A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate the Safety and Efficacy of Pitolisant in Patients With Prader-Willi Syndrome, Followed by an Open Label Extension
Phase: PHASE2
Conditions: Prader-Willi Syndrome
Sponsor: Harmony Biosciences Management, Inc.

Official Title of Study: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to 
Evaluate the Safety and Efficacy of Pitolisant in Patients with Prader-Willi Syndrome, Followed 
by an Open Label Extension 
 
NCT Number: NCT04257929 
 
Protocol Date (last revision date): August 10, 2023 

Confidentiality Statement 
This document contains confidential information of Harmony Biosciences, LLC. 
Do not copy or distribute without prior written permission of the Sponsor. 
Any unauthorized use, reproduction, publication, or dissemination is strictly prohibited. 
CLINICAL STUDY PROTOCOL: HBS-101-CL-002 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled Phase 2 
Study to Evaluate the Safety and Efficacy of Pitolisant in 
Patients with Prader-Willi Syndrome, Followed by an Open 
Label Extension 
IND Number 
143663 
Investigational Product: 
Pitolisant (also referred to as HBS-101) 
Phase of Development: 
2 
Sponsor: 
Harmony Biosciences, LLC 
630 W. Germantown Pike, Suite 215 
Plymouth Meeting, PA 19462 
USA 
Protocol Version: 
Amendment 6 
Effective Date: 
10AUG2023 
 
 

Protocol No: HBS-101-CL-002 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
2 
Confidential 
SPONSOR SIGNATURE 
 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to 
Evaluate the Safety and Efficacy of Pitolisant in Patients with 
Prader-Willi Syndrome, Followed by an Open-Label Extension 
Protocol Number: 
HBS-101-CL-002, Amendment 6 
 
 
This protocol Amendment 6 has been reviewed and approved by the Sponsor. 
 
 
Signature: 
 
 
 
 
 
Date: 10AUG2023 
 
 
 
 
 
 
 

Protocol No: HBS-101-CL-002 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
Amendment 6, 10AUG2023 
 
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Confidential 
INVESTIGATOR AGREEMENT 
CLINICAL STUDY PROTOCOL: HBS-101-CL-002 
TITLE: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate the 
Safety and Efficacy of Pitolisant in Patients with Prader-Willi Syndrome, Followed by an 
Open-Label Extension 
I have received and read the current Investigator’s Brochure for pitolisant.  I have read the 
HBS-101-CL-002 protocol and agree to conduct the study as outlined.  I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol.  
Confidentiality Statement 
The confidential information in this document is provided to you as the Principal Investigator for 
review by you, your staff, and the applicable Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC).  Your acceptance of this document constitutes agreement that you will 
not disclose the information contained herein to others without written authorization from the 
Sponsor. 
 
Principal Investigator: 
 
Address: 
 
Signature: 
 
Date: 
 
 

Protocol No: HBS-101-CL-002 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
Amendment 6, 10AUG2023 
 
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PROTOCOL SYNOPSIS 
NAME OF SPONSOR: 
Harmony Biosciences, LLC 
NAME OF FINISHED PRODUCT(S): 
Pitolisant tablets (also referred to as HBS-101) 
NAME OF ACTIVE INGREDIENT(S): 
Pitolisant hydrochloride (also referred to as HBS-101)  
PROTOCOL NUMBER: 
HBS-101-CL-002 
PHASE OF DEVELOPMENT: 
2 
PROTOCOL TITLE: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate the 
Safety and Efficacy of Pitolisant in Patients with Prader-Willi Syndrome, Followed by an Open-Label 
Extension 
NUMBER OF PLANNED PATIENTS: Approximately 60 patients (ages 6 to 65 years) with Prader-Willi 
syndrome (PWS) 
STUDY SITES: Approximately 15 sites in the United States (US) 
STUDY OBJECTIVES:  
Primary Objective 
The primary objective of this study is to evaluate the safety and efficacy of pitolisant compared with placebo 
in treating excessive daytime sleepiness (EDS) in patients with PWS ages 6 to 65 years. 
Secondary Objectives 
Key Secondary Objectives 
The key secondary objectives of this study are to evaluate caregiver-rated impressions of severity of EDS 
and clinician-rated impressions of severity of overall clinical status in patients with PWS ages 6 to 65 years 
treated with pitolisant compared with placebo. 
Other Secondary Objectives 
Other secondary objectives of this study are to evaluate the following in patients with PWS ages 6 to 
65 years: 
• 
The impact of pitolisant on behavioral symptoms  
• 
The impact of pitolisant on cognitive function 
• 
Change in caregiver burden  
• 
Safety and effectiveness of pitolisant during long-term treatment 
Exploratory Objectives 
The exploratory objectives of this study are to evaluate the following in patients with PWS ages 6 to 
65 years: 
• 
The impact of pitolisant on hyperphagia 
• 
The impact of pitolisant on changes in ghrelin levels 
• 
The pharmacokinetics (PK) of pitolisant and its major metabolite, BP1.3484 
• 
The relationship between levels of pitolisant (PK) and treatment effect (pharmacodynamics) 

Protocol No: HBS-101-CL-002 
 
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Phase 2 Safety and Efficacy Study 
 
Amendment 6, 10AUG2023 
 
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METHODOLOGY:  
This is a randomized, double-blind, placebo-controlled, parallel group, Phase 2, proof of concept study in 
patients (ages 6 to 65 years) with PWS, followed by an optional Open-Label Extension (OLE) Phase.  
The study will consist of a Screening Period (up to a maximum of 45 days), an 11-week Double-Blind 
Treatment Phase (including a 3-week Titration Period and an 8-week Stable Dose Period), and an optional 
OLE Phase.  The OLE Phase will be multi-year in duration and will continue until the Sponsor elects to 
terminate the study. 
After completing the Screening Period, eligible patients will be enrolled into the Double-Blind Treatment 
Phase of the study.   
The Double-Blind Treatment Phase of the study will be 11 weeks, which includes a 3-week Titration Period 
and an 8-week Stable Dose Period.  Eligible patients will be randomized in a 1:1:1 ratio to receive treatment 
with lower dose pitolisant, higher dose pitolisant, or matching placebo (20 patients per treatment group, ages 
6 to 65 years).  The lower and higher pitolisant doses, respectively in each age group, will be 8.9 mg and 
17.8 mg for children ages 6 to <12 years, 13.35 mg and 26.7 mg for adolescents ages 12 to <18 years, and 
17.8 mg and 35.6 mg for adults ages 18 to 65 years.  In the Double-Blind Treatment Phase, patients will be 
titrated to their randomized stable dose of study drug during the 3-week Titration Period.  After completion 
of the 3-week Titration Period, patients will continue to take study drug at their randomized stable dose once 
daily in the morning upon wakening for an additional 8 weeks of blinded treatment (Stable Dose Period).  
The duration of the Double-Blind Treatment Phase will be 11 weeks.  Patients and/or their caregiver will 
receive telephone calls (TCs) from the study site on Days 8 and 15 (±3 days) (TCs 1 and 2, respectively) 
during the 3-week Titration Period to assess for adverse events (AEs) and concomitant medication use, 
complete the Columbia-Suicide Severity Rating Scale (C-SSRS), and review/confirm titration of study drug.  
During the 8-week Stable Dose Period, patients will complete safety, efficacy, and PK assessments at the 
study site on Day 22 (Visit 3), Day 50 (Visit 4), and Day 77 (Visit 5) (window for Visits 3, 4, and 5 is ±3 
days), and patients and/or their caregiver will receive TCs from the study site on Days 29, 36, and 57 (±3 
days; TCs 3, 4, and 5, respectively) to assess for AEs and concomitant medication use, complete the C-SSRS 
and Anxiety, Depression, and Mood Scale (ADAMS), and confirm study drug dose.  Specific procedures and 
assessments for Screening (Visit 1), Visit 3, and Visit 4 may be conducted remotely as detailed in 
Section 6.6.  
At the end of the Double-Blind Treatment Phase, eligible patients will be given the opportunity to enter an 
optional OLE Phase.  If a patient does not enter the OLE Phase, the patient and/or their caregiver will receive 
Safety Follow-up TCs from the study site 15 days (±3 days) and 30 days (+3 days) after their final dose of 
blinded treatment. 
In the OLE Phase, prior to implementation of Amendment 6 of the protocol, patients received a maximum 
target dose of pitolisant based on their age (17.8 mg for ages 6 to <12 years, 26.7 mg for ages 12 to 
<18 years, or 35.6 mg for ages 18 to 65 years).  
 
  Adjustments to pitolisant dose are 
allowed during the OLE Phase based on Investigator discretion in consultation with the Medical Monitor up 
to the maximum daily dose allowed 
.  
In the OLE Phase, patients and/or their caregivers will receive TCs from the study site on Days 85 and 92 
(±3 days; TCs 6 and 7, respectively) and will return to the study site for assessment of safety and 
effectiveness on Days 99 (Visit 6), 189 (Visit 7), 279 (Visit 8), and 369 (Visit 9) (window for Visits 6, 7, 8, 
and 9 is ±7 days).  After completion of Visit 9, patients and/or their caregivers will receive a TC from the 
study site on Day 459 (TC 8), and patients will complete an on-site study visit on Day 549 (Visit 10); this 
pattern of alternating TCs and on-site study visits approximately every 3 months will be repeated until either 
the patient withdraws from the study or the study is terminated by the Sponsor (window for all TCs and 
study visits after Visit 9 is ±7 days).  During the first year of the OLE Phase of the study, patients will have 
the option to complete up to two of the scheduled on-site study visits remotely (i.e., two of Visits 6, 7, 8, and 
9); thereafter (i.e., after Visit 9/Month 12), patients will have the option to complete one of the two 

Protocol No: HBS-101-CL-002 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
Amendment 6, 10AUG2023 
 
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scheduled on-site study visits remotely per year.  Remote visits cannot be consecutive.  Specific procedures 
and assessments that may be conducted remotely are detailed in Section 6.6. 
STUDY POPULATION:  
Approximately 60 patients with PWS are planned to be enrolled in the study at approximately 15 sites in the 
US. 
Inclusion Criteria 
Each patient must meet all of the following criteria to be enrolled in this study: 
1. Is able to provide voluntary, written informed consent (patient or parent[s]/legal guardian[s]) and, 
where applicable, voluntary, written assent (patient, as appropriate). 
2. Has a diagnosis of PWS confirmed by genetic testing and/or patient medical records. Genetic testing 
will be provided by the Sponsor, if not confirmed based on the review of the patient’s medical 
records. 
3. Male or female patients ages 6 to 65 years at the time of enrollment. 
4. Demonstrates adequate sleep duration via patient sleep diary during Screening, defined as at least 
8 hours of sleep per night for patients ages 6 to <12 years, at least 7 hours for patients ages 12 to 
<18 years, or at least 6 hours for patients ages ≥18 years, based on the mean number of hours from 
up to 14 nights (at least 7 nights must be recorded for evaluation).  
5. Has EDS as determined by Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) 
(parent/caregiver version) score of ≥12. 
6. If taking hormone treatments (including growth hormone, testosterone, and estrogen supplements) 
and/or allowed chronic concomitant medication or supplements, patient must be on a stable dose of 
these medications for 3 months prior to randomization and for the duration of the Double-Blind 
Treatment Phase of the study; a 10% variability in hormone dose is allowed.  
7. If taking a wake-promoting treatment that could affect EDS (including stimulants, modafinil, and 
armodafinil), must be on a stable dose for at least 28 days prior to Screening and remain on a stable 
dose during the Double-Blind Treatment Phase of the study (dose adjustments will be permitted in 
the OLE Phase) or agree to wash out of treatment for 5 half-lives or 14 days, whichever is longer. 
8. If taking a chronically administered sedating medication for management of behavioral 
manifestations (e.g., hypnotics, benzodiazepines, antipsychotics, alpha agonists, anticholinergics, 
and antidepressants) must be on a stable dose for at least 28 days prior to Screening and remain on a 
stable dose during the Double-Blind Treatment Phase of the study (dose adjustments will be 
permitted in the OLE Phase) or agree to wash out of treatment for 5 half-lives or 14 days, whichever 
is longer.  
9. If using cannabidiol and/or tetrahydrocannabinol, patient must be on a stable dose for 28 days prior 
to randomization and agree to continue the stable dose for the duration of the Double-Blind 
Treatment Phase of the study (dose adjustments will be permitted in the OLE Phase). 
10. If taking oxytocin or carbetocin, patient must be on a stable dose during the 28 days prior to 
randomization and agree to continue the stable dose for the duration of the Double-Blind Treatment 
Phase of the study (dose adjustments will be permitted in the OLE Phase) or agree to wash out of 
treatment for 5 half-lives or 14 days, whichever is longer. 

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Phase 2 Safety and Efficacy Study 
 
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11. A patient who is a female of child-bearing potential (FCBP) must have a negative serum pregnancy 
test at the Screening Visit and a negative urine pregnancy test at the Baseline Visit and agree to 
remain abstinent or use an effective method of nonhormonal contraception to prevent pregnancy for 
the duration of the study and for 21 days after final dose of study drug. 
12. Has a consistent caregiver (preferably the same person throughout the Double-Blind Treatment 
Phase of the study) who is willing and able to complete the required assessments. 
13. In the opinion of the Investigator, patient/parent(s)/legal guardian(s) is capable of understanding and 
complying with the requirements of the protocol and administration of oral study drug. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from enrollment in the study: 
1. Has a diagnosis of another genetic or chromosomal disorder distinct from PWS. 
2. Has untreated obstructive sleep apnea (OSA) or is at high risk for OSA based on medical history and 
clinical assessment; or, has another relevant underlying sleep disorder that in the opinion of the 
Investigator is the primary contributing factor to the patient’s EDS. 
3. Consistently consumes >600 mg of caffeine per day and is unable/unwilling to reduce caffeine 
intake to <600 mg per day for the duration of the Double-Blind Treatment Phase of the study; 
caffeine intake should remain consistent during Screening and throughout the Double-Blind 
Treatment Phase of the study. 
4. Does not agree to discontinue any prohibited medication or substance listed in the protocol 
(Section 5.7.2). 
5. Participation in an interventional research study involving another investigational medication or 
device in the 28 days prior to enrollment and for the duration of the Double-Blind Treatment Phase 
of the study, unless the Investigator consults with the Medical Monitor and obtains written approval 
for the patient to enroll; patients who complete a washout of an investigational medication of at least 
5 half-lives or 14 days (whichever is longer) may be enrolled in the Double-Blind Treatment Phase 
of the study.  Patients considering participation in another interventional research study in the OLE 
Phase must consult with the Investigator who will consult with the Medical Monitor. 
6. Has a primary psychiatric diagnosis with current active symptoms of psychosis or schizophrenia. 
7. Has a diagnosis of end-stage renal disease (estimated glomerular filtration rate [eGFR] of 
<15 mL/minute/1.73 m2) or severe hepatic impairment (Child-Pugh C). 
8. Has a diagnosis of moderate or severe renal impairment (eGFR ≥15 to ≤59 mL/minute/1.73 m2) or 
moderate hepatic impairment (Child-Pugh B) at Screening or during the Double-Blind Treatment 
Phase. 
9. Has abnormal laboratory values at Screening that are clinically significant as determined by the 
Investigator.  
10. Has a known history of long QT syndrome or any significant history of a serious abnormality of the 
electrocardiogram (ECG; e.g., recent myocardial infarction, clinically significant arrhythmia) or QT 
interval corrected for heart rate according to Fridericia’s formula (QTcF) >442 ms for patients ages 0 
to <10 years and >439 ms for patients ages 10 to <20 years, regardless of gender, and >450 ms for 

Protocol No: HBS-101-CL-002 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
Amendment 6, 10AUG2023 
 
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male patients and >470 ms for female patients ages 20 to 65 years. (ECG QTcF = QT/3√ RR) 
(Mason et al 2007). 
11. Has a family history of sudden/unexplained death, cardiac death, or death from a primary 
dysrhythmia potentially associated with QT prolongation in any family member. 
12. If receiving any new or initiating a change in allied health therapies or interventions for symptoms of 
PWS, must be on a stable course of therapy for at least 28 days prior to randomization.  
13. Has a current or recent (within one year) history of a substance use disorder or dependence disorder, 
including alcohol and caffeine use disorders as defined in the Diagnostic and Statistical Manual of 
Mental Disorders, 5th Edition (DSM-V).  
14. Has planned surgery during the Double-Blind Treatment Phase of the study; planned surgery is 
permitted during the OLE Phase. 
15. Is receiving a concomitant medication that is known to be a strong cytochrome P450 (CYP) 2D6 
inhibitor, a strong CYP3A4 inducer, or a centrally acting histamine 1 (H1) receptor antagonist; 
patients who complete a washout of these medications of at least 5 half-lives or 14 days (whichever 
is longer) can be enrolled in the Double-Blind Treatment Phase of the study.  Use of strong CYP2D6 
inhibitors and strong CYP3A4 inducers is allowed during the OLE Phase; however, adjustment of 
pitolisant dose is required (Section 5.7.3).  Although not prohibited during the OLE Phase of the 
study, use of H1 receptor antagonists should be avoided. 
16. Is receiving a medication known to prolong the QT interval. 
17. Has a significant risk of committing suicide based on history, routine psychiatric examination, 
Investigator’s judgment, or an answer of “yes” on any question other than questions 1 to 3 on the 
Very Young Child/Cognitively Impaired-Lifetime Recent Columbia-Suicide Severity Rating Scale 
(C-SSRS) (Appendix L).  
18. Has a history of seizures that have recently (within 6 months) been treated with antiepileptic 
medications that are strong CYP3A4 inducers.  Patients with a history of seizures must have a stable 
seizure history (e.g., frequency and severity) for at least 6 months prior to enrollment.  
19. Is currently breastfeeding or planning to breastfeed over the course of the study.  Lactating women 
must agree not to breastfeed for the duration of the study (Double-Blind Treatment Phase and OLE 
Phase) and for 21 days after final dose of study drug. 
20. Based on the judgment of the Investigator, patient is unsuitable for the study for any reason, 
including but not limited to unstable or uncontrolled medical conditions (including psychiatric and 
neurological conditions) or a medical condition that might interfere with the conduct of the study, 
confound interpretation of study results, pose a health risk to the patient, or compromise the integrity 
of the study. 
INVESTIGATIONAL PRODUCT, DOSE, AND MODE OF ADMINISTRATION: Pitolisant tablets 
containing 4.45 mg and 17.8 mg pitolisant base will be administered orally once daily in the morning upon 
wakening.  
REFERENCE THERAPY, DOSE, AND MODE OF ADMINISTRATION: During the Double-Blind 
Treatment Phase of the study, matching placebo tablets will be administered orally once daily in the morning 
upon wakening. 

Protocol No: HBS-101-CL-002 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
Amendment 6, 10AUG2023 
 
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DURATION OF TREATMENT: The study is expected to be multi-year in duration.  The Double-Blind 
Treatment Phase will remain open until the last patient completes this phase of the study and the OLE Phase 
will remain open until the Sponsor elects to terminate the study.  
The duration of participation for individual patients in the Double-Blind Treatment Phase is expected to be 
up to approximately 21 weeks, including a maximum of 45 days of screening, 11 weeks of double-blind 
treatment (includes a 3-week Titration Period and an 8-week Stable Dose Period), and 30 days of safety 
follow-up for patients who do not enter the OLE Phase.  For patients who enter the OLE Phase of the study, 
individual patient participation is expected to be multi-year in duration. 
STUDY ASSESSMENTS: Efficacy, safety, and PK will be assessed.  
Efficacy assessments will include ESS-CHAD (parent/caregiver version), Caregiver Global Impression of 
Severity (CaGI-S) for EDS, Clinical Global Impression of Severity (CGI-S) for overall clinical status related 
to PWS, Aberrant Behavior Checklist-Community, Second Edition (ABC-C), Montefiore-Einstein Rigidity 
Scale – Revised for Research Studies in PWS (MERS-R-PWS), Cogstate Detection Test, Cogstate 
Identification Test, Cogstate One Back Test, 22-item Zarit Burden Interview (ZBI-22), Hyperphagia 
Questionnaire for Clinical Trials (HQ-CT) in conjunction with the Food Safe Zone Questionnaire (FSZQ), 
and acylated and unacylated fasting ghrelin levels. 
Safety assessments will include evaluation of AEs, vital signs, 12-lead ECGs, physical examinations, clinical 
laboratory test results, and other safety assessments (suicidality, anxiety, and monitoring of seizures in 
patients with seizure disorder). 
Pharmacokinetic assessments will include maximum observed concentration (Cmax), area under the 
concentration-time curve (AUC) from time 0 to the last collection time (AUClast), and time to observed 
maximum concentration (tmax) of pitolisant and its major metabolite, BP1.3484. 
Some assessments associated with on-site study visits may be completed remotely, as directed and overseen 
by the Investigator and detailed in Section 6.6. 
STUDY ENDPOINTS: 
EFFICACY ENDPOINTS 
Double-Blind Treatment Phase:  
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change in mean ESS-CHAD (parent/caregiver version) score from 
Baseline to Week 11 for pitolisant compared with placebo. 
Key Secondary Efficacy Endpoints 
Change from Baseline to Week 11 for pitolisant compared with placebo in:  
• 
CaGI-S for EDS  
• 
CGI-S for overall clinical status related to PWS 
Other Secondary Efficacy Endpoints 
Change from Baseline to Week 11 for pitolisant compared with placebo in: 
• 
Behavior as measured by the ABC-C 
• 
Behavioral and cognitive rigidity as measured by the MERS-R-PWS 
• 
Psychomotor function as measured by the Cogstate Detection Test 
• 
Attention as measured by the Cogstate Identification Test  

Protocol No: HBS-101-CL-002 
 
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• 
Working memory as measured by the Cogstate One Back Test  
• 
Measure of caregiver burden using the ZBI-22  
Exploratory Endpoints 
Change from Baseline to Week 11 for pitolisant compared with placebo in: 
• 
Total score of the HQ-CT in conjunction with the FSZQ 
• 
Acylated and unacylated ghrelin levels 
 
Open-Label Extension Phase 
Long-term effectiveness of pitolisant as measured by ESS-CHAD (parent/caregiver version), CaGI-S for 
EDS, CGI-S for overall clinical status related to PWS, ABC-C, MERS-R-PWS, Cogstate Detection Test, 
Cogstate Identification Test, Cogstate One Back Test, ZBI-22, and HQ-CT in conjunction with the FSZQ 
will be assessed during the first year of participation (through Visit 9) in the OLE Phase of the study.  After 
the first year, only ESS-CHAD (parent/caregiver version), CaGI-S, and CGI-S will continue to be assessed. 
PHARMACOKINETIC AND PHARMACODYNAMIC ENDPOINTS 
• 
Cmax of pitolisant and its major metabolite, BP1.3484 
• 
AUClast after administration of pitolisant  
• 
tmax of pitolisant 
• 
Exposure-response relationship between pitolisant levels and change in efficacy measures 
SAFETY ENDPOINTS 
Safety will be assessed by monitoring the incidence of AEs and changes in clinical laboratory test results, 
vital signs, and 12-lead ECG results, along with additional safety assessments (suicidality, anxiety, and 
monitoring of seizures in patients with seizure disorder) from Baseline to Week 11 in the Double-Blind 
Treatment Phase and from Baseline to study completion in the OLE Phase. 
STATISTICAL METHODS: All analyses will be performed using SAS® version 9.4 or higher, unless 
otherwise specified. 
Primary Efficacy Analyses: Summary statistics (mean, standard deviation, median, minimum, maximum) for 
the primary efficacy endpoint of change in mean ESS-CHAD (parent/caregiver version) score from Baseline 
to Week 11 for pitolisant compared with placebo will be reported by treatment group and for the active 
groups combined.  The change from Baseline will be analyzed in a mixed model repeated measures 
(MMRM) analysis.  Fixed effects will be included for treatment, visit, treatment*visit interaction, Baseline 
value, and site.  An unstructured covariance matrix will be utilized and if this fails to converge, then first-
order autoregressive and compound symmetry will be attempted in that order; Kenward-Rogers degrees of 
freedom will be used.  Least square (LS) means, standard errors, and the LS mean differences (each 
treatment vs placebo and the pooled active groups vs placebo) will be reported.  All estimates will be 
generated from a single model, i.e., the pooled estimates will be created via model contrasts.  The primary 
contrast of interest is the difference in the higher dose group versus placebo at Week 11.   
Secondary Efficacy Analyses: Continuous outcomes collected at multiple time points will be analyzed with 
summary statistics (mean, standard deviation, median, minimum, maximum) for the absolute values and 
change from baseline at each timepoint by treatment group and for the active groups combined.  The change 
from Baseline will be analyzed using an MMRM approach.  Fixed effects will be included for treatment, 
visit, treatment×visit interaction, and baseline value.  An unstructured covariance matrix will be utilized and 
if this fails to converge, then first-order autoregressive and compound symmetry will be attempted in that 

Protocol No: HBS-101-CL-002 
 
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Amendment 6, 10AUG2023 
 
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order; Kenward-Rogers degrees of freedom will be used.  Least square means, standard errors, and the LS 
mean differences (each treatment vs placebo and the pooled active groups vs placebo) at each time point will 
be reported.  All estimates will be generated from a single model, i.e., the pooled estimates will be created 
via model contrasts.  The primary contrast of interest is the difference in the higher dose group versus 
placebo at Week 11. 
OLE Efficacy Analyses: Results in the OLE Phase will be tabulated with summary statistics for continuous 
outcomes and frequencies and percentages for categorical outcomes.  No p-values will be reported for the 
OLE Phase.  Baseline for the OLE will be the pre-double-blind-treatment baseline (identical to that used for 
the double-blind analyses).  Details of open-label analyses will be fully described in the statistical analysis 
plan (SAP). 
Safety Analyses: All safety data will be listed and summarized for the Double-Blind Treatment Phase and 
OLE separately in a similar tabulation format as for efficacy.  No formal statistics will be performed for the 
safety analysis. 
Determination of Sample Size: The sample size is 60 patients (20 in the lower dose pitolisant group, 20 in 
the higher dose pitolisant group, and 20 in the placebo group).  Prior research suggests that the ESS-CHAD 
(parent/caregiver version) SD falls between 5 to 6; at the lower end of this range, the study would be 
powered at 80% to detect a difference of 3.9 between the pooled pitolisant groups and placebo group.  
However, as a proof of concept study, statistical separation is not a strict objective of the trial.  The proposed 
sample size will yield a 95% confidence interval of ±2.7 with an SD of 5 and ±3.2 with an SD of 6; this will 
give sufficient precision to inform future studies. 

