such as moderate or severe psychosis or dementia, 
depression, history of seizure disorder or other problem that, in the investigator’s opinion, 
would preclude the patient’s participation and completion of this trial or comprise reliable 
representation of subjective symptoms. 
13) Active clinically significant illness, including unstable cardiovascular, endocrine, 
neoplastic, gastrointestinal, haematological, hepatic, immunologic, metabolic, neurological 
(other than narcolepsy/cataplexy), pulmonary, and/or renal disease which could interfere 
with the study conduct or counter-indicate the study treatments or place the patient at risk 
during the trial or compromise the study objectives. 
14) Prior severe adverse reactions to CNS stimulants. 
15) Known hypersensitivity to the tested treatment including active substance and excipients. 
16) The inability to continue daily activities safely, without the use of treatment against EDS. 
17) Any patient presenting congenital galactosemia, glucose-galactose malabsorption or lactase 
deficiency due to the presence of lactose in investigational treatments. 
18) Patients participating in another study or being in a follow–up period for another study. 
19) Cannot be contacted in case of emergency. 
 
3.5. STUDY TREATMENT 
Patients will be outpatients followed in ambulatory way during the whole study period and they 
will all receive the investigational study treatment pitolisant or placebo as described § 4.2.  
Patients will be asked to take the study drug every day before breakfast, according to the 
investigator’s prescription regarding the dose regimen of patients, based on the product efficacy 
and tolerance.  
 
The total treatment duration of this double blind study is 8 weeks. Patients will start pitolisant 
treatment with escalating doses scheme on the first 4 weeks, as follows: 
• V2 - 5 mg of BF2.649 or placebo / day during the first week,  
     - 10 mg of BF2.649 or placebo /day during the second week,  
• V3 - Increase to 20 mg/d or maintain at 10 mg/d or reduce to 5 mg/d of BF2.649 (or 
placebo) per day for 7 days depending on efficacy and tolerability.  


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• V4 – It will also be possible to reduce the dose administered to the patients, or to 
increase it without exceeding 40 mg/d. Patients with a weight less than 40kg could 
be treated with a maximum daily dose of 20mg. 
• V5 – It will be possible to reduce the dose administered to the patients, but not to 
increase it. 
As from V5 onwards, no dosage change of the study treatment will be authorized. 
• At the end of the double blind treatment (V7), the investigator will provide placebo 
to all patients for the one-week wash out period. 
 
In open-label period patients will start pitolisant treatment with escalating doses scheme, as 
follows: 
•  V8 - 5 mg of BF2.649 or placebo / day during the first week.  
     - 10 mg of BF2.649 or placebo /day during the second week.  
• V9 – The third week according to investigator prescription and evaluation on 
efficacy and tolerance, the dose will be maintained or increased at 20 mg/d or 
reduced at 5 mg/d.  
• V10 – According to investigator prescription and evaluation on efficacy, tolerance 
and weight, the dose will be maintained, reduced or increased at 5, 10, 15, 20, 30 or 
40 mg/d (only if patient weight is above 40kg) for the next 4-week 
During the phone contact (T2), in opinion of investigator, the dose could be re-
adjusted according the effectiveness/tolerability of treatment to patient.   
In case of need, it is possible to plan a visit on site within the week following phone 
contact for obtaining new bottles of treatment with the corresponding dose.  
• V11 – According to investigator prescription and evaluation on efficacy, tolerance 
and weight, the dose will be maintained, reduced or increased at 5, 10, 15, 20, 30 or 
40 mg/d (only if patient weight is above 40kg) for the next 3-month. 
• V12 – According to investigator prescription and evaluation on efficacy, tolerance 
and weight, the dose will be maintained, reduced or increased at 5, 10, 15, 20, 30 or 
40 mg/d (only if patient weight is above 40kg) for the next 6-month. 
• All subsequent visits, the treatment dispensation will be done like V12. 
 
3.6. CONCOMITANT TREATMENTS 
The investigator must report all concomitant medications in the CRF and record all changes in 
the dosages during the study.  


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3.6.1. 
Authorized concomitant treatments 
Double-blind period:  
 If Patients are treated with sodium oxybate, a stable dosage is required for a minimum 
period of 4 weeks prior to inclusion (V2), and this dosage should be maintained stable 
throughout the study. 
 Other purported anticataplectic treatments e.g. SSRI (fluoxetine, fluvoxamine, citalopram, 
sertraline, paroxetine) or norepinephrine/serotoninergic uptake inhibitor (venlafaxine), 
norepinephrine uptake inhibitors (viloxazine, duloxetine, reboxetine, atomoxetine) are 
authorized only if they are maintained at stable dose for a minimum period of 4 weeks prior 
to inclusion (V2), and their dose should not be changed throughout the trial. 
 Antihistamic H1 which do not cross blood brain barrier (BBB) (2nd and 3rd generation).  
 Any change in the dosage of the other authorized concomitant treatments should be 
recorded in the CRF.  
 
Open label period:  
Concomitant treatments against EDS and cataplexy such as modafinil, sodium oxybate, 
methylphenidate or antidepressants (except tricyclics) are authorized. The investigator will be 
free to adapt posology.  
 
3.6.2. 
Prohibited concomitant treatments 
Double-blind period:  
At V0, all ongoing prohibited treatments are discontinued. At V1, first visit with baseline 
assessment, all prohibited treatments should have been stopped for at least 2 weeks.   
 
 From screening visit (V0) throughout V8, patients should be free of all other drugs or 
substances, namely: 
- with a psychotropic effect, including psychostimulants for the treatment of EDS 
(amphetamine and amphetamine-like CNS stimulants, methylphenidate or others, such as 
modafinil);  
- medication with sedating properties (e.g. benzodiazepines, non-benzodiazepine 
anxiolytics, hypnotics sedatives, neuroleptics, opioids, antihistaminic products (1st generation), 
and anticonvulsants). 
 Tricyclic 
antidepressants 
such 
as 
clomipramine, 
imipramine, 
Mirtazapine, 
desmethylimipramine and protriptyline are not authorized because they display histamine 


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H1 receptor antagonist activity and possibly interfere with the effect of pitolisant by 
abrogating the effect of endogenous histamine released in brain by pitolisant. 
 
Open label period:  
Medication with sedating properties (e.g. benzodiazepines, non-benzodiazepine anxiolytics, 
hypnotics sedatives, neuroleptics, opioids, antihistaminic products (1st generation), and 
anticonvulsants) are prohibited. 
Tricyclic 
antidepressants 
such 
as 
clomipramine, 
imipramine, 
mirtazapine, 
desmethylimipramine and protriptyline are not authorized because they display histamine H1 
receptor antagonist activity and possibly interfere with the effect of pitolisant by abrogating the 
effect of endogenous histamine released in brain by pitolisant. 
 
3.7. EVALUATION CRITERIA 
Medical history and demographic data including age, height, weight, gender will be obtained 
for each patient screened for entry into the study.  
The following measures will be used to assess the safety and efficacy of pitolisant: 
 
3.7.1. 
Efficacy criteria 
3.7.1.1. Primary endpoint: Ullanlinna Narcolepsy Scale score (UNS) 
The Ullanlinna Narcolepsy Scale (Appendix 1) is an 11-item scale used to measure the intensity 
and frequency of symptoms of narcolepsy (EDS and cataplexy). The first four items address 
typical manifestations of cataplexy occurring in situation as laughing, feeling glad or angry or any 
exciting situation. The 7 other items measure the sleep latency and the propensity to fall asleep in 
various situations. The total score varies from 0 to 44. 
The UNS will be evaluated at Visits V1 and V2 (i.e., prior to randomization) as baseline 
evaluation and at Visits V6 and V7 (i.e., end of the double-blind treatment period) and reviewed 
by the investigator.  
 
The difference of baseline UNS and during the treatment are computed (V1-V2 and V6-V7). 
The primary measure of efficacy is based on the change from baseline of the score of the UNS 
by comparing the mean of UNS performed at [(V6 + V7)/2] (end of double-blind period) to the 
mean of UNS performed at [(V1 + V2)/2] (baseline period). A comparison between pitolisant 
and placebo will be made on the score difference between baseline and the end of the treatment 
period. 


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3.7.1.2. Secondary endpoints 
 
3.7.1.2.1. 
Child and Adolescent Sleepiness Scale (CASS) 
In the ESS version adapted for children (6 and over) and adolescents (CASS), this is a simple 
instrument constituted by 10 items (Sitting and reading, Watching TV, Playing a video or 
computer game, Playing outside with friends, Travelling in a car or train for longer than one 
hour, In class during the morning, In class just after lunch, During break time (recess) at school, 
On Sundays if you lie down for a rest, In the morning when you wake up) each of them scored 
in 4 categories (Appendix 2). Each of the ten questions is rated from 0 = never, 1 = sometimes, 
2 = often to 3 = always (want to sleep). The scores are summarized to yield a score between 0 
and 30 with higher scores representing greater sleepiness. 
A score greater than 14 is considered as abnormal sleepiness. 
 
CASS will be evaluated at each study visit of double-blind phase and reviewed by the 
investigator. CASS should be handed out to the patient at approximately the same time of the 
visit day and with same delay after the investigational treatment intake in order to standardize 
the possible impact of the treatment on the evaluation. 
The patient should be helped in the comprehension of the questionnaire until he/she fully 
understands the ten questions of the score. It will be reminded to patients, parents, and/or 
teachers that the CASS measures the subjective sleepiness with regard to the immediate past 
week. 
It occurs frequently that some questions on specific situations are not encountered by the patient 
in his/her daily life. It is advised to give the patient equivalence to a similar situation in order 
to have a complete questionnaire filled. 
The sum of the rated questions will be made by the investigator and reported in the CRF. 
As supportive measure the calculation of responders’ rate defined as a reduction of 3 points of 
the CASS score from baseline or the normalization of the CASS score at 10 or below.  
 
3.7.1.2.2. 
Pediatric Daytime Sleepiness Scale scores (PDSS) 
This is a simple instrument constituted by 8 items (“How often do you fall asleep or get drowsy 
during class periods”, “How often do you get sleepy or drowsy while doing your homework”, 
“Are you usually alert most of the day”, “How often are you ever tired and grumpy during the 
day”, “How often do you have trouble getting out of bed in the morning”, “How often do you 
fall back to sleep after being awakened in the morning”, “How often do you need someone to 


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awaken you in the morning”, “How often do you think that you need more sleep”) each of them 
scored in 5 categories (Appendix 3). 
Each of the eight questions is rated from 0 = never, 1 = seldom, 2 = sometimes, 3 = often, 
frequently to 4 = very often, always. The total score ranges between 0 and 32 with higher scores 
representing greater sleepiness. A score greater than 13 is considered as abnormal sleepiness. 
PDSS will be evaluated at each study visit and reviewed by the investigator. PDSS should be 
administrated to the patient at approximately the same time of the visit day and with same delay 
after the investigational treatment intake in order to standardize the possible impact of the 
treatment on the evaluation. 
The patient should be helped in the comprehension of the questionnaire until he fully 
understands the eight questions of the score. It will be reminded to the patient that the PDSS 
measures the subjective sleepiness with regard to the immediate past week. 
It occurs frequently that some questions on specific situations are not encountered by the patient 
in his/her daily life. It is advised to give the patient equivalence to a similar situation in order 
to have a complete questionnaire filled. The sum of the rated questions will be made by the 
investigator and reported in the CRF. 
 
3.7.1.2.3. 
Clinical Global Impressions of Change 
The severities of EDS and of cataplexy will be measured at baseline period V1 and V2 by the 
Clinical Global Impression of Severity (CGI-S) in order to describe the population : a 6-grade 
scale ranging from “no sign of illness”, “borderline ill”, “slightly ill”, “moderately ill”, 
“markedly ill”, “among the most extremely ill patients” (Appendix 5). This corresponds to the 
first version of the test. When the patient is on treatment, the test enables to assess the 
improvement. 
 
At visits V6 and V7 (during double-blind phase) and all visits of open-label period, the patients’ 
change in EDS and in cataplexy (for narcoleptic patients also experiencing cataplexy) compared 
to baseline will be rated by the same investigator using Clinical Global Impression of Change 
(CGI-C) to document the perceived change in patients’ illness: a 7-grade scale ranging from 
“very much improved”, “much improved”, “minimally improved”, “no change”, “minimally 
worse,” “much worse”, “very much worse”.  
 
3.7.1.2.4. 
Test of Everyday Attention for Children (TEA-Ch) 
The Test of Everyday Attention for Children (TEA-Ch) assesses the cognitive functions with a 
version intended for children and another one for adolescents. This cognitive test shall be 
performed at V1 and at V6 visits. 


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3.7.1.2.5. 
Maintenance of Wakefulness Test 30-minute version 
The Maintenance of Wakefulness Test (MWT) is used in this study to assess an individual’s 
ability to maintain awake while resisting the pressure to fall asleep.  
Patients will be administrated four 30-minute MWT sessions at 2-hour intervals at inclusion 
visit (V2) and at endpoint visit (V7 or the last on-study visit), according to validated standard 
[Doghramji K et al, Electroencephalogr Clin Neurophysiol. 1997; 103:554-62]8.  
Patients will be required to have sufficient nocturnal sleep (minimum 6 hours) and not drink 
alcohol during the night prior to this visit. The patient will be required to take their morning 
treatment and a light breakfast before 8.00 a.m. and arrive in the trial center around 9.00 a.m.; 
lunch immediately after the termination of the second session. They should refrain from 
drinking any stimulatory beverage such as coffee, tea or Coca-Cola this morning until the end 
of this visit.  
The first session begins at 10.00 a.m. Patients are required to recline comfortably in a quiet, 
dimly lit bedroom at ambient temperature (as close to 22°C as possible). Patients are instructed 
to remain awake for as long as possible. Sleep onset is defined by either 3 consecutive 30-s 
epochs of stage 1 sleep or any single 30-s epoch of stage 2, 3, 4 or REM sleep. 
Each session is terminated either at the first unequivocal onset of sleep defined as above or, if 
sleep onset is not achieved, after maximum in-bed duration of 30 minutes. Polysomnographic 
recordings are made to determine sleep onset, and mean sleep latency is calculated (maximum 
score 30 minutes).  
 
3.7.1.2.6. 
Patient sleep diary 
Patient sleep diary (Appendix 6) information from V1 (or from V0 when applicable) to V8 will 
be analyzed. 
Patients (or assisted by their parents or legal representative or teacher) shall fill in the document 
on a daily basis throughout the double blind phase (13 weeks) and the 7-day prior to the next 
visit during the open-label period. During the first screening visit (V1 or from V0 when 
applicable), patients will be instructed on the daily use of diary by study investigators. 
At each visit the patient should bring back his/her diary to the site for review by the investigator. 
The investigator should review these records with the patient. 
In the active treatment group and in the placebo group, the score difference between the average 
number of cataplexy episodes (partial and total) per weeks between the 2 weeks of baseline and 
the 2 weeks of end study treatment period (V6, V7) and the differences in weekly frequency of 
cataplexy episodes between baseline and the 4 weeks of stable treatment period (V4 to V7). 
In the open-label period, the difference between, the average number of cataplexy episodes 


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(partial and total) per weeks, the differences in weekly frequency of cataplexy episodes, 
between baseline and the 7-day prior all visits of the open-label period will be compared. 
 
From the sleep diary, it will also be possible to check: Investigator should review the patients’ 
and parents’ estimate with them 
• Hour of bedtime in the evening, wake-time in the morning. 
• Number of diurnal involuntary sleep attacks and episodes of severe daytime sleepiness. 
• Occurrence and number of cataplexy attacks (total or partial). 
• Number of hallucinations and sleep paralysis. 
 
3.7.1.2.7. 
Patient’s Global Opinion on the effect of treatment 
At V7 and all visits of open-label period, patients’ global opinion will be reported by patient if 
able to express himself. If not, either their parents or their main teachers should evaluate the 
Global effect of the treatment by comparing the period prior to that visit with the patient’s pre-
study condition. 
The following six-level scale will be used: 
- Marked effect (complete or nearly complete remission of EDS) 
- Moderate effect (partial remission of EDS) 
- Minimal effect (slight decrease in EDS that does not substantially alter the status of the 
patient) 
- No change 
- Minimally worse (slight increase in EDS) 
- Much worse (substantial increase in EDS) 
 
3.7.1.3. Compliance 
The compliance with study medication will be assessed by comparing the amount of medication 
remaining at each visit with the amount predicted to remain if the patient is compliant with the 
prescription.  
 
3.7.2. 
Safety criteria 
The safety criteria will include:  
• Adverse and unexpected events, emergent or not, reported during the study course 
(frequency, severity, relationship to study drug, incidence and occurrence) 
• Change of vital signs parameters (heart rate, blood pressure, body weight) from 
baseline values 


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• Physical examination: abnormalities in each system class and change from baseline 
• ECG parameters: in particular, calculation of the QTcF value and comparison with 
the QTcF value of the ECG performed at baseline. If the QTcF is ≥ 500 ms or Δ 
between the QTcF on treatment and the QTcF at baseline is ≥ 60 ms, the treatment 
shall be discontinued and the corresponding ECG forwarded to Bioprojet. 
• Laboratory abnormalities (e.g. AEs will be defined as laboratory test results that are 
outside the reference range as defined by the normal range for laboratory test and 
clinically signification). 
• Occurrence of withdrawal symptoms (to be checked during the phone call at D59 ± 
1 and at V8 end-of-study visit (D63). 
 
3.7.2.1. Cardiovascular safety: vital signs and ECG 
Vital signs including blood pressure, heart rate and body weight will be checked at the each 
visit.  
ECG will be performed at each visit from the screening visit (V1) to the end of the double blind-
phase (V8) or at early withdrawal visit and all visits of the open-label period. The main ECG 
parameters including calculation of Fridericia’s corrected QTc interval (QTcF = QT/3√ 
(60/HR)) and intra individual changes in these parameters will be reported and analyzed locally. 
If the QTcF value is ≥ 500 ms, or if the change from baseline is ≥ 60 ms, (observed on two 
consecutive occasions, i.e. after performing a recheck a few hours later) the treatment shall be 
discontinued and ECGs (baseline and abnormal ECG) shall be dispatched to Bioprojet. 
All ECGs will be reviewed a posteriori by a central reviewer.  
 
3.7.2.2. Physical examination 
A full physical examination will be performed at screening period (V0 (when applicable) and 
V1) and at each visit from V2 to V8 (or at early withdrawal visit) and all visits of the open-
label period. Any significant abnormality and change from baseline will be recorded in the CRF 
and in the source document and will be analyzed as safety parameters. Any significant changes 
will be reported in the AE pages of the CRF. 
 
3.7.2.3. Adverse events and Treatment Emergent Adverse Events 
The safety will be assessed by the occurrence of adverse events, spontaneously reported by the 
patient or discovered during investigator’s interview at each visit.  
All of them must be reported by the investigator in the special form placed at the end of the 
CRF, whatever the nature, the intensity, the severity and the supposed causality from the study 


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compound. 
 
For each adverse event, the investigator shall report the nature, the anteriority (emergent or not), 
the date of apparition, the intensity, the severity and the action taken in regard to the study 
treatment, and the concomitant therapies. 
When the event ends or at the end of the study, the investigator must report the evolution from 
the event and evaluate the relationship to the study compound.  
The events will be categorized by System Organ Class and Preferred Terms (MedDRA) and 
type, severity and relationship to the treatment. 
All Adverse Events and unexpected events, emergent or not, reported during the study course 
(frequency, severity, relationship to study drug, incidence and occurrence) will be analyzed. 
Treatment Emergent Adverse Events (TEAE) defined as any event not present prior the 
initiation of the study treatment or any event already present that worsens in either intensity or 
frequency following exposure to the study treatment, will be analyzed as the main safety 
parameters.  
 