Protocol No: HBS-101-CL-002 
 
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SCHEDULE OF ASSESSMENTS DOUBLE-BLIND TREATMENT PHASE 
 
Screening/Baselinea 
(Maximum 45 days) 
Double-Blind Treatment Phase 
(11 Weeks) 
 
 
 
Screening 
VISIT 1 
Day -45 to -2 
Baseline 
VISIT 2 
Day -1 
Titration Period (3 weeks)b 
Day 1 to 21 
Stable Dose Period (8 weeks)c 
Day 22 to 77 
 
Unsch 
visitsh 
Visit/TC 
 
Study Day 
Day 1b 
(+2 days) 
TC 1 
Day 8 
(±3 days) 
TC 2 
Day 15 
(±3 days) 
VISIT 3d 
Day 22 
(±3 day) 
TC 3 
Day 29 
(±3 days) 
TC 4 
Day 36 
(±3 days) 
VISIT 4d 
Day 50 
(±3 days) 
TC 5 
Day 57 
(±3 days) 
EOTe/ETf 
VISIT 5 
Day 77 
(±3 days) 
Safety 
F-Up 
TCsg 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Assess/confirm 
eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(FCBP)i 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Urine drug screenj 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
Physical examinationk 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Body weightl 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
Heightl 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Vital signsm 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
12-lead ECG  
(in triplicate)n 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
C-SSRSo 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ADAMS 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory 
testsp 
X 
Xq 
 
 
 
X 
 
 
X 
 
Xq 
 
 
Ghrelin measurements 
 
Xq 
 
 
 
 
 
 
 
 
Xq 
 
 
Genetic testingr 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense study diarys 
X 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol No: HBS-101-CL-002 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
Amendment 6, 10AUG2023 
 
13 
Confidential 
 
Screening/Baselinea 
(Maximum 45 days) 
Double-Blind Treatment Phase 
(11 Weeks) 
 
 
 
Screening 
VISIT 1 
Day -45 to -2 
Baseline 
VISIT 2 
Day -1 
Titration Period (3 weeks)b 
Day 1 to 21 
Stable Dose Period (8 weeks)c 
Day 22 to 77 
 
Unsch 
visitsh 
Visit/TC 
 
Study Day 
Day 1b 
(+2 days) 
TC 1 
Day 8 
(±3 days) 
TC 2 
Day 15 
(±3 days) 
VISIT 3d 
Day 22 
(±3 day) 
TC 3 
Day 29 
(±3 days) 
TC 4 
Day 36 
(±3 days) 
VISIT 4d 
Day 50 
(±3 days) 
TC 5 
Day 57 
(±3 days) 
EOTe/ETf 
VISIT 5 
Day 77 
(±3 days) 
Safety 
F-Up 
TCsg 
Adverse eventst 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispense study drugu 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Administer/titrate 
study drug 
 
 
Xb 
Xb 
Xb 
Xc 
 
 
Study drug 
compliance/ 
accountability 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Blood sample for PK  
 
 
 
 
 
Xv 
 
 
Xw 
 
Xv 
 
 
ESS-CHAD 
(parent/caregiver 
version) 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
CaGI-S (of EDS) 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
CGI-S (overall clinical 
status related to PWS) 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
ABC-C 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
MERS-R-PWS 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Cogstate Detection 
Xx 
X 
 
 
 
 
 
 
X 
 
X 
 
 
Cogstate Identification 
Xx 
X 
 
 
 
 
 
 
X 
 
X 
 
 
Cogstate One Back 
Xx 
X 
 
 
 
 
 
 
X 
 
X 
 
 
ZBI-22 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
HQ-CT  
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
FSZQ 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 

Protocol No: HBS-101-CL-002 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
Amendment 6, 10AUG2023 
 
14 
Confidential 
ABC-C = Aberrant Behavior Checklist-Community, Second Edition; ADAMS = Anxiety, Depression, and Mood Scale; AE = adverse event; CaGI-S = Caregiver Global Impression of 
Severity; CDC = Centers for Disease Control and Prevention; CGI-S = Clinical Global Impression of Severity; C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; EDS = excessive daytime sleepiness; EOT = end of treatment; ESS-CHAD = Epworth Sleepiness Scale for Children and Adolescents; ET = early 
termination; FCBP = female of child-bearing potential; FSZQ = Food Safe Zone Questionnaire; F-Up = follow-up; HbA1c = hemoglobin A1c; HQ-CT = Hyperphagia Questionnaire 
for Clinical Trials; MERS-R-PWS = Montefiore-Einstein Rigidity Scale – Revised for Research Studies in PWS; OLE = Open-Label Extension; PK = pharmacokinetic(s); 
PWS = Prader-Willi syndrome; TC = telephone call; Unsch = unscheduled; ZBI-22 = 22-item Zarit Burden Interview 
a In the event that a portion of the Screening Visit is conducted remotely, specific procedures for both the Screening Visit and Baseline Visit will be conducted as detailed in 
Section 6.6.  
b The 3-week Titration Period for the Double-Blind Treatment Phase will be from Days 1 to 21 (±3 days).  Patients should take their first dose of study drug on the day after the 
Baseline Visit (Day 1), and study drug dose will be titrated on Day 8 and again on Day 15 (as appropriate based on randomized stable dose, Table 7); all patients will be at their 
randomized stable dose of study drug by Day 15.  Patients and/or their caregivers will receive TCs on Days 8 and 15 (±3 days) to assess for AEs and concomitant medication use, 
complete the C-SSRS, and review/confirm titration of study drug. 
c The 8-week Stable Dose Period in the Double-Blind Treatment Phase will be from Days 22 to 77 (±3 days); patients will take their last dose of blinded treatment on Day 77 ±3 days; 
study drug compliance will be monitored at TCs and study visits as detailed in Section 5.5. 
d In the event that Visit 3 and/or Visit 4 are conducted remotely, specific procedures will be conducted as detailed in Section 6.6.1.2.  
e Visit 5 (Day 77 ±3 days) is the EOT visit for the Double-Blind Treatment Phase.  Eligible patients who enter the optional OLE Phase will be dispensed open-label pitolisant at this 
visit (Section 5.2.2); eligibility criteria must be confirmed before a patient can participate in the OLE Phase. 
f Patients who prematurely discontinue study drug are required to complete the ET Visit.  Procedures to be performed are the same as for the EOT Visit (Section 7.3.3).  Reasons for 
discontinuation must be recorded. 
g Patients who do not enter the optional OLE Phase will receive Safety Follow-up TCs from the study site 15 (±3 days) and 30 days (+3 days) after their final dose of blinded 
treatment to assess for AEs (including inquiries regarding signs and symptoms of arrhythmia, any other cardiac manifestations [e.g., syncope], and psychiatric events 
[e.g., suicidality, compulsive behavior, anxiety]) and concomitant medication use.  
h Unscheduled visits and assessments may be conducted by telephone or at an on-site study visit and should be performed if clinically indicated in the opinion of the Investigator 
(Section 7.6). 
i Serum pregnancy test is to be performed at Screening and a urine pregnancy test is to be performed at all other visits, as indicated. 
j Urine drug screen as detailed in Table 11 is to be performed at the Screening Visit, Baseline Visit (Visit 2), and at Visit 5 (Day 77). 
k Full physical examination is to be performed at the Screening Visit and Visit 5 (Day 77); abbreviated physical examination is to be performed at Visits 2, 3 and 4 (Section 6.5.2). 
l Height and weight will be measured using standardized methods and recorded on a standardized growth chart (CDC Clinical Growth Charts). 
m Vital signs include blood pressure, heart rate, respiratory rate, and body temperature; patients should be resting for at least 5 minutes before measuring vital signs. 
n Perform 12-lead ECGs (in triplicate) after the patient has been resting for at least 5 minutes.  Any clinically significant ECG reading should be promptly addressed by the 
Investigator as detailed in Section 6.5.4. 
o At Screening, suicidality is to be assessed through use of the Very Young Child/Cognitively Impaired–Lifetime Recent C-SSRS. (Appendix L).  At all other study visits and TCs, 
suicidality will be assessed through use of the Very Young Child/Cognitively Impaired–Since Last Contact C-SSRS (Appendix M). 
p Clinical laboratory tests (serum chemistry, hematology, urinalysis) to include lipid profile and HbA1c (Table 11); laboratory tests may be repeated at unscheduled visits if necessary.  
q Ghrelin measurement is to be done fasting; clinical laboratory tests, including PK sample at Visit 5, may be done with the fasting ghrelin test.  
r Genetic testing will be provided by the Sponsor for patients who do not have documented genetic confirmation of PWS diagnosis based on the review of the patient’s medical 
records. 
s Patients will be dispensed a study diary containing a sleep diary section and a study drug dosing section at the Screening Visit (Appendix B). 
t All AEs regardless of seriousness, severity, or causality will be collected from the time the patient/parent(s)/legal guardian(s) provides written informed consent/assent through 
30 days (+3 days) after final dose of study drug (Safety Follow-up TCs, Section 7.5).  At the Safety Follow-up TCs, AEs (including inquiries regarding signs and symptoms of 
arrhythmia, any other cardiac manifestations [e.g., syncope], and psychiatric events [e.g., suicidality, compulsive behavior, anxiety]) and concomitant medication use will be 
recorded, and the C-SSRS and ADAMS will be completed. 
u Patients will be instructed to take study drug once daily in the morning upon wakening; exception is on the morning of Visit 4, when study drug administration will be at the study 
site, with the timing of administration based on the PK sampling schedule.  Patients will be instructed to record in the study drug dosing section of the study diary (with the 

Protocol No: HBS-101-CL-002 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
Amendment 6, 10AUG2023 
 
15 
Confidential 
assistance of their caregiver if needed) the number of tablets administered from each bottle daily (Appendix B); the time of study drug dosing will be recorded on the day before 
Study Visit 4.  
v Blood sample collection for PK analyses at Visit 3 and Visit 5 may be at any time after the morning dose of study drug and samples may be collected at the same time as the clinical 
laboratory sample (including the fasting ghrelin sample at Visit 5).  Time of last dose of study drug and time of blood sample collection for PK analyses must be recorded. 
w Patients and/or their caregiver will be instructed to record in the study drug dosing section of the study diary the time of day that they take study drug on the day before Visit 4.  On 
the day of Visit 4, patients will not take their daily dose of study drug before arriving at the study site.  Study drug administration will be at the study site and timing will be 
based on the PK sampling schedule.  At the study site, a blood sample for PK analyses will be collected before administration of the daily dose of study drug.  The time of study 
drug administration will be recorded. Blood sample collection for PK analyses will be at the following times after study drug administration: between 45 and 75 minutes after 
dosing, between 1.5 and 2.5 hours after dosing, between 3.0 and 4.0 hours after dosing, and between 5.0 and 6.0 hours after dosing.  The time of each blood sample collection for PK 
analyses is to be recorded.  The total volume of blood collected is not to exceed the maximal allowable of 3.0 mL/kg per day (Appendix A and Table 10).  
x To familiarize patients with the Cogstate Computerized Cognitive Test Battery, the tests are to be administered twice during Screening with a break of at least 15 minutes between 
battery administrations. 
Assessments associated with on-site study visits during the Double-Blind Treatment Phase may be completed remotely under the oversight of the Investigator, as 
detailed in Section 6.6. 

Protocol No: HBS-101-CL-002 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
Amendment 6, 10AUG2023 
 
16 
Confidential 
SCHEDULE OF ASSESSMENTS OPEN-LABEL EXTENSION PHASE 
 
OLE Titration Perioda 
Day 78 to Day 98 
OLE Long-Term Dosing Periodb 
Day 99 to End of Treatmentc 
 
 
Month 3 
On-site Visits 
Months 4, 6, 9, and 12d 
Telephone Calls 
Month 15 then 
every 6 months 
On-site Visits 
Month 18 then 
every 
6 monthsd 
EOTf/ET
g Visit 
Visit/TC 
Study Day 
Day 78 
(±3 days) 
TC 6 
Day 85 
(±3 days) 
TC 7 
Day 92 
(±3 days) 
VISIT 6 
Day 99 (±3 days) 
and VISIT 8 
Day 279 (±7 days) 
VISIT 7 
Day 189 (±7 days) 
and VISIT 9 
Day 369 (±7 days) 
TC 8e 
Day 459 (±7 days) 
then every 
180 Days (±7 days) 
through EOS 
VISIT 10e 
Day 549 
(±7 days) 
then every 
180 Days 
(±7 days) 
through EOS 
Safety 
F-Up 
TCsh 
Unsch 
visitsi 
Urine pregnancy test 
(FCBP) 
 
 
 
X 
X 
 
X 
X 
 
 
Full physical 
examination 
 
 
 
X 
X 
 
X 
X 
 
 
Body weight and 
heightj 
 
 
 
X 
X 
 
X 
X 
 
X 
Clinical laboratory 
testsk 
 
 
 
X 
X 
 
X 
X 
 
 
Urine drug screenl 
 
 
 
X 
X 
 
X 
X 
 
 
Vital signsm 
 
 
 
X 
X 
 
X 
X 
 
X 
12-lead ECG (in 
triplicate)n 
 
 
 
X 
X 
 
X 
X 
 
 
C-SSRSo 
 
X 
X 
X 
X 
X 
X 
X 
 
 
ADAMS 
 
 
 
X 
X 
 
X 
X 
X 
 
Dispense/confirm 
receipt of pitolisantp 
 
 
 
X 
X 
X 
X 
 
 
 
Study drug 
compliance and 
accountability 
 
X 
X 
X 
X 
X 
X 
X 
 
X 

Protocol No: HBS-101-CL-002 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
Amendment 6, 10AUG2023 
 
17 
Confidential 
 
OLE Titration Perioda 
Day 78 to Day 98 
OLE Long-Term Dosing Periodb 
Day 99 to End of Treatmentc 
 
 
Month 3 
On-site Visits 
Months 4, 6, 9, and 12d 
Telephone Calls 
Month 15 then 
every 6 months 
On-site Visits 
Month 18 then 
every 
6 monthsd 
EOTf/ET
g Visit 
Visit/TC 
Study Day 
Day 78 
(±3 days) 
TC 6 
Day 85 
(±3 days) 
TC 7 
Day 92 
(±3 days) 
VISIT 6 
Day 99 (±3 days) 
and VISIT 8 
Day 279 (±7 days) 
VISIT 7 
Day 189 (±7 days) 
and VISIT 9 
Day 369 (±7 days) 
TC 8e 
Day 459 (±7 days) 
then every 
180 Days (±7 days) 
through EOS 
VISIT 10e 
Day 549 
(±7 days) 
then every 
180 Days 
(±7 days) 
through EOS 
Safety 
F-Up 
TCsh 
Unsch 
visitsi 
Administer/titrate 
pitolisant 
X 
X 
X 
X 
 
 
Adverse eventsq 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ESS-CHAD 
(parent/caregiver 
version) 
 
 
 
X 
X 
 
X 
X 
 
 
CaGI-S (of EDS) 
 
 
 
X 
X 
 
X 
X 
 
 
CGI-S (overall 
clinical status related 
to PWS) 
 
 
 
X 
X 
 
X 
X 
 
 
ABC-C 
 
 
 
X 
X 
 
 
 
 
 
MERS-R-PWS 
 
 
 
 
X 
 
 
 
 
 
Cogstate Detection 
 
 
 
 
X 
 
 
 
 
 
Cogstate 
Identification 
 
 
 
 
X 
 
 
 
 
 
Cogstate One Back 
 
 
 
 
X 
 
 
 
 
 
ZBI-22 
 
 
 
X 
X 
 
 
 
 
 
HQ-CT 
 
 
 
X 
X 
 
 
 
 
 
FSZQ 
 
 
 
X 
X 
 
 
 
 
 

Protocol No: HBS-101-CL-002 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
Amendment 6, 10AUG2023 
 
18 
Confidential 
ABC-C = Aberrant Behavior Checklist-Community, Second Edition; ADAMS = Anxiety, Depression, and Mood Scale; AE = adverse event; CaGI-S = Caregiver Global Impression of 
Severity; CDC = Centers for Disease Control and Prevention; CGI-S = Clinical Global Impression of Severity; C-SSRS = Columbia-Suicide Severity Rating; 
ECG = electrocardiogram; EDS = excessive daytime sleepiness; EOS = end of study; EOT = end of treatment; ESS-CHAD = Epworth Sleepiness Scale for Children and Adolescents; 
ET = early termination; FCBP = female of child-bearing potential; FSZQ = Food Safe Zone Questionnaire; F-Up = follow-up; HbA1c = hemoglobin A1c; HQ-CT = Hyperphagia 
Questionnaire for Clinical Trials; MERS-R-PWS = Montefiore-Einstein Rigidity Scale – Revised for Research Studies in PWS; OLE = Open-Label Extension; PWS = Prader-Willi 
syndrome; TC = telephone call; Unsch = unscheduled; ZBI-22 = 22-item Zarit Burden Interview 
a Eligible patients who enter the OLE Phase will begin a titration period after completion of the Double-Blind Treatment Phase of the study.  The Titration Period for the OLE Phase 
will start on Day 78 (±3 days), i.e., the day after the EOT visit (Visit 5) in the Double-Blind Treatment Phase.  Patients and/or their caregivers will receive TCs on Days 85 and 
92 (±3 days) to assess for AEs and concomitant medication use, complete the C-SSRS, and review/confirm pitolisant doses.  Pitolisant doses may be adjusted as detailed in 
Section 3.1.5.2. 
b At the end of the OLE Titration Period, patients will continue to take open-label pitolisant once daily in the morning upon wakening through the end of the study (Long-Term Dosing 
Period).  Adjustments to pitolisant dose are permitted as detailed in Section 3.1.5.2. 
c The Long-Term Dosing Period for the OLE Phase will continue until the Sponsor elects to terminate the study.  
d Patients will have the option to complete up to two of the scheduled on-site study visits (i.e., Visits 6, 7, 8, and 9) remotely; thereafter (i.e., after Visit 9/Month 12), patients may 
complete one of the scheduled on-site visits remotely per year.  Assessments associated with on-site study visits that may be completed remotely, under the oversight of the 
Investigator, are detailed in Section 6.6.  
e Patients and/or their caregivers will receive a TC on Day 459 (±7 days; TC 8) and will return with their caregivers to the study site for an on-site visit on Day 549 (±7 days; Visit 10).  
Patients will continue to have alternating TCs and on-site study visits approximately every 3 months (90 days ±7 days) thereafter until the end of the study.  The TCs will be to record 
AEs and concomitant medication use, complete the C-SSRS, confirm the current dose of study drug and compliance with dosing, and confirm shipment/receipt of study drug in a 
quantity sufficient for 3 months (i.e., 90 days) of once daily administration.  Safety and efficacy evaluations performed at the on-site study visits will be the same as those outlined for 
Visit 10.  Study drug compliance will be monitored at TCs and study visits as detailed in Section 5.5. 
f All patients will complete an EOT Visit (Section 7.4.2.4).  The safety and efficacy evaluations to be performed are the same as those listed for Visit 10. 
g Patients who prematurely discontinue study drug are required to complete the ET Visit (Section 7.4.3).  Reasons for discontinuation must be recorded. 
h All patients and/or their caregiver will receive Safety Follow-up TCs from the study site 15 (±3 days) and 30 days (+3 days) after their final dose of open-label pitolisant to assess for 
AEs (including inquiries regarding signs and symptoms of arrhythmia, any other cardiac manifestations [e.g., syncope], and psychiatric events [e.g., suicidality, compulsive 
behavior, anxiety]) and concomitant medication use. 
i Unscheduled visits and assessments may be conducted by telephone or at an on-site study visit and should be performed if clinically indicated in the opinion of the Investigator 
(Section 7.6). 
j Height and weight will be measured using standardized methods and recorded on a standardized growth chart (CDC Clinical Growth Charts). 
k Clinical laboratory tests (serum chemistry, hematology, urinalysis) to include lipid profile and HbA1c (Table 11); laboratory tests may be repeated at unscheduled visits if necessary. 
l Table 11 provides a list of drugs that are tested. 
m Vital signs include blood pressure, heart rate, respiratory rate, and body temperature; patients should be resting for at least 5 minutes before measuring vital signs. 
n Perform 12-lead ECGs (in triplicate) after the patient has been resting for at least 5 minutes.  Any clinically significant ECG reading should be promptly addressed by the 
Investigator as detailed in Section 6.5.4. 
o Suicide risk/suicidality will be assessed at all study visits and TCs using the Very Young Child/Cognitively Impaired-Since Last Contact C-SSRS (Appendix M). 
p During the OLE Phase, open-label pitolisant in a quantity sufficient for 90 days of once daily administration will be provided to patients every 3 months (90 days) either via mail or 
at the on-site study visits.  Patients will be instructed to take pitolisant once daily in the morning upon wakening.  
q All AEs regardless of seriousness, severity, or causality will be collected from the time the patient/parent(s)/legal guardian(s) provides written informed consent/assent through 
30 days (+3 days) after final dose of open-label pitolisant (Safety Follow-up TCs, Section 7.5).  At the Safety Follow-up TCs, AEs (including inquiries regarding signs and 
symptoms of arrhythmia, any other cardiac manifestations [e.g., syncope], and psychiatric events [e.g., suicidality, compulsive behavior, anxiety]) and concomitant medication use 
will be recorded, and the ADAMS will be completed. 
Assessments associated with on-site study visits during the OLE Phase may be completed remotely, as directed and overseen by the Investigator and detailed in Section 6.6. 

Protocol No: HBS-101-CL-002 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
Amendment 6, 10AUG2023 
 
19 
Confidential 
TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL: HBS-101-CL-002 ...................................................................1 
SPONSOR SIGNATURE ................................................................................................................2 
INVESTIGATOR AGREEMENT...................................................................................................3 
PROTOCOL SYNOPSIS.................................................................................................................4 
SCHEDULE OF ASSESSMENTS DOUBLE-BLIND TREATMENT PHASE ..........................12 
SCHEDULE OF ASSESSMENTS OPEN-LABEL EXTENSION PHASE .................................16 
TABLE OF CONTENTS ...............................................................................................................19 
LIST OF FIGURES .......................................................................................................................26 
LIST OF TABLES .........................................................................................................................26 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................................................27 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ........................................................30 
SUMMARY OF CHANGES, AMENDMENT 6 ..........................................................................30 
SUMMARY OF CHANGES, AMENDMENT 5, ADMINISTRATIVE LETTER ......................31 
SUMMARY OF CHANGES, AMENDMENT 5 ..........................................................................32 
SUMMARY OF CHANGES, AMENDMENT 4 ..........................................................................35 
SUMMARY OF CHANGES, AMENDMENT 3 ..........................................................................37 
SUMMARY OF CHANGES, AMENDMENT 2, ADMINISTRATIVE LETTER ......................40 
SUMMARY OF CHANGES, AMENDMENT 2 ..........................................................................41 
SUMMARY OF CHANGES, AMENDMENT 1 ..........................................................................41 
1. 
INTRODUCTION ......................................................................................................44 
1.1. 
Background Information and Study Rationale ...........................................................44 
1.2. 
Rationale for Study Design .........................................................................................45 
1.3. 
Dose Rationale ............................................................................................................49 
1.3.1. 
Age-Based Dosing (Double-Blind Treatment Phase and OLE Phase Prior to 
Implementation of Protocol Amendment 6) ...............................................................49 
1.3.2. 
Dosing (OLE Phase After Implementation of Protocol 
Amendment 6) ............................................................................................................49 
1.4. 
Potential Risks and Benefits .......................................................................................50 
2. 
STUDY OBJECTIVES ..............................................................................................51 
2.1. 
Primary Objective .......................................................................................................51 
2.2. 
Secondary Objectives .................................................................................................51 
2.2.1. 
Key Secondary Objectives ..........................................................................................51 

Protocol No: HBS-101-CL-002 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
Amendment 6, 10AUG2023 
 
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Confidential 
2.2.2. 
Other Secondary Objectives .......................................................................................51 
2.3. 
Exploratory Objectives ...............................................................................................51 
3. 
INVESTIGATIONAL PLAN AND ENDPOINTS ....................................................52 
3.1. 
Description of the Study Design .................................................................................52 
3.1.1. 
Overall Study Design ..................................................................................................52 
3.1.2. 
Screening and Baseline Visits ....................................................................................54 
3.1.3. 
Double-Blind Treatment Phase ...................................................................................55 
3.1.4. 
Open-Label Extension Phase ......................................................................................56 
3.1.5. 
Dose Adjustments .......................................................................................................58 
3.1.5.1. 
Double-Blind Treatment Phase ...................................................................................58 
3.1.5.2. 
Open-Label Extension Phase ......................................................................................58 
3.1.6. 
Dose Interruptions ......................................................................................................58 
3.2. 
Study Endpoints ..........................................................................................................59 
3.2.1. 
Efficacy Endpoints ......................................................................................................59 
3.2.1.1. 
Double-Blind Treatment Phase ...................................................................................59 
3.2.1.2. 
Open-Label Extension Phase ......................................................................................59 
3.2.2. 
Pharmacokinetic and Pharmacodynamic Endpoints ...................................................59 
3.2.3. 
Safety Endpoints .........................................................................................................60 
3.3. 
Study Duration ............................................................................................................60 
4. 
STUDY ENROLLMENT AND WITHDRAWAL ....................................................61 
4.1. 
Study Population .........................................................................................................61 
4.1.1. 
Inclusion Criteria ........................................................................................................61 
4.1.2. 
Exclusion Criteria .......................................................................................................62 
4.2. 
Method of Assigning Patients to Treatment Groups ..................................................64 
4.2.1. 
Procedures for Handling Randomized Patients Who Do Not Meet the Study 
Eligibility Criteria .......................................................................................................64 
4.3. 
Blinding ......................................................................................................................64 
4.3.1. 
Breaking the Blind ......................................................................................................64 
4.4. 
Patient Withdrawal and Follow-up .............................................................................65 
4.4.1. 
Patient Withdrawal .....................................................................................................65 
4.4.2. 
Temporary Interruption of Study Drug During the OLE Phase .................................65 
4.4.3. 
Procedures for Patient Follow-up ...............................................................................66 
4.4.4. 
Withdrawal of Consent for Contact ............................................................................66 

Protocol No: HBS-101-CL-002 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
Amendment 6, 10AUG2023 
 
21 
Confidential 
4.4.5. 
Patients Deemed Lost to Follow-up ...........................................................................66 
4.5. 
Patient Replacement ...................................................................................................67 
4.6. 
Study and Patient Completion ....................................................................................67 
4.6.1. 
Study Completion .......................................................................................................67 
4.6.2. 
Patient Completion .....................................................................................................67 
4.7. 
Screen Failures ............................................................................................................67 
5. 
STUDY TREATMENT ..............................................................................................68 
5.1. 
Description of Treatments ..........................................................................................68 
5.1.1. 
Pitolisant (Investigational Product) ............................................................................68 
5.1.2. 
Placebo (Comparator) .................................................................................................68 
5.2. 
Manufacturing, Packaging, and Labeling ...................................................................68 
5.2.1. 
Study Drug Packaging and Labeling for the Double-Blind Treatment Phase ............68 
5.2.2. 
Study Drug Packaging and Labeling for the Open-Label Extension Phase ...............70 
5.3. 
Storage ........................................................................................................................70 
5.4. 
Study Drug Administration .........................................................................................70 
5.4.1. 
Study Drug Administration During the Double-Blind Treatment Phase ....................70 
5.4.2. 
Study Drug Administration During the Open-Label Extension Phase .......................70 
5.5. 
Study Drug Compliance .............................................................................................71 
5.6. 
Study Drug Accountability .........................................................................................71 
5.7. 
Prior and Concomitant Therapy ..................................................................................71 
5.7.1. 
Permitted Concomitant Medications ..........................................................................72 
5.7.2. 
Prohibited Medications ...............................................................................................72 
5.7.3. 
Medications Requiring Adjustment to the Dose of Pitolisant ....................................73 
6. 
STUDY PROCEDURES AND ASSESSMENTS ......................................................74 
6.1. 
Medical History and Demographics ...........................................................................74 
6.1.1. 
Medical History ..........................................................................................................74 
6.1.2. 
Demographics .............................................................................................................74 
6.2. 
Dosing and Sleep Diary ..............................................................................................74 
6.3. 
Efficacy Assessments .................................................................................................74 
6.3.1. 
Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD); 
Parent/Caregiver Version ............................................................................................75 
6.3.2. 
Caregiver Global Impression of Severity for Excessive Daytime Sleepiness ............75 

Protocol No: HBS-101-CL-002 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
Amendment 6, 10AUG2023 
 
22 
Confidential 
6.3.3. 
Clinical Global Impression of Severity of Overall Clinical Status Related to 
PWS ............................................................................................................................75 
6.3.4. 
Aberrant Behavior Checklist-Community, Second Edition .......................................76 
6.3.5. 
Montefiore-Einstein Rigidity Scale – Revised for Research Studies in PWS 
(MERS-R-PWS) .........................................................................................................76 
6.3.6. 
Cogstate Computerized Cognitive Tests ....................................................................76 
6.3.6.1. 
Cogstate Detection Test (Psychomotor Function) ......................................................76 
6.3.6.2. 
Cogstate Identification Test (Attention) .....................................................................77 
6.3.6.3. 
Cogstate One Back Test (Working Memory) .............................................................77 
6.3.7. 
22-Item Zarit Burden Interview ..................................................................................77 
6.3.8. 
Hyperphagia Questionnaire for Clinical Trials (HQ-CT) ...........................................77 
6.3.9. 
Food Safe Zone Questionnaire (FSZQ) ......................................................................77 
6.3.10. 
Ghrelin Levels ............................................................................................................78 
6.4. 
Pharmacokinetic Assessments ....................................................................................78 
6.5. 
Safety Assessments .....................................................................................................79 
6.5.1. 
Adverse Events ...........................................................................................................79 
6.5.2. 
Physical Examinations ................................................................................................79 
6.5.3. 
Vital Signs ..................................................................................................................79 
6.5.4. 
12-Lead Electrocardiograms .......................................................................................79 
6.5.5. 
Clinical Laboratory Tests ...........................................................................................80 
6.5.6. 
Additional Safety Assessments ...................................................................................81 
6.6. 
Potential Use of Alternative Methods for Completing Study Assessments ...............82 
6.6.1. 
Assessments that may be Completed Remotely .........................................................82 
6.6.1.1. 
Remote Screening Visit ..............................................................................................82 
6.6.1.2. 
Assessments that may be Completed at the Patient’s Home for Visit 3 and/or 
Visit 4 and for Remote Visits During the Open-Label Extension Phase ....................84 
6.6.2. 
Other Considerations ..................................................................................................85 
7. 
TIMING OF PROCEDURES AND ASSESSMENTS ..............................................87 
7.1. 
Screening (Visit 1) ......................................................................................................87 
7.2. 
Baseline (Visit 2; Day -1) ...........................................................................................88 
7.3. 
Double-Blind Treatment Phase (Day 1 to Day 77) ....................................................89 
7.3.1. 
Titration Period, Double-Blind Treatment Phase (Days 1 to 21) ...............................89 
7.3.2. 
Stable Dose Period, Double-Blind Treatment Phase (Days 22 to 77) ........................89 