3.7.2.4. Blood Laboratory tests, urinalysis, urinary drug testing 
A full laboratory test should be performed at screening (V1), at the final double-blind treatment 
phase evaluation visit (V7) and at early withdrawal visit and during the open-label period at 
V10, V13 and all subsequent visits. Blood samples will be collected and all laboratory tests 
will be performed according to the Good Laboratory Practice (OECD GLP Principles) by site-
dependent Laboratory. The results of laboratory tests will be interpreted by the investigator. 
Laboratory abnormalities will be defined as laboratory test results that are outside the reference 
range as defined by the normal range from the testing laboratory. Clinically significant 
abnormal value at V1 will be determined by the investigator and will exclude patients from 
study participation. The results of abnormal values of laboratory tests will be reported in the 
CRF beside the normal range value given by the testing laboratory, the original document 
containing all the tested values will be kept in the patient study file. 
 
Blood laboratory test parameters and intra individual changes in these parameters will be 
reported and analyzed in all patients.  
- Hematology: Red Blood Cells, White Blood Cells (differential count, absolute value), 
hemoglobin, haematocrit, Mean corpuscular volume (MCV), platelet count. 
- Biochemistry: sodium, potassium, chloride, creatinine, alkaline phosphatases, urea, 
alanineaminotransferase (ALAT), aspartate aminotransferase (ASAT), gamma glutamyl 


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transpeptidase (GGT), total bilirubin, glucose, triglycerides, total cholesterol, quick time. 
- Hormonology: βHCG (only for pubescent female). 
- Urinalysis: semi-quantitative ("dipstick") analysis for pH, ketone bodies, proteins, glucose, 
blood. If any of these parameters gives a positive result, a quantitative analysis will be 
performed to characterize or count: crystals, casts, epithelial cells, white blood cells, red blood 
cells and bacteria if required by the investigator. 
- Urine drug testing: test of abuse of drugs will be performed on urine samples from 12 years. 
Screened drugs are amphetamines, barbiturates, benzodiazepines, cannabinoids (THC) and 
Opioids. 
 
3.7.2.5. Childhood Depression Inventory 
The Childhood Depression Inventory scale is a self-administrated 27-item questionnaire 
commonly used in research to assess depression. The short version 2 of 12 items is used in the 
study (Appendix 4). The patient is asked to pick out the statement in each of the 12 items which 
best describes the way he feels right now at the moment of the assessment.  
The range of scores for the scale are 0-4 = none or minimal; 4-7 = mild; 8-15 = moderate; ≥ 16 
= severe depression. 
The CDI questionnaire will be evaluated during double blind period at visits V1, V4, V6 and 
V8 and all subsequent visits for the open-label period. Patients presenting severe depression 
(CDI ≥ 16) should be immediately withdrawn from the study for security. 
 
3.7.2.6. Columbia-Suicide Severity Rating Scale 
The Columbia-Suicide Severity Rating Scale (C-SSRS) will be evaluated at all visits of the 
study. 
This scale is intended to be used by individuals who have received training in its administration. 
The questions contained in the C-SSRS are suggested probes. Ultimately, the determination of 
the presence of suicidal ideation or behavior depends on the judgment of the individual 
administering the scale. 
The interview is semi-structured with a flexible format. Questions are provided as helpful tools 
– it is not required to ask any or all questions – just enough to get the appropriate answer.  
Most important: gather enough clinical information to determine whether patient is suicidal or 
not. If it is established that a patient has not engaged in any suicidal behavior and/or ideation, 
then no further questions are required. 
 
3.7.2.7. Withdrawal symptoms 
A specific questionnaire provided 1 week after discontinuation of the study drug will investigate 


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the possible occurrence and pattern of amphetamine like withdrawal symptoms (DSM-IV) 
which are defined as dysphoria and two or more of the following symptoms: fatigue, vivid and 
unpleasant dreams, insomnia or hypersomnia, increased appetite and psychomotor retardation 
or agitation. 
 




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The ingredients of unitary BF2.649 tablets are described in the table below: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo tablets will contain only lactose to ensure that neither the patient nor the investigator 
nor members of the clinical staff know the identity of the study medication.  
 
4.2. 
DOSAGE REGIMEN 
Following the completion of inclusion procedures, patients will start pitolisant (BF2.649) 
treatment with escalating doses scheme as follows: 
- V2 (D0):  
- Week 1: BF2.649 at 5 mg/day: 1 tablet of BF2.649 5 mg or placebo in the morning during 
7 days. 
- Week 2: BF2.649 at 10 mg/day: 2 tablets of BF2.649 5 mg or placebo in the morning during 
7 days. 
 
- V3 (D14± 2):  
- Week 3: according to the investigator’s prescription patients for whom the optimal dose level 
is estimated will continue at the same dose or if not sufficiently improved in their symptoms, 
and with a good tolerance, will increase to a higher dose or the level dose will be reduced based 
on the tolerance to the product.  
BF2.649 at 5 mg/day: 1 tablet of BF2.649 5 mg or placebo in the morning during 7 days, or 
BF2.649 at 10 mg/day: 2 tablets of BF2.649 5 mg or placebo in the morning during 7 days, or 
BF2.649 at 20 mg/day: 1 tablet of BF2.649 20 mg or placebo in the morning during 7 days. 
 


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- V4 (D21± 2):  
- Week 4: according to the investigator’s prescription patients for whom the optimal dose level 
is estimated will continue at the same dose or if not sufficiently improved in their symptoms, 
and with a good tolerance, will increase to a higher dose or the level dose will be reduced based 
on the tolerance to the product.  
BF2.649 at 5 mg/day: 1 tablet of BF2.649 5 mg or placebo in the morning during 7 days, or 
BF2.649 at 10 mg/day: 2 tablets of BF2.649 5 mg or placebo in the morning during 7 days, or 
BF2.649 at 20 mg/day: 1 tablet of BF2.649 20 mg or placebo in the morning during 7 days, or 
BF2.649 at 40 mg/day: 2 tablets of BF2.649 20 mg or placebo in the morning during 7 days. 
Treatment dosage at 40mg/day not allowed for patient with a weight less than 40 kg.  
 
- V5 (D28± 2): No increase of BF2.649 dosage will be authorized, but it will be possible to 
decrease the dose, if the tolerance requires it. From this visit onwards, no dose change will 
be allowed. 
- Week 5 to week 8: according to the investigator’s prescription patients for whom the optimal 
dose level is estimated will continue at the same dose or the level dose will be reduced based 
on the tolerance to the product. 
BF2.649 at 5 mg/day: 1 tablet of BF2.649 5 mg or placebo in the morning during 28 days, or 
BF2.649 at 10 mg/day: 2 tablets of BF2.649 5 mg or placebo in the morning during 28 days, or 
BF2.649 at 20 mg/day: 1 tablet of BF2.649 20 mg or placebo in the morning during 28 days, or 
BF2.649 at 40 mg/day: 2 tablets of BF2.649 20 mg or placebo in the morning during 28 days. 
Treatment dosage at 40mg/day not allowed for patient with a weight less than 40kg. 
 
- V7 (D56± 2): Prescription of 1-week of placebo for all patients.  
In open-label period patients will start pitolisant treatment with escalating doses scheme, as 
follows: 
- V8 (D63 ± 2) 
- Week 10: BF2.649 at 5 mg/day: 1 tablet of BF2.649 5 mg in the morning during 7 days. 
- Week 11: BF2.649 at 10 mg/day: 2 tablets of BF2.649 5 mg in the morning during 7 days. 
 
- V9 (D77± 2):  
- Week 12: according to the investigator’s prescription patients for whom the optimal dose level 
is estimated will continue at the same dose or if not sufficiently improved in their symptoms, 
and with a good tolerance, will increase to a higher dose or the level dose will be reduced based 
on the tolerance to the product. 
BF2.649 at 5 mg/day: 1 tablet of BF2.649 5 mg in the morning during 7 days, or 


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BF2.649 at 10 mg/day: 2 tablets of BF2.649 5 mg in the morning during 7 days, or 
BF2.649 at 20 mg/day: 1 tablet of BF2.649 20 mg in the morning during 7 days, or 
 
- V10 (D84± 2):  
- From Week 13: according to the investigator’s prescription patients for whom the optimal 
dose level is estimated will continue at the same dose or if not sufficiently improved in their 
symptoms, and with a good tolerance, will increase to a higher dose or the level dose will be 
reduced based on the tolerance to the product. 
BF2.649 at 5 mg/day: 1 tablet of BF2.649 5 mg in the morning during 28 days, or 
BF2.649 at 10 mg/day: 2 tablets of BF2.649 5 mg in the morning during 28 days, or 
BF2.649 at 15 mg/day: 3 tablets of BF2.649 5 mg in the morning during 28 days, or 
BF2.649 at 20 mg/day: 1 tablet of BF2.649 20 mg in the morning during 28 days, or 
BF2.649 at 30 mg/day: 2 tablets of BF2.649 5 mg and 1 tablet of BF2.649 20 mg in the morning 
during 28 days, or 
BF2.649 at 40 mg/day: 2 tablets of BF2.649 20 mg or placebo in the morning during 28 days. 
Treatment dosage at 40mg/day not allowed for patient with a weight less than 40 kg. 
 
At D91 during the phone contact the dose will be reduce in case of poor tolerance, when 
applicable. 
 
- V11 (D112± 2):  
According to the investigator’s prescription patients for whom the optimal dose level is 
estimated will continue at the same dose or if not sufficiently improved in their symptoms, and 
with a good tolerance, will increase to a higher dose or the level dose will be reduced based on 
the tolerance to the product. 
BF2.649 at 5 mg/day: 1 tablet of BF2.649 5 mg in the morning during 3-month, or 
BF2.649 at 10 mg/day: 2 tablets of BF2.649 5 mg in the morning during 3-month, or 
BF2.649 at 15 mg/day: 3 tablets of BF2.649 5 mg in the morning during 3-month, or 
BF2.649 at 20 mg/day: 1 tablet of BF2.649 20 mg in the morning during 3-month, or 
BF2.649 at 30 mg/day: 2 tablets of BF2.649 5 mg and 1 tablet of BF2.649 20 mg in the morning 
during 3-month, or 
BF2.649 at 40 mg/day: 2 tablets of BF2.649 20 mg or placebo in the morning during 3-month. 
Treatment dosage at 40mg/day not allowed for patient with a weight less than 40 kg. 
 
- V12 (D196± 2):  
According to the investigator’s prescription patients for whom the optimal dose level is 


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estimated will continue at the same dose or if not sufficiently improved in their symptoms, and 
with a good tolerance, will increase to a higher dose or the level dose will be reduced based on 
the tolerance to the product. 
BF2.649 at 5 mg/day: 1 tablet of BF2.649 5 mg in the morning during 6-month, or 
BF2.649 at 10 mg/day: 2 tablets of BF2.649 5 mg in the morning during 6-month, or 
BF2.649 at 15 mg/day: 3 tablets of BF2.649 5 mg in the morning during 6-month, or 
BF2.649 at 20 mg/day: 1 tablet of BF2.649 20 mg in the morning during 6-month, or 
BF2.649 at 30 mg/day: 2 tablets of BF2.649 5 mg and 1 tablet of BF2.649 20 mg in the morning 
during 6-month, or 
BF2.649 at 40 mg/day: 2 tablets of BF2.649 20 mg or placebo in the morning during 6-month. 
Treatment dosage at 40mg/day not allowed for patient with a weight less than 40 kg. 
 
- All subsequent visits, the treatment dispensation will be done as V12. 
 
4.3. 
PACKAGING AND LABELLING OF TREATMENT 
The medications will be supplied, packaged and labelled in compliance with the Good 
Manufacturing Practices (GMP) appendix 13 of drugs and ICH of used in clinical trial.  
Each label will be labelled in the local language of the investigational centre. 
Each treatment unit will contain the study medication for all the duration of the study, i.e. 
9 weeks. 
 
4.4. 
MANAGEMENT AND STORAGE OF THERAPEUTIC UNITS 
Storage conditions:  
The investigational treatments do not require any special storage conditions.  
 
Management of therapeutic units: 
The therapeutic units will be provided to each investigational site. Bioprojet will provide the 
pharmacist or investigator with all necessary documents on BF2.649 information, in accordance 
with the Good Clinic Practice (GCP) (ICH topic E6 and local regulations). The hospital 
pharmacist (or investigator) will be responsible for the correct storage and handling of the study 
products (reception, storage, dispensation log, update of the delivery list, return of empty 
packaging and unused units and return of therapeutic units to the sponsor).  
 
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enclosed acknowledgement of receipt sheet to Bioprojet representative, filled and signed. 
 
Treatments under the Pharmacist’s or investigator’s responsibility have to be stored in a secure 
limited access area in accordance with required storage conditions, and disclosed only to 
authorized persons having access to this storage room.  
 
In accordance with GCP regulations (ICH topic E6 and local regulations) all study materials 
(unused treatment units, packaging as well as individual code envelopes) have to be returned 
by the pharmacy to Bioprojet supplier at the end of the study, the attestation of return will 
indicate for each patient:  
- 
Date of treatment reception and quantity,  
- 
Number of administered and unused therapeutic units,  
- 
Number of undelivered units,  
- 
Number of therapeutic units finally returned and dispatch date. 
In case of a therapeutic unit loss, the investigator or the hospital’s Pharmacist in charge of the 
treatment management will have to justify this loss in a written statement, signed and dated, 
enclosed with the attestation of return.  
The unused therapeutic units will be retrieved by the supplier at the end of the study (i.e. after 
final study report signature) and after reconciliation of dispensation log of therapeutic units. 
 
4.5. 
TREATMENT DISPENSATION 
4.5.1. 
Patient Study Number 
The investigational treatment will be assigned to each patient after the completion of the 
inclusion visit (V2) and verification of all inclusion and exclusion criteria. A study number will 
be assigned to the patient by following the sequential number of the study site. The number is 
composed by the site number on 2 digits, followed by a sequential number on 2 digits starting 
by 01, e.g. first patient included by site number 01 will be 0101, and the second patient will be 
0102. The study number will be assigned chronologically and in the sequential order without 
skipping any number.  
 
A tracking list of the number allocated with the identification of patients i.e. the first letter of 
first name and of family name of patients will be filled by the investigator and kept in his study 
records.  
 


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4.5.2. 
Investigational treatment allocation 
When the patient receives his/her study number, the corresponding investigational treatment 
identified by the treatment number will be allocated to the patient according to the 
randomization list established by an independent company and managed by Interactive Web 
Response Services (IWRS) according to randomization. 
 
4.5.3. 
Procedure to open the individual randomization code in emergency 
The double blind design of the study will result in the ignorance of the assigned treatment to 
the patients. In the situation where the knowledge of the treatment appears imperative and 
urgent, a procedure to open the code for the individual patient exists. A set of sealed envelopes, 
identified by the study number, will contain the type of treatment assigned to the corresponding 
patient. These envelopes must be only opened in cases where there is an imperative need to 
know the assign treatment to protect the patient health and well-being such as voluntary or not 
overdosing. The code break will be documented on the envelope and in the patient's CRF, with 
date and time and reasons of disclosure and signed by investigator. All envelopes will be tracked 
by the sponsor at the completion of the study. 
 
4.6. 
TREATMENT COMPLIANCE AND ACCOUNTABILITY 
PROCEDURES 
The study treatment will be dispensed only under the restricted condition defined in the present 
protocol. The treatment will be dispensed only by the investigator under his direct supervision 
or the pharmacist. Time of dispensation and initials of the person dispensing the drug will be 
recorded in the CRF. The tear-off label of each pack will be stuck on the prescription form. 
At each visit the compliance to the treatment will be investigated. Details of the quantities of 
each medication dispensed will be entered into the accountability form. The patients will be 
asked whether the investigational treatment is taken as prescribed. If not, any change in the 
treatment and the number of forgotten tablets will be recorded in the case report form (CRF). 
In addition, the number of remaining tablets in the pill-box will be counted and compared to 
the theoretical number. Any mismatch will be investigated with the patient.  
 
5. CONDUCT OF THE STUDY 
 
5.1. 
EXPECTED DURATION OF SUBJECT PARTICIPATION 
The expected duration of patient participation from the screening visit (V0) until the final visit 


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(V8) will be 13 weeks: 
Baseline period without investigational treatments (from V0 to V2): 4 weeks. 
• Low and medium dose titration phase (from V2 to V3): 2 weeks 
• Individual dose adjustments (from V3 to V5): 2 weeks  
• Stable dose phase (from V5 to V7): 4 weeks 
• 1-week study drug wash out (placebo) after study drug discontinuation 
 
During the double blind phase, the patient will be followed in an ambulatory way by 9 visits on 
the site.  
The double blind phase will be followed by a prolonged open-label period if patient wishes, 
until BF2.649 (pitolisant) is available on the marketfor children/adolescent from 6 to 17 years 
included or as soon as the patient becomes older than 18 years. Then, he will have access to the 
treatment already on the market for adults.  
 
The first inclusion of this study is scheduled in Q1 2016. The end of the double-blind phase is 
expected by Q1 2022. 
 
5.2. 
STUDY PROCEDURES AT EACH VISIT 
All visits should be done in the morning at the same time to ensure identical evaluation 
conditions along the study, if possible. 
 
5.2.1. 
V0-screening visit and start of wash-out period: at D-28 
Visit V0 is applying only for patients under prohibited medications and for cataplectic 
patients under anti-cataplectic treatment. 
The investigator will provide the patient with the necessary information regarding the study 
objectives, the investigational product pitolisant (BF2.649), the expected benefit, the potential 
risks and the study procedures.  
Then, the signed informed consent will be obtained prior to the study entry and before any study 
procedure for patient willing to participate.  
Both parents and the patient, if old enough to understand, will sign the inform consent 
form after carefully read and signed the patient information sheet about the 
investigational medical product and the study requirements. 
 
Prohibited treatments will be discontinued at V0 and duration of authorized treatments will be 
checked. 


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Patients with cataplexy treated by sodium oxybate shall continue this treatment at stable dose 
during four (4) weeks prior to inclusion and throughout the study. The same applies to all other 
purported anticataplectic treatments, if any. 
The patient will undergo the following tests and procedures: 
-A complete medical examination (including age, gender), detailed questionnaires on his/her 
medical history and narcolepsy history will be recorded. 
- A complete physical examination including height (cm), weight (kg) and BMI kg/m². 
-Vital signs including: blood pressure (SBP and DBP) and heart rate. 
-Questioning on previous and concomitant medication used and possible occurrence of adverse 
events. 
-Delivery of two sleep diaries (one per week) which has to be daily completed by the patient (if 
old enough to understand) and/or parents every evening. (Hour of bedtime in the evening, wake-
time in the morning. Number of diurnal involuntary sleep attacks and episodes of severe 
daytime sleepiness. Occurrence and number of cataplexy attacks (total or partial). Number of 
hallucinations and sleep paralysis). 
 
5.2.2. 
V1-screening visit and Baseline period: at D-14 
If no V0 visit is required, the investigator will provide the patient with the necessary information 
regarding the study objectives, the investigational product pitolisant (BF2.649), the expected 
benefit, the potential risks and the study procedures.  
Then, the signed informed consent will be obtained prior to the study entry and before any study 
procedure for patient willing to participate.  
Both parents and the patient, if old enough to understand, will sign the inform consent form 
after carefully read and signed the patient information sheet about the investigational medical 
product and the study requirements. 
 