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7.3.2.1. 
Visit 3 (Day 22 ±3 Days) ............................................................................................90 
7.3.2.2. 
Telephone Calls; TC 3, TC 4, and TC 5 (Days 29, 36, and 57 [±3 Days]) ................90 
7.3.2.3. 
Visit 4 (Day 50 ±3 Days) ............................................................................................91 
7.3.2.4. 
Visit 5 (Day 77 ±3 Days); End of Treatment in the Double-Blind Treatment 
Phase ...........................................................................................................................92 
7.3.3. 
Early Termination Visit for Double-Blind Treatment Phase ......................................93 
7.4. 
Open-Label Extension Phase (Day 78 To End of Treatment) ....................................93 
7.4.1. 
Titration Period; OLE Phase (Days 78 to 98) .............................................................94 
7.4.2. 
Long-Term Dosing Period, OLE Phase (Day 99 to End of Treatment) .....................94 
7.4.2.1. 
Visits 6, 7, 8, and 9 (Days 99, 189, 279, and 369) ......................................................94 
7.4.2.2. 
Telephone Calls; Day 459 (TC 8) and Every 6 Months (180 Days) 
Thereafter Until End of Treatment .............................................................................95 
7.4.2.3. 
Visit 10 (Day 549) and Every 6 Months (180 Days) Thereafter Until End of 
Treatment ....................................................................................................................96 
7.4.2.4. 
End of Treatment Visit for the Open-Label Extension Phase ....................................96 
7.4.3. 
Early Termination Visit for Open-Label Extension Phase .........................................97 
7.5. 
Safety Follow-Up Telephone Calls ............................................................................97 
7.6. 
Unscheduled Visits and Assessments .........................................................................97 
8. 
SAFETY MONITORING AND REPORTING .........................................................99 
8.1. 
Definition of Safety Parameters ..................................................................................99 
8.1.1. 
Definition of an Adverse Event ..................................................................................99 
8.1.2. 
Definition of a Serious Adverse Event .....................................................................100 
8.1.3. 
Definition of a Suspected Adverse Reaction ............................................................100 
8.1.4. 
Definition of a Serious Suspected Adverse Reaction ...............................................101 
8.1.5. 
Definition of Unanticipated Problems ......................................................................101 
8.2. 
Classification of Adverse Events ..............................................................................101 
8.2.1. 
Severity of Adverse Events ......................................................................................101 
8.2.2. 
Relationship to Study Drug ......................................................................................101 
8.3. 
Time Period and Frequency for Adverse Event Assessment and Follow-up ...........102 
8.3.1. 
Adverse Event and Serious Adverse Event Monitoring ...........................................102 
8.3.2. 
Follow-up of Events .................................................................................................102 
8.4. 
Reporting Procedures ................................................................................................103 
8.4.1. 
Reporting Serious Adverse Events to the Sponsor ...................................................103 

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8.4.2. 
Reporting Unanticipated Problems to the Sponsor ...................................................104 
8.4.3. 
Regulatory Reporting Requirements ........................................................................104 
8.4.4. 
Pregnancy Reporting ................................................................................................105 
9. 
STATISTICAL CONSIDERATIONS .....................................................................106 
9.1. 
General Considerations .............................................................................................106 
9.1.1. 
Estimand ...................................................................................................................106 
9.1.2. 
Multiple Comparisons ..............................................................................................106 
9.1.3. 
Missing Data .............................................................................................................107 
9.2. 
Determination of Sample Size ..................................................................................108 
9.3. 
Analysis Populations ................................................................................................108 
9.3.1. 
Intent-to-Treat Population ........................................................................................108 
9.3.2. 
Double-Blind Safety Population ...............................................................................108 
9.3.3. 
Open-Label Safety Population ..................................................................................108 
9.3.4. 
Pharmacokinetic Population .....................................................................................108 
9.4. 
Statistical Analysis Methods .....................................................................................108 
9.4.1. 
Disposition and Demographics .................................................................................108 
9.4.2. 
Efficacy Analysis ......................................................................................................109 
9.4.2.1. 
Double-Blind Treatment Phase .................................................................................109 
9.4.2.2. 
Open-Label Extension Analyses ...............................................................................110 
9.4.3. 
Safety Analysis .........................................................................................................110 
9.4.4. 
Pharmacokinetic Analyses ........................................................................................111 
9.5. 
Interim Analysis ........................................................................................................111 
10. 
QUALITY ASSURANCE AND QUALITY CONTROL .......................................112 
11. 
REGULATORY AND ETHICAL CONSIDERATIONS ........................................113 
11.1. 
Regulatory Authority Approval ................................................................................113 
11.2. 
Ethical Conduct of the Study ....................................................................................113 
11.3. 
Institutional Review Board Approval .......................................................................113 
11.4. 
Informed Consent/Assent Process ............................................................................113 
11.5. 
Confidentiality ..........................................................................................................114 
12. 
STUDY ADMINISTRATION .................................................................................116 
12.1. 
Clinical Monitoring ..................................................................................................116 
12.2. 
Management of Protocol Amendments and Deviations ...........................................116 
12.2.1. 
Protocol Modification ...............................................................................................116 

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12.2.2. 
Protocol Violations and Deviations ..........................................................................116 
12.3. 
Financial Disclosure .................................................................................................117 
12.4. 
Suspension or Termination of Study or Investigational Site ....................................117 
12.4.1. 
Suspension of Study .................................................................................................117 
12.4.2. 
Termination of Study or Investigational Site ............................................................117 
12.5. 
Publication and Information Disclosure Policy ........................................................117 
13. 
REFERENCE LIST ..................................................................................................119 
APPENDIX A. MAXIMUM ALLOWABLE BLOOD DRAW VOLUMES ..........................123 
APPENDIX B. STUDY DIARY: PATIENT PITOLISANT STUDY DRUG DOSING 
AND SLEEP DIARY ...............................................................................................125 
APPENDIX C. EXAMPLES OF STRONG CYP2D6 INHIBITORS, STRONG 
CYP3A4 INDUCERS, MEDICATIONS THAT PROLONG QT 
INTERVAL, AND CENTRALLY ACTING H1 RECEPTOR 
ANTAGONISTS ......................................................................................................141 
APPENDIX D. EPWORTH SLEEPINESS SCALE FOR CHILDREN AND 
ADOLESCENTS (ESS-CHAD [PARENT/CAREGIVER VERSION]) .................142 
APPENDIX E. CAREGIVER GLOBAL IMPRESSIONS OF SEVERITY (CAGI-S) 
FOR EXCESSIVE DAYTIME SLEEPINESS .........................................................144 
APPENDIX F. CLINICAL GLOBAL IMPRESSION OF SEVERITY OF OVERALL 
CLINICAL STATUS ................................................................................................145 
APPENDIX G. ABERRANT BEHAVIOR CHECKLIST-COMMUNITY, SECOND 
EDITION (ABC-C) ..................................................................................................146 
APPENDIX H. MONTEFIORE-EINSTEIN RIGIDITY SCALE – REVISED FOR 
RESEARCH STUDIES IN PWS (MERS-R-PWS) .................................................152 
APPENDIX I. 22-ITEM ZARIT BURDEN INTERVIEW (ZBI-22) .......................................163 
APPENDIX J. HYPERPHAGIA QUESTIONNAIRE FOR CLINICAL TRIALS 
(HQ-CT) ...................................................................................................................167 
APPENDIX K. FOOD SAFE ZONE QUESTIONNAIRE (FSZQ) .........................................170 
APPENDIX L. COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
VERY YOUNG CHILD/COGNITIVELY IMPAIRED-LIFETIME 
RECENT ...................................................................................................................172 
APPENDIX M. COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
VERY YOUNG CHILD/COGNITIVELY IMPAIRED-SINCE LAST 
CONTACT ...............................................................................................................176 
APPENDIX N. ANXIETY, DEPRESSION, AND MOOD SCALE (ADAMS) .....................180 

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LIST OF FIGURES 
Figure 1: 
Overall Study Design ..................................................................................................53 
 
LIST OF TABLES 
Table 1: 
Summary of Changes of Amendment 6 ......................................................................30 
Table 2: 
Summary of Changes of Amendment 5 ......................................................................32 
Table 3: 
Summary of Changes for Amendment 4 ....................................................................36 
Table 4: 
Summary of Changes for Amendment 3 ....................................................................37 
Table 5: 
Summary of Changes for Amendment 2 ....................................................................41 
Table 6: 
Summary of Changes for Amendment 1 ....................................................................42 
Table 7: 
Study Drug Dosing in the Double-Blind Treatment Phase ........................................55 
Table 8: 
Pitolisant Dosing in the Open-Label Extension Phase Prior to 
Implementation of Amendment 6 ...............................................................................56 
Table 9: 
Pitolisant Dosing in the Open-Label Extension Phase After Implementation 
of Amendment 6 .........................................................................................................57 
Table 10: Estimated Total Blood Draw Volumes on Pharmacokinetic Sampling Days ............78 
Table 11: Clinical Laboratory Tests ...........................................................................................81 
Table 12: Remote Screening Visit Combined with On-Site Baseline Visit ...............................83 
Table 13: Alternative Methods for Completing Study Assessments for Visit 3 and/or 
Visit 4 and Remote Visits During the OLE Phase ......................................................85 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ABC-C 
Aberrant Behavior Checklist-Community, Second Edition 
ADAMS 
Anxiety, Depression, and Mood Scale 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
AUC 
Area under the concentration-time curve 
AUClast 
AUC from time 0 to the last collection time 
AUCtau 
AUC during a dosing interval at steady state 
BMI 
Body mass index 
CaGI-S 
Caregiver Global Impression of Severity 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression of Severity 
cGCP 
Current Good Clinical Practice 
COVID-19 
Coronavirus disease 2019 
Cmax 
Maximum observed concentration 
CSF 
Cerebrospinal fluid 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV% 
Coefficient of variation  
CYP 
Cytochrome P450 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
EC 
Ethics Committee 
ECG 
Electrocardiogram, electrocardiography 
eCRF 
Electronic case report form 
EDS 
Excessive daytime sleepiness 
eGFR 
Estimated glomerular filtration rate 
EOT  
End of Treatment 
ESS 
Epworth Sleepiness Scale 
ESS-CHAD 
Epworth Sleepiness Scale for Children and Adolescents 
ET 
Early Termination 

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Abbreviation 
Definition 
EU 
European Union 
FCBP 
Female of child-bearing potential 
FDA 
Food and Drug Administration 
FSZQ 
Food Safe Zone Questionnaire 
GCP 
Good Clinical Practice 
H1 
Histamine 1  
H3 
Histamine 3  
ICF 
Informed consent form 
HQ-CT  
Hyperphagia Questionnaire for Clinical Trials 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
ID 
Identification 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ITT 
Intent-to-Treat 
LOE 
Lack of efficacy 
LS 
Least square 
MAR 
Missing at random 
MCMC 
Markov Chain Monte Carlo 
MERS-R 
Montefiore-Einstein Rigidity Scale-Revised 
MERS-R-PWS 
Montefiore-Einstein Rigidity Scale – Revised for Research Studies 
in PWS 
MMRM 
Mixed effect model repeated measures 
MI 
Multiple imputation 
NIH 
National Institutes of Health  
OSA 
Obstructive sleep apnea 
OLE 
Open-Label Extension 
PK 
Pharmacokinetic(s) 
POC 
Proof of concept 

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Abbreviation 
Definition 
PWS 
Prader-Willi syndrome 
QTcF 
QT interval corrected for heart rate based on Fridericia’s formula 
REM 
Rapid eye movement 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOP 
Standard operating procedure 
sTST 
Subjective total sleep time 
TC 
Telephone call 
TEAE 
Treatment-emergent adverse event 
tmax  
Time to observed maximum concentration  
TOB 
Time Out of Bed 
US 
United States (of America) 
USPI 
United States Prescribing Information  
ZBI-22 
22-item Zarit Burden Interview 
Note: abbreviations used only in tables, figures, or an appendix are defined in the table or figure footnotes or in 
the appendix. 
 

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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document History 
Effective Date 
Amendment 6  
10AUG2023 
Amendment 5, Administrative letter  
04APR2023 
Amendment 5 
13DEC2021 
Amendment 4 
02AUG2021 
Amendment 3 
05MAY2021 
Amendment 2, Administrative letter 
15AUG2020 
Amendment 2 
19JUN2020 
Amendment 1 
08MAY2020 
Original Protocol 
05MAR2020 
SUMMARY OF CHANGES, AMENDMENT 6 
Table 1 describes the changes made in Amendment 6 of the protocol.  Minor editorial changes 
and changes related to abbreviations, punctuation, template language, and formatting 
(i.e., changes in numbering, word order, location), in the table of contents, in the list of 
abbreviations and definitions of terms, and in the synopsis are not listed. 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 

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SUMMARY OF CHANGES, AMENDMENT 5, ADMINISTRATIVE 
LETTER 
 
 
 
 
 
This change was sent to Investigators in an administrative letter dated 04APR2023. 

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SUMMARY OF CHANGES, AMENDMENT 5 
Table 2 describes the changes made in Amendment 5 of the protocol.  Changes related to 
punctuation and formatting (i.e., changes in numbering, word order, location, etc.), in the table of 
contents, in the list of abbreviations and definitions of terms, and in the synopsis are not listed.   
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
  
 
  
 
  
 
 
  
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 

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SUMMARY OF CHANGES, AMENDMENT 4 
Table 3 describes the changes made in Amendment 4 of the protocol.  Changes related to 
punctuation and formatting (i.e., changes in numbering, word order, location, etc.), in the table of 
contents, in the list of abbreviations and definitions of terms, and in the synopsis are not listed. 
 
. 

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SUMMARY OF CHANGES, AMENDMENT 3 
Table 4 describes the changes made in Amendment 3 of the protocol.  Changes related to 
punctuation and formatting (i.e., changes in numbering, word order, location, etc.), in the table of 
contents, in the list of abbreviations and definitions of terms, and in the synopsis are not listed. 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 

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Section Number and 
Title 
Description of Change 
Rationale 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
SUMMARY OF CHANGES, AMENDMENT 2, ADMINISTRATIVE 
LETTER 
 
 
 

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Amendment 6, 10AUG2023 
 
 
 
 
SUMMARY OF CHANGES, AMENDMENT 2 
Table 5 describes the changes made in Amendment 2 of the protocol.  Changes related to 
punctuation and formatting (i.e., changes in numbering, word order, location, etc.), in the table of 
contents, in the list of abbreviations and definitions of terms, and in the synopsis are not listed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
SUMMARY OF CHANGES, AMENDMENT 1 
Table 6 describes the changes made in Amendment 1 of the protocol.  Changes related to 
punctuation and formatting (i.e., changes in numbering, word order, location, etc.), in the table of 
contents, in the list of abbreviations and definitions of terms, and in the synopsis are not listed. 
   

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Section Number and 
Title 
Description of Change 
Rationale 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. 
INTRODUCTION 
1.1. 
Background Information and Study Rationale 
Prader-Willi syndrome (PWS) is a rare complex genetic disorder characterized by a myriad of 
symptoms including short stature, hypotonia, hyperphagia, early onset childhood obesity, 
hypogonadism, behavioral problems, excessive daytime sleepiness (EDS), and cognitive 
dysfunction (Holm et al 1993).  The disease is due to deletion of paternal copies of imprinted 
genes at chromosomal region 15q11.2-q13 (65 to 75% of individuals), maternal uniparental 
disomy 15 (20 to 30%), or an imprinting defect (1 to 3%) (Cassidy et al 2012; Driscoll et al 
2017).  
In addition to genetic defects, neuroanatomical abnormalities have been found in the postmortem 
hypothalamus in patients with PWS, and many of the clinical manifestations of PWS are 
associated with or have been hypothesized to arise from hypothalamic dysfunction (Hertz et al 
1993; Swaab et al 1995; Vgontzas et al 1996; Swaab 1997; Manni et al 2001; Goldstone et al 
2008).  Notably, the hypothalamus is a crucial brain region for regulating sleep-wake timing and 
stability (Scammell et al 2017; España and Scammell 2011; Saper et al 2005), as well as 
hunger/satiety (Bruni et al 2010).  Additionally, structural brain defects identified in imaging 
studies are increasingly being recognized as contributing to cognitive and behavioral problems 
that are characteristic of patients with PWS (Miller et al 2006). 
Excessive daytime sleepiness is prevalent in this population; studies show 50 to 100% of patients 
with PWS have EDS, based on subjective (parent/caregiver reports) and/or objective (multiple 
sleep latency test [MSLT]) measures (Camfferman et al 2008).  The impact of EDS on the 
severity of PWS has been recognized as being underappreciated, and there is an unmet need for 
effective treatments to address EDS in patients with PWS (Camfferman et al 2008).  Patients 
with PWS have a tendency to wake early, which could be related to underlying behavioral 
problems associated with the disease, such as anxiety, compulsive behavior, and depression 
(Richdale et al 1999; Bingeliene et al 2015; Clarke et al 1989).  Importantly, EDS appears to be 
continuously present across a patient’s lifetime (Angriman et al 2015).  
WAKIX® (pitolisant) is currently approved in the United States (US) for the treatment of EDS or 
cataplexy in adult patients with narcolepsy and in the European Union (EU) for the treatment of 
narcolepsy with or without cataplexy in adults.  Pitolisant is also approved for narcolepsy in 
multiple other countries.  
Pitolisant is a potent and highly selective histamine 3 (H3) receptor antagonist/inverse agonist 
with a novel mechanism of action.  It triggers activation of histaminergic neurons in the brain, a 
neuronal system involved in the maintenance of wakefulness, attention, and cognition.  Pitolisant 
binds to H3 receptors and blocks the normal negative feedback mechanism for histamine 
synthesis and release.  It also functions as an inverse agonist, resulting in enhanced histamine 
synthesis and release from presynaptic neurons. 
Pitolisant easily crosses the blood-brain barrier so that after low oral doses it elicits histamine 
release in the central nervous system.  It also increases the release of other wake-promoting 
neurotransmitters (dopamine, noradrenaline, serotonin, and acetylcholine) via heteroreceptors 
within those neuronal systems.  Importantly, pitolisant does not increase dopamine release in the 

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striatum, including the nucleus accumbens, which differentiates pitolisant from other wake-
promoting agents that have abuse liability, such as amphetamines.   
In patients with narcolepsy, loss of hypocretin signaling destabilizes sleep-wake states, resulting 
in frequent shifts between sleep and wakefulness.  Pitolisant is hypothesized to compensate for 
the hypocretin deficiency by binding to H3 receptors, which increases histaminergic transmission 
in the brain, helping to stabilize states of sleep and wakefulness.  
Although patients with PWS exhibit narcolepsy-like symptoms, the sleep abnormalities in PWS 
are different from those of narcolepsy (Esbensen and Schwichtenberg 2016).  Narcolepsy type 1 
is characterized by EDS plus cataplexy; most people with PWS have chronic sleepiness and 
about 20% have brief episodes of muscle weakness suggestive of cataplexy (Tobias et al 2002; 
Weselake et al 2014).  As in people with narcolepsy, patients with PWS have poor regulation of 
rapid eye movement (REM) sleep with abnormal REM sleep cycles, sleep onset REM periods, 
more episodes of REM sleep, and variable REM latency (Hertz et al 1993; Vgontzas et al 1996; 
Priano et al 2006; Camfferman et al 2008).  In narcolepsy type 1 (with cataplexy), cerebrospinal 
fluid (CSF) hypocretin level is usually very low (≤110 pg/mL), and some people with PWS have 
moderately low CSF hypocretin levels (192 pg/mL on average compared to about 320 pg/mL in 
controls).  In contrast to narcolepsy, sleep paralysis and hypnagogic/hypnopompic hallucinations 
are uncommon in PWS (Ghergan et al 2017).  Also, the genetic markers associated with 
narcolepsy (e.g., variations in the human leukocyte antigen complex) are not associated with 
PWS (Camfferman et al 2008; Manni et al 2001). 
Given the role of the hypothalamus in PWS, the role of hypocretin in sleep-wake state stability, 
and the potential synergy between hypocretin and histamine signaling in the brain, there is a 
scientific rationale as to why pitolisant may improve EDS in patients with PWS.  
1.2. 
Rationale for Study Design 
This Phase 2 randomized, double-blind, placebo-controlled, proof of concept (POC) study with 
an optional Open-Label Extension (OLE) will evaluate the safety and efficacy of pitolisant 
compared with placebo in the treatment of EDS and other symptoms (including behavioral 
problems and cognition) in patients with PWS ages 6 to 65 years.  In addition, this study will 
evaluate the effect of treatment with pitolisant compared with placebo on the perceived caregiver 
burden with these patients. 
In the randomized Double-Blind Treatment Phase, investigators, patients, and their 
caregivers/parent(s)/legal guardian(s) will be blinded to treatment assignment, which will 
minimize the potential bias in safety and efficacy assessments.  The OLE Phase will allow for 
eligible patients (regardless of their treatment assignment in the Double-Blind Treatment Phase) 
to receive pitolisant until the Sponsor elects to terminate the study.  The OLE will also allow for 
the assessment of long-term safety and effectiveness of pitolisant in this patient population.  
Approximately 60 eligible patients ages 6 to 65 years will be enrolled in the study and will be 
randomized 1:1:1 by treatment (20 patients at a lower dose of pitolisant, 20 patients at a higher 
dose of pitolisant, and 20 patients on placebo) in the Double-Blind Treatment Phase.  In the OLE 
Phase, 
 The inclusion of pediatric patients in the 
study was based on the manifestation of the syndrome in early childhood, and the minimum 
enrollment age of 6 years was selected based on pediatric data for pitolisant that are available to 

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date.  The maximum age of 65 years allows for a representative proportion of each patient age 
group with PWS. 
The primary efficacy endpoint of change in mean ESS-CHAD (parent/caregiver version) score 
from Baseline to Week 11 for pitolisant compared with placebo was selected because EDS is 
prevalent in the PWS population, EDS has a significant impact on the daily lives of patients with 
PWS and their families, and pitolisant is FDA-approved for the treatment of EDS in adult 
patients with narcolepsy.  To assess EDS, the ESS-CHAD (parent/caregiver version), a 
parent/caregiver-rated impression of the patient’s level of daytime sleepiness, will be utilized.  
The original Epworth Sleepiness Scale (ESS) is a validated measure with high specificity and 
sensitivity for assessing subjective sleepiness in adults with sleep disorders (Johns 1991).  The 
ESS was used as the primary subjective measure of EDS in controlled clinical trials that 
supported FDA approval of modafinil, armodafinil, sodium oxybate, and pitolisant for EDS in 
patients with narcolepsy.  The measure also supported the approval of pitolisant for narcolepsy in 
the EU.  The ESS-CHAD is a modified version of the ESS, with minor changes to make the 
questionnaire more appropriate for adolescents and younger children; the instructions are easier 
to comprehend, and the descriptions of activities are more applicable to children and adolescents 
(Johns 2015).  The ESS-CHAD has been shown to be a valid, reliable, and unidimensional 
measure of daytime sleepiness in adolescents 12 to <18 years old (Janssen et al 2017).  Most 
children ≥9 years old and most adolescents can answer the ESS-CHAD without assistance, 
whereas younger children may require parental assistance.  In this study, the ESS-CHAD 
parent/caregiver version will be used.  Because PWS is a neurodevelopmental disorder, with 
approximately 30 to 40% of patients who also have autism spectrum disorder, it is expected that 
the parent/caregiver will be able to provide the most reliable information regarding the patient’s 
degree of EDS.  The questionnaire will be administered to the parent/caregiver, who will answer 
questions regarding the patient’s likelihood of falling asleep during specified activities 
(Section 6.3.1). 
Key secondary efficacy endpoints of caregiver-rated impression of severity of the patient’s 
symptoms of EDS and clinician-rated impression of the severity of the patient’s overall clinical 
status will be evaluated using caregiver and clinical global impression scales.  The Caregiver 
Global Impression of Severity (CaGI-S) will be assessed at every study visit and will evaluate 
the caregiver’s impression of the patient’s symptoms of EDS over the past week (Section 6.3.1).  
The Clinical Global Impression of Severity (CGI-S) will also be assessed at every study visit and 
will evaluate the clinician’s overall assessment of the severity of the patient’s current overall 
clinical status related to PWS based on his/her experience with this patient population 
(Section 6.3.3).  The scales were chosen in order to minimize recall bias as the caregiver or 
clinician is not required to relate his/her rating of the patient’s symptoms to a baseline score.  
Other secondary efficacy endpoints of changes from Baseline to Week 11 in behavior and 
cognition and changes in perceived caregiver burden for pitolisant compared with placebo were 
selected to investigate the impact of pitolisant on other symptoms of PWS.  The following 
provides brief descriptions of the scales and questionnaires to be used to evaluate these 
endpoints, with additional details presented in Section 6.3:  
• The Aberrant Behavior Checklist-Community, Second Edition (ABC-C) 
(Section 6.3.4):  The ABC-C covers a wide range of symptoms and is commonly used 
to assess problematic behavior at home, in educational and work settings, and in 

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residential and community-based facilities.  This second edition of the checklist 
incorporates >30 years of research, including extensive data on validity, reliability, 
and documentation of intervention effects.  
• The Montefiore-Einstein Rigidity Scale –Revised for Research Studies in PWS 
(MERS-R-PWS) will be used to evaluate rigidity, a core behavioral feature of 
patients with PWS (Section 6.3.5).  The MERS-R-PWS, developed by Dr. B Taylor 
and Dr. E Hollander, is an adaptation of the Montefiore-Einstein Rigidity Scale-
Revised (MERS-R), which was developed in response to the limitations of available 
outcome measures to evaluate rigid behaviors in patient populations (Hollander 
2016).  For example, scales commonly used to measure repetitive behaviors in other 
conditions (e.g., the Children's Yale-Brown Obsessive Compulsive Scale and the 
Repetitive Behavior Scale-Revised) are either non-specific (do not specifically focus 
on rigidity) or overly specific (use very specific examples of rigid behaviors but omit 
others).  In collaboration with parents of children with PWS and the PWS Clinical 
Trials Consortium Behavioral Biomarker Working Group, the MERS-R was revised 
to evaluate rigid behaviors in children and adults with PWS in research studies 
(MERS-R-PWS).  The MERS-R-PWS is a clinician-rated, semi-structured interview 
conducted with both the patient with PWS and their caregiver present.  The scale 
measures three domains of rigid behavior (behavioral rigidity, cognitive rigidity, and 
protest) that result from a real or perceived interruption to rigidity.  The MERS-R-
PWS is currently being used as a secondary outcome measure in a US Food and Drug 
Administration (FDA)-funded study (ClinicalTrials.gov Identifier: NCT03197662) 
examining the efficacy of oxytocin in a double-blind, randomized, placebo-controlled 
8-week trial of 50 children with PWS and in a Phase 2 study (ClinicalTrials.gov 
Identifier: NCT03848481) examining the efficacy of cannabidivarin in a 
double-blind, randomized, placebo-controlled trial of 26 individuals with PWS. 
• The Cogstate Computerized Cognitive Test Battery evaluates cognition and changes 
in cognition (Section 6.3.6).  Peer reviewed publications have examined the clinical 
utility and psychometric properties of the Cogstate test battery and have demonstrated 
its validity and reliability in assessing cognitive function in children and adults in 
various indications, e.g., attention deficit hyperactivity disorder, mild cognitive 
impairment, concussion, fatigue, alcohol use, and cognitive effects of various 
medications (Mollica et al 2004; Maruff et al 2004; Collie et al 2003; Falleti et al 
2003; Collie et al 2006; Maruff et al 2006). 
• The 22-item Zarit Burden Interview (ZBI-22) (Zarit and Zarit 1990) is a widely 
accepted and frequently used instrument to assess the psychosocial and health toll of 
being the caregiver for an individual with a disability or chronic illness 
(Section 6.3.7).  The measure has been shown to have good internal consistency, 
content validity, and reliability, and in a study by Kayadjanian et al (2018), ZBI-22 
was shown to be a good predictor of the impact of PWS on many aspects of the 
caregiver’s quality of life. 
• Hyperphagia in patients with PWS will be evaluated as an exploratory endpoint using 
the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) in conjunction with the 

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Food Safe Zone Questionnaire (FSZQ).  Serum levels of ghrelin (acylated and 
unacylated) will also be evaluated. 
• Changes in hyperphagia will be assessed using the HQ-CT (Section 6.3.8).  The 
HQ-CT measures food-related preoccupations and problems as well as the severity of 
these concerns, focusing on food-seeking behaviors common among patients with 
PWS (Dykens et al 2007; Fehnel et al 2015).  The severity items scale is based on the 
definition of symptom-related impairment per the American Psychiatric Association, 
and this questionnaire has been used in more than 10 studies and clinical trials in 
PWS and is recognized by the FDA as reliable and sensitive to treatment effects in 
patients with PWS. In conjunction with the HQ-CT, the FSZQ (Section 6.3.9) will be 
used to assess environmental controls that are in place to manage hyperphagia in 
patients with PWS.  The FSZQ was developed by Elizabeth Roof (Vanderbilt 
Kennedy Center for Research on Human Development, Vanderbilt University, 
Nashville, TN) to assess strategies developed by caregivers to control food behaviors.  
The questionnaire was developed based on the input of caregivers and has been tested 
in over 300 parents with children with PWS and in adults with PWS and is currently 
being used in four ongoing clinical trials in PWS.  
• The appetite-stimulating hormone ghrelin is produced by ghrelinergic cells in the gut 
and acts as a peripheral orexigenic signal that communicates with the arcuate nucleus 
of the hypothalamus to increase appetite and food intake in response to fasting (Khan 
et al 2018).  In healthy individuals, fasting promotes increased secretion of ghrelin in 
the gut, and levels decrease after eating; however, this does not occur in patients with 
PWS.  Children and adults with PWS have between 3.0- and 4.5-fold higher fasting 
plasma levels of ghrelin compared with matched control patients with obesity 
(Cummings et al 2002; DelParigi et al 2002; Haqq et al 2003), and ghrelin levels may 
influence eating behavior in these patients (Allas et al 2018).  The mechanism 
underlying ghrelin dysregulation and the functional impact of elevated ghrelin levels 
on symptoms of PWS, including hyperphagia, are currently unknown; however, a link 
between ghrelin and the histaminergic system has been suggested by studies 
investigating the gastroprotective role of ghrelin in the gut (Adami et al 2010).  In this 
study, serum ghrelin levels (acylated and unacylated) will be evaluated 
(Section 6.3.10).  
Standard safety and tolerability assessments will include adverse event (AE) monitoring, clinical 
laboratory tests, vital signs, 12-lead electrocardiograms (ECGs), physical examinations, and 
suicidality.  In addition, anxiety will be assessed using the Anxiety, Depression, and Mood Scale 
(ADAMS), and the frequency, type, and duration of seizures in patients with a history of seizure 
disorder will be collected (Section 6.5.6). 
Characterization of the pharmacokinetics (PK) of pitolisant will inform the optimal dose 
selection strategy.  Pitolisant is primarily metabolized by cytochrome P450 (CYP) 2D6 and to a 
lesser extent by CYP3A4; metabolites are further metabolized or conjugated with glycine or 
glucuronic acid.  None of the pitolisant metabolites are pharmacologically active.  BP1.3484 is 
the most predominant metabolite after repeat dosing with pitolisant, and PK analyses in this 
study will include evaluation of this major metabolite. 

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1.3. 
Dose Rationale 
 
 
  
1.3.1. 
Age-Based Dosing 
 
 
Eligible patients (60 in total) will be randomized at a 1:1:1 ratio to one of three treatment groups: 
higher dose pitolisant, lower dose pitolisant, or placebo (20 patients per group).   
The doses for each age range (Table 8) were selected based on safety and efficacy data from the 
clinical development program for adults with narcolepsy and PK data from 24 pediatric patients 
with narcolepsy (ages 7 to <18 years) receiving a single dose of pitolisant.  The pitolisant dose 
for adult patients is consistent with the FDA-approved United States Prescribing Information 
(USPI).  The pediatric age-based doses were chosen based on modeling using the PK data 
available from the 24 pediatric patients with narcolepsy, which suggest that pediatric patients 
have higher exposure to pitolisant than adults.  The titration period is consistent with the FDA-
approved United States Prescribing Information (USPI).  
1.3.2. 
Dosing (OLE Phase After Implementation of Protocol 
Amendment 6) 
The 
dosing regimens (Table 9) were selected based on: 
• Efficacy signals that were observed for the higher dose pitolisant treatment group in 
the completed Double-Blind Treatment Phase of this study, suggesting a target for 
dosing of approximately 
 mg/kg. 
• Population PK simulations: 
− Area under the curve during a dosing interval at steady state (AUCtau) and 
maximum observed concentration (Cmax) in patients with PWS receiving the 
dosing regimens were similar to those in patients with narcolepsy 
receiving the doses included in the FDA-approved prescribing information for 
WAKIX (pitolisant). 
− The estimated risk of QT interval prolongation in patients with PWS using the 
 dosing regimens described in Table 9 is consistent with the risk 
described in patients with narcolepsy in the FDA-approved prescribing 
information for WAKIX (pitolisant).  
• Safety data: 
− Pitolisant is well tolerated in adult and pediatric patients with narcolepsy and in 
ongoing clinical development programs at doses up to 35.6 mg once daily.  
− Pitolisant is well tolerated in adult and pediatric patients with PWS at doses up to 
35.6 mg in the Double-Blind Treatment Phase of this study and up to
 mg in 
studies HBS-101-CL-003 and HBS-101-CL-004. 

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− The safety/tolerability profile of pitolisant in pediatric patients is generally 
consistent with the established safety/tolerability profile in adult patients. 
− No dose-related adverse effects were identified in the pooled narcolepsy New 
Drug Application (NDA) safety population of 1513 patients who received 
pitolisant 17.8 mg or 35.6 mg once daily for a mean of 33 weeks. 
During the OLE Phase, pitolisant dose can be adjusted (higher or lower) based on Investigator 
discretion (Section 3.1.5.2). 
1.4. 
Potential Risks and Benefits 
The overall safety/tolerability profile of pitolisant at doses of 4.45 to 35.6 mg once daily has 
been well characterized from 41 completed studies.  Of the 41 completed studies, 19 were 
Phase 1 studies and 22 were Phase 2/3 studies in the indications of narcolepsy, obstructive sleep 
apnea, Parkinson’s disease, epilepsy, schizophrenia, Lewy body dementia, and attention deficit 
hyperactivity disorder (i.e., 8 narcolepsy and 14 non narcolepsy studies).  The Phase 2/3 data 
comprised a total of 1513 patients who were treated with pitolisant; 1043 of these patients 
received pitolisant in double-blind, placebo-controlled studies.  The most frequently reported 
(≥5%) treatment-emergent AEs (TEAEs) in patients who received pitolisant in the 
Phase 2/3 studies were headache (13.5%), insomnia (8.5%), and nausea (5.8%); the majority of 
these events were considered treatment-related. 
Pitolisant is extensively metabolized by the liver and there is a significant increase in pitolisant 
exposure in patients with moderate hepatic impairment.  Pitolisant prolongs the QT interval.  The 
use of pitolisant should be avoided in patients with known QT prolongation or in combination 
with other drugs known to prolong the QT interval.  Pitolisant should also be avoided in patients 
with a history of cardiac arrhythmias, as well as other circumstances that may increase the risk of 
the occurrence of torsade de pointes or sudden death, including symptomatic bradycardia, 
hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the QT 
interval.  The risk of QT prolongation may be greater in patients with hepatic or renal 
impairment due to higher concentrations of pitolisant.  Pitolisant is contraindicated in patients 
with severe hepatic impairment and is not recommended in patients with end-stage renal disease. 
In the clinical development program for pitolisant, there was no evidence of withdrawal 
syndrome from pitolisant or rebound effect upon discontinuation of therapy, and long-term 
studies did not demonstrate evidence of the development of tolerance to pitolisant.  There were 
no clinically relevant effects of pitolisant on vital signs, electrocardiographic parameters, or 
laboratory findings across the database of patients exposed to pitolisant. 
Additional information is provided in the WAKIX (pitolisant) Investigator’s Brochure (IB) and 
current prescribing information for WAKIX (pitolisant). 

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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of this study is to evaluate the safety and efficacy of pitolisant compared 
with placebo in treating EDS in patients with PWS ages 6 to 65 years. 
2.2. 
Secondary Objectives 
2.2.1. 
Key Secondary Objectives 
The key secondary objectives of this study are to evaluate caregiver-rated impressions of severity 
of EDS and clinician-rated impressions of severity of overall clinical status in patients with PWS 
ages 6 to 65 years treated with pitolisant compared with placebo. 
2.2.2. 
Other Secondary Objectives 
Other secondary objectives of this study are to evaluate the following in patients with PWS ages 
6 to 65 years: 
• The impact of pitolisant on behavioral symptoms  
• The impact of pitolisant on cognitive functions 
• Change in caregiver burden  
• Effectiveness of pitolisant during long-term treatment 
2.3. 
Exploratory Objectives 
The exploratory objectives of this study are to evaluate the following in patients with PWS ages 
6 to 65 years: 
• The impact of pitolisant on hyperphagia 
• The impact of pitolisant on ghrelin levels 
• The PK of pitolisant and its major metabolite, BP1.3484 
• The relationship between levels of pitolisant (PK) and treatment effect 
(pharmacodynamics) 

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3. 
INVESTIGATIONAL PLAN AND ENDPOINTS 
3.1. 
Description of the Study Design 
3.1.1. 
Overall Study Design 
This is a randomized, double-blind, placebo-controlled, parallel group, Phase 2 POC study in 
patients (ages 6 to 65 years) with PWS, followed by an optional OLE Phase.  
The study will consist of a Screening Period (up to a maximum of 45 days), an 11-week 
Double-Blind Treatment Phase (including a Titration Period and an 8-week Stable Dose Period), 
and an optional OLE Phase.  The OLE Phase will be multi-year in duration and will continue 
until the Sponsor elects to terminate the study.  An overall schema of the study design is 
provided in Figure 1. 
During Screening, patients who meet all eligibility criteria will be enrolled in the study, 
randomized in a 1:1:1 ratio to receive treatment with lower dose pitolisant, higher dose pitolisant, 
or matching placebo (20 patients per treatment group, ages 6 to 65 years) (Section 3.1.2).  The 
lower and higher pitolisant doses, respectively in each age group, will be 8.9 mg and 17.8 mg for 
children ages 6 to <12 years, 13.35 mg and 26.7 mg for adolescents ages 12 to <18 years, and 
17.8 mg and 35.6 mg for adults ages 18 to 65 years.  In the Double-Blind Treatment Phase, 
patients will be titrated to their randomized stable dose of study drug during the Titration Period 
(Section 3.1.3).  After completion of the Titration Period, patients will continue to take study 
drug at their randomized stable dose once daily in the morning upon wakening for an additional 
8 weeks of blinded treatment (Stable Dose Period).  The duration of the Double-Blind Treatment 
Phase will be 11 weeks.  
Eligible patients who complete the Double-Blind Treatment Phase will be given the opportunity 
to participate in an optional OLE Phase.   
In the OLE Phase, prior to implementation of Amendment 6, patients received a maximum target 
dose of pitolisant based on their age (17.8 mg for ages 6 to <12 years, 26.7 mg for ages 12 to 
<18 years, or 35.6 mg for ages 18 to 65 years; Section 3.1.4). 
 
 
Safety, efficacy, and PK will be evaluated as detailed in Section 3.1.3 (Double-Blind Treatment 
Phase) and Section 3.1.4 (OLE Phase). 

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Figure 1: 
Overall Study Design 
 
AE = adverse event; EOT = End of Treatment; F-Up =follow-up; OLE = Open Label Extension; PK = pharmacokinetics; TC = telephone call; V = Visit. 
 
 
 

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3.1.2. 
Screening and Baseline Visits 
At the Screening Visit (Visit 1), after written informed consent/assent is provided, patients will 
complete screening assessments and will be provided with a sleep diary to measure daily sleep 
activity.  Specific procedures and assessments for the Screening Visit (Visit 1) may be conducted 
remotely as detailed in Section 6.6.1.   
The sleep diary is to be completed daily for 14 days (minimum of 7 days required for 
evaluation); patients will record (with the assistance of their caregiver if needed) the time they go 
to bed each evening and the time they wake up each morning (an example of the study diary, 
which includes a sleep diary section and a study drug dosing section, is provided in Appendix B).  
The patient will return the sleep diary to the site at the end of the 14-day period.  
To be eligible for the study, patients must have a minimum of 7 evaluable nights from the 
14 nights of sleep diary data.  Using the patient-recorded times, a qualified study team member 
will calculate the evaluable hours and minutes the patient slept per night.  Using all evaluable 
nights, the mean subjective total sleep time (sTST) per night must be at least 8 hours for patients 
ages 6 to <12 years, at least 7 hours for patients 12 to <18 years, or at least 6 hours for patients 
≥18 years.   
At the Baseline Visit (Visit 2), patients who continue to meet all eligibility criteria based on their 
screening sleep diary will be randomized at a 1:1:1 ratio to receive once daily treatment with 
lower dose pitolisant, higher dose pitolisant, or matching placebo in the Double-Blind Treatment 
Phase (Section 3.1.3).  Patients will not be stratified by age.   
The stable doses of pitolisant (lower or higher) in the Double-Blind Treatment Phase are: 
• 8.9 mg or 17.8 mg pitolisant in children ages 6 to <12 years 
• 13.35 mg or 26.7 mg pitolisant in adolescents ages 12 to <18 years 
• 17.8 mg or 35.6 mg pitolisant in adults ages 18 to 65 years 
If the Screening Visit (Visit 1) was conducted remotely, refer to Section 6.6.1 for the procedures 
that will be conducted at the Baseline Visit (Visit 2). 
After completion of all Baseline assessments eligible patients will be dispensed study drug at the 
Baseline Visit (Day -1) and will be instructed to take study drug once daily, beginning the 
following morning upon wakening (Day 1) in accordance with the schedule presented in Table 7.  
Patients will be instructed to record daily the number of tablets administered (and from which 
bottle) in the study drug dosing section of the study diary (with the assistance of their caregiver if 
needed).  The study diary will be used in the Double-Blind Treatment Phase only (an example of 
the study diary is provided in Appendix B). 
Study drug administration should begin in the morning on the day after the Baseline Visit; the 
first day of study drug administration is Day 1. 
Patients who fail screening for any reason (e.g., sleep diary, laboratory test) may be rescreened 
once at the discretion of the Investigator. 

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3.1.3. 
Double-Blind Treatment Phase 
The day after the Baseline Visit, patients will take their first dose of study drug in the 3-week 
Titration Period (Day 1) (Figure 1).  Patients will be titrated to their randomized stable dose of 
study drug in accordance with the schedule presented in Table 7; study drug dose will be titrated 
on Day 8 and again on Day 15 (as appropriate based on randomized stable dose, per Table 7), 
with all patients at their randomized stable dose by Day 15 of the Titration Period.  At the end of 
the 3-week Titration Period, patients will continue to take study drug (pitolisant or placebo) in 
accordance with their randomized stable dose once daily in the morning upon wakening for an 
additional 8 weeks (Stable Dose Period; Days 22 to 77) for a total of 11 weeks of double-blind 
treatment.  
Table 7: 
Study Drug Dosing in the Double-Blind Treatment Phase  
 
Titration Perioda 
(3 Weeks) 
Stable Dose Periodb 
(8 Weeks) 
Age/Treatment Groups 
Week 1 
(Days 1 - 7) 
Week 2 
(Days 8 - 14) 
Week 3 
(Days 15 - 21) 
Weeks 4 - 11 
(Days 22 - 77) 
Pediatric patients (6 to <12 years) 
Lower dose pitolisant 
4.45 mg 
8.9 mg  
8.9 mg 
8.9 mg 
Higher dose pitolisant 
4.45 mg 
8.9 mg 
17.8 mg 
17.8 mg 
Placebo 
Matching tablets 
Matching tablets 
Matching tablets 
Matching tablets 
Adolescent patients (12 to <18 years) 
Lower dose pitolisant 
4.45 mg 
8.9 mg 
13.35 mg 
13.35 mg 
Higher dose pitolisant 
8.9 mg 
17.8 mg 
26.70 mg 
26.70 mg 
Placebo  
Matching tablets 
Matching tablets 
Matching tablets 
Matching tablets 
Adult patients (18 to 65 years) 
Lower dose pitolisant 
4.45 mg 
8.9 mg 
17.8 mg 
17.8 mg 
Higher dose pitolisant 
8.9 mg 
17.8 mg 
35.6 mg 
35.6 mg 
Placebo  
Matching tablets 
Matching tablets 
Matching tablets 
Matching tablets 
a Study drug dose will be titrated on Day 8 and again on Day 15 (as appropriate based on randomized stable dose); all patients 
will be at their randomized stable dose by Day 15.  
b Study drug doses for the Stable Dose Period; dose adjustments outside the protocol-specified titration schedule are not 
permitted in the Double-Blind Treatment Phase. 
 
Adjustments to study drug dosing outside the protocol-specified titration schedule are not 
permitted during the 11-week Double-Blind Treatment Phase of the study. 
Patients and/or their caregivers will receive telephone calls (TCs) from the study site on Days 8 
and 15 (±3 days) (TCs 1 and 2, respectively) during the 3-week Titration Period to assess for 
AEs and concomitant medication use, complete the C-SSRS, and review/confirm titration of 
study drug dose.  During the 8-week Stable Dose Period, patients will complete safety, efficacy, 
and PK assessments at the study site on Day 22 (Visit 3), Day 50 (Visit 4), and Day 77 (Visit 5) 
(window for Visits 3, 4, and 5 is ±3 days), and patients and/or their caregivers will receive TCs 

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from the study site on Days 29, 36, and 57 (±3 days) to assess for AEs and concomitant 
medication use, complete the C-SSRS and ADAMS, and confirm study drug dose.  
At the end of the Double-Blind Treatment Phase, eligible patients will be given the opportunity 
to enter an optional OLE Phase (Section 3.1.4).  If a patient does not enter the OLE Phase, the 
patient and/or their caregiver will receive Safety Follow-up TCs from the study site 15 (±3 days) 
and 30 days (+3 days) after their final dose of blinded treatment to assess for AEs (including 
inquiries regarding signs and symptoms of arrhythmia, any other cardiac manifestations [e.g., 
syncope], and psychiatric events [e.g., suicidality, compulsive behavior, anxiety]) and use of 
concomitant medications and to complete the C-SSRS and ADAMS (Section 7.5). 
3.1.4. 
Open-Label Extension Phase 
Before patients can enter the OLE Phase of the study, eligibility criteria must be confirmed at 
Visit 5 in the Double-Blind Treatment Phase.  
Patients who discontinue early from the Double-Blind Treatment Phase of the study but wish to 
enter the OLE Phase will require approval from the Medical Monitor in consultation with the 
Investigator (eligibility criteria must be confirmed).  
In the OLE Phase, prior to implementation of Amendment 6, patients received a maximum target 
dose of pitolisant based on their age (17.8 mg for ages 6 to <12 years, 26.7 mg for ages 12 to 
<18 years, or 35.6 mg for ages 18 to 65 years) as detailed in Table 8. 
 
 
   
Adjustments to pitolisant dose are permitted in the OLE Phase.  Details for pitolisant dose 
adjustments are provided in Section 3.1.5.2. 
Eligible patients will be dispensed open-label pitolisant at Visit 5 (Day 77 ±3 days) of the 
Double-Blind Treatment Phase and will take their first dose of open-label pitolisant in the 
morning the following day (Day 78 ±3 days).  Patients will continue to take open-label pitolisant 
once daily in the morning upon wakening through the end of the study.   
Table 8: 
Pitolisant Dosing in the Open-Label Extension Phase 
 
 
 
Titration Period 
(3 Weeks) 
Long-Term Dosing 
Period 
Age Groups 
Week 12 
Days 78 - 84 
Week 13 
Days 85 - 91 
Week 14 
Days 92 - 98 
Week 15 
(Day 99) to EOT 
Pediatric patients (6 to <12 years) 
4.45 mg 
8.9 mg 
17.8 mg 
17.8 mg 
Adolescent patients (12 to <18 
years) 
8.9 mg 
17.8 mg 
26.7 mg  
26.7 mg  
Adult patients (18 to 65 years) 
8.9 mg 
17.8 mg 
35.6 mg 
35.6 mg 
EOT = End of Treatment; OLE = Open-Label Extension 
 

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Patients and/or their caregivers will receive TCs from the study site on Days 85 and 92 (±3 days) 
to assess for AEs and concomitant medication use, complete the C-SSRS, and review/confirm 
pitolisant dose titration.  Patients and their caregivers will complete safety and effectiveness 
assessments on Day 99 (±3 days; Visit 6) and approximately every 90 days (±7 days) thereafter 
up to Day 369 (i.e., Days 189 [Visit 7], 279 [Visit 8], and 369 [Visit 9]).   
After completion of Visit 9, patients and/or their caregivers will be contacted by telephone on 
Day 459 (±7 days; TC 8), after which patients and their caregivers will return for an on-site study 
visit on Day 549 (±7 days; Visit 10).  This pattern of alternating TCs and on-site study visits 
approximately every 3 months will be repeated until either the patient withdraws from the study, 
or the study is terminated by the Sponsor.  During the first year of the OLE Phase of the study, 
patients will have the option to complete up to two of the scheduled on-site study visits remotely 
(i.e., two of Visits 6, 7, 8, and 9); thereafter (i.e., after Visit 9/Month 12), patients will have the 
option to complete one of the two scheduled on-site study visits remotely per year.  At the TCs, 
AEs and concomitant medications will be recorded, the C-SSRS will be completed, and the 
current dose of pitolisant and receipt of study drug shipments will be confirmed 
(Section 7.4.2.2).  Safety, effectiveness, and study drug compliance will be assessed at the on-
site study visits as detailed in Section 7.4.2.3.  All patients will complete an End of Treatment 
(EOT) Visit as outlined in Section 7.4.2.4.   
Patients and/or their caregivers will receive Safety Follow-up TCs from the study site 15 days 
(±3 days) and 30 days (+3 days) after their final dose of open-label pitolisant to assess for AEs 
(including inquiries regarding signs and symptoms of arrhythmia, any other cardiac 
manifestations [e.g., syncope], and psychiatric events [e.g., suicidality, compulsive behavior, 
anxiety]) and use of concomitant medication and to complete the ADAMS (Section 7.5). 

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3.1.5. 
Dose Adjustments 
3.1.5.1. 
Double-Blind Treatment Phase 
Adjustments to the dose of study drug outside of the protocol-specified titration schedule are not 
permitted during the 11-week Double-Blind Treatment Phase. 
3.1.5.2. 
Open-Label Extension Phase 
Adjustments in pitolisant dose are permitted in the OLE Phase.   
Prior to implementation of Amendment 6, pitolisant doses could be adjusted (higher or lower) in 
4.45 mg increments based on Investigator assessment of clinical response, tolerability and/or 
patient age.   
After implementation of Amendment 6, pitolisant dose may be adjusted (higher or lower) based 
on Investigator discretion in consultation with the Medical Monitor up to the maximum daily 
dose allowed 
(Table 9).  
In the event a patient develops moderate hepatic impairment (Child-Pugh B) or moderate or 
severe renal impairment during the study, the dose of pitolisant may need to be decreased by the 
Investigator in consultation with the Medical Monitor.  Patients who develop either end-stage 
renal disease (estimated glomerular filtration rate [eGFR] of <15 mL/minute/1.73 m2) or severe 
hepatic impairment (Child-Pugh C) must be withdrawn from the study (Section 4.4.1).  
If a patient began taking a strong CYP2D6 inhibitor during the OLE Phase, prior to 
implementation of Amendment 6, pitolisant dose was to be reduced by one half of the maximum 
age-based dose (Table 8).  
 
If a patient begins taking a 
strong CYP3A4 inducer during the OLE Phase, pitolisant dose may be increased up to the 
maximum permitted daily dose based on the patient’s age (prior to implementation of 
Amendment 6) 
. 
3.1.6. 
Dose Interruptions 
Every effort should be made to educate patients/caregivers/parent(s)/legal guardian(s) on the 
importance of remaining compliant with study drug dosing.  
No interruptions in study drug dosing are expected in the Double-Blind Treatment Phase of the 
study.  If a dose is missed in the Double-Blind Treatment Phase, the patient should take the next 
dose the following morning upon wakening.  If dosing is interrupted (e.g., due to an AE) for 7 or 
more days, consult with the Medical Monitor before restarting study drug.  
In the OLE Phase of the study, interruptions in study drug dosing are permitted based on 
tolerability and the discretion of the Investigator.  If a dose is missed in the OLE Phase, the 
patient should take the next dose the following morning upon wakening.  
If a patient is taking a pitolisant dose that is >8.9 mg and has a dosing interruption exceeding 
7 days in the OLE Phase, before restarting study drug, the Investigator should consult with the 
Medical Monitor. 

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3.2. 
Study Endpoints 
3.2.1. 
Efficacy Endpoints 
3.2.1.1. 
Double-Blind Treatment Phase 
3.2.1.1.1. Primary Efficacy Endpoint 
The primary efficacy endpoint is the change in mean ESS-CHAD (parent/caregiver version) 
score from Baseline to Week 11 for pitolisant compared with placebo. 
3.2.1.1.2. Key Secondary Efficacy Endpoints 
Change from Baseline to Week 11 for pitolisant compared with placebo in:  
• CaGI-S for EDS  
• CGI-S for overall clinical status related to PWS  
3.2.1.1.3. Other Secondary Efficacy Endpoints 
Change from Baseline to Week 11 for pitolisant compared with placebo in: 
• Behavior as measured by the ABC-C 
• Behavioral and cognitive rigidity as measured by the MERS-R-PWS 
• Psychomotor function as measured by the Cogstate Detection Test 
• Attention as measured by the Cogstate Identification Test  
• Working memory as measured by the Cogstate One Back Test  
• Measure of caregiver burden using the ZBI-22  
3.2.1.1.4. Exploratory Endpoints 
Change from Baseline to Week 11 for pitolisant compared with placebo in: 
• Total score of the HQ-CT in conjunction with the FSZQ 
• Acylated and unacylated ghrelin levels 
3.2.1.2. 
Open-Label Extension Phase 
Long-term effectiveness of pitolisant as measured by ESS-CHAD (parent/caregiver version), 
CaGI-S for EDS, CGI-S for overall clinical status related to PWS, ABC-C, MERS-R-PWS, 
Cogstate Detection Test, Cogstate Identification Test, Cogstate One Back Test, ZBI-22, and 
HQ-CT in conjunction with the FSZQ will be assessed during the patient’s first year of 
participation in the OLE Phase of the study.  After the first year of participation, effectiveness 
measures will include the ESS-CHAD (parent/caregiver version) as reported by caregivers, 
CaGI-S, and CGI-S. 
3.2.2. 
Pharmacokinetic and Pharmacodynamic Endpoints 
• Cmax of pitolisant and its major metabolite, BP1.3484 

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• Area under the concentration-time curve from time 0 to the last collection time 
(AUClast) after administration of pitolisant  
• Time to observed maximum concentration (tmax) of pitolisant 
• Exposure-response relationship between pitolisant levels and change in efficacy 
measures  
3.2.3. 
Safety Endpoints 
Safety will be assessed by monitoring the incidence of AEs and changes in clinical laboratory 
test results, vital signs, and 12-lead ECG results, along with additional safety assessments 
(suicidality, anxiety, and monitoring of seizures in patients with seizure disorder) from Baseline 
to Week 11 in the Double-Blind Treatment Phase and from Baseline to study completion in the 
OLE Phase. 
3.3. 
Study Duration 
The study is expected to be multi-year in duration.  The Double-Blind Treatment Phase will 
remain open until the last patient completes this phase of the study, and the OLE Phase will 
remain open until the Sponsor elects to terminate the study.   
The duration of participation for individual patients in the Double-Blind Treatment Phase is 
expected to be up to approximately 21 weeks, including a maximum of 45 days of screening, 
11 weeks of double-blind treatment (includes a 3-week Titration Period and an 8-week Stable 
Dose Period), and 30 days of safety follow-up for patients who do not enter the optional OLE 
Phase of the study.  For patients who enter the OLE Phase of the study, individual patient 
participation is expected to be multi-year in duration. 

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4. 
STUDY ENROLLMENT AND WITHDRAWAL 
4.1. 
Study Population 
Approximately 60 patients with PWS are planned to be enrolled in the study at approximately 
10 sites in the US. 
4.1.1. 
Inclusion Criteria 
Each patient must meet all of the following criteria to be enrolled in this study: 
1. Is able to provide voluntary, written informed consent (patient or parent[s]/legal 
guardian[s]) and, where applicable, voluntary, written assent (patient, as appropriate). 
2. Has a diagnosis of PWS confirmed by genetic testing and patient medical records.  
Genetic testing will be provided by the Sponsor, if not confirmed based on the review of 
the patient’s medical records. 
3. Male or female patients ages 6 to 65 years at the time of enrollment. 
4. Demonstrates adequate sleep duration via patient sleep diary during Screening defined as 
at least 8 hours of sleep per night for patients ages 6 to <12 years, at least 7 hours for 
patients ages 12 to <18 years, or at least 6 hours for patients ages ≥18 years, based on the 
mean number of hours from up to 14 nights (at least 7 nights must be recorded for 
evaluation).  
5. Has EDS as determined by ESS-CHAD (parent/caregiver version) score ≥12. 
6. If taking hormone treatments (including growth hormone, testosterone, and estrogen 
supplements) and/or allowed chronic concomitant medication or supplements, patient 
must be on a stable dose of these medications for 3 months prior to randomization and for 
the duration of the Double-Blind Treatment Phase of the study; 10% variability in 
hormone dose is allowed.  
7. If taking a wake-promoting treatment that could affect EDS (including stimulants, 
modafinil, and armodafinil), must be on a stable dose for at least 28 days prior to 
Screening and remain on a stable dose during the Double-Blind Treatment Phase of the 
study (dose adjustments will be permitted in the OLE Phase) or agree to wash out of 
treatment for 5 half-lives or 14 days, whichever is longer. 
8. If taking a chronically administered sedating medication for management of behavioral 
manifestations (e.g., hypnotics, benzodiazepines, antipsychotics, alpha agonists, 
anticholinergics, and antidepressants) must be on a stable dose for at least 28 days prior 
to Screening and remain on a stable dose during the Double-Blind Treatment Phase of the 
study (dose adjustments will be permitted in the OLE Phase) or agree to wash out of 
treatment for 5 half-lives or 14 days, whichever is longer.   
9. If using cannabidiol and/or tetrahydrocannabinol, patient must be on a stable dose for 
28 days prior to randomization and agree to continue the stable dose for the duration of 
the Double-Blind Treatment Phase of the study (dose adjustments will be permitted in the 
OLE Phase). 