The patient will undergo the following tests and procedures: All tests performed at V0 will be 
not repeated at V1. 
A complete medical examination (including age, gender), detailed questionnaires on his/her 
medical history and narcolepsy history will be recorded.  
The 
history 
of 
a 
substance 
abuse 
including 
alcohol 
dependence 
and 
other 
psychiatric/neurological disorders should be ruled out. 
Narcolepsy diagnosis history including the patient actual symptoms of narcolepsy (nature, 
severity, and duration), and documentation of the previously performed examinations about 
illness such as: polysomnography, MSLT (to be performed if not available during the year prior 
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Complete physical examination (including height and body weight),  
Questioning on previous and concomitant medication used (including any current and previous 
treatments of EDS and cataplexy and any other types of treatment), and possible occurrence of 
adverse events, 
 
The patient will undergo the following tests and procedures: 
Vital signs (blood pressure, heart rate), 
A complete physical examination including height (cm), weight (kg) and BMI kg/m². 
12-lead ECG recording with calculation and control of QTcF,  
A blood sample will be taken for routine haematological and biochemical test (including β-
HCG pregnancy test for pubescent female) and semi-quantitative urinalysis (dipstick), 
A urine drug testing (for patients from 12 years),  
 
The following questionnaires should be performed:  
- Pediatric Daytime Sleepiness Scale (PDSS), 
- Child and Adolescent Sleepiness Scale (CASS) 
- Ullanlinna narcolepsy scale (UNS), 
- Test of Everyday Attention for Children (TEA-Ch), 
- Clinical Global Impression of Severity (CGI-S) on EDS and on cataplexy, 
- Childhood Depression Inventory (CDI), 
- Columbia-Suicide Severity Rating Scale (C-SSRS), 
- Retrieval of the first sleep diary (when applicable) and check by the investigator. Delivery of 
a new sleep diary which has to be daily completed by the patient (if old enough to understand) 
and/or parents every evening. (Hour of bedtime in the evening, wake-time in the morning. 
Number of diurnal involuntary sleep attacks and episodes of severe daytime sleepiness. 
Occurrence and number of cataplexy attacks (total or partial). Number of hallucinations and 
sleep paralysis). 
 
Patients who meet all inclusion criteria and none of the non-inclusion criteria will be allowed 
to participate in the study.  
- 
The HLA typing for DQB1*06:02 will be asked if not known in advance and recorded 
if available. 
- 
The value of the CSF hypocretin-1 (measured with standardized RIA) will be stored in 
the CRF if it is known. (This helps to analyze the results separately for type 1 and type 
2 narcolepsy according to the new ICSD-3 classification).  
 


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5.2.3. 
V2- Randomization and start of escalating period: at D0 
This visit should be imperatively done in the morning (around 9.30 a.m.) and all further visits 
should be done at the same time of day, if possible, to ensure identical evaluation conditions 
along the study. 
Patients will be required to have sufficient nocturnal sleep (minimum 6 hours) and not 
drink alcohol during the night prior to this visit. The patient will be required to take a light 
breakfast before 8.00 a.m. and arrive at the trial center around 9.00 a.m. They should refrain 
from drinking any stimulatory beverage such as coffee, tea or Coca-Cola this morning until the 
end of this visit.  
The first session of MWT will approximately start at 10.00 a.m. 
 
A complete interrogation including occurred of possible adverse events and concomitant 
medication used will be done and recorded, 
A physical examination including vital signs shall be carried out. 
12-lead ECG recording with calculation and control of QTcF,  
Polysomnography with Multiple Sleep Latency Test will be performed the day preceding V2, 
if this exam was not performed during the previous year, 
The following questionnaires should be performed:  
- PDSS,  
- CASS, 
- UNS, 
- CGI-S on EDS and on cataplexy, 
- C-SSRS, 
- Retrieval of the 2 first sleep diaries (when applicable) and check by the investigator. Delivery 
of two other sleep diaries which have to be completed every day throughout the baseline period, 
 
Patients who meet all inclusion criteria and none of the non-inclusion criteria will be allowed 
to participate in the study.  
Treatment dispensation for the next two weeks: 
- First week with 5mg/day of pitolisant or placebo in the morning, before breakfast, 
- Second week with a 10mg/day of pitolisant or placebo in the morning before breakfast. 
Investigator will remind patient to bring back the investigational treatment packs at the next 
visit. 
 
5.2.4. 
V3 – Dose adjustment visit (Day 14 ± 2 days) 
A complete interrogation including occurred of possible adverse events and concomitant 


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medication used will be done and recorded, 
A physical examination including vital signs shall be carried out, 
12-lead ECG recording with calculation and control of QTcF, 
The following questionnaires should be performed:  
- PDSS, 
- CASS, 
- C-SSRS, 
- Retrieval of sleep diary of the previous visit and check by the investigator. Delivery of one 
other sleep diary which have to be completed every evening until the next visit, 
 
Investigational treatment allocation: the dose of pitolisant will be individually adjusted 
according to the investigator’s prescription patients for whom the optimal dose level is 
estimated will continue at the same dose or if not sufficiently improved in their symptoms, and 
with a good tolerance, will increase to a higher dose or the level dose will be reduced based on 
the tolerance to the product. Dose allocation: either 5, 10 or 20 mg/day or placebo in the 
morning during 7 days.  
The treatment pack bring back from previous visit by patient is checked by investigator for the 
compliance. Investigator will remind patient to bring back the investigational treatment packs 
at the next visit. 
 
5.2.5. 
V4 – Dose adjustment visit (Day 21 ± 2 days) 
A complete interrogation including occurred of possible adverse events and concomitant 
medication used will be done and recorded, 
A physical examination including vital signs shall be carried out, 
12-lead ECG recording with calculation and control of QTcF, 
The following questionnaires should be performed:  
- PDSS, 
- CASS, 
- CDI, 
- C-SSRS, 
- Retrieval of sleep diary of the previous visit and check by the investigator. Delivery of one 
other sleep diary which have to be completed every evening until the next visit. 
 
Investigational treatment allocation: the dose of pitolisant will be individually adjusted 
according to the investigator’s prescription patients for whom the optimal dose level is 
estimated will continue at the same dose or if not sufficiently improved in their symptoms, and 


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with a good tolerance, will increase to a higher dose or the level dose will be reduced based on 
the tolerance to the product. Dose allocation: either 5, 10, 20 or 40 mg/day or placebo in the 
morning during 7 days. Patients with a weight less than 40kg could be treated with a maximum 
daily dose up to 20 mg. 
The treatment pack bring back from previous visit by patient is checked by investigator for the 
compliance. Investigator will remind patient to bring back the investigational treatment packs 
at the next visit. 
 
5.2.6. V5 – Dose adjustment visit (Day 28 ± 2 days) 
A complete interrogation including occurred of possible adverse events and concomitant 
medication used will be done and recorded, 
A physical examination including vital signs shall be carried out, 
12-lead ECG recording with calculation and control of QTcF, 
- The following questionnaires should be performed:  
- PDSS, 
- CASS, 
- C-SSRS, 
- Retrieval of sleep diary of the previous visit and check by the investigator. Delivery of one 
other sleep diary which have to be completed every evening until the next visit, 
 
Investigational treatment allocation: No increase of pitolisant dosage will be authorized, the 
dose of pitolisant will be individually adjusted according to the investigator’s prescription 
patients for whom the optimal dose level is estimated will continue at the same dose or the level 
dose will be reduced based on the tolerance to the product. Dose allocation: either 5, 10, 20 or 
40 mg/day or placebo in the morning during 28 days.  
The treatment pack bring back from previous visit by patient is checked by investigator for the 
compliance. Investigator will remind patient to bring back the investigational treatment packs 
at the next visit. 
 
5.2.7. V6 – Control treatment visit (Day 49 ± 2 days) 
A complete interrogation including occurred of possible adverse events and concomitant 
medication used will be done and recorded, 
A physical examination including vital signs shall be carried out, 
12-lead ECG recording with calculation and control of QTcF, 
The following questionnaires should be performed:  
- PDSS,  


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- CASS, 
- CDI, 
- C-SSRS, 
- UNS,  
- TEA-Ch, 
- Clinical Global Impression of Change (CGI-C) on EDS and on cataplexy, 
- Retrieval of sleep diary of the previous visit and check by the investigator. Delivery of one 
other sleep diary which have to be completed every evening until the next visit. 
 
No dispensation performed at V6. 
 
5.2.8. V7 – End of Double Blind period (Day 56 ± 2 days) 
This visit should be imperatively done in the morning (around 9.30 a.m.) and all further visits 
should be done at the same time of day, if possible, to ensure identical evaluation conditions 
along the study. 
Patients will be required to have sufficient nocturnal sleep (minimum 6 hours) and not 
drink alcohol during the night prior to this visit. An optional polysomnography can be done in 
accordance with the processes of sites, the evening preceding the MWT test to confirm a sufficient 
nocturnal sleep. The patient will be required to take a light breakfast before 8.00 a.m. and arrive 
at the trial center around 9.00 a.m. They should refrain from drinking any stimulatory beverage 
such as coffee, tea or Coca-Cola this morning until the end of this visit.  
The first session of MWT will approximately start at 10.00 a.m. 
 
A complete interrogation including occurred of possible adverse events and concomitant 
medication used will be done and recorded, 
A physical examination including vital signs shall be carried out, 
12-lead ECG recording with calculation and control of QTcF, 
A blood sample will be taken for routine haematological and biochemical test (including β-
HCG pregnancy test for pubescent female) and semi-quantitative urinalysis (dipstick), 
A urine drug testing (for patients from 12 years),  
The following questionnaires should be performed:  
- PDSS,  
- CASS, 
- C-SSRS, 
- UNS,  
- CGI-C on EDS and on cataplexy, 


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- Retrieval of sleep diary of the previous visit and check by the investigator. Delivery of one 
other sleep diary which have to be completed every evening until the next visit, 
-Patient’s Global Opinion on the effect of investigational treatment if able to express himself. 
If not will be reported either by parents or teachers. 
 
Investigational treatment allocation: start 1-week wash-out period. 
The treatment pack bring back from previous visit by patient is checked by investigator for the 
compliance. 
 
5.2.9. T1 – Telephone contact (Day 59± 1 day) 
This phone call between patients (or their parents) and the investigator (or his/her deputy) will 
allow to record all adverse events having occurred since the latest visit (AE recorded at visit 
V8), and to fill in the withdrawal symptoms questionnaire and ascertain that the treatment 
discontinuation is well tolerated. 
 
5.2.10. V8 – End of study visit or Start of Open-Label after 1 week of placebo wash out 
(Day 63 ± 2 days) / Premature withdrawal visit (Double blind phase) 
The premature withdrawal patients from the study should be followed by a visit performed 
within a maximum of 5 days after the last dose of study drug. 
A complete interrogation including occurred of possible adverse events and concomitant 
medication used will be done and recorded, 
A physical examination including vital signs shall be carried out, 
12-lead ECG recording with calculation and control of QTcF, 
A blood sample will be taken for routine haematological and biochemical test (including β-
HCG pregnancy test for pubescent female) and semi-quantitative urinalysis (dipstick), (only for 
premature withdrawal patient), 
The following questionnaires should be performed:  
- PDSS,  
- CASS, 
- CDI, 
- C-SSRS, 
- Ullanlinna narcolepsy scale, (only for premature withdrawal patient), 
- CGI-C on EDS and on cataplexy, 
- Patient’s Global Opinion on the effect of investigational treatment if able to express himself. 
If not will be reported either by parents or teachers, (only for premature withdrawal patient), 
- Retrieval of sleep diary and check by the investigator, 


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-Withdrawal symptoms questionnaires. 
 
The treatment pack bring back from previous visit by patient is checked by investigator for the 
compliance. 
Patients willing to continue the study in the prolonged open label period will receive a new 
pack of investigational treatment and will start an escalating dose treatment. Week 1 at 
5 mg/day then week 2 at 10 mg/day. Those patients will receive one sleep diary which have to 
be filled out daily during the 7 days prior to the next visit. Patients not willing to continue in 
the study will be followed under usual practice. 
 
When a patient has already performed the visit V8, the follow up control visits will be scheduled 
and an end of study visit should be planned as soon as the BF2.649 (pitolisant) is 
commercialized in children from 6 to 17 years included or as soon as the patient reaches 18 
years and it has at its disposal the commercialized treatment in adult. 
 
5.2.11. V9- Dose adjustment visit (Day 77± 2 days) 
A complete interrogation including occurred of possible adverse events and concomitant 
medication used will be done and recorded, 
A physical examination including vital signs shall be carried out, 
12-lead ECG recording with calculation and control of QTcF, 
The following questionnaires should be performed:  
- PDSS,  
- CGI-C on EDS and on cataplexy, 
- CDI, 
- C-SSRS, 
- Patient’s Global Opinion on the effect of investigational treatment if able to express himself. 
If not will be reported either by parents or teachers, 
- Retrieval of sleep diary. (Sleep diary will be filled out daily during the 7 days prior to the next 
visit) and delivery of one other.  
 
Investigational treatment allocation: the dose of pitolisant will be individually adjusted 
according to the investigator’s prescription patients for whom the optimal dose level is 
estimated will continue at the same dose or if not sufficiently improved in their symptoms, and 
with a good tolerance, will increase to a higher dose or the level dose will be reduced based on 
the tolerance to the product. Dose allocation: either 5, 10, 20 or placebo in the morning during 
7 days.  


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The treatment pack bring back from previous visit by patient is checked by investigator for the 
compliance. Investigator will remind patient to bring back the investigational treatment packs 
at the next visit. 
 
5.2.12. T2- Telephone contact at D98 (± 1 day) 
This phone call between patients (or their parents) and the investigator (or his/her deputy) will 
allow to record all adverse events having occurred since the latest visit (AE recorded at visit 
V10).  
The investigator should assess the efficacy and tolerance and the dose of treatment should be 
adjusted accordingly, when applicable. 
In opinion of investigator, the dose could be re-adjusted according the effectiveness/tolerability 
of treatment to patient.  
In case of need, it is to plan a visit on site within the week following phone contact for obtaining 
new bottles of treatment with the corresponding dose.  
The other doses decrease, from 40 to 20 and 10 to 5 mg, in agreement with investigator don't 
need a visit. The bottles contain a suitable number of tablets to decrease the dose. 
 
5.2.13. V10- Dose adjustment visit (Day 84± 2 days) 
Idem to the visit V9. 
Investigational treatment allocation: the dose of pitolisant will be individually adjusted 
according to the investigator’s prescription.  
A blood sample will be taken for routine haematological and biochemical test (including β-
HCG pregnancy test for pubescent female) and semi-quantitative urinalysis (dipstick), 
Dose allocation: either 5, 10, 15, 20, 30 or 40 mg/day or placebo in the morning during 28 days. 
Patients with a weight less than 40 kg could be treated with a maximum daily dose up to 20 mg. 
 
 
5.2.14. V11- Dose adjustment visit (Day 112± 7 days) 
Idem to the visit V9. 
Dose allocation: either 5, 10, 15, 20, 30 or 40 mg/day or placebo in the morning during 3-month. 
Patients with a weight less than 40 kg could be treated with a maximum daily dose up to 20 mg. 
 
5.2.15. V12- Dose adjustment visit (Day 196± 7 days) 
Idem to the visit V11. 
Dose allocation: either 5, 10, 15, 20, 30 or 40 mg/day or placebo in the morning during 6-month. 
Patients with a weight less than 40 kg could be treated with a maximum daily dose up to 20 mg. 


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5.2.16. V13- Dose adjustment visit (Day 364± 7 days) 
Idem to the visit V12. 
A blood sample will be taken for routine haematological and biochemical test (including β-
HCG pregnancy test for pubescent female) and semi-quantitative urinalysis (dipstick),  
Dose allocation: either 5, 10, 15, 20, 30 or 40 mg/day or placebo in the morning during 6-month. 
Patients with a weight less than 40 kg could be treated with a maximum daily dose up to 20 mg. 
 
All subsequent visits are performed each 6 months as V13. 
 
The investigator should instruct each patient to report any subsequent event(s) that the patient 
or his personal physician believes might reasonably be related to participation of this study.  
In case of occurrence of adverse event or in case of unresolved adverse event, the investigator 
should schedule an additional follow-up in order to follow any adverse events until they are 
resolved. Thereafter, the patient will be discharged from the study. 
 
5.2.17. Early withdrawal visit (Open label phase) 
The premature withdrawal patients from the study should be followed by a visit performed 
within a maximum of 5 days after the last dose of study drug. 
Tests and exams are applied as V13 with no dispensation. 
Patients will be followed under usual practice after their study discontinuation. 
 
5.2.18. Phone visits during the COVID-19 pandemic 
During the COVID-19 pandemic, while patients are unable to attend any visit in the 
investigative sites and to limit the risk for the patient to spread/acquire the infection, special 
measures are put in place to maintain the participants in the study. During that period and until 
return to normal situation at sites, study visits at can be replaced by phone visits. 
The investigator should assess during these calls the efficacy and tolerance and the dose of 
treatment should be adjusted accordingly, when applicable.  
Direct shipment of study treatment from the site, or hospital pharmacy, to the patient’s home is 
allowed via a courier with the full documentation of shipment and receipt by the patient/parents. 
Patients will return all medication at his/her subsequent site visit. Diaries to be documented 
daily are sent to the patient with the study treatment. 
 


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5.3. 
PATIENT WITHDRAWAL CRITERIA 
5.3.1. 
Criteria to withdraw subject from the trial treatment 
In accordance with the Declaration of Helsinki, patients will be free to withdraw from the study 
at any time if they wish to do so, for any reason specified or unspecified.  
Before the final scheduled study visit the investigator have the responsibility and the right to 
interrupt the patient participation. Out of emergency cases (listed below), the investigator will 
have to contact the sponsor or his representative before the application of his decision. 
• Voluntary withdrawal of patient consent, or loss to follow-up, or inability to remain 
under medical observation 
• Severe depression indicated by Childhood Depression Inventory (CDI ≥ 16) or suicidal 
risk with a positive Columbia-Suicide Severity Rating Scale (C-SSRS). 
• Non-compliance or major deviation from the protocol 
• Appearance of a Serious Adverse Event (SAE) or any other situation where, in the 
opinion of the investigator, continuation of the study would not be in the interest of the 
subject.  
Should any of the patients be withdrawn from the study, the reason for withdrawal has to be 
recorded in the CRF for all withdrawn patients. 
 
5.3.2. 
Type and timing of data to be collected from withdrawn patients 
When a patient is prematurely withdrawn from the study before the “End of study visit” V8, the 
investigator has to perform a complete visit, within a maximum of 5 days after the last dose of 
study drug. This will also apply for open label phase. 
 
5.3.3. 
The follow -up for withdrawn patients 
The investigator should make every effort to contact the prematurely withdrawn patient and to 
identify the reason why he fails to attend the visit and to determinate his health status. In case 
of adverse event no recovered at the time of study withdrawal, the investigator will have to plan 
a follow-up visit in order to complete the adverse events evolution. 
 
5.4. STUDY DISCONTINUATION CRITERIA 
5.4.1. 
Criteria for terminating the trial 
Bioprojet reserves the right to terminate the study but intends only to exercise this right for 
valid scientific or administrative reasons, and reasons related to protection of patients. In all 
cases the Ethics Committee (IRB/IEC) and Health Authorities should be informed.  


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Possible reason for the study termination can include but are not limited to: 
• The discovery of an unexpected, significant or unacceptable risk to patients enrolled in 
the study 
• A decision on the part of Bioprojet to suspend or discontinue the development of the 
investigational product 
• Request of the relevant regulatory agency 
If the study is prematurely discontinued, enrolled patients should be called for an “end of study” 
visit” 
 
5.4.2. 
Criteria for terminating site 
Bioprojet reserves the right to terminate the study at a given centre at any time after the study 
initiation if: 
• ICH GCP regulations are not observed 
• The protocol is violated without justification 
• The data generated are of poor quality 
• Changes in personnel or facilities adversely affect performance of the study (e.g. low 
rate of inclusion). 
 
6. 
SAFETY 
ASSESSMENT 
AND 
REPORTING 
6.1. 
DESCRIPTION OF SAFETY PARAMETERS 
6.1.1. Vital signs 
Vital signs including systolic and diastolic blood pressures, heart rate and body weight will 
be measured at each visit. Measurements will be recorded in the CRF. 
 
6.1.2. Physical examination 
A complete physical examination (including the height at screening only) will be performed 
at screening visit (V1, or V0 when applicable) and at each visit for the purpose to observe the 
child’s overall appearance, general health, and behavior. The examination includes 
cardiovascular, respiratory, abdominal, neurological, locomotive and dermatologic systems. 
Any significant abnormalities should be recorded in the CRF. 
 


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6.1.3. Electrocardiogram (ECG) 
ECG will be performed at the screening visit (V1), at each subsequent visit from V2 to V8 for 
the double blind phase, and all visits of the open-label period, using the internationally 
recognized 12-lead ECG recording which includes date, time, initials of the technician/nurse, 
initials of the investigator or its deputy, at least 2 complexes for each lead and a single lead run. 
The corresponding source data will consist of the Cardiograph paper print-outs that should be 
kept in the file and a copy provided to Bioprojet. Main ECG parameters including heart rate, 
sinusal rhythm PR, QRS, and Fridericia’s corrected QTc interval (QTcF = QT/3√ (60/HR)) QTc 
interval will be analyzed and should be recorded.  
All ECGs will be reviewed a posteriori by a central reviewer.  
 
6.1.4. Blood Laboratory tests and Urinalysis 
A full laboratory test should be performed at screening visit (V1), at the end of the double blind 
treatment (V7 or at early withdrawal visit), and at during open-label period at V10, V13, then 
every 6-month. All laboratory tests will be performed according to the Good Laboratory 
Practice by site-dependent Laboratory and tests data should be analyzed, reported and duly 
signed by its responsible. The results of laboratory tests as paper print outs should be reviewed 
and assessed (dated and signed) by the investigator at the next visit and reported in the specific 
form of the CRF. 
 
The following blood parameters should be evaluated:  
 Hematology: Red Blood Cell Count, White Blood Cell Count including differential 
(absolute value), Hemoglobin, Haematocrit, Mean corpuscular volume (MCV), Platelet 
Count (Absolute). 
 Biochemistry Tests (Serum/plasma): Sodium (Na), Potassium (K), Chloride (Cl), 
Creatinine, Alkaline phosphatases, Urea, Alanine aminotransferase (ALAT), Aspartate 
aminotransferase (ASAT), Gamma-glutamyltranspeptidase (GGT), Total Bilirubin, Blood 
glucose, triglycerides, total cholesterol, Quick Time. 
 β-hCG serum Pregnancy Test should be performed in all pubescent female patients with 
child-bearing potential. The absence of pregnancy should be confirmed before entering the 
study. 
 


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All laboratory test results will be coded by using the 3 points scale as following:  
- 0 = within the normal limits 
- 1 = anomaly but no clinical significant 
 2 = anomaly clinically significant   
Results of the clinical laboratory tests performed at screening will be included in the subject’s 
CRF and considered as baseline values before the product administration.  
 
In addition a semi-quantitative ("dipstick") analysis for pH, ketone bodies, proteins, glucose 
and blood should be evaluated. If any of these parameters gives a positive result, a quantitative 
analysis will be performed to characterize or count: crystals, casts, epithelial cells, white blood 
cells, red blood cells and bacteria if required by the investigator. 
 
Follow-up of laboratory test abnormalities 
The best interest of the subjects will always come before that of the trial. Abnormalities of any 
laboratory tests considered to represent a significant danger to the subject will lead to immediate 
discontinuation of the drug and the study monitor and Sponsor must be informed immediately. 
 
In the event of abnormalities considered not to represent a danger, continuation of the drug will 
be allowed after discussion with the study monitor. These subjects will be followed up with 
appropriate medical management until they return to normal or baseline values or clinical 
diagnostics of undercurrent illness is confirmed. The results of all known laboratory tests 
required by the protocol will be held / recorded in the subject's CRFs. All clinically important 
abnormal laboratory tests occurring during the study will be repeated at appropriate intervals 
until they return to baseline or to a level deemed acceptable by the investigator and the study 
monitor. 
 
6.1.5. 
Adverse Events 
6.1.5.1. 
Definitions 
• Period of observation 
For the purpose of this study, the period of observation extends from the time the patient gives 
informed consent (Visit 0) until one month after the last drug administration and until resolution 
of ongoing drug related adverse event. Any adverse events observed by the investigator or 
reported by the patient during the period of observation must be documented in the CRF. 
• Adverse event 
The term Adverse Event covers any sign, symptom, syndrome, or illness which appears or 


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worsens in a patient during the observation period in the clinical study, and which may impair 
the patient’s well-being. 
 
The term also covers laboratory findings or results of other diagnostic procedures which are 
considered to be clinically relevant (e.g., requiring unscheduled diagnostic procedures or 
treatment measures, or result in withdrawal from the study). 
 
An adverse event may be: 
A new illness; 
The worsening of a sign or symptom of the condition under treatment, or of a concomitant 
illness; 
An effect of the study medication; 
A combination of two or more of these factors. 
No causal relationship with the study medication or with the clinical study itself is implied by 
the use of the term “Adverse Event.” 
 
• Exemption conditions 
In this study in narcoleptic patients, symptoms like hallucinations, sleep attacks and sudden 
onset of sleep should be considered as symptoms of the underlying condition and not as adverse 
event, and should only be reported as Adverse Event in case of worsening or unusual form. 
 
• Treatment-Emergent Adverse Event (TEAE) 
A treatment-emergent adverse event is defined as any event not present prior to the initiation 
of the study treatments, or any event already present which worsens either in intensity, or 
frequency following the exposure to the study treatment.  
 
• Adverse Drug Reaction (ADR) 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered as an Adverse Drug Reaction. The responses to a medicinal product means that a 
causal relationship between a medicinal product and an Adverse Event is at least a reasonable 
possibility, i.e. the relationship cannot be ruled out. The causal relationship should be assessed 
as defined below §7.2.5.3 (assessment of causality). 
 
• Unexpected Adverse Drug Reaction  
An Adverse Reaction, the nature or severity of which is not consistent with the applicable 


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product information (e.g. Investigator Brochure). 
 
• Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR)  
A Serious Adverse Event is one that at any dose: 
- 
Results in death; 
- 
Is life-threatening1; 
- 
Requires patient hospitalization or prolongation of existing hospitalization; 
- 
Results in persistent or significant disability/incapacity2; 
- 
Is a congenital anomaly/birth defect; 
- 
Is medically important3. 
 
1 “Life-threatening” means that the patient was at immediate risk of death at the time of the 
serious adverse event; it does not refer to a serious adverse event that hypothetically might have 
caused death if it were more severe. 
2 “Persistent or significant disability or incapacity” means that there is a substantial 
disruption of a person’s ability to carry out normal life functions. 
3 Medical and scientific judgment should be exercised in deciding whether other adverse events 
may be considered serious because they jeopardize the patient, or may require intervention to 
prevent one of the other outcomes listed in the definition above. The List of Critical Terms 
(1998 adaptation of WHO Adverse Reaction Terminology Critical Terms List) should be used 
as guidance for adverse events that may be considered serious because they are medically 
important.  
Cases involving cancer as an Adverse Event should be reported as “serious” using the criterion 
“medically important” if no other serious criterion is met.  
Cases of overdose with an adverse event that meets one of the criteria given above should of 
course be reported as “serious”. There is no antidote; in case of overdose, the patient has to be 
hospitalized in order to control his/her vital functions. 
 
A serious adverse drug reaction is a serious adverse event which is related to the medicinal 
product whatever the dose. 
 
• Clarification of the difference in meaning between “severe” and “serious” 
The terms “severe” and “serious” are not synonymous:  
- 
"severe" is used to describe the intensity (severity) of a specific event, which 
could be rated mild, moderate or severe. The event itself, however, may be of relatively 


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minor medical significance (such as severe headache).  
- 
“serious” is based on patient/event outcome or action criteria usually 
associated with events that pose a threat to a patient’s life or functioning. “Seriousness” (not 
severity) serves as a guide for defining regulatory reporting obligations. 
 
6.1.5.2. 
Monitoring and recording of adverse events 
The tolerance will be assessed by the occurrence of adverse and unexpected events, 
spontaneously reported by the patient or discovered during investigator’s interview. The 
investigator or a designed member of his/her staff will probe each patient on any adverse 
experiences which may have occurred. The investigator should always ask the same question 
when conducting the verbal probe in order to ensure uniformity between patients. The 
investigator should ask:  
- 
How are you doing (feeling)?  
 
Based on the patient’s response to this question, the investigator should ask additional questions 
relevant to the specific compliant such as: 
- 
How severe is/was the symptom? 
- 
How often did the symptom occur? 
- 
How long did the symptom last? 
For each unexpected or adverse effect, regardless the suspected causal relationship to study 
drug, the investigator have to report on the Adverse Event page(s) of the CRF the relevant 
information of AE including the nature, the anteriority (emergent or not), the timing of event 
occurrence and resolution, the frequency (intermittent or continuous), the severity, the 
seriousness (serious/non-serious), the relationship with the study compound, and actions taken 
to counteract the adverse experience. The investigator has also to pursue and obtain adequate 
information in order to determine the outcome of the adverse event and also to assess whether 
it meets the criteria for classification as a serious adverse event requiring immediate notification 
to the sponsor (see below). Follow-up of AEs is required until the event or its after-effects will 
be resolved or stabilized at an acceptable level with respect to the investigator opinion, even 
after the date of therapy discontinuation 
 
6.1.5.3. 
Analysis of adverse events 
Adverse events will be coded according to the Medical Dictionary for Regulatory Activity 
(MedDRA current version). 
Adverse events will be individually listed per subject number, presenting System Organ Class 


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(SOC), preferred term, emergence, description, date and time of onset, date and time of last 
study drug administration before adverse event, duration, time from onset since last study drug 
administration, frequency, severity and seriousness, relationship to study drug, the required 
action taken (corrective treatment, hospitalization….) required, and outcome if any. 
It consists in the evaluation of the number of adverse events and in the number of subjects 
reporting these adverse events. 
 
• Treatment Emergent Adverse Events (TEAE) 
Adverse events will be classified into pre-defined standard categories according to 
chronological criteria: 
- Treatment Emergent AEs (TEAE): AEs that occurred for the first time, or if present before 
that worsened during the exposure to the study drug(s). 
- Non-Treatment Emergent AEs (NTEAE): AEs that occurred before the study drug 
administration. 
 
• Assessment of Intensity 
An assessment of the relative intensity of an adverse experience is based on the investigator’s 
clinical judgment by using the following scale. The maximum intensity encountered during the 
evaluation period should be checked. 
 
The assessment of intensity should be independent of the assessment of the seriousness of the 
AE. 
• Mild: No significant interference with the subject’s usual activities: acceptable, 
disappeared without residual effect 
• Moderate: moderate interference with study the subject’s usual activities. 
• Severe: major interference with study the subject’s usual activities, considered 
as unacceptable by the physician or required specific treatment or required 
discontinuation from the study. 
 
• Assessment of Causality 
The investigator will make judgment considering whether or not, in his opinion, the AEs are 
related to the study drug according to the following causal relationship assessment of suspected 
adverse reactions: 
• Related / likely: Clearly related to the investigational agent / procedure, i.e. an 
event that follows a reasonable temporal sequence from administration of the 


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study intervention, follows a known or expected response pattern to the 
suspected intervention, that is can be confirmed by improvement on stopping 
and reappearance of the event after rechallenge and that could not be reasonably 
explained by the known characteristics of the subject’s clinical state. 
• Possibly related / Possible: Follows a reasonable temporal sequence from 
administration of the study intervention, follows a known or expected response 
pattern to the suspected intervention, but that could readily have been produced 
by a number of other factors. 
• Not related / Unlikely: Clearly and incontrovertibly due only to extraneous 
causes, and does not meet criteria listed under possible (possibly related) or 
likely (related). 
 
• AE outcome 
All adverse Event outcomes should be documented at the last visit at the latest according to the 
following criteria: 
− Ongoing *  
− Resolved 
− Unknown 
− Recovered with sequelae ** 
− Recovered without sequelae 
− Death related to adverse reaction 
− Death not related to adverse reaction 
*  If an adverse event is still ongoing at the last visit the patient must be follow-up until the 
outcome can be documented without using the “ongoing” assessment. 
* *  A description of sequelae must be provided in the CRF 
 
6.1.5.4. 
Reporting Serious Adverse Event or Serious Adverse Drug Reaction  
All serious adverse events (SAE) or Serious Adverse Drug Reaction (SADR), whatever the 
dose, the therapeutic or diagnostic reason, have to be reported immediately (within 24 hours), 
by any means to the Sponsor’s defined representative: 
Pharmacovigilance Responsable contact:  
 
 
 
 
 
 
 Bioprojet   9, rue Rameau, 75002 PARIS, France 


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The investigator must inform the site monitor. 
In case of SAE the investigator must complete the specific form “Serious Adverse Event” and 
send it within 48 hours to Bioprojet and the duplicated SAE form dully completed and signed 
to the monitor. After the initial report, the SAE should be promptly followed by a detailed 
writing report including all data allowing to document the event and notably the anonymous 
copies (subject identification code: treatment number and initials) from hospitalization’s report 
and additional performed examination(s). The list of the pertinent documents deemed necessary 
to assess the gravity and the potential relationship is given at the end of the case report form. 
The investigator should also report to the monitor all elements concerning the follow-up of the 
serious adverse event.  
 
For reported death, the investigators should supply the Sponsor and the IRB/IEC with any 
additional requested information such as autopsy reports if available and terminal medical 
reports. 
 
The "Serious Adverse Event" form and the instructions on completion are provided in the 
investigator’s study file. The “Instructions for Completing the SAE Form” give more detailed 
guidance on the reporting of serious adverse events, significant overdose cases, and Adverse 
Events initially reported as non serious that become serious. 
 
7. 
STATISTICAL ANALYSIS 
 
7.1. SUMMARY 
The study is a 13-week, randomized, double-blind, placebo controlled, parallel-group, multi-
center trial assessing the effects of BF2.649 (B) compared with Placebo (P) in the relief of 
Excessive Daytime Sleepiness (EDS): children from 6 to less than 12 years of age and 
adolescents from 12 to less than 18 years of age, all of them suffering from narcolepsy with or 
without cataplexy. 
 
7.2. STATISTICAL METHODS 
The Primary selection will be the Full Analysis Set (FAS), defined as all the randomized 
patients irrespective of their outcome, this analysis with the best conformity with Intent To 
Treat principle.  
 


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7.3. MAIN ENDPOINT 
The main endpoint is the UNS measuring the quantity and intensity of symptoms if narcolepsy 
in particular EDS and cataplexies. 
Metric properties of this scale are summarized as follows: Total scores range from 0 to 44 with 
higher scores denoting greater narcoleptic tendencies. 
 
7.4. STATISTICAL INFERENCE 
The significance of the active tested drug compared with placebo on the change of UNS will 
be assessed by Analysis of Covariance on Final UNS estimate (the summary mean of the two 
Final UNS measures V6 and V7) adjusted for baseline (summary mean of the two pre-treatment 
UNS values V1 and V2). ANCOVA will be conducted with a Mixed Linear Model taking into 
account centre heterogeneity. 
 
7.5. SAMPLE SIZE DETERMINATION 
By assuming a Pearson correlation coefficient of R=0.5 between pre-baseline and final values 
of PDSS, two pre-baseline measurements [(V1+V2)/2] and two post-baseline measurements 
[(V6+ V7)/2], a standardized mean difference of at least 0.5 (considered as the minimum 
clinically significant difference) will be detected at a two-sided 0.05 confidence level with a 
power of at least 0.8, when the sample size/group is at least 20 and 40 patients for control and 
tested drug groups, respectively. 
In the last sample size calculation as detailed in section 7.7.2, a recruitment of 96 patients was 
decided, based on the following assumptions: a standardized mean difference of at least 0.5 
(considered as the minimum clinically significant difference) will be detected at a two-sided 
0.05 confidence level with a power ≥ 0.75. Since then, the main endpoint becomes the UNS 
measuring EDS and cataplexy instead of the PDSS. The validation of UNS provided good 
metric properties, but a residual variability slightly larger than PDSS. The power 0.75 was also 
considered risky and increased to 0.85. 
Further to those changes, a recalculation of the sample size was performed on a standardized 
mean difference of 0.5 on the UNS (considered as the minimum clinically significant 
difference), a ratio 1:2, and a correlation R=0.4. Under these assumptions, and ANCOVA test 
at 0.05 two-sided confidence level, the probability of a significant effect will be found with a 
power of 0.85 when the sample size exceeds 36+72 patients for control and tested drug groups, 
respectively, thus a total of 108 patients. 
 
7.6. HANDLING OF MISSING DATA 
For patients terminating the trial before completion, the final value will be calculated as the 


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mean of the two last known values (baseline if needed).  
 
7.7. INTERIM ANALYSIS 
7.7.1. 
DSMB 
According to ICH E9 an independent Data Safety Monitoring Board (DSMB) will regularly 
follow the progress of the clinical trial, monitor safety data and critical efficacy variables and 
be consulted concerning the opportunity of modifying the sample size (see next point), or 
terminate a trial for futility (see next point). 
 
The DSMB will have written operating procedures and maintain records of all its meetings, 
including interim results; these should be available for review when the trial is complete. The 
independence of the DSMB is intended to control the sharing of important comparative 
information and to protect the integrity of the clinical trial from adverse impact resulting from 
access to trial information. The DSMB is a separate entity from an Institutional review Board 
(IRB) or an Independent Ethics Committee (IEC), and its composition should include clinical 
trial scientists knowledgeable in the appropriate disciplines including statistics. 
Operating procedures will define clearly the roles and responsibilities, the membership -with 
independent experts in the clinical aspects and one biostatistician -, and organization of the 
meetings. The procedures should also address the way to keep confidential the data analyzed, 
the voting rules and the control of dissemination of interim trial results within the sponsor 
organization. 
 
7.7.2. 
Adaptive sample size to 96 patients 
We based our sample size on the value of the assumed standardize mean difference and the 
correlation between baseline and final values (R). Over- or under-estimation or R is possible. 
An estimation of R will be found, blind to treatment, when at least 20 patients have completed 
the study (producing an 80% half interval length of R. In case where the difference between the 
observed R’ values and the expected R is such that |R-R’|>.1 the sample size will be recalculated 
and discussed with the DSMB.  
Initially, at least 60 patients are required to evaluate the primary endpoints (40 patients being 
administered pitolisant, and 20 patients receiving placebo). Besides, the analysis of sample size 
justified in the context of an adaptive sample size was performed on 29 enrolled patients 
including 27 randomized patients and among them 25 patients provided endpoints values at V6 
and V7. The statistical outcomes highlighted the need for increase of the sample size. At least 
96 patients (64 patients being administrated pitolisant, and 32 patients receiving placebo) 
should be needed for a power of at least 0.75, given the observed values of SD and baseline 


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correlation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.7.4. 
References 
Lan K. Wittes J: The B-value: a tool for monitoring data . Biometrics 44:579-585, 1988 
Lan K., Zucker D: Sequential monitoring of clinical trials: the role of information and Brownian 
Motion, Stat Med 12: 753-765, 1993 
Proschan M.A., Statistical methods for monitoring Clinical Trials , J Bioph Stat, 9 (4) 599-615 
(1999) 
 
8. 
DIRECT 
ACCESS 
TO 
SOURCE 
DATA/DOCUMENTS 
In conformity with GCP (ICH E6), the investigator should provide direct access to source 
data/documents for trial-related monitoring, audits, IRB/IEC review, and regulatory inspection. 
Any authorized party with direct access should take all reasonable precautions within the 
constraints of the applicable regulatory requirement(s) to maintain the confidentiality of 
subjects’ identities and sponsor’s proprietary information. 
Each patient should consent in writing, to direct access to his/her original medical records.  
 


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9. 
QUALITY CONTROL AND QUALITY 
ASSURANCE 
 
9.1. 
MORNITORING AND GOOD CLINICAL PRACTICE 
The trial will be run with respect to the Good Clinical Practice, following the international 
regulations (ICH) and the European directives (EMA) or national ones.  
The quality control of the study and the audit of the Good Clinical Practice could be performed 
by Bioprojet or delegated auditor or by an inspector of Authority Agency.  
 