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10. If taking oxytocin or carbetocin, patient must be on a stable dose during the 28 days prior 
to randomization and agree to continue the stable dose for the duration of the Double-
Blind Treatment Phase of the study (dose adjustments will be permitted in the OLE 
Phase) or agree to wash out of treatment for 5 half-lives or 14 days, whichever is longer. 
11. A patient who is a female of child-bearing potential (FCBP) must have a negative serum 
pregnancy test at the Screening Visit and a negative urine pregnancy test at the Baseline 
Visit and agree to remain abstinent or use an effective method of nonhormonal 
contraception to prevent pregnancy for the duration of the study and for 21 days after 
final dose of study drug. 
12. Has a consistent caregiver (preferably the same person throughout the Double-Blind 
Treatment Phase of the study) who is willing and able to complete the required 
assessments. 
13. In the opinion of the Investigator, patient/parent(s)/legal guardian(s) is capable of 
understanding and complying with the requirements of the protocol and administration of 
oral study drug.  
4.1.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from enrollment in the study: 
1. Has a diagnosis of another genetic or chromosomal disorder distinct from PWS. 
2. Has untreated OSA or is at high risk for OSA based on medical history and clinical 
assessment; or, has another relevant underlying sleep disorder that in the opinion of the 
Investigator is the primary contributing factor to the patient’s EDS. 
3. Consistently consumes >600 mg of caffeine per day and is unable/unwilling to reduce 
caffeine intake to <600 mg per day for the duration of the Double-Blind Treatment Phase 
of the study; caffeine intake should remain consistent during Screening and throughout 
the Double-Blind Treatment Phase of the study. 
4. Does not agree to discontinue any prohibited medication or substance listed in the 
protocol (Section 5.7.2). 
5. Participation in an interventional research study involving another investigational 
medication or device in the 28 days prior to enrollment and for the duration of the 
Double-Blind Treatment Phase of the study, unless the Investigator consults with the 
Medical Monitor and obtains written approval for the patient to enroll; patients who 
complete a washout of an investigational medication of at least 5 half-lives or 14 days 
(whichever is longer) may be enrolled in the Double-Blind Treatment Phase of the study.  
Patients considering participation in another interventional research study in the OLE 
Phase must consult with the Investigator who will consult with the Medical Monitor. 
6. Has a primary psychiatric diagnosis with current active symptoms of psychosis or 
schizophrenia. 
7. Has a diagnosis of end-stage renal disease (eGFR of <15 mL/minute/1.73 m2) or severe 
hepatic impairment (Child-Pugh C). 

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8. Has a diagnosis of moderate or severe renal impairment (eGFR ≥15 to 
≤59 mL/minute/1.73 m2) or moderate hepatic impairment (Child-Pugh B) at Screening or 
during the Double-Blind Treatment Phase. 
9. Has abnormal laboratory values at Screening that are clinically significant as determined 
by the Investigator.  
10. Has a known history of long QT syndrome or any significant history of a serious 
abnormality of the ECG (e.g., recent myocardial infarction, clinically significant 
arrhythmia) or QT interval corrected for heart rate according to Fridericia’s formula 
(QTcF) >442 ms for patients ages 0 to <10 years and >439 ms for patients ages 10 to 
<20 years, regardless of gender, and >450 ms for male patients and >470 ms for female 
patients ages 20 to 65 years (ECG QTcF = QT/3√ RR) (Mason et al 2007). 
11. Has a family history of sudden/unexplained death, cardiac death, or death from a primary 
dysrhythmia potentially associated with QT prolongation in any family member. 
12. If receiving any new or initiating a change in allied health therapies or interventions for 
symptoms of PWS, must be on a stable course of therapy for at least 28 days prior to 
randomization. 
13. Has a current or recent (within one year) history of a substance use disorder or 
dependence disorder, including alcohol and caffeine use disorders as defined in the 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V).  
14. Has planned surgery during the Double-Blind Treatment Phase of the study; planned 
surgery is permitted during the OLE Phase. 
15. Is receiving a concomitant medication that is known to be a strong CYP2D6 inhibitor, a 
strong CYP3A4 inducer, or a centrally acting H1 receptor antagonist; patients who 
complete a washout of these medications of at least 5 half-lives or 14 days (whichever is 
longer) can be enrolled in the Double-Blind Treatment Phase of the study.  Use of strong 
CYP2D6 inhibitors and strong CYP3A4 inducers is allowed during the OLE Phase; 
however, adjustment of pitolisant dose is required (Section 5.7.3).  Although not 
prohibited during the OLE Phase of the study, use of H1 receptor antagonists should be 
avoided. 
16. Is receiving a medication known to prolong the QT interval. 
17. Has a significant risk of committing suicide based on history, routine psychiatric 
examination, Investigator’s judgment, or who has an answer of “yes” on any question 
other than questions 1 to 3 on the Very Young Child/Cognitively Impaired-Lifetime 
Recent Columbia-Suicide Severity Rating Scale (C-SSRS) (Appendix L).  
18. Has a history of seizures that have recently (within 6 months) been treated with 
antiepileptic medications that are strong CYP3A4 inducers.  Patients with a history of 
seizures must have a stable seizure history (e.g., frequency and severity) for at least 
6 months prior to enrollment. 
19. Is currently breastfeeding or planning to breastfeed over the course of the study.  
Lactating women must agree not to breastfeed for the duration of the study (Double-
Blind Treatment Phase and OLE Phase) and for 21 days after final dose of study drug. 

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20. Based on the judgment of the Investigator, patient is unsuitable for the study for any 
reason, including but not limited to unstable or uncontrolled medical conditions 
(including psychiatric and neurological conditions) or a medical condition that might 
interfere with the conduct of the study, confound interpretation of study results, pose a 
health risk to the patient, or compromise the integrity of the study.  
4.2. 
Method of Assigning Patients to Treatment Groups 
Patients who meet all eligibility criteria will be randomized to treatment and will be assigned a 
unique identification (ID) number prior to dosing using interactive response technology (IRT).  
All randomization information will be kept in a secure location accessible only by the 
randomization personnel (e.g., study drug supplier) until the time of unblinding.  No patient may 
receive study drug prior to being randomized in the study. 
4.2.1. 
Procedures for Handling Randomized Patients Who Do Not Meet the Study 
Eligibility Criteria 
Patients who fail to meet the eligibility criteria should not receive study drug.  In the event a 
patient does not meet study eligibility criteria, but is enrolled and receives study drug, the 
Investigator should inform the Sponsor immediately.  The Sponsor’s Medical Monitor and the 
Investigator will determine whether to allow the patient to continue in the study.  
For patients who opt to enter the OLE Phase of the study, entrance eligibility criteria must be 
confirmed before administration of open-label pitolisant.  
4.3. 
Blinding 
For the Double-Blind Treatment Phase of the study, patients, caregivers, parent(s)/legal 
guardian(s), Investigators, personnel involved in the conduct and interpretation of the study, site 
personnel involved in safety and efficacy assessments, and Sponsor staff will be blinded to the 
treatment assignments.  
Patients are not receiving blinded study drug in the OLE Phase of the study; however, in the 
OLE Phase, patients, parents/caregivers, Investigators, personnel involved in the conduct and 
interpretation of the study, and site personnel involved in safety and efficacy assessments will 
remain blinded to a patient’s treatment assignment in the Double-Blind Treatment Phase. 
4.3.1. 
Breaking the Blind 
The study blind should not be broken except in medical emergencies when the appropriate 
medical management of the patient requires knowledge of the study drug he/she received or to 
ensure patient safety in the trial.  If it is necessary to unblind a patient’s treatment assignment to 
manage medical treatment, unblinding will occur through the IRT system. 
The Investigator should notify the Sponsor’s Medical Monitor in a timely manner if unblinding 
is necessary.  An attempt should be made to contact the Sponsor before breaking the blind.  
All circumstances leading to premature unblinding must be clearly documented. 

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4.4. 
Patient Withdrawal and Follow-up 
4.4.1. 
Patient Withdrawal 
Patients are free to withdraw from the study at any time for any reason.  A patient may also be 
withdrawn from the study by the Investigator or the Sponsor at any time for safety, behavioral, or 
administrative reasons if either determines that it is not in the patient’s best interest to continue 
participation. 
Possible reasons for early withdrawal include: 
• AE 
• Lack of effect 
• Patient/parent(s)/legal guardian(s) decision 
• Lost to follow-up 
• No longer meets eligibility criteria 
• Non-compliance with study protocol 
• Non-compliance with study drug treatment  
• Other, with specific reason (e.g., pregnancy) 
Patients who develop end-stage renal disease (eGFR of <15 mL/minute/1.73 m2), severe hepatic 
impairment (Child-Pugh C), or any other medical condition that in the opinion of the Investigator 
may pose a risk to the patient must be discontinued from the study.  
The following ECG findings, based on the mean of triplicate 12-lead ECGs, require 
discontinuation from the study:  
• Mean QTcF >500 ms 
• Mean QTcF increase from Screening >60 ms AND mean QTcF >470 ms 
• Heart rate increase from Baseline >65% or decrease from Baseline >40% 
Any patient with a new positive response on question 4 (active suicidal ideation with some intent 
to act, without specific plan) and/or question 5 (active suicidal ideation with specific plan and 
intent) of the Very Young Child/Cognitively Impaired-Since Last Contact C-SSRS 
(Appendix M) will be discontinued and will require further evaluation by the Investigator. 
The date and primary reason for early withdrawal will be recorded in the electronic case report 
form (eCRF).  At the time of withdrawal from the study, every attempt should be made to 
complete the Early Termination (ET) Visit assessments (Section 7.3.3 and Section 7.4.3). 
4.4.2. 
Temporary Interruption of Study Drug During the OLE Phase 
As noted in Section 6.5.4, in the event of clinically significant ECG findings (other than those 
that require discontinuation of study drug treatment [Section 4.4.1]), in consultation with the 
Medical Monitor, the Investigator may decide to temporarily stop (interrupt) pitolisant dosing for 
2 to 3 days.  During this interruption, ECGs will be performed daily (locally or at the study site).  
Upon resolution of the ECG abnormality, pitolisant administration may resume at the same dose 

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as before the interruption, or the pitolisant dose may be lowered by 50%.  If the condition 
persists after the interruption in dosing, the Investigator, in consultation with the Medical 
Monitor, will decide whether treatment should be permanently discontinued.  
4.4.3. 
Procedures for Patient Follow-up 
All patients who complete the Double-Blind Treatment Phase of the study are required to 
complete the safety assessments outlined in the EOT Visit (Section 7.3.2.4).  Patients who 
prematurely discontinue study drug during the Double-Blind Treatment Phase are required to 
complete the safety assessments outlined in the ET Visit, and the reasons for discontinuation 
must be recorded (Section 7.3.3).  Additionally, patients in the Double-Blind Treatment Phase 
who do not enter the OLE Phase will be contacted by telephone 15 days (±3 days) and 30 days 
(+3 days) after taking the final dose of blinded study drug to assess for AEs (including inquiries 
regarding signs and symptoms of arrhythmia, any other cardiac manifestations [e.g., syncope], 
and psychiatric events [e.g., suicidality, compulsive behavior, anxiety]) and use of concomitant 
medication (Safety Follow-up TCs; Section 7.5). 
All patients who complete the optional OLE Phase of the study are required to complete the 
safety assessments outlined in the EOT Visit (Section 7.4.2.4).  Patients who prematurely 
discontinue study drug during the OLE Phase are required to complete the safety assessments 
outlined in the ET Visit, and the reasons for discontinuation must be recorded (Section 7.4.3).  
Additionally, patients in the OLE Phase will be contacted by telephone 15 (±3 days) and 30 days 
(+3 days) after taking the final dose of open-label study drug to assess for AEs (including 
inquiries regarding signs and symptoms of arrhythmia, any other cardiac manifestations [e.g., 
syncope], and psychiatric events [e.g., suicidality, compulsive behavior, anxiety]) and use of 
concomitant medication (Safety Follow-up TCs; Section 7.5).  
Every effort should be made to educate patients/caregivers/parent(s)/legal guardian(s) on the 
importance of remaining in the study and attending scheduled study visits, including those 
required after early discontinuation of study drug.   
4.4.4. 
Withdrawal of Consent for Contact 
Patients/parent(s)/legal guardian(s) who no longer wish to attend study visits will be asked if 
they may be contacted by telephone or other methods.  However, if a patient/parent(s)/legal 
guardian(s) specifically withdraws consent to be contacted for additional information, no further 
study visits or study-related TCs will be conducted.  For any patient who withdraws consent for 
contact, the Investigator will document the reason for withdrawal of consent in the eCRF. 
4.4.5. 
Patients Deemed Lost to Follow-up 
Investigators should make every effort to contact patients/parent(s)/legal guardian(s) who are 
potentially lost to follow-up, including pursuing any alternative contact methods permitted by 
local regulations or agreed by the patient/parent(s)/legal guardian(s).  All attempts to contact the 
patient/parent(s)/legal guardian(s) will be documented in the patient’s eCRF and source notes.  
At a minimum, three documented attempts to contact the patient/parent(s)/legal guardian(s), 
including at least one certified letter, should be performed before a patient is deemed lost to 
follow-up.  

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4.5. 
Patient Replacement 
Patients who withdraw from the study will not be replaced.  Patients who are randomized to 
treatment but withdraw prior to receiving any study drug may be replaced.  
4.6. 
Study and Patient Completion 
4.6.1. 
Study Completion 
The Double-Blind Treatment Phase of the study will be completed when the last patient 
completes the EOT Visit after the final dose of blinded treatment. 
The OLE Phase of the study will continue until the Sponsor elects to terminate the study. 
4.6.2. 
Patient Completion 
Patients who complete the EOT visit in the Double-Blind Treatment Phase will be considered to 
have completed the Double-Blind Treatment Phase.  The OLE Phase of the study is optional and 
open-ended in duration.  
4.7. 
Screen Failures 
Patients who fail to meet eligibility criteria should not receive study drug.  
Patients who fail to meet eligibility criteria at either the Screening or Baseline Visit will be 
screen-failed without receiving study drug.  Patients may be rescreened at any point after failing 
any criterion, but only once for study entry. 
If a patient is re-screened for enrollment, a new informed consent form (ICF) must be signed, 
and a new patient number will be assigned by IRT.  If the patient is out of the initial 45-day 
screening window, all screening procedures must be repeated. 
In the event a patient does not meet eligibility criteria, but is enrolled and receives study drug, 
the Investigator should inform the Sponsor immediately (Section 4.2.1). 

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5. 
STUDY TREATMENT 
Study drug, defined as pitolisant (investigational product) or placebo (comparator), will be 
provided by the Sponsor.  All patients should take their study drug once daily in the morning 
upon wakening.  Dose adjustments are permitted in the OLE Phase of the study at the discretion 
of the Investigator as described in Section 3.1.5.2. 
5.1. 
Description of Treatments 
5.1.1. 
Pitolisant (Investigational Product) 
Pitolisant tablets will be provided in strengths of 4.45 mg and 17.8 mg to accommodate the study 
doses:  
• Pitolisant 4.45 mg tablets: white, round, plain, biconvex film-coated tablet, 3.7 mm in 
diameter.  Each tablet contains 5 mg of pitolisant hydrochloride equivalent to 4.45 mg 
of pitolisant. 
• Pitolisant 4.45 mg tablets: white, round, biconvex film-coated tablet, 3.7 mm in 
diameter, marked with “S” on one side and plain on the other side.  Each tablet 
contains 5 mg of pitolisant hydrochloride equivalent to 4.45 mg of pitolisant.   
• Pitolisant 17.8 mg tablets: white, round, plain, biconvex film-coated tablet, 7.5 mm in 
diameter.  Each tablet contains 20 mg of pitolisant hydrochloride equivalent to 
17.8 mg of pitolisant. 
• Pitolisant 17.8 mg tablets: white, round, biconvex film-coated tablet, 7.5 mm in 
diameter, marked with “H” on one side and plain on the other side. Each tablet 
contains 20 mg of pitolisant hydrochloride equivalent to 17.8 mg of pitolisant. 
5.1.2. 
Placebo (Comparator)  
Placebo tablets will be provided that match the exact individual physical attributes (as described 
in Section 5.1.1) for each strength of active pitolisant film-coated tablets (4.45 mg and 17.8 mg). 
5.2. 
Manufacturing, Packaging, and Labeling 
Study drug will be manufactured according to current Good Manufacturing Practices. 
Study drug will be packaged and labeled by the Sponsor or designee and will be packed and 
dispatched to comply with controlled shipping and storage conditions.  Study drug labeling will 
comply with all applicable national and local laws and regulations. 
5.2.1. 
Study Drug Packaging and Labeling for the Double-Blind Treatment Phase 
Study drug for the Double-Blind Treatment Phase will be packaged as individual patient-specific 
kits assigned by IRT.  Each kit will consist of three boxes, one box for the Titration Period 
(titration sub-kit) and two boxes for the Stable Dose Period (stable dosing sub-kits; one box 
containing supplies for Days 22 to 49 and a second box containing supplies for Days 50 to 77).  
For individual patients, the number of bottles and contents of the bottles will be based on the 
patient’s randomized treatment assignment and age (Table 7). 

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The kit for the Double-Blind Treatment Phase for ADULTS will contain: 
• Titration sub-kit: 
− Two 10-count bottles, one labeled “A” and one labeled “B” for Week 1 (Days 1 to 
7), containing pitolisant 4.45 mg or matching placebo tablets 
− Two 20-count bottles, one labeled “A” and one labeled “B” for Week 2 (Days 8 to 
14), containing pitolisant 4.45 mg or matching placebo tablets 
− Two 10-count bottles, one labeled “A” and one labeled “B” for Week 3 (Days 15 
to 21), containing pitolisant 17.8 mg or matching placebo tablets 
• Stable dosing sub-kits: 
− Two 30-count bottles, one labeled “A” and one labeled “B” for Weeks 4 to 7 
(Days 22 to 49), containing pitolisant 17.8 mg or matching placebo tablets 
− Two 30-count bottles, one labeled “A” and one labeled “B” for Weeks 8 to 11 
(Days 50 to 77), containing pitolisant 17.8 mg or matching placebo tablets 
The kit for the Double-Blind Treatment Phase for ADOLESCENTS will contain: 
• Titration sub-kit: 
− Two 10-count bottles, one labeled “A” and one labeled “B” for Week 1 (Days 1 to 
7), containing pitolisant 4.45 mg or matching placebo tablets 
− Two 20-count bottles, one labeled “A,” one labeled “B,” for Week 2 (Days 8 to 
14), containing pitolisant 4.45 mg or matching placebo tablets 
− Two 20-count bottles, one labeled “A,” one labeled “B,” and two 10-count 
bottles, one labeled “C,” and one labeled “D” for Week 3 (Days 15 to 21), 
containing pitolisant 4.45 mg or matching placebo tablets 
• Stable dosing sub-kits: 
− Six 30-count bottles, two labeled “A,” two labeled “B,” one labeled “C,” and one 
labeled “D” for Weeks 4 to 7 (Days 22 to 49), containing pitolisant 4.45 mg or 
matching placebo tablets 
− Six 30-count bottles, two labeled “A,” two labeled “B,” one labeled “C,” and one 
labeled “D” for Weeks 8 to 11 (Days 50 to 77), containing pitolisant 4.45 mg or 
matching placebo tablets 
The kit for the Double-Blind Treatment Phase for CHILDREN will contain: 
• Titration sub-kit: 
− One 10-count bottle, labeled “A” for Week 1 (Days 1 to 7), containing pitolisant 
4.45 mg or matching placebo tablets  
− One 20-count bottle, labeled “A” for Week 2 (Days 8 to 14), containing pitolisant 
4.45 mg or matching placebo tablets 

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− Two 20-count bottles, one labeled “A” and one labeled “B” for Week 3 (Days 15 
to 21), containing pitolisant 4.45 mg or matching placebo tablets 
• Stable dosing sub-kits: 
− Four 30-count bottles, two labeled “A” and two labeled “B” for Weeks 4 to 7 
(Days 22 to 49), containing pitolisant 4.45 mg or matching placebo tablets 
− Four 30-count bottles, two labeled “A” and two labeled “B” for Weeks 8 to 11 
(Days 50 to 77), containing pitolisant 4.45 mg or matching placebo tablets 
5.2.2. 
Study Drug Packaging and Labeling for the Open-Label Extension Phase 
Study drug dosing in the OLE Phase will be as described in Table 8 (prior to implementation of 
Amendment 6) or Table 9 (following implementation of Amendment 6).  Study drug for the OLE 
Phase will be provided to patients as individual bottles. 
Open-label pitolisant for Day 78 through the end of treatment will be provided as 30-count 
bottles containing pitolisant 4.45 mg or 17.8 mg tablets.  
5.3. 
Storage 
At the study site, the Investigator is responsible for ensuring that study drug is stored in a secure 
location.  Responsibilities may be delegated to the pharmacy or other appropriate members of the 
study team.  Responsibilities that are delegated must be documented.  
Study drug should be stored at a temperature of 20° to 25° C (68° to 77° F); excursions are 
permitted between 15° to 30° C (59° to 86° F), in accordance with United States Pharmacopeia 
(USP) Controlled Room Temperature. 
Temperature logs for monitoring proper storage conditions must be maintained by the site. 
5.4. 
Study Drug Administration 
Study drug administration for the Double-Blind Treatment Phase and OLE Phase is described in 
Section 5.4.1 and Section 5.4.2, respectively; additional information for study drug 
administration will be provided in a separate instructional document. 
5.4.1. 
Study Drug Administration During the Double-Blind Treatment Phase 
During the Double-Blind Treatment Phase, patients will take study drug (pitolisant or placebo) 
once daily in the morning upon wakening in accordance with their randomized dose, as detailed 
in Table 7.  Patients will be instructed to record daily the number of tablets administered from 
each bottle in the study drug dosing section of the study diary (with the assistance of their 
caregiver if needed); the time of study drug dosing will be recorded on the day of Visits 3 and 5 
and on the day before Visit 4. 
5.4.2. 
Study Drug Administration During the Open-Label Extension Phase 
During the OLE Phase, patients will take open-label pitolisant once daily in the morning upon 
wakening as detailed in Table 8 (prior to implementation of Amendment 6) or Table 9 (after 
implementation of Amendment 6). 

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5.5. 
Study Drug Compliance 
Patients/caregivers will be instructed to return all used and unused bottles of study drug at each 
on-site study visit.  
Study drug compliance during the Double-Blind Treatment Phase of the study will be monitored 
by reviewing the patient study diary in conjunction with the Investigator or designee conducting 
tablet counts based on the returned study drug.  The patient’s study diary will be reconciled with 
tablet counts, and any discrepancies investigated and documented.  During TCs, compliance will 
be monitored by confirming the patient’s adherence to study drug administration. 
Study drug compliance during the OLE Phase will be monitored during on-site study visits by 
conducting tablet counts based on the returned study drug.  During the OLE TCs, compliance 
will be monitored by confirming the patient’s current dose of study drug and adherence to 
dosing, as well as shipment/receipt of study drug. 
5.6. 
Study Drug Accountability 
The study drug provided for this study will be used only as directed in the study protocol.  In 
accordance with current Good Clinical Practice (cGCP) (International Council for Harmonisation 
[ICH]-GCP E6 guidelines), Investigators are required to maintain accurate and current records of 
all study drug to allow reconciliation.  The Investigator or designee will acknowledge receipt of 
study drug, documenting the date received, number and units received, lot numbers, and 
condition.  The Investigator or designee must maintain adequate records of all study drug 
dispensed, used, returned, and/or destroyed (i.e., accountability or dispensing logs).  Sites may 
destroy drug on site per their own standard operating procedures (SOPs) or study drug may be 
returned to the Sponsor or designee if necessary. 
All study drug records must be readily available for inspection by the site’s clinical monitor 
and/or auditor.  No study drug can be returned to the Sponsor or designee or disposed of at the 
study site until the clinical monitor has reconciled study drug and applicable records at the study 
site. 
5.7. 
Prior and Concomitant Therapy 
Prior medications in the patient’s medical record and prior and concomitant medications reported 
by the patient/parent(s)/legal guardian(s) will be collected.  Concomitant medications include 
prescription and over-the-counter medications (including herbal products and vitamins).  
All medications taken by patients between signing of informed consent/assent and the second 
Safety Follow-up Call (30 days after final dose of study drug, Section 7.5) will be recorded, 
including dose, regimen, reason for administration, and start date.  Changes in concomitant 
medication will be recorded in the eCRF.  Nonpharmacologic therapies/procedures and changes 
in therapies/procedures will also be recorded in the eCRF.  Any prior or concomitant medication 
used to treat seizure disorders should be recorded in the eCRF. 
For patients entering the study on a stable dose of an allowed medication (Section 5.7.1), 
changes in dosing during the Double-Blind Treatment Phase are not permitted unless medically 
necessary; if a change in dose is required, the change should be recorded in the eCRF.  Any prior 
or concomitant medication used to treat seizure disorders should be recorded in the eCRF. 

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5.7.1. 
Permitted Concomitant Medications 
All treatments that the Investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the Investigator and in keeping with the standard of medical 
care. 
With the exception of the prohibited medications specified in Section 5.7.2, patients will be 
allowed to continue medication(s) for the treatment of PWS or other comorbidities as currently 
prescribed by their physicians.  Patients who are chronically administered sedating medications 
for management of behavioral manifestations (e.g., hypnotics, benzodiazepines, antipsychotics, 
alpha agonists, anticholinergics, and antidepressants) must be on stable doses for at least 4 weeks 
prior to enrollment and remain stable during the Double-Blind Treatment Phase of the study. 
The use of diazoxide choline, carbetocin, and oxytocin are permitted if on a stable dose for at 
least 28 days.  Short term use (up to 7 days) of systemic corticosteroids or glucocorticoid use is 
allowed in consultation with the Medical Monitor. 
For concomitant medications administered due to an AE/serious AE (SAE), the Investigator or 
designee will indicate in the AE/SAE eCRF the concomitant medication administered for the 
event. 
5.7.2. 
Prohibited Medications 
The use of medications that may prolong the QT interval is not permitted in the study.  
Use of opiates is not permitted in the study. 
Except for diazoxide choline, use of investigational drugs (i.e., drugs that are not FDA-approved 
for any indication) are prohibited. 
The use of strong CYP2D6 inhibitors or strong CYP3A4 inducers is not permitted during the 
Double-Blind Treatment Phase of the study, and if being used, should be discontinued at 
Screening; washout of 5 half-lives or 1 week (whichever is longer) of these medications is 
required prior to enrollment and initiating study drug.  These medications are allowed during the 
OLE Phase of the study, but adjustment of the dose of pitolisant is required (Section 5.7.3).  
Pitolisant increases the levels of histamine in the brain; therefore, centrally acting H1 receptor 
antagonists that cross the blood-brain barrier may reduce the effectiveness of pitolisant.  
Concomitant use of centrally acting H1 receptor antagonists is not permitted during the Double-
Blind Treatment Phase of the study (requires a washout of 5 half-lives or 1 week, whichever is 
longer, prior to randomization).  Although not prohibited during the OLE Phase of the study, use 
of these medications should be avoided and, if needed, will require consultation with the Medical 
Monitor.  
Examples of centrally acting H1 receptor antagonists, strong CYP2D6 inhibitors, strong CYP3A4 
inducers, and medications that may prolong the QT interval are provided in Appendix C. 
The investigator should consult with the Medical Monitor for any questions regarding use of 
prohibited medications during the study. 