In particular, the current protocol will be submitted to the approval of the Ethics Committee 
and Competent Authority by BIOPROJET. The conformity of the study progress will be 
reviewed.  
The investigator will carefully explain the participating conditions to each proposed patient. 
Each patient will receive a detailed and written information letter including the name of the 
product, a summary of its properties, the potential unexpected and adverse events, the doses to 
be administered, the treatment duration, the number of visits, the kind and number of scheduled 
exams.  
 
The patient will be informed that he can dropout from the study whenever he wants, without 
any justification.  
 
The system to attribute treatment number to patients is based on the anonymity obligation. 
Patients will receive a number according to their order of inclusion in the study on a site. The 
patients will be identified by the sponsor with: the centre number, the inclusion number. 
 
Study progress conformity to the protocol will be controlled from the patients’ selection, and 
all along the study. Each investigator has to allow the monitor, or sponsor’s mandated 
representative, the access to any control of the study progress, and to any required documents 
to control data reported in case report forms (hospitalization file, consultation file, results of 
additional exams …).  
The investigator will be available to the telephone for each patient whom he has included. 
The anonymity respect shall be applied to the filling of the case report form as to any other 
archived documents considered as source data (blood tests, informed consent form…). 
 


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9.2. 
QUALITY CONTROL AND AUDIT 
Control actions are implemented within the framework of the Quality Assurance System to 
check that the quality requirements of the study are respected.  
The original documents generated in the course of the study will be controlled at each step of 
the study, both by the sponsor’s representative and the investigator, in order to guarantee the 
accuracy of the analyzed data.  
The conduct of the study may be audited by the Sponsor and/or inspected by the Competent 
Authorities where the study is performed. Auditors and/or inspectors should have access to any 
study records (CRFs, site files, trial master files…) and sources patients’ medical 
documentation. Investigators accept the possibility to be audited / inspected and agree to 
dedicate necessary time to the proper conduct of the audit / inspection at their sites. It will 
enable to check that the study is being run in conformity to the protocol and to current rules and 
regulations.  
 
9.3. 
MONITORING 
The Monitors of Bioprojet or delegates will conduct initiation visits at each study center after 
approval of the study has been obtained from the Independent Ethics Committees and 
Competent Authorities to discuss the clinical protocol and review data collection procedures, 
safety monitoring and reporting procedures, and regulatory requirements.  
 
Monitoring visits to the study centers will be conducted periodically during the study 
performance, in order to:  
• Review the status of the study with respect to patient enrolment, occurrence of adverse 
events, etc. 
• Ensure that the clinical investigators continue to meet their contractual, clinical and 
regulatory obligations with regard to protocol compliance (and compliance to protocol 
amendments, if applicable), adherence to regulatory and ethical requirements and the 
protection of the patients’ rights and safety, 
• Ensure the scientific integrity of the study by reviewing the integrity and completeness 
of the data collected on the CRFs on the basis of the raw data (refer to Declaration of 
Helsinki) 
• Review the completeness and accuracy of the study Site Records 
 
Source documents will be reviewed for verification of agreement with data on the CRFs. The 
study center guarantees direct access to source documents by designated Bioprojet personnel 


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or their designees and appropriate regulatory authorities. Monitoring will be conducted 
according to the internal Standard Operating Procedures.  
The study may also be subject to a quality assurance audit by Bioprojet Corporation or its 
designees, as well as inspection by appropriate regulatory authorities. 
It is important that the Investigator and the relevant study personnel are available during the 
monitoring visits and possible audits and that sufficient time is devoted to the process. 
 
9.4. 
INVESTIGATOR QUALIFICATIONS/RESPONSIBILITIES 
• Level of experience in Narcolepsy disease and study procedures/testing adequate for 
participation in study trial  
• Previous clinical research experience  
• The number of narcolepsy patients that would suffice to meet the enrolment goals  
• Agree to participate in an appropriate training program prior to first patient enrolled 
• Be willing to comply with the scheduled follow-up visits as described in the protocol. 
• Agree to obtain Informed Consent before conducting any study-specific tests or 
procedures 
• Complete all CRFs promptly 
• Be willing to spend time to complete the administrative work involved in the study 
• Be willing to spend time with the Bioprojet Clinical Research Associate, monitors or 
delegates during the monitoring visits. 
• Be willing to change hospital routine required by protocol 
 
10. 
ETHICS 
 
10.1. 
DECLARATION IF HELSINKI AND CONFORMITY WITH OTHER INTERNATIONAL 
STANDARDS 
The trial will be carried out in accordance with the Declaration of Helsinki (Edinburgh, 2000) 
completed by Notes of Clarification to articles 29 (Washington, 2002) and 30 (Tokyo, 2004) 
respectively, as revised in 2008 (59th WMA General Assembly, Seoul) and 2013 (64th WMA 
General Assembly, Brazil). The trial will also be conducted in compliance with the protocol, 
the ICH Guidelines for Good Clinical Practice (ICH E6), the European directives on clinical 
trials (Directive 2001/20/EC), and the applicable local country laws/regulations. 
 


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10.2. 
ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD APPROVAL 
It is the Sponsor’s responsibility to obtain and maintain written approval of the final Study 
protocol, including the Patient Information and Informed Consent, from the appropriate Ethics 
Committee. It is also the Sponsor’s responsibility to notify the Independent Ethics Committee 
(IEC) about any amendments to these documents. In case the protocol amendment changes the 
scope of the study or increases the risks of the study patients, the investigator should wait for 
approval of this amendment by the Independent Ethics Committee before implementing the 
protocol amendment. A copy of the written approval and the approved versions of the 
documents and a list of the Ethics Committee members, their titles and occupations should be 
obtained from the IEC. The written approval should identify the study and document the date 
of review.  
The Sponsor should file all correspondences with the Ethics Committee. It is the Sponsor's 
responsibility to issue a final report and to provide it to the regulatory agencies as required by 
the applicable regulatory requirements. 
 
10.3. 
EMERGENCY ACTIONS 
Bioprojet accepts the right of the Investigator to deviate from the protocol in an emergency 
when necessary to safeguard the life or the well-being of a study patient. The Investigator must 
give notice of any emergency deviations and justification for the deviation to the study 
personnel responsible at Bioprojet. The Ethics Committee will be informed as quickly as 
possible after the episode, in any event no later than 24 hours after the emergency, depending 
on local regulation. 
 
10.4. 
PATIENT INFORMED CONSENT PROCEDURE 
It is the responsibility of the Investigator to give each patient and to their parents (or the patient’s 
legally authorized representative) prior to inclusion in the study, full and adequate verbal and 
written information about the objectives and the procedures of the study, potential risks 
involved, and personal and societal benefits. The patient and their parents must be informed 
about their right to withdraw from the study at any time and for any reason without sanction, 
penalty, or loss of benefits to which they are otherwise entitled and that withdrawal from the 
study will not jeopardize their future medical care.  
 
Before deciding on whether or not to participate, the patient and their parents (or their legal 
representative) should have sufficient time to think about the study and to discuss the study 
with third parties. The investigators and their staff will be available to answer questions from 
the subject at all times. Written Patient Information should be given to each patient (if old 


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enough to understand) and both parents (or their legal representative) before enrolment. 
Furthermore, it is the responsibility of the Investigator to obtain, in accordance with the 
pertinent local regulations, a signed Informed Consent form from each patient and their parents 
(or their legal representative) prior to performing any study-related procedures. (ICH – E11). 
 
The Patient Information and Informed Consent form should be updated or amended whenever 
new important information becomes available that may be relevant to the patient and their 
parents (or their legal representative). Modifications to these documents must be approved by 
Bioprojet and by the IEC before being implemented.  
 
10.5. 
AMENDING THE PROTOCOL 
Any change to the study must be documented in a protocol amendment. Such protocol 
amendments will be made jointly by Bioprojet and the investigators. Both parties will sign the 
protocol amendment.  
Bioprojet shall submit the protocol amendment for review by the Independent Ethics 
Committee if the change or deviation from the original protocol could increase the risks to the 
study patients or could adversely affect the validity of the investigation or the rights of the 
human subjects and shall obtain approval from the Independent Ethics Committees before such 
change or deviation is implemented.  
 
When the change or deviation to the original protocol will eliminate or reduce the risk to the 
study patients, the protocol amendment will be implemented before approval has been received 
from the Independent Ethics Committee. In such cases, the Sponsor shall notify the Independent 
Ethics Committees within ten working days after implementation and shall submit the protocol 
amendment as soon as possible for information/favorable opinion from the Independent Ethics 
Committees.  
If the protocol amendment is of the administrative kind, it will be sent to the Ethics Committees 
for information.  
 


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11. 
DATA 
HANDLING 
AND 
RECORD 
KEEPING 
 
11.1. IDENTIFICATION OF ANY DATA TO BE RECORDED ON THE CRF, CONSIDERED AS SOURCE 
DATA 
Source data are all information reported directly in the CRF and certified copies of original 
records of clinical findings, observations or other activities in the trial necessary for the 
reconstruction and evaluation of the trial. CRF should have the initial of the patient’s first name 
(first letter) and the initial of the last name (first letter), as well as the center number, the 
inclusion number in the study. Source data relate to but not limited to: 
• Subject identification, demographic data (age, weight, height, birth’s date), general 
examination, medical history, last participation to a clinical trial if any, 
•  Narcolepsy diagnosis history and documentation of the previously performed 
evaluation (tests, questionnaires…) about illness 
• A complete interrogation including the patient actual symptoms of narcolepsy (severity 
and duration), possible complication, details of concomitant treatments including any 
current and previous treatments of EDS and cataplexy and any other types of treatment. 
• Dates and times of each visit and for drug administration, concomitant medication 
during the study. 
• All data related to efficacy assessment: PDSS, MWT, CASS, CGI, UNS, TEA-Ch, 
Sleep diary, patient’s global opinion on the effect of treatment (if able to express himself 
if not global opinion will be reported either by parents or teachers). 
• All data related to safety assessment: adverse events, vital signs, ECG, results of 
biological tolerance. 
 
11.2. DATA HANDLING AND RECORD KEEPING 
Data management procedure will be fully detail in a separate document, data management plan. 
Anyway to be noticed that data bases corresponding to each study part (Double blind part on 
one hand and Open label part on the other hand) will be frozen separately in order to allow a 
fast double blind part results analysis. 
Bioprojet will contract out the data capture to a CRO (Contract Research Organization).  
In order to constitute evidence with respect to product safety or regulatory or legal compliance, 
the Investigators, investigational sites and Ethics Committees agree to retain study-related 


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documents in a location that is secure and to which access can be gained if required. The 
following documents must be archived: the Investigator’s File containing all required GCP 
documents, including signed Informed Consent forms and patient-related records, CRFs and 
Data Clarification Forms. The Investigator and the site should retain records for until at least 
2 years after the last approval of the marketing application or at least 2 years after the formal 
discontinuation of clinical development of the investigational product. At the end of these 
regulatory delays, the investigator will inform Bioprojet of his intention to proceed to the 
destruction of archived data.  If the records need to be retained after that duration, the 
investigator and the site will be notified by Bioprojet. These documents must be available for 
audit by authorized representative of Bioprojet or inspection by regulatory authorities. 
Bioprojet will keep in the same conditions the original CRFs and appendices (correction sheets, 
sheets with comments…). 
Audits may be performed for quality assurance of data handling. 
 
11.3. DATA PROTECTION AND CONFIDENTIALITY 
All documents that concern the studied medication and the company’s operations belonging to 
sponsor such as patent applications, formula, manufacturing process, basic scientific data and 
analysis bulletins; information supplied by the company and not previously published are 
considered confidential and shall remain the sole property of the sponsor. The investigator 
agrees to use this information only in accomplishing this study and they will not use it for other 
purposes without written consent from sponsor. 
 
Confidentiality of study source documents:  
The information included in this document, as the investigator’s brochure of the product, the 
CRF and the results of the present study are considered as confidential and should not be 
divulged, only in case of legal requirements.  
 
In any event, persons to whom the information is disclosed must be informed that the 
information is privileged or confidential and may not be further disclosed by them. The 
signature of the present protocol is equivalent to a confidential agreement.  
 
It is understood by the investigator that the information from the clinical study will be used by 
the company in connection with the development of the tested drug and, therefore, may be 
disclosed as required to other clinical investigators or to government agencies. In order to allow 
for the use of the information derived from the clinical studies, it is understood that there is an 
obligation to provide the sponsor with the complete test results as well as all data developed 


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during this study, under the form of a written document or computerized with the following 
software: Word or SAS under Windows, saved on CD-Rom.  
 
The trial drug and the information in this document and in any future information supplied 
contain trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by law or regulations. 
 
All or part of the information should only be divulged, submitted for publication or claim for 
industrial proprietary act with the written consent of Bioprojet.  
 
In compliance with the French law “Informatique et Liberté” of January 6th 1978 modified by 
the law N°94-548 of July 1er 1994 and the decree N°2005-1309 of October 20th 2005, all 
information relative to this study shall be declared to the “Commission Nationale de 
l’Informatique et des Libertés” (CNIL), all computerized data relative to this study shall be 
declared to the “Commission Nationale de l’Informatique et des Libertés”. All data obtained in 
this study will be processed according to the European Regulation n°2016/679 on General Data 
Protection (“GDPR”) and its French application MR-001. 
 
12. 
REGULATORY ASPECTS 
Notification/application to Relevant Competent Authorities 
According to the individual country law/regulation, the study will not be initiated before it has 
been approved by the relevant Competent Authorities and Ethics Committee. 
 
13. 
FINANCING AND STUDY INSURANCE 
Bioprojet will cover the additional costs related of this study. These costs will be defined and 
agreed before the start of the study. A financial agreement will be made between the parties, 
institution, investigator and the sponsor, in accordance with each administrative procedure. 
Bioprojet will contract a specific insurance policy for the coverage of the patients in conformity 
to the National regulation.  
 


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14. 
PUBLICATION POLICY 
All information resulting from the study will be considered as confidential, and must not be 
divulged without the sponsor’s prior agreement. 
The study results may be published or presented by the investigator or analysis experts, in 
collaboration with Bioprojet, with the Bioprojet‘s written permission. Bioprojet may use the 
study results for any publication or communication, with the written agreement of the 
investigator, or the analysis experts if they are quoted. 
 
15. 
CALENDAR FORECAST 
- 
First patient visit is scheduled in Q1 2016. 
- 
For each patient, the study will last 13 weeks, of which a 8-week treatment period with the 
investigational medical product or placebo. 
- 
The end of study (double blind period) is expected in Q1 2022. 
 


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16. 
APPENDICES 
 
Appendix 1: Ullanlinna Narcolepsy Scale (UNS) 
Appendix 2: Epworth sleepiness scale adapted for children and 
adolescents (CASS) 
Appendix 3: Paediatric Daytime Sleepiness Scale (PDSS) 
Appendix 4: Childhood Depression Inventory (CDI) 
Appendix 5: Clinical Global Impression (CGI) 
Appendix 6: Sleep Diary 
 
 
 
 
 


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17. 
REFERENCES 
1- Lin JS et al. An inverse agonist of the histamine H(3) receptor improves wakefulness in narcolepsy: 
studies in orexin-/- mice and patients. Neurobiol Dis 2008;30:74-83 
2- Chemelli RM et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 
1999;98:437-451 
3- Willie et al. Distinct Narcolepsy Syndromes in Orexin Receptor-2 and Orexin Null Mice Neuron. 
2003;38:715-30 
4- Mochizuki T et al. Behavioral State Instability in Orexin Knock-Out Mice. J. Neurosci. 
2004;24:6291-300 
 
6- Billiard M et al. EFNS guidelines on management of Narcolepsy. Eur J Neurol 2006;13:1035-48 
7- Dauvilliers Y et al. Clinical aspects and pathophysiology of narcolepsy. Clinical Neurophysiology 
2003;114:2000-2017 
8- Doghramji K et al, Electroencephalogr Clin Neurophysiol. 1997; 103:554-62 
                                                 

SAP_001.pdf: 
NCT number: 
NCT02611687    
Protocol ID:  P11-06/BF2.649 
 
 
 
Title: 
Double 
blind, 
mulƟcentre, 
randomized, 
placebo-controlled trial to evaluate safety and 
eﬃcacy of pitolisant in children from 6 to less 
than 18 years with narcolepsy with/without 
cataplexy, followed by a prolonged open-label 
period. 
 
 
 
Document: StaƟsƟcal Analysis Plan, Version 2.0_15 
November 2021 
 


 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
BIOPROJET - 1106 
 
PROTOCOL P11-06/ BF2.649 
 
EUDRACT NUMBER: 2013-001506-29 
 
 
Double blind, multicenter, randomized, placebo-controlled trial to evaluate safety and 
efficacy of pitolisant in children from 6 to less than 18 years with narcolepsy with/without 
cataplexy, followed by a prolonged open-label period.   
 
 
 
 
Final version v2.0 
 November 15th, 2021 
 
 
 
 
 
 
Sponsor: 
Bioprojet Pharma 
9 Rue Rameau  
75002 Paris 
France 
 
Author(s): 
 
 
 
 
 
 
 
 
 
DocuSign Envelope ID: AA3BA31A-0809-4F4D-9793-D207E0C36B77




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TABLE OF CONTENTS 
 
1 
List of abbreviations and definition of terms ......................................................................... 5 
2 
Introduction ......................................................................................................................... 6 
3 
Study description .................................................................................................................. 6 
3.1 
Study objectives .................................................................................................................... 7 
3.1.1 Primary objective ............................................................................................................... 7 
3.1.2 Secondary objectives ......................................................................................................... 7 
3.2 
Study design .......................................................................................................................... 7 
3.3 
Study plan ............................................................................................................................. 8 
3.3.1 Study duration .................................................................................................................... 8 
3.3.2 Data collected..................................................................................................................... 8 
3.3.3 Administration of IMPs ................................................................................................... 11 
3.4 
Changes in the conduct of the study ................................................................................. 11 
3.5 
 11 
4 
Statistical methods ............................................................................................................. 11 
4.1 
General statistical considerations ..................................................................................... 11 
4.1.1 Software used ................................................................................................................... 11 
4.1.2 Descriptive statistics ........................................................................................................ 11 
4.1.3 IMP groups comparison ................................................................................................... 12 
4.1.3.1 
Main Inferential model ............................................................................................ 12 
4.1.3.2 
Multiple Testing ....................................................................................................... 12 
4.1.4 Missing data ..................................................................................................................... 13 
4.1.4.1 
General considerations ............................................................................................. 13 
4.1.4.2 
Dates ........................................................................................................................ 14 
4.1.5 Derived variables ............................................................................................................. 15 
4.1.5.1 
General definitions ................................................................................................... 15 
4.1.5.2 
First and last IMP intake dates ................................................................................. 16 
4.1.5.3 
Completers ............................................................................................................... 16 
4.1.5.4 
Baseline characteristics ............................................................................................ 16 
4.1.5.5 
Efficacy data ............................................................................................................ 18 
4.1.5.6 
Safety data ................................................................................................................ 20 
4.1.6 Miscellaneous .................................................................................................................. 22 
4.2 
Sample size calculation ...................................................................................................... 22 
4.3 
Analysis populations and subgroups ................................................................................ 22 
4.4 
Protocol deviations ............................................................................................................. 23 
4.5 
Statistical analyses ............................................................................................................. 23 
4.5.1 Disposition and Baseline characteristics .......................................................................... 23 
4.5.1.1 
Patients disposition .................................................................................................. 24 
4.5.1.2 
Protocol deviations................................................................................................... 24 
4.5.1.3 
Demographic data and other baseline characteristics .............................................. 24 
4.5.2 Treatments of patients ...................................................................................................... 24 
4.5.2.1 
Extent of exposure and treatment compliance ......................................................... 24 
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4.5.2.2 
Concomitant treatments ........................................................................................... 24 
4.5.3 Efficacy analysis .............................................................................................................. 24 
4.5.3.1 
Primary endpoints .................................................................................................... 24 
4.5.3.1.1 Primary analysis ................................................................................................. 25 
4.5.3.1.2 Sensitivity and other analyses ............................................................................ 25 
4.5.3.2 
Secondary endpoints ................................................................................................ 26 
4.5.3.2.1 Pediatric Daytime Sleepiness Scale scores (PDSS) ........................................... 26 
4.5.3.2.2 Ullanlinna Narcolepsy Scale Cataplexy subscore (UNS-CTP) .......................... 26 
4.5.3.2.3 Weekly rate of Cataplexy (WRC) ...................................................................... 27 
4.5.3.2.4 Maintenance of Wakefulness Test 30-minute version ....................................... 27 
4.5.3.3 
Exploratory analysis................................................................................................. 28 
4.5.3.3.1 Ullanlinna Narcolepsy Scale EDS subscore (UNS-EDS) .................................. 28 
4.5.3.3.2 Clinical Global Impression of improvement ...................................................... 29 
4.5.3.3.3 Response to treatment according to the CGI-C .................................................. 29 
4.5.3.3.4 Child and Adolescent Sleepiness Scale (CASS) ................................................ 29 
4.5.3.3.5 Test of Everyday Attention for Children (TEA-Ch) .......................................... 30 
4.5.3.3.6 Patient sleep diary .............................................................................................. 30 
4.5.3.3.7 Patient’s Global Opinion on the effect of treatment .......................................... 30 
4.5.3.3.8 Withdrawal symptoms questionnaire (DSM IV) ............................................... 31 
4.5.4 Safety data ........................................................................................................................ 31 
4.5.4.1 
Adverse events ......................................................................................................... 31 
4.5.4.2 
Vital signs ................................................................................................................ 32 
4.5.4.3 
Laboratory evaluations............................................................................................. 32 
4.5.4.4 
Physical examination ............................................................................................... 33 
4.5.4.5 
Electrocardiogram .................................................................................................... 33 
4.5.4.6 
Childhood depression inventory (CDI) .................................................................... 34 
4.5.4.7 
Columbia-suicide severity rating scale (C-SSR) ..................................................... 34 
4.6 
Modifications from the statistical section of the protocol .............................................. 34 
4.7 
Interim analysis .................................................................................................................. 34 
5 
Tables, Listings and Graphs (TLG) ........................................................................................ 34 
6 
Template of tables, listings and graphs ............................................................................... 34 
7 
References ......................................................................................................................... 34 
 
 
 
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1 
List of abbreviations and definition of terms 
 
Abbreviations 
Definitions 
AEs 
Adverse events  
ANCOVA  
Analysis of Covariance test 
BMI 
Body mass index 
CASS 
Child and Adolescent Sleepiness Scale 
CDI 
Childhood Depression Inventory 
CGI-C 
Clinical Global Impression of Change 
CGI-S 
Clinical Global Impression of Severity 
CNS  
Central nervous system 
CRF 
Case report form  
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSM-IV 
Diagnostic System Medical, fourth version 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
EDS 
Excessive Daytime Sleepiness 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
ICSD  
International Classification of Sleep Disorders  
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
KLS 
Keyrus Life Science 
MAR 
Missing At Random 
MCMC 
Markov chain Monte Carlo  
MD 
Missing Data 
MI 
Multiple Imputation 
MNAR 
Missing Not At Random 
MSLT 
Multiple Sleep Latency Test 
MWT 
Maintenance of Wakefulness Test 
OSA  
Obstructive Sleep Apnoea syndrome 
PDSS 
Pediatric Daytime Sleepiness Scale 
PPS 
Per Protocol Set 
PS 
Paradoxical sleep 
PSG 
Polysomnography 
REM 
Rapid Eye Movement 
RS 
Randomised Set 
SAF 
Safety Set 
SAE 
Serious Adverse Event 
SD  
Standard Deviation 
TEA-Ch 
Test of Everyday Attention for Children 
UNS 
Ullanlinna Narcolepsy Scale 
UNS-CTP 
Ullanlinna Narcolepsy Scale - Cataplexy 
UNS-EDS 
Ullanlinna Narcolepsy Scale - Excessive Daytime Sleepiness 
TLG  
Tables, Graphs and Listings  
WRC 
Weekly rate of Cataplexy 
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2 
Introduction 
This document describes the frame of the statistical analyses that will be conducted for the study 
P11-06/ BF2.649: A double blind, multicenter, randomized, placebo-controlled trial to evaluate safety 
and efficacy of pitolisant in children from 6 to less than 18 years with narcolepsy with/without 
cataplexy, followed by a prolonged open-label period.   
This Statistical Analysis Plan has been written in agreement with: 
- 
The Clinical Study Protocol Version 3.0 dated September 30th, 2020 
- 
The Case Report Form (CRF) Version 7.0 dated December 16th , 2020 
This document is the reference document for all the statistical analyses of the blind part of this study. 
The purpose of this document is to describe: 
- 
The characteristics of the study as defined in the protocol: objectives, design and conduct of 
the study 
- 
The criteria/variables analysed and the derived variables to be created. 
- 
The planned statistical analysis and the methodology to be used. 
3 
Study description 
According to guidelines published by European task force [Billiard M et al, Eur J Neurol. 2006] i, 
management of narcolepsy with or without cataplexy relies on several classes of drugs, namely 
stimulants for EDS, antidepressants for cataplexy and hypnosedative drugs for disturbed nocturnal 
sleep [Dauvilliers Y et al, Clin Neurophysiol. 2003] ii.  
Narcolepsy is a neurological disorder frequently occurring from childhood and persisting through 
adolescence and adulthood. Individuals suffering from narcolepsy exhibit excessive daytime 
somnolence, sleep attacks, cataplexy, dysomnia, metabolic perturbations including weight gain, and 
problems in social interaction and academic performance. The prevalence of narcolepsy in childhood 
is not known but can be estimated from adult studies to be greater than 20-60 per 100,000 in 
Western countries. (Handb Clin Neurol. 2013; 112:839-45. doi: 10.1016/B978-0-444-52910-7.00003-
9. Pediatric narcolepsy: clinical and therapeutical approaches. Lecendreux M.) 
Narcolepsy occurs during childhood in combination with cataplexy in one-third of the subjects. 
Symptoms may develop rapidly over a few weeks or months, with excessive daytime sleepiness and 
cataplexy being the most dramatic and observable symptoms. It can be secondary to brain tumors or 
several rare diseases, but in most cases narcolepsy with or without cataplexy is a primary condition, 
better explained by the selective loss of hypocretin neurons in posterolateral hypothalamus. 
(Paediatr Drugs. 2014 Oct; 16(5):363-72. doi: 10.1007/s40272-014-0083-3. Pharmacological 
management of narcolepsy and cataplexy in pediatric patients. Lecendreux M) 
Pitolisant is an H3R inverse agonist that promotes significantly vigilance in narcoleptic patients. The 
results obtained in the previous studies showed that BF2.649 reduced significantly the diurnal 
somnolence compared to placebo confirming its wakening effect against EDS with a gain of 4.5 points 
on the ESS and demonstrating its anti-cataplectic effect when administrated on an individual titration 
scheme established on basis of individual benefit/tolerance ratio. Phase III studies compared 
pitolisant to Placebo and to modafinil the current first line treatment of narcolepsy: the results are 
in favour of pitolisant compared to Placebo and do not show any statistically significant difference 
compared to modafinil. 
The purpose of this study is to check whether Pitolisant (BF2.649) is efficient to decrease EDS and the 
supportive symptoms of narcolepsy in children from 6 to less than 18 years of age, as well as to 
reduce the number of cataplexy crises (for patients with cataplexy). 
 
 
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3.1 
Study objectives 
3.1.1 Primary objective 
The primary objective of this study is to compare pitolisant to placebo, with regard to Excessive 
Daytime Sleepiness (EDS) on the one hand, and to the number of cataplexy episodes, if any, on the 
other hand. 
This trial will characterize the efficacy of pitolisant (5-, 10-, 20-, 40 mg/d in Double Blind Period and 
5-, 10-, 15-, 20-, 30-, 40 mg/d in Open Label Period) compared to placebo in showing an incremental 
improvement to the situation particularly in terms of a reduction of EDS as measured by the 
Ullanlinna Narcolepsy Scale (UNS), and also on the number of cataplexy episodes, if any. 
3.1.2 Secondary objectives 
The secondary objectives of this study are to assess, between groups: 
- 
Changes in EDS measured: 
• 
by the maintenance of wakefulness test (MWT) 
• 
by the Paediatric Daytime Sleepiness Scale (PDSS) 
• 
by the Child and Adolescent Sleepiness Scale (CASS) 
- 
Changes in number of cataplexy episodes per weeks, recorded in sleep diary by patient and/or 
parent/teacher;  
- 
Severity of EDS and cataplexy measured by the clinical Global Impression of severity and 
change 
- 
Differences in weekly frequency of cataplexy episodes, recorded in sleep diary by patient 
and/or parent/teacher; 
- 
Changes in the TEA-Ch test 
- 
Comparison in withdrawal symptoms questionnaire 
- 
Comparison in patients' Global Opinion on treatment effect at the end of treatment.  
- 
To check the clinical and biological tolerance of pitolisant. 
3.2 
Study design 
This is a double blind, multicenter, randomized trial followed by a prolonged open-label period.   
This SAP only deals with the blind part. 
 
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3.3 
Study plan 
3.3.1 Study duration 
The expected duration of patient participation from the screening visit (V0) until the final blind visit 
(V8) will be 13 weeks, including:   
- 
Baseline period without investigational treatments (from V0 to V2): 4 weeks,  
- 
Low and medium dose titration phase (from V2, randomisation, to V3): 2 weeks,  
- 
Individual dose adjustments (from V3 to V5): 2 weeks,  
- 
Stable dose phase (from V5 to V7): 4 weeks,  
- 
1-week study drug wash out (placebo) after study drug discontinuation.  
During the blind phase, the patient will be followed in an ambulatory way by 9 visits (8 visits during double blind period 
and 1 visit for the single blind period) on the site. 
3.3.2 Data collected 
A detailed list of procedures performed at each visit is presented in table1. 
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Table 1: Study Schedule measurement in blind period 
 
 
 
 
 
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3.3.3 Administration of IMPs 
When the patient receives his/her study number, the corresponding investigational treatment 
identified by the treatment number will be allocated to the patient according to the randomization 
list established by an independent company and managed by Interactive Web Response Services 
(IWRS) according to randomization. 
The study treatment will be dispensed only under the restricted condition defined in the protocol. 
The treatment will be dispensed only by the investigator under his direct supervision or the 
pharmacist. Time of dispensation and initials of the person dispensing the drug will be recorded in 
the CRF. The tear-off label of each pack will be stuck on the prescription form. 
At each visit the compliance to the treatment will be investigated. Details of the quantities of each 
medication dispensed will be entered into the accountability form. The patients will be asked 
whether the investigational treatment is taken as prescribed. If not, any change in the treatment and 
the number of forgotten tablets will be recorded in the case report form (CRF). In addition, the 
number of remaining tablets in the pillbox will be counted and compared to the theoretical number. 
Any mismatch will be investigated with the patient. 
3.4 
Changes in the conduct of the study 
The last version of the protocol is version 3.0, dated September, 30th 2020. The original protocol was 
amended 3 times. The list of exhaustive changes is described in the summary of changes from each 
protocol amendment. 
 
  
 
 
 
 
 
 
  
4 
Statistical methods 
4.1 
General statistical considerations 
4.1.1 Software used 
All statistical analyses will be performed with the SAS software version 9.4 or higher. 
4.1.2 Descriptive statistics  
Continuous variables will be described using: number of non-missing observations (N), number of 
missing observations (Nmiss), arithmetic mean (Mean), standard deviation (SD), minimum (MIN), 
quartile 1 (Q1), median (Median), quartile 3 (Q3) and maximum (MAX). MIN, Q1, Median, Q3 and 
MAX will be given at the data number of decimal points. Mean and SD will be given at 1 additional 
decimal point.  95% two-sided confidence interval (CI) will be calculated when appropriate using the 
standard method (Standard normal distribution).  
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Categorical variables will be presented using N, Nmiss and percentages (%). Missing data or 
unknown responses will not be included in the denominator for the calculation of percentages but 
will be presented in the results tables. Proportions will be displayed with one decimal. 
4.1.3 IMP groups comparison 
4.1.3.1 Main Inferential model  
Unless otherwise specified, all the endpoints referred in detail in the following section will be 
analyzed according the same statistical model allowing a comparison of results between the studied 
endpoints. The significance of the difference between the IMP compared with placebo will be 
assessed through a general model of analysis of Covariance (ANCOVA) in which the studied endpoint 
at final time (noted Yf) constitutes the dependent variable of the model. Independent variables are 
(1) the baseline value of the studied endpoint (noted Yb) analyzed as a fixed covariate, (2) the 
treatment effect (Noted Trt) coded 0 (placebo) or 1 (IMP)  (cell mean contrast formulation),  and (3) 
the center considered as a random factor of the intercept constituted by a fixed part k0 and a random 
component N(0,σc). This model is summarized by the following expression:   
Yif = (k0+ζ) + kb Yb + kt Trt + ϵi     ϵi = N(0,σ )  and  ζ = N(0,σc)   [general Model -1 ] 
Note 1-This model does not assume a treatment-baseline interaction term (as required in CPMP, 
2003). Our decision of using center as a random factor is justified by the useless estimate of each 
center, in focusing on the measurement of the standard deviation of the intercept. The treatment 
will be considered as fixed factor without center random component.  
Note 2- This model is a Linear Mixed Model (LMM) as it combines random and fixed factors, assumes 
linearity of baseline and hypothesizes the studied endpoint distributed according to a normal 
(Gaussian) distribution.  This model constitutes the main model used in this trial for all the studied 
endpoints unless otherwise specified. 
4.1.3.2 Multiple Testing 
(ICH E3; 9.7.1, 11.4.2.5. ICH E9; 2.2.5, FDA-2017) 
The main analysis is defined as the analysis of covariance following general Model 1 [section 4.1.3.1] 
conducted on the main selection (FAS), on the primary endpoint (UNS) considered as a global 
endpoint aggregating both EDS and cataplexy symptoms. Secondary endpoints will be PDSS and the 
UNS-CTP subscale measuring the IMP effect on EDS and cataplexy, respectively. Two other secondary 
endpoints will be the weekly rate of cataplexy measured by the patient diary (WRC) and the MWT. All 
the other endpoints will be considered as exploratory and supportive. 
The main endpoint (UNS) and the four secondary endpoints necessitate 5 tests. We will use the fixed-
sequence strategy testing the endpoints in the pre-defined order UNS, PDSS, UNS-CTP, WRC and 
MWT, each one tested at two-sided α=.05 significance, moving to the following endpoint 
conditionally to a significant difference reached on the previous endpoints (FDA, section C.5).  This 
strategy protects the results with type 1 risk bounded by P=.05. 
Our choice is justified as follows: UNS constitutes a global appraisal of both EDS and cataplexy in 
pediatric narcolepsy and must regarded as a relevant general first endpoint. PDSS and UNS-CTP are 
validated scales to measure EDS alone and cataplexy alone, respectively. Conditionally to a significant 
effect on the main UNS endpoints, the effect of the IMP will be assessed on the two symptoms, 
separately. Finally MWT and WRC are alternative endpoints to measure EDS and cataplexy, 
respectively, and will be assessed conditionally to the significance obtained on UNS, PDSS and UNS-
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CTP. Besides, EDS is a more frequent symptom, thus it was tested before cataplexy, and PDSS and 
UNS-CTP were shown with a higher power than MWT and WRC, respectively [ref-validation]  
4.1.4 Missing data  
4.1.4.1 General considerations 
(ICH E3; 9.7.1, 11.4.2.2. ICH E9; 5.3. EMA Guideline on Missing Data in Confirmatory Clinical Trials) 
Missing data will be imputed for five main endpoints of this study (UNS, PDSS, UNS-CTP, WRC and 
MWT).  For the other endpoints no missing value will be imputed.   
A Multiple Imputation (MI) procedure will be used to impute the missing evaluations, as a prior step, 
assuming that those patients would be in their randomized arm. The partially complete datasets will 
be generated with a model including the following covariates age, gender and the main model 
components (section 2.2).  
A total of 100 imputed partially complete datasets will be generated. 
MI inference involves 3 consecutives phases: 
- 
1/ Imputation step: 
The missing pattern is supposed to be monotone, so the regression method will be used to impute 
missing data.  
The partially complete datasets will be generated with a model including age, gender factors and 
taking into account the baseline score of the primary endpoint, based on patient which every post-
baseline measurement available. It is of note that this imputation step might be preceded by one MI 
approach based on MCMC method, in case of arbitrary missing pattern. A total of 100 imputed 
partially-complete datasets will be generated. 
The mean MD imputation will based on Missing at Random (MAR) corresponding to the hypothesis 
that missingness is assumed independent of the outcome, or to estimate a “de jure” (per protocol) 
estimand, censoring after any protocol deviation. This hypothesis was considered as the most likely 
in this particular context.  
Despite the likelihood of this option, a secondary MD imputation will be conducted according to the 
Missing at Random hypothesis (MNAR), for which several options to construct the joint distribution 
of the observed and unobserved data have been proposed, each reflecting a different MNAR 
mechanism (Carpenter et al., 2013). This appropriate choice was discussed in the general context of 
narcolepsy. We assumed that after dropping out, participants from the active arm have the same 
outcomes as the reference group individuals, hypothesizing that the treatment effect is lost after the 
individual leaves the study. This option is called Jump to reference (J2R), after dropout, the 
participant's conditional outcomes are associated to those of the control arm. The joint distribution 
is a Multivariate Normal model with mean parameters from the randomised arm until date of 
interruption (Di) and from the reference group afterward. The covariance matrix corresponds to the 
parameters from the randomised arm until Di and to the reference group for the conditional 
components of the post‐dropout variables, given the pre‐dropout measurements. 
Concerning the J2R, the jump-to-placebo approach will be set up for these patients’ imputations, by 
using the %mistep macro from James Roger (https://www.lshtm.ac.uk/research/centres-projects-
groups/missing-data#dia-missing-data , zip file MISTEP20180327).  
Usualy, a sequence of %mistep is run, the subsequent models include the residuals of the previous 
model. In this study only one model will be used (for the endpoint value imputation). 
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- 
The mean of V6 and V7 values. In case of a visit missing value, the End value will be equal to 
the non-missing value. 
4.1.5.2 First and last IMP intake dates 
For patients having taken at least one dose of IMP over the period V2-V7, the dates of first and last 
IMP intake on the analysis period will be defined as follows: 
- The date of the first IMP intake at the first visit performed within the analysis period, 
- The date of the last IMP intake at the last visit performed within the analysis period. 
After selection of the dates of first and last IMP intake as defined above, if these dates are missing or 
incomplete, substitution rules will be applied to identify baseline value and emergent adverse events. 
4.1.5.3 Completers 
 Completers the double blind period 
Patients who completed the study until the visit V7. 
 Completers the blind period 
Patients who completed the study until the visit V8. 
4.1.5.4 Baseline characteristics 
 Previous treatments 
The existence of a previous treatment (Yes/No) is defined from the presence, or not, of an 
Anatomical therapeutic chemical classification and/or Preferred name. 
Previous treatment is defined as any treatment with associated stop date strictly inferior to the 
first IMP intake date. 
Note: In case of patient randomised but not treated the previous treatment is defined as any 
treatment with an associated stop date strictly inferior to the date of the randomisation visit. 
 Concomitant treatment 
The existence of a concomitant treatment (Yes/No) is defined from the presence, or not, of an 
Anatomical therapeutic chemical classification and/or Preferred name. 
The periods considered for the analysis are: 
- At inclusion for which treatments with start date ≤ inclusion date (V2) and stop date ≥ inclusion 
date (V2) or missing are taken into account. 
- During the treatment period for V2-V7 period for which treatments: 
 with start date ≥ first IMP intake date and < last IMP intake date, or 
 with start date ≤ first IMP intake date and stop date ≥ first IMP intake date or missing date 
are taken into account.  
Concomitant treatments could be considered in one or several of the possible analysis periods. 
Intake of oxybate sodium (Yes/No): A patient will be considered to have taken at inclusion or 
during the treatment period a concomitant treatment which the Standardized Medication 
Name="OXYBATE SODIUM".  
 Narcolepsy duration (years) 
(Inclusion visit date (V2) - confirmed diagnosis date +1) /365.25 
 Study duration (in days) 
Last visit date until V8– Inclusion visit date (V2) + 1 
 Treatment duration (in days) on V2-V7 period  
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 Age (in classes) 
Two age classes will be computed: 
o [6-11] years,  
o [12-18[ years, 
 BMI 
For weight, only one decimal should be kept for the analysed values. 
The Body Mass Index is calculated at a visit in the database: 
BMI (kg/m²) = Weight (kg) / (Height (cm) x 0.01)², 
using the height and the weight recorded at the corresponding visit. 
The result is rounded to one decimal place. 
The BMI Classes refer to the statistical methodology used by the WHO standards. 
This methodology is computed according to the sex and the age in months. 
For each visit, the calculated age at the concerned visit is taken into account. 
- If it’s a boy, the reference table is the table « BMI-for-age_WHO.xls» sheet « Boys » 
- If it’s a girl, the reference table is the table « BMI-for-age_WHO.xls» sheet « Girls » 
According to these tables: 
- If the BMI < -2SD then BMI class= « underweight » 
- If the -2SD ≤ BMI ≤ +1 SD then BMI class= « normal range » 
- If the +1SD < BMI ≤ +2 SD then BMI class= « overweight » 
- If the BMI > +2 SD then BMI class= « obese » 
4.1.5.5 Efficacy data 
 Ullanlinna Narcolepsy Scale (UNS) 
For the subscores recalculation the correspondence between the character and numerical 
modalities: 
For questions about « Knees unlocking symptoms » (UNS01), « Mouth opening symptoms » 
(UNS02), « Head nodding symptoms » (UNS03) and « Falling down symptoms » (UNS04) : 
Character 
Numeric 
NEVER 
0 
1-5 TIMES DURING LIFETIME 
1 
MONTHLY 
2 
WEEKLY 
3 
DAILY OR ALMOST DAILY 
4 
For questions about « Fall asleep during reading » (UNS07), « Fall asleep during travelling » 
(UNS08), « Fall asleep during standing » (UNS09), « Fall asleep during eating » (UNS10) and 
« Fall asleep during other unusual » (UNS11) : 
Character 
Numeric 
NEVER 
0 
1-5 TIMES DURING LIFETIMES 
1 
MONTHLY 
2 
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WEEKLY 
3 
DAILY OR ALMOST DAILY 
4 
For the question « Fast to feel asleep the evening » (UNS05): 
Character 
Numeric 
>40 MIN. 
0 
31-40 MIN. 
1 
21-30 MIN. 
2 
10-20 MIN. 
3 
<10 MIN. 
4 
For the question « Sleep during the day» (UNS06): 
Character 
Numeric 
NO NEED 
0 
I WANTED BUT CANNOT SLEEP 
1 
2 DAYS OR LESS EACH WEEK 
2 
3-5 DAYS EACH WEEK 
3 
6-7 DAYS EACH WEEK 
4 
Two sub-scores are derived: 
 The cataplexy score:  
Sum of the first four items (UNS01 + UNS02 + UNS03 + UNS04) 
 The EDS score:  
Sum of the seven other items (UNS05 + UNS06 + UNS07 + UNS08 + UNS09 + UNS10 + 
UNS11) 
 CGI 
Two scores are computed within the ranges of 0 -7 (0 = Not assessed): 
o Global Improvement (CGI-I) score 
o Severity (CGI-S) score 
The response to treatment according to CGI-I is derived at a visit as:  
- If CGI-I score = 1 (very much improved) or 2 (much improved) or 3 (minimally improved) then 
response to treatment at the visit = Yes.   
- If CGI-I score > 3 then response to treatment at the visit = No. 
- Otherwise, response to treatment at the current visit is not calculated. 
 Pediatric Daytime Sleepiness Scale scores (PDSS) 
The response to treatment according to PDSS is derived at a visit as a score reduction of 3 
Between the baseline and the final value: 
- If PDSSB-PDSSF ≥ 3 then response to treatment at the visit = Yes.   
- If PDSSB-PDSSF < 3 then response to treatment at the visit = No. 
- Otherwise, response to treatment at the current visit is not calculated. 
 Maintenance of Wakefulness Test 30-minute version 
For this assessment the four test have been considered. Therefore, arithmetic means and sum 
on these 4 tests are computed. 
 