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5.7.3. 
Medications Requiring Adjustment to the Dose of Pitolisant 
Use of strong CYP2D6 inhibitors or strong CYP3A4 inducers is allowed during the OLE Phase; 
however, if used, the following adjustments to the dose of pitolisant apply: 
• Strong CYP2D6 inhibitors: Systemic exposure of pitolisant is increased 2.2-fold in 
the presence of strong CYP2D6 inhibitors.  If initiating treatment with a strong 
CYP2D6 inhibitor during the OLE Phase, pitolisant dose should be reduced by half. 
• Strong CYP3A4 inducers: Systemic exposure of pitolisant is reduced by 50% in the 
presence of strong CYP3A4 inducers.  If initiating treatment with a strong CYP3A4 
inducer during the OLE Phase, clinical symptoms should be monitored, and pitolisant 
dose may need to be increased.  Pitolisant dose may only be increased up to the 
maximum permitted dose based on the patient’s age (prior to implementation of 
Amendment 6; Table 8)
 (following implementation of Amendment 6; 
Table 9). 
Procedures for pitolisant dose adjustments are provided in Section 3.1.5.2. 

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6. 
STUDY PROCEDURES AND ASSESSMENTS 
The following sections describe the study procedures and assessments that will be performed 
during the study.  Additional information about the timing of assessments is provided in 
Section 7 and in the Schedule of Assessments for the Double-Blind Treatment Phase and the 
Schedule of Assessments for the OLE Phase. 
6.1. 
Medical History and Demographics 
6.1.1. 
Medical History 
A complete medical history (including any history of seizure disorder and hospitalizations) will 
be obtained at Screening to ensure patients qualify for the study and will be updated at the 
Baseline Visit if needed and as necessary thereafter.  Confirmation of a patient’s diagnosis of 
PWS will be obtained via review of the patient’s medical records; genetic testing will be 
performed during Screening for patients who do not have documented genetic testing results 
confirming diagnosis of PWS. 
6.1.2. 
Demographics 
Demographic information collected will include date of birth, sex, race, ethnicity, weight, and 
body mass index (BMI). 
6.2. 
Dosing and Sleep Diary 
Patients will be provided with a study diary at the Screening Visit, which will include a study 
drug dosing section and a sleep diary section.   
Patients will be instructed to record in their sleep diary (with the assistance of their caregiver if 
needed) the time they go to bed each evening and the time they wake up each morning for 14 
consecutive nights during the Screening Period, and to return the diary to the study site at the 
Baseline Visit.  Using the patient-recorded times from the sleep diary (at least 7 nights must be 
recorded for evaluation), a qualified study team member will calculate the evaluable hours and 
minutes the patient slept per night; patients must have a minimum of 7 evaluable nights from the 
14 nights of sleep diary data.  Using all evaluable nights, the mean sTST per night for a patient 
must be at least 8 hours of sleep per night for patients ages 6 to <12 years, at least 7 hours for 
patients ages 12 to <18 years, or at least 6 hours for patients ages ≥18 years to be eligible to 
enroll in the study.  
Patients will record the number of tablets taken daily from each bottle, starting on the first day of 
study drug dosing (Day 1) throughout the Double-Blind Treatment Phase.  Patients will bring the 
study drug diary to the site at each visit for review. 
An example of the study diary, which includes a sleep diary section and a study drug dosing 
section, is provided in Appendix B. 
6.3. 
Efficacy Assessments 
Patients will be assessed for efficacy using known scales, assessments, and questionnaires.  
Various symptoms of PWS will be evaluated, including EDS, caregiver and clinician global 
impressions of severity (for EDS and overall clinical status related to PWS, respectively), 

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behavior, cognition, and hyperphagia.  In addition, the effect of treatment with pitolisant 
compared with placebo on the perceived caregiver burden with these patients will be evaluated.  
In addition, the MERS-R-PWS, which is a modified version of a known scale (the MERS-R) that 
has been adapted for use in patients with PWS, will be used to assess rigidity in behavior.  
6.3.1. 
Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD); 
Parent/Caregiver Version  
The parent/caregiver version of the ESS-CHAD is an 8-item, 4-point Likert rating scale where 
parents/caregivers rate their child’s/care recipient’s likelihood of falling asleep over the past 
month while engaging in eight different activities: sitting and reading; sitting and watching TV 
or a video; sitting in a classroom at school during the morning; sitting and riding in a car or bus 
for approximately half an hour; lying down to rest or nap in the afternoon; sitting and talking to 
someone; sitting quietly by himself/herself after lunch; sitting and eating a meal.  If the patient 
has not engaged in an activity, the parent/caregiver is asked to imagine how the activity would 
have affected the patient.  Responses are rated on a scale where 0 = ‘would never fall asleep’, 
1 = ‘slight chance of falling asleep’, 2 = ‘moderate chance of falling asleep’, and 3 = ‘high 
chance of falling asleep’.  A global score, which represents the sum of responses across all eight 
items, ranges from 0 to 24; higher scores correspond to greater daytime sleepiness.  This 
assessment will be administered at every on-site study visit.  The ESS-CHAD (parent/caregiver 
version) is provided in Appendix D. 
6.3.2. 
Caregiver Global Impression of Severity for Excessive Daytime Sleepiness 
The CaGI-S for EDS is a one-item, 5-point Likert rating scale completed by the patient’s 
parent/caregiver to rate their overall impression of the patient’s EDS.  At Baseline and at each 
on-site study visit, caregivers will be asked to rate their impression of the overall severity of the 
patient’s symptoms of EDS over the past week, based on the impact these symptoms have on the 
patient’s ability to function during the day.  The CaGI-S for EDS asks the caregiver to rate the 
patient’s likelihood of falling asleep during daytime activities over the past week.  The responses 
for the caregiver completed scale range from 0 = ‘not at all” to 4 = “very high likelihood”.  The 
CaGI-S for EDS is provided in Appendix E. 
6.3.3. 
Clinical Global Impression of Severity of Overall Clinical Status Related to PWS  
The CGI-S is a one-item, 4-point Likert-type rating scale and is a widely used assessment in 
clinical psychopharmacology trials to assess severity of illness.  At Baseline and at each on-site 
study visit, the Investigator will rate his/her impression of the severity of the patient’s current 
overall clinical status related to PWS relative to the Investigator’s experience with this patient 
population, based on observed and reported symptoms, behavior, and function.  The CGI-S asks 
the clinician one question: “Considering your total clinical experience with this particular 
population, please rate the patient’s condition at this time”.  The responses for this investigator-
completed scale range from 1 = ‘normal’ to 4 = ‘among the most severely symptomatic’ (Busner 
2007).  The CGI-S is provided in Appendix F.  

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6.3.4. 
Aberrant Behavior Checklist-Community, Second Edition 
The ABC-C assesses problematic behavior at home, in educational and work settings, and in 
residential and community-based facilities.  The checklist rates 58 specific symptoms and 
provides comprehensive descriptions for each assessed behavior, divided into five subscales 
(irritability, social withdrawal, stereotypic behavior, hyperactive/noncompliance, and 
inappropriate speech).  The ABC-C will be completed by the patient’s caregiver who will score 
the items on a 4-point Likert scale ranging from ‘not at all a problem’ to ‘the problem is severe 
in degree’.  The ABC-C is provided in Appendix G. 
6.3.5. 
Montefiore-Einstein Rigidity Scale – Revised for Research Studies in PWS 
(MERS-R-PWS) 
The MERS-R-PWS is a clinician-rated, semi-structured interview conducted with both the 
patient with PWS and caregiver present.  The MERS-R-PWS measures the following three 
domains of rigid behavior:  
• Behavioral Rigidity Domain: difficulty adjusting/managing behavior in new, unfamiliar 
or unexpected situations (e.g., insistence on sameness, things must be done in his/her 
way, difficulty when a change interrupts plans/activities, etc.) 
• Cognitive Rigidity Domain: lack of flexible thinking (e.g., repetitive/perseverative 
questioning in response to lack of flexible thinking, need to know or check for 
reassurance, difficulty shifting “gears” and/or conversation topics) 
• Protest Domain: the behavioral response (i.e., protest) that results from a real or 
perceived interruption to rigidity (i.e., severity of protest [irritability, verbal objections, 
tantrums, nonresponsive, etc.], length of protest, interference due to protest, and the effort 
needed to calm the patient down from the protest) 
Within each domain, four items are rated on a scale of 0 to 4, the scores for each domain are 
added, and the total sum of all three domains is calculated.  A higher score reflects more rigid 
behavior.  The MERS-R-PWS is provided in Appendix H. 
6.3.6. 
Cogstate Computerized Cognitive Tests 
Cognition will be assessed using the Cogstate Computerized Cognitive Test Battery, a 
standardized, fully automated, modular battery of tests designed specifically for repeated 
assessment with minimal practice effects (Collie et al 2003; Falleti et al 2006).  The test battery 
has a short administration time, contains multiple alternate forms, and yields data appropriate for 
detecting cognitive change.  In this study, the cognitive domains of psychomotor function, 
attention, and working memory will be assessed using the Detection, Identification, and One 
Back tests, respectively.  A pediatric battery will be used for patients 6 to <10 years and an adult 
battery will be used for patients 10 years and older.  Patients will complete two short training 
sessions to become familiar with the test and to ensure they understand the instructions/task 
demands.  
6.3.6.1. 
Cogstate Detection Test (Psychomotor Function) 
The Cogstate Detection Test is a computerized measure of psychomotor function and uses a 
validated simple reaction time paradigm with playing card-like stimuli displayed on a computer 

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screen.  In this test, the playing cards all depict the same image.  The patient is asked to press the 
“yes” key as soon as the card in the center of the screen turns face up.  The software measures 
the speed and accuracy of each response.  The main outcome measure for the test is speed of 
performance (mean of the log10-transformed reaction times for correct responses).  Decreasing 
scores represent improved test performance. 
6.3.6.2. 
Cogstate Identification Test (Attention)  
The Cogstate Identification Test is a computerized measure of visual attention and uses a 
validated choice reaction time paradigm with playing card-like stimuli displayed on a computer 
screen.  In this test, the playing cards are all either red or black.  The patient is asked whether the 
card displayed in the center of the screen is red.  The patient responds by pressing the “yes” key 
when the card is red and “no” when it is black.  The software measures the speed and accuracy of 
each response.  The main outcome measure for the test is speed of performance (mean of the 
log10-transformed reaction times for correct responses).  Decreasing scores represent improved 
test performance. 
6.3.6.3. 
Cogstate One Back Test (Working Memory) 
The Cogstate One Back Test is a computerized measure of working memory and uses a validated 
n-back paradigm with playing card stimuli displayed on a computer screen.  The patient is asked 
whether the card displayed in the center of the screen is the same as the card presented 
immediately previously.  The patient responds by pressing the “yes” or “no” key.  The software 
measures the speed and accuracy of each response. 
6.3.7. 
22-Item Zarit Burden Interview 
The ZBI-22 (Zarit and Zarit 1990) is a self-reported questionnaire in which caregivers are asked 
to rate their experience on a 5-point Likert scale (0 = ‘never’ and 4 = ‘nearly always’) for 
22 questions related to caregiver health and psychological well-being, finances, impact on social 
life, and relationship with the individual with the disability.  Responses are used to derive the 
ZBI total score, where higher scores represent greater burden.  The ZBI-22 is provided in 
Appendix I. 
6.3.8. 
Hyperphagia Questionnaire for Clinical Trials (HQ-CT) 
The HQ-CT is a 9-item questionnaire designed to measure food-related preoccupations and 
problems in PWS, as well as the severity of these concerns.  The questionnaire is an 
observer-reported outcome measure, completed by caregivers who report on the patient’s 
hyperphagic symptoms.  Higher scores are related to increased hyperphagia.  The maximum 
possible score is 36 and scores of approximately 11 to 13 are considered indicative of moderate 
hyperphagia that may be amenable to treatment.  The HQ-CT is provided in Appendix J.  The 
HQ-CT is used in conjunction with the FSZQ, which assesses the level of food environmental 
control required for patients (Section 6.3.9).  
6.3.9. 
Food Safe Zone Questionnaire (FSZQ) 
The FSZQ is a 20-item observer-reported measure of environmental controls that are in place to 
manage hyperphagia in patients with PWS.  The FSZQ will be performed in conjunction with the 

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HQ-CT (Section 6.3.8).  The measure includes four factors: supervision, restricting, avoiding, 
and checking.  Caregivers will complete this assessment.  Higher scores are associated with 
higher levels of environmental food control, and as patients with PWS respond favorably to 
treatment, scores are expected to decrease as the level of control over their food environment 
lessens.  The FSZQ questionnaire is provided in Appendix K. 
6.3.10. 
Ghrelin Levels 
Serum ghrelin levels (acylated and unacylated) will be assessed during the study as outlined in 
Section 7.3.  Blood samples for ghrelin testing must be performed while the patient is fasting and 
may be collected at the same time as sample collection for clinical laboratory tests (Table 11).  
6.4. 
Pharmacokinetic Assessments 
Pharmacokinetic parameters will include Cmax, tmax, and AUClast of pitolisant and its major 
metabolite, BP1.3484.   
Blood samples for PK evaluations will be collected during the Stable Dose Period of the Double-
Blind Treatment Phase (Visits 3, 4, and 5), as detailed in Section 7.3.  Consistent with the 
National Institutes of Health (NIH) Pediatric Blood Volume for Research Guidelines (Howie 
2011), the total volume of blood collected is not to exceed the maximal allowable amount of 3.0 
mL/kg per day (Appendix A).  The estimated total volume of blood to be drawn on PK sampling 
days, including samples for PK analyses (4.0 mL per sample), serum chemistry tests (5.0 mL per 
sample), and hematology tests (4.0 mL per sample) is presented in Table 10.  
The concentration-time data from this study may be combined with data from previous studies 
that utilized the same bioanalytical method, and population PK analysis may be conducted.  If a 
population PK analysis is performed, results will be reported separately. 
Detailed instructions on PK sample collection, processing, storage, and shipping procedures are 
provided in the Laboratory Manual. 
Table 10: 
Estimated Total Blood Draw Volumes on Pharmacokinetic Sampling Days 
 
Blood Sample Volume (mL) 
Visit 
PK 
Serum Chemistry 
Hematology  
Total  
Visit 3 (Day 22 ±3 days) 
4 
5 
4 
13 
Visit 4 (Day 50 ±3 days) 
20a 
5 
4 
29b 
Visit 5 (Day 76 to 77 ±3 
days) 
4 
5 
4 
13 
PK = pharmacokinetics 
a Five blood samples (4.0 mL per sample) are to be collected for PK analyses at Visit 4. 
b Blood draw volume is within the maximum allowable for patients weighing ≥15 kg (Appendix A). 
Note: Serum chemistry and hematology parameters are listed in Table 11. 
 

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6.5. 
Safety Assessments 
6.5.1. 
Adverse Events 
All AEs, regardless of causality or seriousness, will be collected from the time the 
patient/parent(s)/legal guardian(s) provides written informed consent/assent through 30 days 
after final dose of study drug (Safety Follow-up TCs, Section 7.5).  Adverse event recording at 
the Safety Follow-up TCs will include inquiries regarding signs and symptoms of arrhythmia, 
any other cardiac manifestations [e.g., syncope], and psychiatric events [e.g., suicidality, 
compulsive behavior, anxiety]).  Additional safety information, including the definition of an 
AE/SAE and reporting requirements, is provided in Section 8.  
Clinically significant findings for laboratory test results, vital signs, ECGs, and abnormal 
physical examination findings should be recorded as AEs; a clinical diagnosis, rather than the 
changes in laboratory analyte or other assessment should be recorded. 
6.5.2. 
Physical Examinations 
Full or abbreviated physical examinations will be performed at study visits as detailed in 
Section 7.  Full physical examinations will include an evaluation of the head and neck as well as 
cardiovascular, respiratory, gastrointestinal, neurological, dermatological, and musculoskeletal 
systems.  Abbreviated physical examinations will be performed based on 
patient/caregiver-reported symptoms.  
Height and weight will be measured using standardized methods and recorded on a standardized 
growth chart per Centers for Disease Control and Prevention (CDC) recommendations (CDC 
Clinical Growth Charts).  Height will be recorded at Screening and at the EOT/ET Visit during 
the Double-Blind Treatment Phase and at every on-site visit during the OLE Phase.  Body weight 
will be recorded at every on-site study visit.  
6.5.3. 
Vital Signs 
Vital signs will include blood pressure, heart rate, respiratory rate, and body temperature and will 
be measured at on-site study visits as detailed in Section 7.  Patients should be resting for at least 
5 minutes before measuring vital signs.  
Vital sign measurements will be performed before blood samples are collected for clinical 
laboratory testing. 
6.5.4. 
12-Lead Electrocardiograms 
12-lead ECGs will be obtained in triplicate for all patients at every on-site study visit as detailed 
in Section 7.  Patients should be resting for at least 5 minutes before the first ECG is performed.  
All pediatric 12-lead ECGs will be read by a pediatric cardiologist. 
ECG testing is to be performed before blood samples are collected for clinical laboratory testing.  
Electrocardiogram findings that require discontinuation from the study are specified in 
Section 4.4.1. 

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In the Double-Blind Treatment Phase, clinically significant ECG findings (other than those 
requiring discontinuation from treatment) will require evaluation by the Investigator in 
consultation with the Medical Monitor. 
In the OLE Phase and as noted in Section 4.4.2, any ECG reading that demonstrates QT 
prolongation should be promptly addressed by the Investigator.  For clinically significant ECG 
findings, a follow-up ECG should be performed within 24 hours and again 7 days later to ensure 
the abnormality is not worsening.  Follow-up 12-lead ECGs may be performed locally, with the 
results sent to the Investigator.  At the discretion of the Investigator and in consultation with the 
Medical Monitor, pitolisant dosing may be temporarily stopped (interrupted) for 2 to 3 days 
based on clinically significant ECG findings.  During an interruption, 12-lead ECGs will be 
performed daily.  Upon resolution of the ECG abnormality, pitolisant administration may resume 
at the same dose as before the interruption, or the pitolisant dose may be lowered by 50%.  If the 
condition persists after the interruption in dosing, the Investigator, in consultation with the 
Medical Monitor, will decide whether treatment should be permanently discontinued. 
6.5.5. 
Clinical Laboratory Tests 
Clinical laboratory tests will include serum chemistry, hematology, urinalysis, pregnancy tests 
(serum and/or urine), and urine drug screens as detailed in Table 11.  Samples for clinical 
laboratory tests (serum chemistry and hematology) will be collected as outlined in Section 7.   
Consistent with the NIH Pediatric Blood Volume for Research Guidelines (Howie 2011), the 
total volume of blood collected is not to exceed the maximal allowable amount of 3.0 mL/kg per 
day (Appendix A).  The approximate amount of blood to be collected for clinical laboratory tests 
at each visit is 9.0 mL (5.0 mL for serum chemistry tests and 4.0 mL for hematology tests). 
The Laboratory Manual provides detailed instructions on sample collection, processing, and 
shipping procedures. 
Laboratory test results will be reviewed by the Investigator.  Any laboratory value outside of the 
normal reference range will be evaluated for clinical significance and, if deemed clinically 
significant, should be reported as an AE with an appropriate diagnosis. 

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Table 11: 
Clinical Laboratory Tests 
Urine Drug Screen 
-Amphetamines/stimulantsa 
-Barbiturates 
-Benzodiazepines 
-Cocaine metabolites 
-Opiates 
-Tetrahydrocannabinol  
-Phencyclidine 
Urinalysis 
-Specific gravity 
-pH 
-Blood 
-Glucose 
-Protein 
-Leukocyte esterase 
-Ketones 
-Bilirubin 
-Nitrites 
-Casts 
-Crystals 
-Erythrocytes 
-Renal tubular epithelial cells 
-WBCs 
-Bacteria 
Serum Drug Screen 
-Cannabidiola 
Pregnancy Screen (FCBP only) 
-Serum (at Screening only) 
-Urine (as scheduled after 
screening) 
Serum Chemistry (5.0 mL blood sample) 
-Albumin 
-Alkaline phosphatase 
-Alanine aminotransferase 
-Aspartate aminotransferase 
-Blood urea nitrogen 
-Calcium 
-Chloride 
-Creatinine 
-Creatine kinase 
-Glucose 
-High-density lipoprotein 
-Low-density lipoprotein 
-Phosphorus 
-Potassium 
-Sodium 
-Total bilirubin 
-Direct bilirubin 
-Total cholesterol 
-Total protein 
-Triglycerides 
-Uric acid 
-Ghrelina,b  
Hematology (4.0 mL blood sample) 
-Complete blood count, including platelet count and WBC count with 
differential 
-Hemoglobin 
-Hematocrit 
-HbA1c 
FCBP = female of child-bearing potential; HbA1c = hemoglobin A1c; WBC = white blood cell 
a Required to be tested in the Double-Blind Treatment Phase only. 
b Acylated and unacylated ghrelin; patient must be fasting.  Blood sample for ghrelin measurement may be taken at 
the same time as clinical laboratory test sample. 
Note: Parameters will be assessed at study visits as detailed in the Schedule of Assessments for the Double-Blind 
Treatment Phase and the Schedule of Assessments for the OLE Phase.  
6.5.6. 
Additional Safety Assessments 
Suicide Risk/Suicidality 
Suicide risk at Screening will be assessed through the use of the Very Young Child/Cognitively 
Impaired–Lifetime Recent C-SSRS (Appendix L).  After Screening, suicidality will be evaluated 
at study visits and TCs through use of the Very Young Child/Cognitively Impaired-Since Last 
Contact C-SSRS (Appendix M).  Any patient with active suicidal behavior or suicidal ideation 
will be excluded/withdrawn from the study (Section 4.1.2 and Section 4.4.1). 

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Seizure Disorder 
In patients with a history of seizure disorders, the worsening of seizures or new onset seizures 
will be reported as AEs and the type, duration, and frequency of occurrence will be recorded in 
the eCRF.  Patients who experience worsening of their seizure disorder should be withdrawn 
from the study. 
Anxiety 
The worsening of anxiety or new onset anxiety will be recorded as an AE.  In addition, the 
ADAMS, a 28-item informant-rated scale designed to assess mood and anxiety symptoms will be 
administered (Esbensen et al 2003).  The ADAMS questionnaire is provided in Appendix N.  
6.6. 
Potential Use of Alternative Methods for Completing Study 
Assessments 
To allow for greater flexibility and potentially decrease patient burden related to travel to the 
study site, specific study assessments may be completed by alternative methods (Table 12 and 
Table 13).  
6.6.1. 
Assessments that may be Completed Remotely 
Specific safety assessments including the assessment of AEs, administration of the C-SSRS and 
ADAMS, and the review of concomitant medications may be completed by the Investigator 
and/or site staff remotely using telemedicine technology. 
Specific efficacy assessments including administration of the ESS-CHAD (parent/caregiver 
version), CaGI-S (EDS), CGI-S (overall clinical status related to PWS), ABC-C, MERS-R-PWS, 
ZBI-22, HQ-CT, and FSZQ may be completed by the Investigator and/or site staff remotely 
using telemedicine technology. 
Other procedures including completing the informed consent process and study drug 
compliance/accountability review may be completed by the Investigator and/or site staff 
remotely using telemedicine technology.  For patients utilizing the remote visit option, an on-site 
visit is required once a year.  Remote visits cannot be consecutive. 
6.6.1.1. 
Remote Screening Visit 
The following assessments for the Screening Visit may be completed remotely by the 
Investigator or designee using telemedicine technology: 
• Informed consent 
• Assess/confirm eligibility 
• Demographics 
• Medical history 
• C-SSRS 
• ADAMS 
• Dispense study diary 

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• Adverse events 
• Concomitant medications 
• ESS-CHAD (parent/caregiver version) 
The remaining Screening Visit procedures and assessments may be combined with and 
performed during the Baseline Visit (Visit 2): 
• Pregnancy test 
• Urine drug screen 
• Physical examination 
• Body weight 
• Height 
• Vital signs 
• 12-lead ECG 
• Clinical laboratory tests  
• Genetic testing 
Table 12: 
Remote Screening Visit Combined with On-Site Baseline Visit 
Assessment/Procedure 
Performed via Telemedicine 
Screening Visit 
Performed at 
On-Site 
Baseline Visit 
Informed Consent 
X 
 
Assess/confirm eligibility 
X 
X 
Demographics 
X 
 
Medical history 
X 
X 
Urine drug screen 
 
X 
Physical examination 
 
X 
Body weight 
 
X 
Height 
 
X 
Vital signs 
 
X 
12-lead ECG (in triplicate) 
 
X 
C-SSRS 
X 
X 
ADAMS 
X 
X 
Clinical laboratory tests 
 
X 
Ghrelin measurements (fasting) 
 
X 
Genetic testing 
 
X 

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Assessment/Procedure 
Performed via Telemedicine 
Screening Visit 
Performed at 
On-Site 
Baseline Visit 
Dispense study diary 
X 
 
Adverse events 
X 
X 
Concomitant medications 
X 
X 
Dispense study drug 
 
X 
Administer/titrate study drug 
 
X 
ESS-CHAD (parent/caregiver version) 
X 
X 
CaGI-S (of EDS) 
 
X 
CGI-S (overall clinical status related to PWS) 
 
X 
ABC-C 
 
X 
MERS-R-PWS 
 
X 
Cogstate Detectiona 
 
X 
Cogstate Identificationa 
 
X 
Cogstate One Backa 
 
X 
ZBI-22 
 
X 
HQ-CT 
 
X 
FSZQ 
 
X 
ABC-C = Aberrant Behavior Checklist-Community, Second Edition; ADAMS = Anxiety, Depression, and Mood Scale; 
AE = adverse event; CaGI-S = Caregiver Global Impression of Severity; CGI-S = Clinical Global Impression of Severity; 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; EDS = excessive daytime sleepiness; ESS-CHAD 
= Epworth Sleepiness Scale for Children and Adolescents; FCBP = female of child-bearing potential; FSZQ = Food Safe Zone 
Questionnaire; HQ-CT = Hyperphagia Questionnaire for Clinical Trials; MERS-R-PWS = Montefiore-Einstein Rigidity Scale – 
Revised for Research Studies in PWS; PK = pharmacokinetic(s); ZBI-22 = 22-item Zarit Burden Interview 
a The Cogstate battery practice test is to be administered prior to the actual test. 
6.6.1.2. 
Assessments that may be Completed at the Patient’s Home for Visit 3 and/or 
Visit 4 and for Remote Visits During the Open-Label Extension Phase 
The following assessments may be completed by a home healthcare professional at the patient’s 
home under the guidance and supervision of the Investigator:  
• Weight 
• Height 
• Vital signs 
• Physical examination 
• 12-lead ECG (in triplicate) 

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• Laboratory assessments  
• Other assessments including the Visit 3 PK sampling and study drug accountability 
Visit 4 PK samples may be collected at the next on-site study visit, at an unscheduled visit, or at 
Visit 5 if not able to be collected earlier. 
6.6.2. 
Other Considerations 
The Cogstate tests cannot be completed remotely and are required to be completed at the site.  
• Visit 4 includes conducting the Cogstate battery of tests.  If this visit is not performed 
as an on-site study visit, the Cogstate testing may either be omitted or completed at a 
future unscheduled visit prior to Visit 5, should one occur.  
• The Cogstate tests to be completed at the EOT visit (Visit 5) are required to be 
completed at the site.  Every effort should be made for Visit 5/EOT to be completed 
at the study site according to the study schedule.   
• Visits 7 and 9 include conducting the Cogstate battery of tests.  If either of these visits 
are completed remotely, the Cogstate testing should be completed at the next on-site 
visit. 
If patients do not attend an on-site study visit, study drug may be sent to patients per the study 
site’s SOPs. 
Table 13: 
Alternative Methods for Completing Study Assessments for Visit 3 and/or 
Visit 4 and Remote Visits During the OLE Phase 
Assessment Scheduled 
to be Performed at an 
On-Site Study Visit 
Telemedicine 
Performed by a Home 
Healthcare Professional 
Potential to be Conducted at 
the Next On-Site Study Visit 
or at an Unscheduled Visit  
Pregnancy Test (FCBP) 
 
X 
 
Urine Drug Screen 
 
X 
 
Physical Examination 
 
X 
 
Body Weight 
 
X 
 
Height 
 
X 
 
Vital Signs 
 
X 
 
12-Lead ECG (in triplicate) 
 
X 
 
C-SSRS, ADAMS, ESS-
CHAD (parent/caregiver 
version), CaGI-S, CGI-S, 
ABC-C, MERS-R-PWS, 
ZBI-22, HQ-CT, FSZQ 
X 
 
 
Cogstate Detection, 
Identification, One Back  
 
 
Xa 
Clinical Laboratory Tests 
 
X 
 
Blood Sample for PK 
 
Xb 
Xc 

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Assessment Scheduled 
to be Performed at an 
On-Site Study Visit 
Telemedicine 
Performed by a Home 
Healthcare Professional 
Potential to be Conducted at 
the Next On-Site Study Visit 
or at an Unscheduled Visit  
Adverse Events 
X 
X 
 
Concomitant Medications 
X 
X 
 
Dispense Study Drug 
X 
 
 
Study Drug Compliance 
X 
 
 
Study Drug Accountability 
X 
X 
 
ABC-C = Aberrant Behavior Checklist-Community, Second Edition; ADAMS = Anxiety, Depression, and Mood Scale; 
AE = adverse event; CaGI-S = Caregiver Global Impression of Severity; CGI-S = Clinical Global Impression of Severity; 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; EDS = excessive daytime sleepiness; 
ESS-CHAD = Epworth Sleepiness Scale for Children and Adolescents; FCBP = female of child-bearing potential; FSZQ = Food 
Safe Zone Questionnaire; HQ-CT = Hyperphagia Questionnaire for Clinical Trials; MERS-R-PWS = Montefiore-Einstein 
Rigidity Scale –Revised for Research Studies in PWS; PK = pharmacokinetic(s); ZBI-22 = 22-item Zarit Burden Interview 
a For Visit 4, in the event an unscheduled visit occurs prior to Visit 5/EOT. For Visit 7 and Visit 9, Cogstate tests 
should be performed at the next on-site study visit. 
b The Visit 3 PK sample may be collected by the home healthcare professional at the time of collection of other 
laboratory samples. 
c Visit 4 PK samples may be collected at the next on-site study visit, an unscheduled visit, or at Visit 5 if not able to 
be collected earlier. 
 

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7. 
TIMING OF PROCEDURES AND ASSESSMENTS 
Information on study procedures and assessments is provided in Section 6.  The timing for all 
assessments is provided in the Schedule of Assessments for the Double-Blind Treatment Phase 
and the Schedule of Assessments for the Open-Label Extension Phase. 
7.1. 
Screening (Visit 1) 
After providing written informed consent/assent, patients will complete screening assessments to 
assess eligibility to participate in the study.  Only patients who meet all eligibility criteria will be 
enrolled.  The Screening Period will be for a maximum of 45 days.  Specific procedures and 
assessments for the Screening visit may be conducted remotely as detailed in Section 6.6.1. 
The following evaluations will be performed during the Screening Visit (Visit 1), within 45 days 
prior to randomization and the first dose of study drug:  
• Inclusion/exclusion criteria (Section 4.1) 
• Demographics 
• Medical history (Section 6.1.1) 
• Genetic testing (patients with no documented genetic confirmation of PWS diagnosis) 
• Serum pregnancy test (FCBP only)  
• Urine drug screen (Table 11) 
• Full physical examination (Section 6.5.2) 
• Body weight and height (Section 6.5.2)  
• Risk of suicide/suicidality (Section 6.5.6 and Appendix L) 
• ADAMS (Section 6.5.6) 
• Vital signs (Section 6.5.3) 
• 12-lead ECGs (in triplicate) (Section 6.5.4) 
• Clinical laboratory tests (serum chemistry, hematology, urinalysis; Table 11) 
• ESS-CHAD (parent/caregiver version) 
• Cogstate Detection training 
• Cogstate Identification training 
• Cogstate One Back training 
• AEs (since providing written informed consent/assent) 
• Concomitant medications (since providing written informed consent/assent) 
Patients will be provided with a study diary that includes a sleep diary section in which they are 
to record (with the assistance of their caregiver if needed) the time they go to bed each evening 
and the time they wake up each morning for 14 consecutive nights (at least 7 nights must be 
recorded for evaluation) (Section 6.2).  Patients who do not demonstrate adequate sTST for their 

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age group (i.e., at least 8 hours of sleep per night for patients ages 6 to <12 years, at least 7 hours 
for patients ages 12 to <18 years, or at least 6 hours for patients ages ≥18 years), based on their 
sleep diary, will be considered screen failures.  Patients who demonstrate adequate sTST time for 
their age group, based on their sleep diary, will be randomized via IRT in a 1:1:1 ratio to receive 
treatment with lower dose pitolisant, higher dose pitolisant, or matching placebo, as detailed in 
Section 3.1.1.    
Patients who fail screening for any reason may be rescreened once at the discretion of the 
Investigator. 
7.2. 
Baseline (Visit 2; Day -1)  
Patients must meet all requirements for inclusion/exclusion criteria, including adequate sTST for 
their age group based on their sleep diary data (i.e., at least 8 hours of sleep per night for patients 
ages 6 to <12 years, at least 7 hours for patients ages 12 to <18 years, or at least 6 hours for 
patients ages ≥18 years; Section 6.2). 
The following assessments will also be performed at the Baseline Visit:  
• Review of inclusion/exclusion criteria (patients must meet all eligibility criteria) 
• Medical history update, as necessary 
• Urine pregnancy test (FCBP only) 
• Urine drug screen  
• Abbreviated physical examination  
• Body weight  
• Vital signs  
• 12-lead ECG (in triplicate) 
• C-SSRS (Appendix M)  
• ADAMS 
• Clinical laboratory tests (serum chemistry, hematology, urinalysis); may be collected 
with the fasting serum ghrelin measurement 
• Serum ghrelin measurement (fasted; Section 6.3.10; clinical laboratory tests may be 
collected at the same time as the fasting serum ghrelin measurement) 
• Review of AEs 
• Review of concomitant medications 
• ESS-CHAD (parent/caregiver version) 
• CaGI-S (for EDS) 
• CGI-S (for overall clinical status related to PWS) 
• ABC-C 

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• MERS-R-PWS 
• Cogstate Detection Test 
• Cogstate Identification Test 
• Cogstate One Back Test 
• ZBI-22 
• HQ-CT 
• FSZQ 
Eligible patients will be dispensed a study drug titration kit at the Baseline Visit (Section 5.2.1) 
and will be instructed to take study drug once daily in the morning upon wakening.  Patients will 
be instructed to take their first dose of study drug on the day after the Baseline Visit (the first day 
of study drug dosing is Day 1).  
Patients will be instructed to record daily the date and number of tablets of study drug taken from 
each bottle in the study drug dosing section of the study diary (with the assistance of their 
caregiver, if needed) (Appendix B). 
Patients and their caregivers will be instructed to bring the study diary and all used and unused 
bottles of study drug with them to all on-site study visits.  The study diary will be completed 
only during the Double-Blind Treatment Phase of the study. 
7.3. 
Double-Blind Treatment Phase (Day 1 to Day 77) 
Section 3.1.3 provides details on study drug dosing during the Double-Blind Treatment Phase of 
the study. 
7.3.1. 
Titration Period, Double-Blind Treatment Phase (Days 1 to 21) 
Patients will take their first dose of blinded study drug on the day after the Baseline Visit and 
will be titrated to their randomized stable dose during a 3-week Titration Period.  The first dose 
of study drug will be Day 1, and study drug dose will be titrated on Day 8 and again on Day 15 
(as appropriate based on randomized stable dose, as described in Table 7); all patients will be at 
their randomized stable dose of study drug by Day 15. 
No on-site study visits are scheduled during the Titration Period in the Double-Blind Treatment 
Phase.  Patients and/or their caregivers will be contacted by the study site by telephone on 
Days 8 and 15 (±3 days; TCs 1 and 2, respectively) to assess for AEs and concomitant 
medication use, complete the C-SSRS, and review/confirm titration of study drug dose.  
7.3.2. 
Stable Dose Period, Double-Blind Treatment Phase (Days 22 to 77) 
Patients will continue to take study drug at their randomized stable dose during the Stable Dose 
Period and will return with their caregivers to the study site on Day 22, Day 50, and Day 77 
(±3 days; Visits 3, 4, and 5, respectively) for safety, efficacy, and PK assessments.  Patients 
and/or their caregivers will be contacted by the study site by telephone on Days 29, 36, and 57 
(±3 days; TCs 3, 4, and 5, respectively) to assess for AEs and concomitant medication use, 
complete the C-SSRS and ADAMS, and confirm compliance with study drug administration.  

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The last dose of blinded treatment is on Day 77 ±3 days (Visit 5; EOT Visit in the Double-Blind 
Treatment Phase). 
7.3.2.1. 
Visit 3 (Day 22 ±3 Days) 
The patient (with the assistance of their caregiver if necessary) should record in the study diary 
the time of study drug dosing on the morning of Visit 3.  The following evaluations will be 
performed at Visit 3: 
• Urine pregnancy test (FCBP only) 
• Abbreviated physical examination  
• Body weight 
• Vital signs  
• 12-lead ECG (in triplicate) 
• C-SSRS (Appendix M) 
• ADAMS 
• Clinical laboratory tests (serum chemistry, hematology, urinalysis) 
• Blood sample collection for PK analyses (sample may be collected at the same time 
as clinical laboratory tests; time of last dose of study drug and time of blood sample 
collection to be recorded) (Section 6.4).  
• Review of AEs 
• Review of concomitant medications 
• ESS-CHAD (parent/caregiver version) 
• CaGI-S (for EDS) 
• CGI-S (for overall clinical status related to PWS) 
• ABC-C 
• MERS-R-PWS 
• ZBI-22 
• HQ-CT 
• FSZQ 
• Review study drug compliance/accountability (Section 5.5 and Section 5.6) 
Patients will be dispensed study drug at this visit.  
7.3.2.2. 
Telephone Calls; TC 3, TC 4, and TC 5 (Days 29, 36, and 57 [±3 Days]) 
Patients and/or their caregivers will be contacted by the study site by telephone on Days 29, 36, 
and 57 (±3 days; TCs 3, 4, and 5, respectively) to assess for AEs and use of concomitant 

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medications, complete the C-SSRS, ADAMS, and confirm compliance with administration of 
study drug.  
7.3.2.3. 
Visit 4 (Day 50 ±3 Days) 
To accommodate PK sample collection at Visit 4, patients will not take their daily dose of study 
drug before arriving at the study site.  Patients and their caregivers will bring study drug and 
study diary with them to the study visit (time of study drug administration on the day before 
Visit 4 should be recorded in the study diary). 
Study drug administration will be at the study site; the timing of study drug administration will 
be based on the PK sampling schedule.  
Blood Sample Collection for PK: 
A blood sample for PK analyses will be collected before administration of study drug at the 
study site (the time of sample collection is to be recorded). 
After the first blood sample for PK analyses is collected, patients will be administered study drug 
(the time of study drug administration is to be recorded). 
Additional blood samples for PK analyses will be collected at the following times after study 
drug administration (the time of each blood sample collection is to be recorded): 
− Between 45 and 75 minutes after dosing  
− Between 1.5 and 2.5 hours after dosing 
− Between 3.0 and 4.0 hours after dosing 
− Between 5.0 and 6.0 hours after dosing 
The following evaluations will also be performed at Visit 4: 
• Urine pregnancy test (FCBP only) 
• Abbreviated physical examination  
• Body weight 
• Vital signs 
• 12-lead ECG (in triplicate) 
• C-SSRS (Appendix M) 
• ADAMS  
• Clinical laboratory tests (serum chemistry, hematology, urinalysis) 
• Review of AEs 
• Review of concomitant medications 
• ESS-CHAD (parent/caregiver version) 
• CaGI-S (for EDS) 
• CGI-S (for overall clinical status related to PWS) 

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• ABC-C 
• MERS-R-PWS 
• Cogstate Detection Test 
• Cogstate Identification Test 
• Cogstate One Back Test 
• ZBI-22 
• HQ-CT 
• FSZQ 
• Review study drug compliance/accountability (Section 5.5 and Section 5.6) 
Blood draw volumes at Visit 3 are not to exceed the maximal allowable of 3.0 mL/kg per day 
(Appendix A and Table 10). 
Patients will be dispensed study drug at this visit.   
7.3.2.4. 
Visit 5 (Day 77 ±3 Days); End of Treatment in the Double-Blind Treatment 
Phase 
Visit 5 (Day 77 ±3 days) is the EOT visit in the Double-Blind Treatment Phase of the study.  A 
fasting blood sample for ghrelin testing will be collected at this visit; therefore, the patient should 
fast on the night before Visit 5.  The patient (with the assistance of their caregiver if necessary) 
should record in the study diary the time of study drug dosing on the morning of Day 77, Visit 5.  
The following evaluations will be performed at Visit 5: 
• Urine pregnancy test (FCBP only) 
• Urine drug screen  
• Full physical examination  
• Body weight and height 
• Vital signs 
• 12-lead ECG (in triplicate) 
• C-SSRS (Appendix M) 
• ADAMS  
• Clinical laboratory tests (serum chemistry, hematology, urinalysis); may be collected 
with the fasting serum ghrelin measurement and the PK blood sample collection 
• Serum ghrelin measurement (fasting) 
• Blood sample collection for PK analyses (sample may be collected at the same time 
as clinical laboratory tests and fasting serum ghrelin measurement; time of last dose 
of study drug and time of blood sample collection for PK is to be recorded) 
• Review of AEs 

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• Review of concomitant medications 
• ESS-CHAD (parent/caregiver version) 
• CaGI-S (for EDS) 
• CGI-S (for overall clinical status related to PWS) 
• ABC-C 
• MERS-R-PWS 
• Cogstate Detection Test 
• Cogstate Identification Test 
• Cogstate One Back Test 
• ZBI-22 
• HQ-CT 
• FSZQ 
• Review study drug compliance/accountability (Section 5.5 and Section 5.6) 
Patients will be given the opportunity to participate in the OLE Phase at this visit.  Eligible 
patients who enter the optional OLE Phase will be dispensed open-label pitolisant 
(Section 5.2.2); eligibility criteria must be confirmed before patients receive open-label 
pitolisant.  Patients will be instructed to begin taking open-label pitolisant on the following day 
in the morning upon wakening (Day 78 ±3 days). 
Patients who do not enter the OLE Phase will be receive Safety Follow-up TCs from the study 
site 15 days (± 3 days) and 30 days (+3 days) after last dose of blinded treatment, as outlined in 
Section 7.5. 
7.3.3. 
Early Termination Visit for Double-Blind Treatment Phase  
Every effort should be made to perform the ET evaluations for patients who terminate early from 
the Double-Blind Treatment Phase of the study.  At the ET Visit, the reason for early termination 
must be recorded.  The safety and efficacy evaluations to be performed at the ET visit are the 
same as those listed for Visit 5 (Section 7.3.2.4). 
Patients who discontinue from the Double-Blind Treatment Phase prior to Day 77 may enroll in 
the OLE Phase following approval from the Medical Monitor in consultation with the 
Investigator (eligibility criteria must be confirmed). 
7.4. 
Open-Label Extension Phase (Day 78 To End of Treatment) 
Section 3.1.4 provides details on study drug dosing for the OLE Phase of the study.  Dose 
adjustments are permitted in the OLE Phase; pitolisant dose can be adjusted (higher or lower) as 
outlined in Section 3.1.5.2. 

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7.4.1. 
Titration Period; OLE Phase (Days 78 to 98) 
Table 8 and Table 9 detail the dosing regimens for the OLE Phase.  Patients will receive their 
first dose of open-label pitolisant on Day 78 (±3 days). 
Patients and/or their caregivers will be contacted by the study site by telephone on Days 85 and 
92 (±3 days; TCs 6 and 7, respectively) to assess for AEs and concomitant medication use, 
complete the C-SSRS, and review/confirm dosing and administration of study drug. 
7.4.2. 
Long-Term Dosing Period, OLE Phase (Day 99 to End of Treatment) 
Patients will continue to take open-label pitolisant at their target dose during the OLE 
Long-Term Dosing Period as detailed in Table 8 (prior to implementation of Amendment 6) and 
Table 9 (after implementation of Amendment 6), with dosing adjustments permitted as described 
in Section 3.1.5.2.  
Patients and their caregiver will return to the study site on Day 99 ±3 days (Visit 6) and again on 
Days 189, 279, and 369 (±7 days) (Visits 7, 8, and 9, respectively) for assessment of safety and 
effectiveness as detailed in Section 7.4.2.1.   
After completion of Visit 9, patients and/or their caregivers will receive a TC from the study site 
on Day 459 (±7 days; TC 8) and approximately every 6 months (180 ±7 days) thereafter as 
detailed in Section 7.4.2.2.  Patients and their caregivers will return to the study site on 
Day 549 (±7 days; Visit 10) and approximately every 6 months (180 ±7 days) thereafter as 
detailed in Section 7.4.2.3.  This pattern of alternating TCs and on-site study visits will be 
repeated until either the patient discontinues from the study or the Sponsor elects to terminate the 
study.  
During the first year of the OLE Phase of the study, patients will have the option to complete up 
to two of the scheduled on-site study visits remotely (i.e., two of Visits 6, 7, 8, and 9; 
(Section 7.4.2.1); thereafter (i.e., after Visit 9/Month 12), patients will have the option to 
complete one of the two scheduled on-site study visits remotely per year (Section 7.4.2.3).  An 
on-site visit is required once a year.  Remote visits cannot be consecutive. 
7.4.2.1. 
Visits 6, 7, 8, and 9 (Days 99, 189, 279, and 369)  
Patients will have the option to complete up to two of the scheduled on-site study visits (Visits 6, 
7, 8, and 9) remotely; assessments associated with on-site study visits that may be completed 
remotely are detailed in Section 6.6.  Except where specified, patients will complete all of the 
following assessments at Visits 6, 7, 8, and 9 (the window for Visit 6 is ±3 days and ±7 days for 
all other visits): 
• Urine pregnancy test (FCBP only) 
• Full physical examination 
• Body weight and height 
• Vital signs 
• 12-lead ECG (in triplicate) 
• C-SSRS (Appendix M) 

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• ADAMS  
• Clinical laboratory tests (serum chemistry, hematology, urinalysis) 
• Urine drug screen 
• Review of AEs 
• Review of concomitant medications 
• ESS-CHAD (parent/caregiver version) 
• CaGI-S (for EDS) 
• CGI-S (for overall clinical status related to PWS) 
• ABC-C 
• MERS-R-PWS (Visits 7 and 9 only) 
• Cogstate Detection Test (Visits 7 and 9 only) 
• Cogstate Identification Test (Visits 7 and 9 only) 
• Cogstate One Back Test (Visits 7 and 9 only) 
• ZBI-22 
• HQ-CT 
• FSZQ 
• Review study drug compliance/accountability (Section 5.5 and Section 5.6) 
Patients will be dispensed study drug in a quantity sufficient for 3 months (i.e., 90 days) of once 
daily treatment at each visit. 
7.4.2.2. 
Telephone Calls; Day 459 (TC 8) and Every 6 Months (180 Days) Thereafter 
Until End of Treatment 
Patients remaining in the study and receiving study drug after Visit 9 will receive a TC on 
Day 459 ±7 days (TC 8) and approximately every 6 months (180 days ±7 days) thereafter until 
either the patient withdraws from the study or the Sponsor elects to terminate the study.  
The following will be assessed at TC 8 and each subsequent TC: 
• Review AEs 
• Review concomitant medications 
• C-SSRS 
• Confirm study drug dose 
• Confirm shipment/receipt of their next 3-month (90-day) supply of study drug   
Additionally, if applicable, patients will receive two safety follow-up TCs, one 15 days (±3 days) 
and one 30 days (+3 days) after taking the final dose of study drug as detailed in Section 7.5.  

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7.4.2.3. 
Visit 10 (Day 549) and Every 6 Months (180 Days) Thereafter Until End of 
Treatment 
Patients remaining in the study and receiving study drug after TC 8 will return with their 
caregivers to the study site on Day 549 ±7 days (Visit 10) and approximately every 6 months 
(180 days ±7 days) thereafter until either the patient withdraws from the study or the Sponsor 
elects to terminate the study; these patients may complete one on-site study visit remotely per 
year (Section 6.6 describes assessments associated with on-site study visits that may be 
completed remotely).   
Patients will be dispensed study drug for 3 months (i.e., 90 days) for once daily administration, 
which is a quantity sufficient until the next scheduled telephone call. 
The following assessments will be performed at Visit 10 and at each subsequent study visit: 
• Urine pregnancy test (FCBP only) 
• Full physical examination 
• Body weight and height 
• Vital signs 
• 12-lead ECG (in triplicate) 
• C-SSRS (Appendix M) 
• ADAMS  
• Clinical laboratory tests (serum chemistry, hematology, urinalysis) 
• Urine drug screen 
• Review of AEs 
• Review of concomitant medications 
• ESS-CHAD (parent/caregiver version) 
• CaGI-S (for EDS) 
• CGI-S (for overall clinical status related to PWS) 
• Review study drug compliance/accountability (Section 5.5 and Section 5.6) 
Patients will be dispensed study drug in a quantity sufficient for 3 months (i.e., 90 days) of once 
daily administration at each visit. 
7.4.2.4. 
End of Treatment Visit for the Open-Label Extension Phase 
Patients are to complete an EOT Visit after they complete the study; the evaluations of safety and 
effectiveness to be performed at the EOT Visit in the OLE Phase are the same as those listed for 
Visit 10 (Section 7.4.2.1). 

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7.4.3. 
Early Termination Visit for Open-Label Extension Phase  
Every effort should be made to perform the ET evaluations for patients who terminate early from 
the OLE Phase of the study.  At the ET Visit, the reason for early termination must be recorded.  
The evaluations of safety and effectiveness to be performed at the ET visit are the same as those 
listed for Visit 10 (Section 7.4.2.1). 
7.5. 
Safety Follow-Up Telephone Calls  
Patients in the Double-Blind Treatment Phase who do not enter the optional OLE Phase will 
receive a TC from the study site 15 days (±3 days) and 30 days (+3 days) after their final dose of 
study drug to assess for AEs (including inquiries regarding signs and symptoms of arrhythmia, 
any other cardiac manifestations [e.g., syncope], and psychiatric events [e.g., suicidality, 
compulsive behavior, anxiety]) and use of concomitant medications and to complete the C-SSRS 
and ADAMs.  
Patients (and/or their caregivers) in the OLE Phase will receive a TC from the study site 15 days 
(±3 days) and 30 days (+3 days) after their final dose of study drug to assess for AEs (including 
inquiries regarding signs and symptoms of arrhythmia, any other cardiac manifestations [e.g., 
syncope], and psychiatric events [e.g., suicidality, compulsive behavior, anxiety]) and use of 
concomitant medications and to complete the ADAMS.  
An on-site unscheduled study visit will be requested for any patient reporting signs and 
symptoms of arrhythmia or cardiac manifestations, and/or a psychiatric event at either of the two 
Safety Follow-up TCs (Section 7.6). 
7.6. 
Unscheduled Visits and Assessments 
Unscheduled visits and assessments in the Double-Blind Treatment Phase and OLE Phase of the 
study may be conducted by telephone or at an on-site study visit and should be performed if 
clinically indicated in the opinion of the Investigator.  
At minimum, the following assessments are to be performed at an unscheduled on-site study 
visit: 
• Abbreviated physical examination 
• Body weight 
• Height 
• Vital signs 
• Review of AEs 
• Review of concomitant medications 
• Review study drug compliance/accountability (Section 5.5 and Section 5.6) 
Other assessments (e.g., 12-lead ECGs, clinical laboratory tests, urine pregnancy test, Very 
Young Child/Cognitively Impaired-Since Last Contact C-SSRS, ADAMS, ABC-C) can be 
completed based on the reason for the unscheduled visit and at the Investigator’s discretion. 

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At a minimum, AEs, concomitant medication use, and study drug accountability/compliance 
should be assessed during unscheduled TCs.  Other assessments (e.g., Very Young 
Child/Cognitively Impaired-Since Last Contact C-SSRS, ADAMS, ABC-C) can be completed 
based on the reason for the unscheduled TC and at the Investigator’s discretion. 

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8. 
SAFETY MONITORING AND REPORTING 
Investigators are responsible for the detection and documentation of events that meet the 
definition of an AE, SAE, suspected adverse reaction, serious suspected adverse reaction, or 
unanticipated problem, as provided in this protocol.  
Investigators must review the WAKIX (pitolisant) IB to be knowledgeable about the study drug 
and aware of its safety profile.  Investigators will also be versed in the latest standard of care 
guidelines. 
8.1. 
Definition of Safety Parameters 
8.1.1. 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
An AE may be any unfavorable or unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a study drug, whether or not 
considered causally associated with the use of the study drug.  Any abnormal physical 
examination findings, laboratory value, vital sign result, or ECG finding that is deemed clinically 
significant by the Investigator, regardless of causal relationship, must be reported as an AE.  A 
clinical diagnosis, rather than the changes in laboratory analyte or other assessment, should be 
recorded (e.g., anemia rather than low hemoglobin value). 
Examples of AEs include: 
• Significant or unexpected worsening or exacerbation of the condition or indication 
under study. 
• Exacerbation of a chronic or intermittent pre-existing condition, including either an 
increase in frequency or intensity of the condition (e.g., abnormal physical 
examination finding related to the condition). 
• Signs, symptoms, or clinical sequelae of a suspected overdose of the study drug or a 
concurrent medication (overdose per se should not be reported as an AE or SAE, 
unless nonserious or serious sequelae occur). 
• A diagnosis related to any clinically significant abnormal laboratory test result. 
• Any laboratory abnormality not associated with a diagnosis or symptom requiring 
further diagnostic investigation. 
The following examples would not be considered AEs: 
• Medical or surgical procedure (e.g., endoscopy, appendectomy), although the 
condition that leads to the procedure would be considered an AE. 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
(including laboratory values) present or detected at the start of the study that do not 
worsen during the study. 