Mean value for each latency parameter, in minutes, for a visit, will be estimated as the arithmetic 
mean of the 4 tests. 
Before this mean computation each latency parameter (sleep onset, Stade I, Stade II, stade III 
and SP) must be recalculed to take into account the “Awake” status and the test duration: 
- 
For a test, if “Awake”= “yes” then the sleep onset latency has to be considered at 30min 
(even if another value is entered). 
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- 
If a reported value is greater than 30min this value will be censured at 30min. 
 
Number of Sleep onset in SP for a visit, will be computed as the sum of Yes (=1) of the 4 tests. 
 
A survival response will be computed according to the “sleep onset latency” recalculed: 
- 
Non-response (0=patient remained awake until 30 minutes) = Mean sleep onset latency ≥ 
30min. 
- 
Response (1=patient falling asleep before 30 minutes) = Mean sleep onset latency < 
30min. 
 
 Patient sleep diary 
- 
Rate of cataplexy (WRC), Number of diurnal involuntary sleep attacks and episodes of severe 
daytime sleepiness  (NSAE) and Number of hallucinations and sleep paralysis episodes (NHS) 
are weekly ratio computed as : 
 [Number of episodes of the concerned parameter in the period / Number of days in the 
period] * 7 
Whith Number of days in the period= Date of the last visit of the period - Date of the 
first visit of the period + 1 
Results are rounded to to the nearest integer number. 
 
- 
Night duration (NightD), in hours, is calculated as: 
Wake-time (morning) - Hour of bedtime (evening) 
The mean of night duration per day during the studied period is computed as: 
Sum of night duration in the period / Number of days in the period 
Whith Number of days in the period= Date of the last visit of the period - Date of the 
first visit of the period + 1 
The result is rounded to one decimal place. 
In case of several hours at the same date the following rule will be applied: 
o For wake-time the last hour will be kept 
o For bedtime the first hour will be kept 
4.1.5.6 Safety data 
 Adverse Event 
o Treatment Emergent Adverse Event 
 A Treatment Emergent Adverse Event (TEAE) corresponds to an Adverse Event (AE) that occurred on 
or after first dose of treatment up to 7 days post-last dose. 
 
In case of partially/fully missing AE start date:  
- 
Following imputation rules should be applied in order to determine whether the AE is 
treatment-emergent or not: 
o If only start day is missing, then it will be replaced by the minimum of (last day of the 
month, last treatment dose intake) 
o If both start day and month are missing then: 
 if year is equal to the year of the first treatment dose intake, then start date will 
be replaced by the first treatment dose intake 
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 if year is greater than the year of the first treatment dose intake and equal to 
the year of the last treatment dose intake, then start date will be replaced by 
the last treatment dose intake 
 if year is greater than the year of the first treatment dose intake and smaller 
than the year of the last treatment dose intake, then start date will be replaced 
by 1-July 
o If start date if fully missing, then start date will be replaced by the date of the first 
treatment dose intake 
- 
Emergence will be checked in accordance with the response to the question « Started before 
study drug intake ». If the response is “Yes” the AE can’t be considered as emergent 
o Treatment Emergent Adverse Events related to study treatment 
An event is considered to be related to the study treatment if the assessment of imputability is likely 
related or possibly related, or if the assessment is missing. 
o Non-Treatment Emergent Adverse Events (non-TEAEs) 
Non-TEAEs are AEs that occurred prior to treatment. 
o Serious Adverse Events 
By definition, a serious AE (SAE) is an AE that, at any time, fulfils one or more of the following criteria: 
- 
results in death, 
- 
is life threatening (patient at risk of death at the time of the event), 
- 
requires in-subject hospitalisation or prolongation of existing hospitalisation, 
- 
results in persistent or significant disability/incapacity, 
- 
is a congenital anomaly/birth defect, 
- 
is any medically important. 
The seriousness of the event will be directly assessed by the investigator (specific variable within the 
AE database); therefore no derivation is needed.   
o Special Interest AEs  
Special Interest AEs are AEs with the following MedDRA Preferred Terms (PTs): 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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o Treatment Emergent Adverse Events in the stable dose period  
The stable dose is the treatment dose taken during the period V5 to V7.  
So TEAE in the stable dose are TEAE occurred between visit V5 (included) and the visit V7 
(included) 
 ECG 
The following classes will be derived for QTCF : <= 450,] 450; 480],] 480; 500] and > 500 
4.1.6 
Miscellaneous  
- All the summarized tables mentioned in this SAP will be provided as RTF/HTML or WinWord 
compatible format (and not as text format). This allows direct insertion of these tables unchanged 
in the Clinical Study Report.  
-Unless otherwise specified, the significance test will be conducted at a two-sided significance 
level of 0.05   
-A third party statistician will independently review the Statistical Analysis Report before 
disclosing the results.  
4.2 
Sample size calculation 
(ICH E3; 9.7.2. ICH E9; 3.5) 
The initial protocol was based in assuming a Pearson correlation coefficient of R=0.5 between pre-
baseline and final values of PDSS, two pre-baseline measurements [(V1+V2)/2] and two post-baseline 
measurements [(V6+ V7)/2]. A standardized mean difference of at least 0.5 (considered as the 
minimum clinically significant difference) will be detected at a two-sided 0.05 confidence level with a 
power of at least 0.8, when the sample size/group is at least 20 and 40 patients for control and tested 
drug groups, respectively. 
At a later stage, UNS measuring EDS and cataplexy was used as the primary outcome instead of the 
PDSS. As UNS was expected with a residual variability larger than PDSS, the initial power of .75 judged 
as too small, a recalculation of the sample size was performed on a standardized mean difference of 
0.5 on the UNS (considered as the minimum clinically significant difference), a ratio 1:2, and a 
correlation R=0.4. Under these assumptions, and ANCOVA test at 0.05 two-sided confidence level, 
the probability of a significant effect will be found with a power of 0.85 when the sample size exceeds 
36+72 patients for control and tested drug groups, respectively, thus a total of 108 patients.  
4.3 
Analysis populations and subgroups 
 Screened Set (ScS):  
All patients with an Informed consent form signed. 
 
 Randomised Set (RS):  
All randomized patients. 
 
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 Full Analysis Set (FAS): 
In accordance with the intention-to-treat principle and Section 5.2.1 of the ICH E9 guideline, all 
randomised patients who received at least one dose of IMP and who have at least one baseline value 
of UNS (primary efficacy criterion). 
 
 Per Protocol Set (PPS): 
Consists of all patients in the FAS without any major protocol deviation and having one total score 
UNS value at V6 or V7.  
A protocol deviation is major when it has a possible effect on the outcome. As to whether a deviation 
is major or minor is fixed during the Blind Review Meeting.  
The Per protocol analysis will be conducted at the condition that its sample size should be less than 
90% of the FAS. 
 
 Safety Set (SAF):  
All patients who receiving at least one treatment dose. 
 
4 subgroups will be used in some analyses, according to: 
- 
Age at baseline ([6-11], [12-18[) 
- 
Sex 
- 
BMI  at baseline (underweight , normal, overweight and obese) 
- 
Type of narcolepsy (Type 1 or Type 2) 
4.4 
Protocol deviations 
PDs will be defined as early as possible during the study conduct.  
All PDs will be carefully identified through eCRF data before the BDRMs. During the BDRMs held 
before database lock (DBL), each PD will be classified as leading to exclusion from the PP population 
(“major”) or not leading to exclusion from the PP population (“minor”).  
All PDs related to study inclusion or non-inclusion criteria, conduct of the trial, patient management 
or patient assessment will be described, such as: 
- Violation of inclusion criteria 
- Violation of exclusion criteria 
- Intake of non-allowed concomitant medications  
- Randomisation error 
- Lack of compliance 
- Etc. 
Additionally, the PDs that could not be identified through eCRF data will also be reviewed during the 
BDRMs. This listing will be based on the PD forms completed by the study team. Any “major” PD or 
information needed to conduct the statistical analyses will be extracted from the listing and imported 
in the database.  
4.5 
Statistical analyses 
Details concerning definitions about derived parameters are provided in section 4.1.5. 
4.5.1 Disposition and Baseline characteristics 
Disposition of patients and baseline characteristics will be described by randomised treatment group, 
to assess their comparability, and overall (treatment groups pooled). 
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4.5.1.1 Patients disposition 
Disposition of patients, including reasons for withdrawal, will be summarized during the study by 
randomised treatment, overall and by center, in the RS and in the FAS. 
If necessary a listing of non-included randomised patients will be provided. 
4.5.1.2 Protocol deviations 
Protocol deviations at inclusion or after inclusion on V2-V8 period, will be described in the RS, by 
category of important deviations (based on ICH E3 guideline and ICH E3 Q&A). 
4.5.1.3 Demographic data and other baseline characteristics 
Demographic data and other baseline characteristics such as age, sex, contraception, narcolepsy 
history, ECG, vital signs, Polysomnography and Multiple Sleep Latency Test, Clinical Global Impression 
of baseline Severity (CGI-S) and baseline value of endpoints characteristics will be described. 
As the populations RS and FAS are identical, only description in the RS will be done. 
All previous treatments will be described. 
4.5.2 Treatments of patients 
Details concerning definitions on extent of exposure, treatment compliance and concomitant 
treatments are provided in section 4.1.5 . 
4.5.2.1 Extent of exposure and treatment compliance 
Extent of exposure (Study duration (days) and treatment duration (days)) and treatment compliance 
(%) will be described in the FAS and the SS. 
The treatment duration will be described on the period V2-V7. 
4.5.2.2 Concomitant treatments 
All concomitant treatments (specific and non-specific) taken at inclusion and during the treatment 
period (over the V2-V7 period) will be described in the RS, by ATC code. 
A listing will be provided for every patient documenting the existing concomitant medication with 
date of start and end of treatment.  
4.5.3 Efficacy analysis 
All efficacy analyses will be performed by randomised treatment group in the FAS and in the PPS. 
For inferential analyses involving several results according to the imputation method (MAR, MNAR 
and observed cases), if there isn’t any missing data in the Per Protocol Set, consequently only results 
with observed cases will be compute. 
4.5.3.1 Primary endpoints 
The Ullanlinna Narcolepsy Scale (UNS) is an 11-item scale measuring the intensity and frequency of 
symptoms of narcolepsy. The first four items address typical manifestations of cataplexy occurring in 
situation as laughing, feeling glad or angry or any exciting situation. The 7 other items measure the 
sleep latency and the propensity to fall asleep in various situations. The total severity score varies 
from 0 to 44. 
Definition:  
The primary efficacy endpoint is defined as the change from baseline to final value in the total UNS 
Raw score. 
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4.5.3.1.1 
Primary analysis 
Analysis:  
In order to meet the primary objective of the study, the superiority of Pitolisant (BF2.649) as 
compared to placebo on efficacy after a 7-week treatment period will be assessed, from the UNS 
total score expressed in terms of change from baseline to Final value. After a Multiple Imputation, 
the main inferential model with the center as random effect described in section 4.1.3.1 will be used. 
The assumptions underlying the model will be checked. 
The difference between treatment groups will be calculated as BF2.649 minus placebo. Thus, 
considering the main analysis, a negative treatment difference will be in favour of BF2.649. 
 
The ICH-E9(R1) addendum on Estimands and Sensitivity Analysis in Clinical Trials (ICH, 2020) provides 
a framework for defining an estimand which is characterized by five attributes: population, endpoint, 
intercurrent events and population-level summary. The primary estimand for the primary endpoint 
of the study is defined with mixed strategies for intercurrent events and described in this table (based 
on the estimand terminology). 
The following table summarizes the main endpoint according to the Estimand Notation (ICH-E9R1):  
Attribute1 
Primary definition 
Rationale (as needed) 
Population 
Intended to include narcoleptic children from 6 to 
less than 18 years of age with/without cataplexy. 
 
Endpoint 
Ullanlinna Narcolepsy Scale (UNS) at V6, V7 
 
 
 
 
Intercurrent 
events 
Event 
Strategy 
Rationale (as needed) 
Receipt of assigned study treatment 
Treatment 
policy 
Strategy applied to align the estimand with 
the application of the ITT principle. 
Prohibited concomitant medication 
during the study treatment period  
While on 
treatment 
Strategy applied to assess the treatment 
effect up to the last observation at or prior to 
the time of the prohibited concomitant 
medication, which marks the end of 
adherence to treatment. 
Premature discontinuation from the 
study at any time 
Hypothetical 
strategy 
Strategy applied to estimate what the 
treatment effect would have been if patients 
adhered to the treatment by assuming that 
missing data arise from a missing at random 
(MAR) mechanism. 
Population 
summary 
Difference in LS means from ANCOVA model 
between treatment groups. 
 
 
Statistical elements: 
For this comparison the following elements will be provided in a summary table: 
- Estimate (standard error) of the difference between adjusted treatment group means. 
- Two-sided 95% CI of the estimate. 
- p-value (to be compared to 0.05). 
4.5.3.1.2 
Sensitivity and other analyses 
Sensitivity analyses will be performed to assess the robustness of the primary analysis results: 
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- Using MNAR option of the MI imputation (removing the treatment effect in the imputation 
model of the partially-complete data sets).  
- Using the same model as for the primary analysis will be performed with the center as fixed 
effect instead of random effect.  
- Using the same model as for the primary analysis will be performed with in addition the 
oxybate sodium intake and treatment-by- oxybate sodium intake interaction as fixed effects.  
- Using an observed Cases analysis: The same model as for the primary analysis will be 
performed in patients having a value of UNS total score at V6 or V7 (i.e. in this case analysis 
restricted to completers the double blind period).  
- Using the same model as for the primary analysis will be performed by actual treatment 
group, only if actual group is different from randomized group.  
 
The same statistical elements to estimate the treatment effect as for primary analysis will be 
provided. 
In addition, value and change from baseline descriptive statistics at each visit by treatment group will 
be provided, overall and by subgroups. 
4.5.3.2 Secondary endpoints 
4.5.3.2.1 
Pediatric Daytime Sleepiness Scale scores (PDSS) 
PDSS is a sum score with 8 items leading to a score range of 0-32. A score greater than 13 is 
considered as abnormal sleepiness. 
Analysis:  
The difference between placebo and BF2.649 will be studied in the same way as the primary analysis 
(Including sensitivity analyses). 
In addition,  
- Descriptive statistics at baseline and at each post-baseline visit by treatment group and an 
évolution graph of Mean ± SE will be provided. 
- Comparison by treatment group of the response to the treatment (between Baseline value 
and End of treatment value) using a Chi2 test will be provided. 
Statistical elements: 
For this comparison the following elements will be provided in a summary table: 
- Estimate (standard error) of the difference between adjusted treatment group means. 
- Two-sided 95% CI of the estimate. 
- p-value (to be compared to 0.05). 
4.5.3.2.2 
Ullanlinna Narcolepsy Scale Cataplexy subscore (UNS-CTP) 
This subscore is defined as the sum Sum of the first four items of the UNS. (Cf. 7 Plazzi, G, P.Lehert, 
2021) 
Analysis:  
The difference between placebo and BF2.649 will be studied in the same way as the primary analysis 
(Including sensitivity analyses), only in the type I Narcolepy patients. 
In addition,  
- Descriptive statistics at baseline and at each post-baseline visit by treatment group and an 
évolution graph of Mean ± SE will be provided. 
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- Descriptive statistics at baseline and at each post-baseline visit by treatment group of the 
response to the treatment will be provided. 
Statistical elements: 
For this comparison the following elements will be provided in a summary table: 
- Estimate (standard error) of the difference between adjusted treatment group means. 
- Two-sided 95% CI of the estimate. 
- p-value (to be compared to 0.05). 
4.5.3.2.3 
Weekly rate of Cataplexy (WRC) 
Patients (or assisted by their parents or legal representative or teacher) shall fill in the document on 
a daily basis throughout the double blind phase (13 weeks) and the 7-day prior to the next visit during 
the open-label period. At each visit the patient should bring back his/her diary to the site for review 
by the investigator. The investigator reviewed these records with the patient. 
One of calculated parameters is the Weekly rate of cataplexy (partial and total). 
Analysis:  
A negative Binomial Regression will be used according to the general model (section 2.2) for WRC 
estimated during the period V6-V7 (Justification Plazzi 2021) only in the type I Narcolepy patients (for 
other patients we don’t have the baseline value). The WRC at baseline will be used as a fixed covariate 
and center as random (In case of non convergence of the model, this one can be updated). 
The same way as the primary analysis (Including sensitivity analyses) will be performed: MAR and 
MNAR imputation and observed cases. 
In addition,  
- Descriptive statistics by treatment group during the following intervals: Baseline (D-28 to D0), 
Final DB last 6 weeks DB4=D21-D63 (i.e. V4-V7), Final DB last 2 weeks: DB2=D49-D63 (i.e. V6-
V7) will be provided 
- A supportive analysis will be to compare the proportion of patients such that WRC <1 between 
treatment groups (simple logistic regression providing OR with 95%CI) 
Missing data handling:  
Multiple Imputation (MI) procedure will be used to impute the missing evaluations (Cf.section 
4.1.4.1). 
Statistical elements: 
For this comparison the following elements will be provided in a summary table: 
- Estimate (standard error) of the difference between adjusted treatment group means. 
- Two-sided 95% CI of the estimate. 
- p-value (to be compared to 0.05). 
 
4.5.3.2.4 
Maintenance of Wakefulness Test 30-minute version 
The Maintenance of Wakefulness Test (MWT) is used in this study to assess an individual’s ability to 
maintain awake while resisting the pressure to fall asleep.  Patients will be administrated four 30-
minute MWT sessions at 2-hour intervals at inclusion visit (V2) and at endpoint visit (V7 or the last 
on-study visit). Each session is terminated either at the first unequivocal onset of sleep defined as 
above or, if sleep onset is not achieved, after maximum in-bed duration of 30 minutes.  
 
 
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Analysis:  
MWT was right censored after 30 minutes, resulting into a truncated asymmetric distribution (Plazzi 
2021).  
A Cox proportional regression will be conducted in considering time to sleep onset (mean of the 4 
tests at final visit) and survival response defined as non-response (0=patient remained awake until 
30 minutes) and response (1=patient falling asleep before 30 minutes). Patients early terminating for 
treatment-related or -unrelated reason will be considered as responders or right-censored at the 
time of interruption, respectively. Center will be considered as a cluster variable in the Cox model to 
allow calculation of robust variance for the model assuming clusters with correlated observations 
[Andersen 1982, Therneau 2000].  
This analysis will be done only in patients with at least a baseline value or a final value (V7 or the last 
on-study visit).  
The same way as the primary analysis (Including sensitivity analyses) will be performed: MAR and 
MNAR imputation, center as fixed effect (in MAR imputation) and observed cases. 
 
Descriptive statistics (mean values for each latency parameter and number of Sleep onset in SP) at 
baseline and V7 by treatment group will be provided. 
Missing data handling:  
Multiple Imputation (MI) procedure will be used to impute the missing evaluations (Cf.section 
4.1.4.1). 
Statistical elements: 
For this comparison the following elements will be provided in a summary table: 
- Estimate (standard error) of the difference between adjusted treatment group means. 
- Two-sided 95% CI of the estimate. 
- p-value (to be compared to 0.05). 
 
4.5.3.3 Exploratory analysis 
4.5.3.3.1 
Ullanlinna Narcolepsy Scale EDS subscore (UNS-EDS) 
This sub-score EDS is computed for all patients. 
Analysis:  
- The difference between BF2.649 and placebo will be studied in the same way as the primary 
analysis (with only one sensitivity analysis: the same model as for the primary analysis by 
actual treatment group, only if actual group is different from randomized group).  
In addition,  
- Descriptive statistics at baseline and at each post-baseline visit by treatment group and an 
évolution graph of Mean ± SE will be provided. 
- Descriptive statistics at baseline and at each post-baseline visit by treatment group of the 
response to the treatment will be provided. 
Missing data handling:  
Missing evaluations are not imputated. 
Statistical elements: 
For this comparison the following elements will be provided in a summary table: 
- Estimate (standard error) of the difference between adjusted treatment group means. 
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- Two-sided 95% CI of the estimate. 
- p-value (to be compared to 0.05). 
4.5.3.3.2 
Clinical Global Impression of improvement 
Clinical Global Impression of improvement is measured for EDS and cataplexy at V6, V7 and V8.   
Definition: 
This endpoint is defined as the value at the end of each period (V2-V7 and V7-V8) in Global 
Improvement (CGI-I). 
Analyses: 
The difference between placebo and BF2.649 will be studied at end of each period using a two-sided 
Student’s t-test for independent samples and a Mann-Whitney test. 
Missing data handling:  
Missing evaluations are not imputated. 
Statistical elements: 
For these comparisons the following elements will be provided in a summary table: 
- Estimate (standard error) of the difference between treatment group means 
- Two-sided 95% CI of the estimate. 
- P-value from two-sided Student’s t-test for independent (to be compared to 0.05). 
- P-value from Mann-Whitney test (to be compared to 0.05). 
4.5.3.3.3 
Response to treatment according to the CGI-C 
An alternative calculation of CGI-C consists in evaluating the number of patients experiencing at least 
an improvement (CGI-CI) and defined as responder to therapy.   
Definition: 
This endpoint is defined as the value at end of each period in the response to treatment (based on 
CGI-I). 
Missing data handling:  
Missing evaluations are not imputated. 
Analyses: 
The difference between placebo and BF2.649 will be studied at end of each period using a Chi-Square 
test. 
In addition, descriptive statistics at baseline and at each post-baseline visit by treatment group. 
Statistical elements: 
For these comparisons the following elements will be provided in a summary table: 
- Estimate (Standard Error) of the difference between the proportions of patients. 
- Two-sided 95% CI of the estimate. 
- P-value from Chi-2 test (to be compared to 0.05). 
4.5.3.3.4 
Child and Adolescent Sleepiness Scale (CASS) 
ESS version adapted for children (6 and over) and adolescents (CASS) with range [0, 30], A score 
greater than 14 is considered as abnormal sleepiness. CASS will be evaluated at each study visit of 
double-blind phase and reviewed by the investigator.  
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Analysis:  
The difference between placebo and BF2.649 will be studied in the same way as the primary analysis 
(Excluding sensitivity analysis). 
In addition,  
- Descriptive statistics at baseline and at each post-baseline visit by treatment group will be 
provided 
Missing data handling:  
Missing evaluations are not imputated 
Statistical elements: 
For this comparison the following elements will be provided in a summary table: 
- Estimate (standard error) of the difference between adjusted treatment group means. 
- Two-sided 95% CI of the estimate. 
- p-value (to be compared to 0.05). 
4.5.3.3.5 
Test of Everyday Attention for Children (TEA-Ch) 
The Test of Everyday Attention for Children (TEA-Ch) assesses the cognitive functions with a version 
A at V1 and a version B at V6.  
A reference table « TeaCH_tests» can do the correspondance between the code in databe and the 
item. 
Analysis:  
Cumulative percentages will be used in analyses (It’s more meaningfull than raw scores to compare 
children according their sex and age) 
The difference between placebo and BF2.649 will be studied, by test, in the same way as the primary 
analysis (Excluding sensitivity analysis). 
In addition,  
- Value and change from baseline descriptive statistics by visit, by treatment group will be 
provided. 
Missing data handling:  
Missing evaluations are not imputated 
4.5.3.3.6 
Patient sleep diary 
The Weekly rate of cataplexy (partial and total) analysis is already done in the secondary endpoint 
(section 4.5.3.2.3). 
The other calculated parameters are: 
- Night duration calculated as the difference between Hour of bedtime and wake-time (NightD)  
- Number of diurnal involuntary sleep attacks and episodes of severe daytime sleepiness (NSAE). 
- Number of hallucinations and sleep paralysis episodes (NHS). 
Analysis:  
Descriptive statistics by treatment group during the following intervals: Baseline (D-28 to D0), Final 
DB last 6 weeks DB4=D21-D63, Final DB last 2 weeks: DB2=D49-D63 will be provided 
Missing data handling:  
Missing evaluations are not imputated 
4.5.3.3.7 
Patient’s Global Opinion on the effect of treatment 
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At V7 patients’ global opinion will be reported by patient if able to express himself. If not, either their 
parents or their main teachers should evaluate the Global effect of the treatment by comparing the 
period prior to that visit with the patient’s pre-study condition. The six-level of the PGO will be 3= 
Marked effect, 2=Moderate, 1=Minimal, 0=No, -1= Minimal Worse, -2=Much worse.  
We also use the binary variable PGO-C defined as patient having Improved (when PGO=3, 2 or 1) and 
considered as responder to therapy 
Definition: 
This endpoint is defined as the value at V7 in the response to treatment (based on PGO-C). 
Analyses: 
The difference between placebo and BF2.649 will be studied at V7 using a Chi-2 test. 
In addition, descriptive statistics of levels by treatment group will be provided 
Missing data handling:  
Missing evaluations are not imputated. 
Statistical elements: 
For these comparisons the following elements will be provided in a summary table: 
- Estimate (Standard Error) of the difference between the proportions of patients. 
- Two-sided 95% CI of the estimate. 
- P-value from Chi-2 test (to be compared to 0.05). 
4.5.3.3.8 
Withdrawal symptoms questionnaire (DSM IV) 
A questionnaire is asked to patients about their feeling of any symptoms during the last week. 
Analyses: 
Descriptive statistics at each visit (T1, V8 and eventually the premature withdrawal visit) by symptom 
by treatment group will be provided. 
4.5.4 Safety data  
All safety analyses will be performed by actual treatment group in the Safety Set. 
 
4.5.4.1 Adverse events 
The Adverse events (AEs) were reported with the following information: Description, Visit number 
when AE was reported, Dose of study drug when AE occurred (10 mg, 20 mg, 40 mg, NA), Date of 
onset or worsening and end date or ongoing, Intensity (mild, moderate, severe), Frequency (once, 
intermittent and number and period, continuous, unknown), Action taken with studied drug (none, 
dose modification, temporary interruption, discontinued), Action taken with event (none, corrective 
treatment, additional exploration, hospitalization ≤ 24 hr, hospitalization > 24 hr), Serious adverse 
event (SAE) (yes, no), Outcome (recovered, recovered with sequelae, worsened, not yet recovered, 
death), Imputability (likely related, possibly related, unlikely related), Etiology (studied drug, 
concomitant treatment, associated disease, other, unknown) 
 
Number of events, number and percentage of patients reporting at least one event, presented by 
primary system organ class (SOC) and preferred term (PT), over the period V2-V8, will be provided 
for: 
- AE 
- Serious AE,  
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- Treatment emergent AE (TEAE), Treatment emergent AE (TEAE) during the stable dose period, 
TEAE leading to IMP withdrawal, TEAE related to IMP, serious TEAE, severe TEAE, non-serious TEAE 
(EUDRACT), Treatment emergent fatal AE. 
- Special Interest TEAE (SITEAE). 
 
TEAE also will be described according to the intensity, dose in the stable dose period and outcome.  
 
In case a same patient presented the same AE (i.e. same AE as defined according to SOC and PT) 
several times during the study, only one occurrence per patient will be reported, but the total number 
of events will be given.  
 
In addition, only TEAEs with incidence >5% (i.e. % of patients with >5 % for a given PT in at least one 
treatment group) will be presented by SOC and PT in the SAF population.  
 
A listing with all the individual AEs with the associated information will be provided. 
4.5.4.2 Vital signs 
Definition:  
The following vital signs and clinical examination will be analysed during the study: 
o Weight (kg) 
o BMI (kg/m²) 
o SBP (mmHg) 
o DBP (mmHg) 
o heart rate (bpm) 
For the description of the values at each planned post-baseline visit, in case of retest, only the first 
analysable one measured at the visit is taken into account. 
Analysis: 
They will be described, in terms of value at baseline, value at each post-baseline visit as well as in 
terms of change from baseline for SBP, DBP and heart rate. 
Moreover, BMI will be described by class calculated by the World Health Organization (2007):  
underweight: < -2SD; normal range: [-2SD; +1 SD]; Overweight:] +1SD; +2SD] and obese: > +2SD, 
taking into account the last post-baseline value in regard to baseline state. 
4.5.4.3 Laboratory evaluations 
The laboratory parameters will not be performed by a central laboratory, so quantitative analysis are 
not possible.  
 
A full laboratory test was performed at screening (V1), at the final double-blind treatment phase 
evaluation visit (V7) and at early withdrawal visit. Blood samples will be collected and all laboratory 
tests will be performed according to the Good Laboratory Practice (OECD GLP Principles) by site-
dependent Laboratory. The results of laboratory tests will be interpreted by the investigator. 
Laboratory abnormalities will be defined as laboratory test results that are outside the reference 
range as defined by the normal range from the testing laboratory. Clinically significant abnormal 
value at V1 will be determined by the investigator and will exclude patients from study participation. 
The results of abnormal values of laboratory tests will be reported in the CRF beside the normal range 
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value given by the testing laboratory, the original document containing all the tested values will be 
kept in the patient study file.  
- Hematology: Red Blood Cells, White Blood Cells (differential count, absolute value), hemoglobin, 
haematocrit, Mean corpuscular volume (MCV), platelet count. 
- Biochemistry: sodium, potassium, chloride, creatinine, alkaline phosphatases, urea, alanine 
aminotransferase (ALAT), aspartate aminotransferase (ASAT), gamma glutamyl transpeptidase 
(GGT), total bilirubin, glucose, triglycerides, total cholesterol and prothrombine ratio. 
- Laboratory parameters will be analysed by abnormality and by clinically significance of the 
abnormality (number and percentage of patients in each class)  
- A listing of patients with at least one clinically significant abnormality will be provided. 
 
A description in term of status (Positive or Negative) will be computed for the following parameters: 
- Only for pubescent female a Serum Pregnancy test (-hCG) will be described. 
- Urinalysis: semi-quantitative ("dipstick") analysis for pH, ketone bodies, proteins, glucose, blood.  
- Urine drug testing: test of abuse of drugs will be performed on urine samples from 12 years. 
Screened drugs are amphetamines, barbiturates, benzodiazepines, cannabinoids (THC) and Opioids. 
4.5.4.4 Physical examination 
A full physical examination will be performed at screening period (V0 (when applicable) and V1) and 
at each visit from V2 to V8 (or at early withdrawal visit). Any significant abnormality and change from 
baseline will be recorded in the CRF and in the source document and will be analyzed as safety 
parameters. Any significant changes will be reported in the AE pages of the CRF. 
A description by visit and by body system of the Physical examination will be provided. 
4.5.4.5 Electrocardiogram 
ECG will be performed at each visit from the screening visit (V1) to the end of the double blind-phase 
(V8) or at early withdrawal visit. The main ECG parameters including Fridericia’s corrected QTc 
interval (QTcF = QT/3 (60/HR)) and intra individual changes in these parameters will be reported and 
analyzed locally 
Definition:  
A value is considered as analysable if a non-missing value was obtained from a Sinusal rhythm ECG 
from the central review (Banook).  
For the description of the values at each planned post-baseline visit, in case of retest, only the first 
analysable one measured at the visit is taken into account. 
Analyses: 
ECG parameters will be described, in terms of values at baseline, values at each post-baseline visit. 
Presence of clinically significant ECG abnormalities (yes/no) will be analysed. 
ECG parameters will be described, in terms of values at baseline, values at each post-baseline visit. 
Presence of clinically significant ECG abnormalities (yes/no) will be analysed. 
Description of the following binary variables (Yes/No) were also presented:  
-QTcF450 =Yes if QTcF post-dose > 450msec  
-ΔQTcF = Yes if the post-dose versus pre-dose QtcD ≥ 60msec  
-QT500 =Yes if the QT post-dose ≥ 500 msec  
A data list will document individual values for any patient presenting with an abnormal clinically 
significant value at any time point post dose. Values will be patient ID, first and second reading, 
treatment, age, gender, and visit.  
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4.5.4.6 Childhood depression inventory (CDI) 
The Childhood Depression Inventory scale is a self-administrated 27-item questionnaire commonly 
used in research to assess depression. The short version 2 of 12 items is used in the study. The patient 
is asked to pick out the statement in each of the 12 items which best describes the way he feels right 
now at the moment of the assessment. The range of scores for the scale are 0-3 = none or minimal; 
4-7 = mild; 8-15 = moderate; ≥ 16 = severe depression.  
Analyses: 
The CDI will be described, in terms of total score at baseline and at each post-baseline visit. 
It also described in term of range of scores. 
4.5.4.7 Columbia-suicide severity rating scale (C-SSR) 
The Columbia-Suicide Severity Rating Scale (C-SSRS) will be evaluated at all visits of the study. This 
scale is intended to be used by individuals who have received training in its administration. The 
questions contained in the C-SSRS are suggested probes. Ultimately, the determination of the 
presence of suicidal ideation or behavior depends on the judgment of the individual administering 
the scale. The interview is semi-structured with a flexible format. Questions are provided as helpful 
tools – it is not required to ask any or all questions – just enough to get the appropriate answer. Most 
important: gather enough clinical information to determine whether patient is suicidal or not. If it is 
established that a patient has not engaged in any suicidal behavior and/or ideation, then no further 
questions are required. 
Analyses 
The CDI will be described, in terms of Suicidal risk (Yes/No) at baseline and at each post-baseline visit. 
4.6 
Modifications from the statistical section of the protocol  
 Not Applicable. 
4.7 
Interim analysis 
Not Applicable. 
 
5 
Tables, Listings and Graphs (TLG) 
BIOPROJET_P11-06_Mock_UP_TFLs_FinalVersion_V1.0.pdf 
 
6 
Template of tables, listings and graphs  
BIOPROJET_P11-06_Mock_UP_TFLs_FinalVersion_V1.0.pdf 
 
7 
References 
- 
Billiard M et al. EFNS guidelines on management of Narcolepsy. Eur J Neurol 2006;13:1035-
48 
- 
Dauvilliers Y et al. Clinical aspects and pathophysiology of narcolepsy. Clinical 
Neurophysiology 2003;114:2000-2017 
- 
Plazzi, G, P.Lehert, 2021, Comparative evaluation of symptom measurement tools in pediatric 
Narcolepsy, submitted to Sleep journal.  
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- 
Andersen, P. and Gill, R. (1982). Cox's regression model for counting processes, a large sample 
study. Annals of Statistics 10, 1100-1120. 
- 
Therneau, T., Grambsch, P., Modeling Survival Data: Extending the Cox Model. Springer-
Verlag, 2000. 
- 
Food and Drug Administration (FDA), Multiple endpoints in clinical trials. Guidance for the 
industry, , January 2017.  
- 
CPMP Working Party on Efficacy of Medical Products. Biostatistical methodology in clinical 
trials in applications for marketing authorizations for medical products. Stat Med 
1995;14:1659–82.  
- 
ICH E9 Statistical Principles for Clinical Trials, CPMP/ICH/363/96 , Mar 1998 
 
 
                                                 
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