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• The disease or disorder being studied, or expected progression, signs, or symptoms of 
the disease or disorder being studied, unless they become more severe or occur with a 
greater frequency than expected for the patient’s condition. 
8.1.2. 
Definition of a Serious Adverse Event 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
Investigator or the Sponsor, it results in any of the following outcomes:  
• Death 
• A life-threatening AE (i.e., presented an immediate risk of death from the event as it 
occurred; this criterion is not intended to include an AE that, had it occurred in a 
more severe form, might have caused death) 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal activities of daily living 
• A congenital anomaly/birth defect  
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
The following events do not meet the definition of an SAE:  
• Hospitalization for elective treatment of a pre-existing condition that does not worsen 
from baseline 
• Hospitalization for a standard procedure for study drug administration and routine 
monitoring of the studied indication not associated with any deterioration in condition 
• Social or convenience admission to a hospital 
• Prolongation of a hospitalization for social or convenience reasons not associated 
with the occurrence of an AE 
• Hospitalization or an emergency room visit that lasts less than 24 hours that does not 
meet the criteria of an important medical or a life-threatening event 
8.1.3. 
Definition of a Suspected Adverse Reaction 
A suspected adverse reaction is defined as any AE for which there is a reasonable possibility that 
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8.1.4. 
Definition of a Serious Suspected Adverse Reaction 
A serious suspected adverse reaction is any suspected adverse reaction that is determined to be 
serious, based on the definition of an SAE described in Section 8.1.2. 
8.1.5. 
Definition of Unanticipated Problems 
Unanticipated problems are incidents, experiences, or outcomes that meet all of the following 
criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the research 
protocol and informed consent document approved by the Ethics Committee (EC; 
includes Institutional Review Boards [IRBs], Independent ECs, and Research Ethics 
Boards) and (b) the characteristics of the participant population being studied 
• Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research) 
• Suggest that the research places patients or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized 
8.2. 
Classification of Adverse Events 
8.2.1. 
Severity of Adverse Events 
The Investigator will assess the severity of each AE based on his/her clinical judgment using one 
of the following categories: 
• Mild: Usually transient and may require only minimal treatment or therapeutic 
intervention.  The event does not generally interfere with usual activities of daily 
living.  
• Moderate: Usually alleviated with additional specific therapeutic intervention.  The 
event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the patient. 
• Severe: Interrupts usual activities of daily living, or significantly affects clinical 
status, or may require intensive therapeutic intervention.  
8.2.2. 
Relationship to Study Drug 
The Investigator will assess the relationship (i.e., causality) of each AE to study drug based on 
his/her clinical judgment.  The Investigator’s assessment of the relationship of an AE to study 
drug is part of the documentation process, but it is not a factor in determining what is or is not 
reported in the study.  If there is any doubt as to whether a clinical observation is an AE, the 
event should be reported.  All AEs must have their relationship to study drug assessed.  The 
Sponsor’s assessment of relationship may differ from the Investigator’s assessment. 
Relationship to study drug will be assessed according to the following guidelines: 

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• Not related:  There is not a temporal relationship to study medication administration, 
or the AE is clearly and incontrovertibly due only to progress of the underlying 
disease or to extraneous causes.  
• Unlikely related:  There is little or no chance that the study treatment caused the 
reported AE; the event is most likely because of another competing cause, including 
concomitant illnesses, progression or expression of the disease state, or a reaction to a 
concomitant medication.  
• Possibly related:  The association of the AE with study treatment is unknown; 
however, the AE is not reasonably attributed to any other condition.  
• Probably related:  A reasonable temporal association exists between the AE and 
study treatment, and based on the Investigator’s clinical experience, there is no other 
obvious competing cause.  The event responds to withdrawal of the study medication 
(positive dechallenge) and rechallenge with administration of the study medication is 
ambiguous or not done.  
• Definitely related:  There is a reasonable causal relationship between study treatment 
and the AE; the event responds to withdrawal of the study medication (positive 
dechallenge) and recurs with rechallenge by administration of the study medication.  
For initially reporting SAEs, even in situations in which minimal information is available, it is 
important that for every event the Investigator make an assessment of causality.  The causality 
assessment is one of the criteria used when determining regulatory reporting requirements.  The 
Investigator may change his or her opinion of causality based on follow-up information and 
amend the SAE information accordingly in the eCRF or the SAE reporting form, as applicable.  
8.3. 
Time Period and Frequency for Adverse Event Assessment and 
Follow-up 
8.3.1. 
Adverse Event and Serious Adverse Event Monitoring 
All AEs regardless of seriousness, severity, or causality will be collected from the time the 
patient/parent(s)/legal guardian(s) provides written informed consent/assent through 30 days 
(+3 days) after final dose of study drug (Safety Follow-up TCs, Section 7.5).  
For patients who receive study drug in the Double-Blind Phase and do not enter the OLE Phase 
of the study, if an Investigator becomes aware of an SAE that occurs at any time after the 
patient’s study participation and the Investigator considers the event to be possibly related to the 
study drug, the Investigator should report the SAE to the Sponsor as described in Section 8.4.1. 
8.3.2. 
Follow-up of Events 
After the occurrence of an AE or SAE, the Investigator is required to follow each patient 
proactively and provide further information on the patient’s condition.  All AEs and SAEs 
documented at a previous visit or contact and designated as ongoing will be reviewed at 
subsequent visits or contacts. 
All AEs and SAEs will be followed after the last scheduled study visit until the event resolves, 
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longer clinically significant (unless the patient is lost to follow-up or the patient/parent(s)/legal 
guardian(s) withdraws consent). 
The Investigator will assess the outcome of each AE using the following categories: 
• Recovered/Resolved: The event resolved, or the patient recovered without sequelae.  
An event (either serious or nonserious) occurred and had an endpoint, and the patient 
experienced no restrictions.  Examples include stent placement for coronary artery 
disease (a device implanted is not a sequela), an appendectomy (a scar is not a 
sequela), a postoperative wound infection, or an upper respiratory tract infection. 
• Recovered/Resolved with sequelae: The event has at least one secondary outcome 
that may result in permanent disability, functional limitation, or both.  Examples 
include hip replacement resulting in foot drop (foot drop is not the intended outcome 
but is a risk of surgery), stroke resulting in paralysis, or emboli formation after a 
bacterial infection resulting in a renal infarct and loss of renal function. 
• Recovering/Resolving: The event is improving. 
• Not recovered/Not resolved: At the end of the study, an event either has not changed 
in intensity or may not have recovered to baseline values, and the outcome is 
unknown.  Examples include headache, low-grade fever, or nausea. 
• Unknown: The patient is lost to follow-up, and the status of the event is unknown. 
• Death 
8.4. 
Reporting Procedures 
8.4.1. 
Reporting Serious Adverse Events to the Sponsor 
During this study, if the Investigator determines that an event meets the protocol definition of an 
SAE, regardless of relationship to study drug, they must notify the Sponsor as soon as possible 
but no later than 24 hours of becoming aware of the SAE.  The SAE report form (completed 
with all available information) must be sent to the Sponsor via e-mail or facsimile as soon as 
possible but no later than within 24 hours of the Investigator becoming aware of the SAE.  
The investigator must be diligent about providing additional information as needed.  The 
Investigator must also enter the SAE information into the eCRF as soon as possible thereafter. 
In the initial email, the Investigator must provide to the Sponsor the following eCRF pages, 
completed to the greatest extent possible: 
• AE record 
• Medical history 
• Prior and concomitant medications 
Also, any laboratory test results, diagnostic test results, or medical reports relevant to the SAE 
should be provided; however, certain patient identifying information (i.e., name, address, and 
other identifying information not collected in the patient’s eCRF) is to be redacted from copies 
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In rare circumstances and in the absence of email capacity, a copy of the SAE reporting form can 
be sent to the Sponsor by overnight mail.  Initial notification of the event via telephone or email 
does not replace the need for the Investigator to complete the appropriate SAE form within the 
time frames outlined and email the form (or in the absence of email/scanning capacity--overnight 
mail is acceptable in rare cases). In addition, the AE/SAE information for the event needs to be 
entered in the eCRF. 
If the Investigator does not have all information regarding an SAE, he/she must not wait to 
receive additional information before notifying the Sponsor of the event.  The SAE must be 
updated when additional information is received.  Follow-up information received on all SAEs 
must be forwarded to the Sponsor using the same 24-hour timelines as for an initial report. 
In the event of a medical emergency in which knowledge of the patient’s treatment assignment 
may influence their clinical care, the Investigator has the option to unblind the patient’s 
treatment assignment via the IRT system.  The Investigator should make every effort to contact 
the Medical Monitor prior to unblinding unless this would adversely delay appropriate medical 
care.  The Medical Monitor will not be unblinded and will only provide assistance to the 
Investigator.  The reasons for unblinding must be noted in the source documents.  The 
Investigator must not disclose the patient’s treatment assignment to anyone who does not need 
the information based on their direct involvement in the patient’s clinical care.  Disposition of 
patients who are unblinded due to a medical emergency will be determined following discussion 
with the Sponsor. 
In the event of death, every effort should be made to obtain a death certificate and if possible, an 
autopsy report.  Death is considered an outcome of an event; however, if the event that resulted 
in death is unknown, death will be recorded as the event. 
8.4.2. 
Reporting Unanticipated Problems to the Sponsor 
If the Investigator determines that an event meets the protocol definition of an unanticipated 
problem, he/she must notify the Sponsor within 24 hours of becoming aware of the problem. 
The following information should be included with unanticipated problem reporting: 
• Protocol identifying information: protocol title, protocol number, and Investigator’s 
name 
• A detailed description of the event, incident, experience, or outcome 
• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an unanticipated problem 
It is the Investigator’s responsibility to report unanticipated problems to the Sponsor and the 
IRB, as required by local regulations. 
8.4.3. 
Regulatory Reporting Requirements 
The Investigator must promptly report all SAEs to the Sponsor in accordance with the 
procedures detailed in Section 8.4.1.  The Sponsor has a legal responsibility to notify, as 
appropriate, both the local regulatory authority and other regulatory agencies about the safety of 
a product under clinical investigation.  Prompt notification of SAEs by the Investigator to the 
appropriate project contact for SAE receipt is essential so that serious suspected adverse 

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reactions that are either unexpected or observed with increasing occurrence can be reported and 
legal obligations and ethical responsibilities regarding the safety of other patients are met.   
Investigator letters are prepared according to Sponsor policy and are forwarded to Investigators 
as necessary.  An Investigator letter is prepared for any suspected adverse reaction that is both 
serious and unexpected.  The purpose of an Investigator letter is to fulfill specific regulatory and 
cGCP requirements regarding the product under investigation. 
The Investigator, or responsible person according to local requirements, must comply with 
requirements related to the reporting of SAEs to the IRB. 
The Sponsor is responsible for informing IRBs, Investigators, and regulatory authorities of any 
finding that could adversely affect the safety of patients or affect the conduct of the study.  
Events will be reported to regulatory authorities in accordance with expedited reporting 
requirements. 
8.4.4. 
Pregnancy Reporting 
Pregnancy is not considered an SAE; however, it is documented and followed in the same 
manner as an SAE.  Any patient who becomes pregnant during the study must be withdrawn 
from the study immediately.  Patients who become pregnant within 30 days after receiving their 
final dose of study drug should also notify the Investigator.  The Investigator must attempt to 
follow the pregnancy to term or termination in order to report on the outcome and health status 
of the mother and child. 
The Investigator must notify the Sponsor of any pregnancy by completing a Pregnancy Form and 
emailing it to the Sponsor within 24 hours of becoming aware of the pregnancy.  

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
General Considerations 
All safety and efficacy data will be listed and summarized.  Unless otherwise specified, Baseline 
is defined as the last observed measurement, whether scheduled or unscheduled, prior to study 
drug administration.  Safety and efficacy endpoints will be summarized by treatment group and 
the active treatment groups pooled.  Continuous variables will be summarized using the number 
of patients with data (n), mean, standard deviation (SD), median, minimum, and maximum.  
Selected continuous variable summaries will also include the standard error.  Categorical 
variables will be summarized using frequency counts and percentages. 
The statistical analysis plan (SAP) will provide further details for statistical methodology. If the 
statistical analyses described in the final SAP and final protocol differ, the statistical analyses in 
the SAP will be used for the analyses presented in the clinical study report (CSR). Substantive 
changes from the analyses specified in the protocol will be described in the SAP and in the CSR. 
In general, continuous variables will be summarized using the number of non-missing values, 
mean, SD, median, minimum, and maximum; categorical variables will be summarized using the 
count and the percentage of patients in each category.  All values summarized will also be 
presented in listings. 
All analyses will be performed using SAS® version 9.4 or higher, unless otherwise specified. 
9.1.1. 
Estimand 
The primary efficacy endpoint is defined as the change in mean ESS-CHAD (parent/caregiver 
version) score from Baseline to Week 11 for higher dose pitolisant compared with placebo. 
The target population is all patients in the intent-to-treat (ITT) population with PWS as defined 
by the inclusion/exclusion criteria. 
A treatment policy strategy will be used to address intercurrent events.  No special data handling 
will be used for patients who initiate concomitant medications, have intermittent missing data, or 
discontinue study medication (even if they report data following discontinuation of study 
medication).  No explicit imputation of missing data will be performed; the mixed model 
repeated measures (MMRM) approach assumes data are missing at random and will provide 
unbiased results if this is the case.  Sensitivity analyses will explore the results under different 
analysis assumptions. 
9.1.2. 
Multiple Comparisons 
The study objective is to evaluate the effectiveness of pitolisant in treating EDS for the purposes 
of informing the design of future studies.  As such, the relative strengths of all measures are of 
interest and p-values will be reported with no formal multiplicity adjustments. 
The following order reflects the endpoints of most interest and greater consideration will be 
given to successful endpoints higher in the list, particularly when all preceding endpoints have a 
significant p-value. 
• Primary endpoint: Change in ESS-CHAD (parent/caregiver version) score from 
Baseline to Week 11 for the higher dose pitolisant group compared with placebo. 

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• Primary endpoint: Change in mean ESS-CHAD (parent/caregiver version) score from 
Baseline to Week 11 for the lower dose pitolisant group compared with placebo. 
• Primary endpoint: Change in mean ESS-CHAD (parent/caregiver version) score from 
Baseline to Week 11 for the combined pitolisant dose groups compared with placebo. 
• Secondary endpoint: Change in CaGI-S for EDS from Baseline to Week 11 for the 
higher dose pitolisant group compared with placebo. 
• Secondary endpoint: Change in CGI-S for overall clinical status from Baseline to 
Week 11 for the higher dose pitolisant group compared with placebo. 
• Secondary endpoint: Change in CaGI-S for EDS from Baseline to Week 11 for the 
lower dose pitolisant group compared with placebo. 
• Secondary endpoint: Change in CGI-S for overall clinical status from Baseline to 
Week 11 for the lower dose pitolisant group compared with placebo.  
Likewise, the effect of treatment with pitolisant (higher dose, lower dose, and pooled) compared 
with placebo on other secondary outcomes will be tested in the order outlined in the SAP.  These 
include the change from Baseline to Week 11 in behavior as measured by ABC-C and MERS-R-
PWS; cognition as measured by Cogstate Detection, Identification and One Back tests; and 
perceived caregiver burden as measured by ZBI-22. 
9.1.3. 
Missing Data 
Every effort will be made to retain patients in the study; however, patients are able to withdraw 
from the study at any time for any reason.  Patients who withdraw early will be asked to return to 
the clinic for an ET visit for completion of assessments (Section 7.3.3 and Section 7.4.3).  No 
explicit imputation will be performed for the primary analysis; however, the MMRM model will 
yield unbiased results under the assumption that data are missing at random (MAR). 
A sensitivity analysis will be performed using a hypothetical strategy.  In this approach, the 
unobserved data following discontinuation for lack of efficacy (LOE) or AEs will be assumed to 
follow the placebo distribution at the matching visit, conditioned on the patient’s observed data 
(including baseline).  Patients who discontinue for all other reasons and intermittent missing data 
will be assumed to be MAR. 
This will be implemented using a three-stage multiple imputation (MI) approach: 
1. Intermittent missing data will be imputed within treatment group using MI under a MAR 
assumption with covariates for site and observed values at all available time points 
(including baseline).  Twenty values will be produced using the Markov Chain Monte 
Carlo (MCMC) method implemented with the SAS MI procedure, producing a monotone 
missing data pattern. 
2. Patients who drop out for reasons other than LOE or AEs will likewise have their missing 
values following dropout imputed within treatment group with covariates for site and 
observed values at all available time points (including baseline). 
3. Finally, patients who withdraw from the study due to LOE or AEs will have their missing 
values following discontinuation imputed using the placebo group distribution, regardless 
of their assigned treatment group. 

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9.2. 
Determination of Sample Size 
The sample size is 60 patients (20 in the lower dose pitolisant group, 20 in the higher dose 
pitolisant group, and 20 in the placebo group).  Prior research suggests that the ESS-CHAD SD 
falls between 5 to 6; at the lower end of this range, the study would be powered at 80% to detect 
a difference of 3.9 between the pooled pitolisant groups and placebo group.  However, as a proof 
of concept, statistical separation is not a strict objective of the trial.  The proposed sample size 
will yield a 95% confidence interval of ±2.7 with an SD of 5 and ±3.2 with an SD of 6; this will 
give sufficient precision to inform future studies. 
9.3. 
Analysis Populations 
The safety analyses will be conducted on the safety population.  The ITT population will be used 
for the primary efficacy analysis.  The PK population will be used for PK analyses.  Patients will 
be analyzed according to randomized treatment assignment for efficacy assessments and 
according to treatment received for safety assessments. 
9.3.1. 
Intent-to-Treat Population 
The ITT population will include all randomized patients who received at least one dose of study 
drug and have one baseline and at least one post-baseline assessment at any visit of any endpoint.  
This population will be used to summarize the primary and other efficacy data.  Patients will be 
analyzed according to randomized treatment assignment.  
9.3.2. 
Double-Blind Safety Population 
The double-blind safety population will include all patients who are enrolled and take at least 
one dose of double-blind study drug.  Patients will be analyzed according to treatment received.  
In the case of mis-dosing, patients will be counted at the highest dose they received in the 
Double-Blind Treatment Phase.  
9.3.3. 
Open-Label Safety Population 
The open-label safety population will include all patients who are enrolled in the OLE Phase and 
take at least one dose of open-label study drug.   
9.3.4. 
Pharmacokinetic Population 
The PK population will include all patients who received at least one dose of pitolisant and have 
calculable PK parameters available for analysis.  
9.4. 
Statistical Analysis Methods 
9.4.1. 
Disposition and Demographics 
The number and percentage of patients in each analysis population will be summarized.  The 
number of patients screened and patients enrolled and treated and the number and percentage of 
patients completing the Double-Blind Treatment Phase of the study, discontinuing from the 
Double-Blind Treatment Phase of the study (including reasons for discontinuation), and entering 

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the OLE Phase (with and without completion of the double-blind) will be summarized.  All 
percentages will be calculated using the number of patients enrolled as the denominator. 
Additionally, for the open-label safety population, the number of patients enrolled in the OLE 
Phase, the number and percentage of patients completing the OLE Phase of the study, and the 
number of patients discontinuing from the OLE Phase of the study (including reasons for 
discontinuation) will be summarized.  All percentages will be calculated using the number of 
patients enrolled in the OLE Phase as the denominator. 
Demographics and baseline characteristics will be reported for the efficacy, double-blind safety, 
and open-label safety populations.  Categorical items will be reported with counts and 
percentages; continuous items will be reported using summary statistics (mean, SD, median, 
minimum, maximum).  Data will not be re-collected at entry to the OLE Phase but will be 
reported for the subset of patients who enter the OLE Phase. 
9.4.2. 
Efficacy Analysis 
9.4.2.1. 
Double-Blind Treatment Phase 
9.4.2.1.1. Primary Efficacy Analysis 
Summary statistics (mean, SD, median, minimum, maximum) for the primary efficacy endpoint 
of change in mean ESS-CHAD (parent/caregiver version) score from Baseline to Week 11 for 
pitolisant compared with placebo will be reported by treatment group and for the active groups 
combined.  The change from Baseline will be analyzed in an MMRM analysis.  Fixed effects 
will be included for treatment, Baseline value, visit, and treatment×visit interaction.  An 
unstructured covariance matrix will be utilized, and if this fails to converge, then first-order 
autoregressive and compound symmetry will be attempted in that order; Kenward-Rogers 
degrees of freedom will be used.  Least square (LS) means, standard errors, and the LS mean 
differences (each treatment vs placebo and the pooled active groups vs placebo) will be reported.  
All estimates will be generated from a single model, i.e., the pooled estimates will be created via 
model contrasts.  The primary contrast of interest is the difference in the higher dose group 
versus placebo at Week 11. 
Sensitivity analyses will utilize an approach identical to the primary analysis but on the dataset 
with imputed values.  The 20 repeats will each be modeled independently, then combined using 
SAS Proc MI analyze and Rubin’s approach (Rubin 1976). 
9.4.2.1.2. Secondary Efficacy Analysis 
Continuous outcomes collected at multiple time points will be analyzed with summary statistics 
(mean, SD, median, minimum, maximum) for the absolute values and change from baseline at 
each timepoint by treatment group and for the active groups combined.  The change from 
baseline will be analyzed using an MMRM approach.  Fixed effects will be included for 
treatment, visit, treatment×visit interaction, and Baseline value.  An unstructured covariance 
matrix will be utilized, and if this fails to converge, then first-order autoregressive and compound 
symmetry will be attempted in that order; Kenward-Rogers degrees of freedom will be used.  
Least square means, standard errors, and the LS mean differences (each treatment vs placebo and 
the pooled active groups vs placebo) at each time point will be reported.  All estimates will be 

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generated from a single model, i.e., the pooled estimates will be created via model contrasts.  
The primary contrast of interest is the difference in the higher dose group versus placebo at 
Week 11. 
9.4.2.1.3. Exploratory Efficacy Analysis 
The analyses used for the secondary outcomes will be applied to the exploratory outcomes for 
the full study cohort and repeated within each age group (i.e., change from Baseline to Week 11 
in HQ-CT and acylated and unacylated ghrelin levels) as feasible.  The MMRM may be replaced 
with an analysis of covariance (ANCOVA) at Week 11 or a simple t-test if sample size does not 
permit more complicated modeling approaches within an age group. 
9.4.2.2. 
Open-Label Extension Analyses 
Results in the OLE Phase will be tabulated with summary statistics for continuous outcomes and 
frequencies and percentages for categorical outcomes.  No p-values will be reported for the OLE 
Phase.  Details of open-label analyses will be described in the SAP.  
9.4.3. 
Safety Analysis 
All safety analyses will be completed for the double-blind safety and open-label safety 
populations.  All safety data will be listed and summarized.  No formal statistics will be 
performed for the safety analysis. 
Adverse events that occur between the time written informed consent/assent is provided and the 
start of study drug administration will be considered pretreatment AEs.  A TEAE is: 
• any AE reported after the first dose of study drug and up to 30 days after last dose of 
study drug, or  
• any worsening of a pre-existing condition reported after first dose of study drug and 
up to 30 days after last dose of study drug. 
All TEAEs will be coded and tabulated by System Organ Class and Preferred Term.  Incidence 
of TEAEs and SAEs will be summarized.  Adverse events leading to study withdrawal, if any, 
will be listed separately. 
Laboratory parameters will be summarized over time using descriptive statistics.  For each 
laboratory test, individual patient values will be listed and values outside of the standard 
reference range will be flagged.  Shift tables will be produced showing the frequency of shifts 
from Baseline to the lowest and to the highest on study value as well as by visit.  Shift tables will 
include the categories of low, normal, and high as defined by the normal ranges provided by the 
central laboratory. 
The change from Baseline to each visit for vital sign variables will be summarized using 
descriptive statistics.  Abnormal vital sign values will be flagged and listed.  Changes from 
baseline in ECG results (heart rate and PR, RR, QRS, QT, QTcF, and QTcB intervals) will be 
summarized.  Categorical summaries based on QTcF will be provided to show changes from 
baseline in QTcF >60 msec, and actual values >442 msec for patients ages 0 to <10 years and 
>439 msec for patients ages 10 to <20 years, regardless of gender, and >450 msec for male 
patients and >470 msec for female patients ages 20 to 65 years, as well as QTcF >500 msec 
regardless of age or gender.  

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Results of C-SSRS and ADAMS will be listed.  
9.4.4. 
Pharmacokinetic Analyses 
Concentration-time profiles will be plotted on semi-log and linear scales for each individual 
patient as spaghetti plots and summarized by treatment group and age. 
The following steady-state PK parameters will be determined using noncompartmental methods:  
Cmax, AUClast, and tmax of pitolisant and its major metabolite, BP1.3484.  Pharmacokinetic 
parameters will be summarized overall and by treatment group and age.  The following summary 
statistics will be considered for concentration-time data:  mean, SD, coefficient of variation 
(CV%), median, minimum, and maximum.  These summary statistics will also be conducted for 
PK parameters (except tmax) along with the geometric mean, geometric SD, and geometric CV%.  
The median, minimum, and maximum will be calculated for tmax.  
The concentration-time data from this study may be combined with data from previous studies 
that utilized the same bioanalytical method, and population PK analyses may be conducted; 
results will be provided in a separate report.  
9.5. 
Interim Analysis  
No interim analyses are planned for this study; results of the Double-Blind Treatment Phase will 
be reported following database lock once all patients have completed or discontinued the 
Double-Blind Treatment Phase of the study. 

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10. 
QUALITY ASSURANCE AND QUALITY CONTROL 
Quality assurance and quality control systems will be implemented and maintained with SOPs by 
the Sponsor and its designee(s), as appropriate, to ensure that the clinical study is conducted and 
the data are generated, documented (recorded), and reported in compliance with the protocol, 
ICH-GCP E6 guidelines, and applicable regulatory requirements.  The accuracy, completeness, 
and reliability of the study data presented to the Sponsor are the responsibility of the 
Investigator.  The Investigator or designee must record all required data using the prespecified 
data collection method defined by the Sponsor or its designee.  
The study will be monitored regularly by the Sponsor (Section 12.1) and may be audited or 
inspected by the Sponsor (or designee), IRB, and/or regulatory authorities at any time during the 
study or after study completion.  In the event of an audit, the Investigator agrees to allow the 
Sponsor, representatives of the Sponsor, the competent authority, or other regulatory agencies 
direct access to all study records.  The Investigator will immediately notify the Sponsor of all 
audits or inspections scheduled by any regulatory authority and promptly forward copies of any 
audit or inspection reports received to the Sponsor. 

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11. 
REGULATORY AND ETHICAL CONSIDERATIONS 
11.1. 
Regulatory Authority Approval 
The Sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country specific regulatory requirements before any site may 
initiate the study in that country. 
11.2. 
Ethical Conduct of the Study 
This study will be conducted in compliance with the protocol and all applicable regulatory 
requirements in accordance with ICH/cGCP and in general conformity with the most recent 
version of the Declaration of Helsinki. 
11.3. 
Institutional Review Board Approval  
The Investigator, Sponsor, or designee is responsible for submitting the following documents to 
the IRBs for review and, if applicable, approval: study protocol, informed consent/assent 
form(s), IB, recruitment materials, information about study compensation to patients, and any 
information provided to potential patients. 
The Investigator is responsible for providing the Sponsor with the written IRB approval prior to 
commencing the study (i.e., before shipment of study drug to the site).  All amendments to the 
protocol require review and approval by the IRB before the changes are implemented to the 
study.  All changes to the informed consent/assent form will be approved by the IRB; a 
determination will be made regarding whether previously consented participants need to be 
reconsented.  If any other information approved by the IRB for presentation to potential patients 
is amended during the study, the Investigator is also responsible for ensuring IRB review and 
approval. 
Study sites must adhere to all requirements stipulated by their respective IRBs.  This may 
include, but is not limited to, notifying the IRB of serious and unexpected AEs or other 
information based on local safety reporting requirements, submitting a final status report, or 
providing a synopsis of the study report upon study completion. 
11.4. 
Informed Consent/Assent Process 
All references to “patient” in this section refer to the study patient or his/her parent(s)/legal 
guardian(s)/legally authorized representative. 
The Sponsor (or its designee) will provide Investigators with an informed consent/assent form 
for this study.  Investigators may adapt the information to suit the needs of their institution, if 
necessary (although it must reflect the required elements of informed consent specified in 
21 Code of Federal Regulations [CFR] Part 50.25).  The final informed consent/assent form must 
be accepted by the Sponsor and approved by the IRB/EC.  Investigators must provide the 
Sponsor with an unsigned copy of the final informed consent/assent form before and after it is 
approved by the IRB/EC.  If any new information becomes available that might affect patients’ 
willingness to participate in the study, or if any amendments to the protocol require changes to 
the informed consent/assent form, the Sponsor will provide Investigators with a revised informed 
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Prior to participating in any study-related procedure, each patient must sign and date an 
IRB/EC-approved informed consent/assent form written in a language the patient can 
understand.  The informed consent/assent form should be as nontechnical as practical and 
understandable to the patient.  The informed consent/assent form must provide the patient with 
all the information necessary to make an informed decision about their participation in the study, 
including the nature and intended purpose of the study, possible benefits, possible risks, and 
disclosures of the patient’s personal and personal health information for purposes of conducting 
the study.  The informed consent/assent form details the requirements of the participant and the 
fact that he/she is free to withdraw at any time without giving a reason and without prejudice to 
his/her further medical care.  Before informed consent/assent is obtained, the patient should be 
given ample time and opportunity to inquire about the details of the study.  All questions must be 
answered to the satisfaction of the patient. 
Once signed, the original informed consent/assent form will be stored in the Investigator’s site 
file and made available for review by the Sponsor.  Documentation of the informed 
consent/assent discussion must be noted in the patient’s case history.  All patients will receive a 
copy of their signed and dated informed consent/assent form. 
If the informed consent/assent form is revised during the study and requires the patient to be 
re-consented/re-assented, informed consent/assent will be obtained in the same manner as for the 
original informed consent/assent form. 
11.5. 
Confidentiality 
All information provided by Harmony Biosciences, LLC and all data and information generated 
by the site as part of the study will be kept confidential by the Investigator and site staff.  This 
information and data will not be used by the Investigator or other site personnel for any purpose 
other than conducting the study and will not be released to any unauthorized third party without 
prior written approval of the Sponsor.  These restrictions do not apply to: 1) information that 
becomes publicly available through no fault of the Investigator or site staff, 2) information that 
must be disclosed in confidence to an IRB solely for the evaluation of the study results, 
3) information that must be disclosed in order to provide appropriate medical care to a study 
patient, or 4) study results that may be published as described in Section 12.5.  If a written 
contract for the conduct of the study is executed and that contract includes confidentiality 
provisions inconsistent with this statement, that contract’s confidentiality provisions shall apply 
rather than this statement, provided, however, that the confidentiality provisions in any written 
contract shall not be less restrictive than this statement. 
The Investigator agrees to comply with all applicable national, state, and local laws and 
regulations relating to the privacy of patients’ health information.  The Investigator shall ensure 
that study patients authorize the use and disclosure of protected health information in accordance 
with the privacy regulations of the Health Insurance Portability and Accountability Act (HIPAA) 
and in a form satisfactory to the Sponsor. 
The patient’s contact information will be securely stored at each clinical site for internal use 
during the study.  Throughout the study, a patient’s source data will only be linked to the 
Sponsor’s clinical study database or documentation via a unique ID number.  Copies of any 
patient source documents that are provided to the Sponsor must have certain personally 
identifiable information removed (i.e., patient name, address, and other identifier fields not 

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collected in the patient’s eCRF).  At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the IRB and institutional regulations. 
To comply with ICH guidelines for cGCP and to verify compliance with this protocol, the 
Sponsor requires that the Investigator permit its monitor or designee’s monitor, representatives 
from any regulatory authority, the Sponsor’s designated auditors, and the appropriate IRBs to 
review the patient’s original medical records (source data or documents), including, but not 
limited to, clinical laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a patient’s study participation, and autopsy 
reports.  Access to a patient’s original medical records requires the specific authorization by the 
patient as part of the informed consent/assent process (Section 11.4). 

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12. 
STUDY ADMINISTRATION 
12.1. 
Clinical Monitoring 
The Sponsor (or its designee) is responsible for ensuring the proper conduct of the study.  This 
includes ensuring the patients’ rights and well-being are protected, the conduct of the study is 
within compliance of an approved protocol and cGCPs, and integrity of the data (i.e., data are 
accurate, complete, and verifiable from source documentation).  At regular intervals during the 
study, the Sponsor’s study monitors, or their designees, will contact the study site via site visits, 
TCs, emails, and letters in order to review study progress and eCRF completion and to address 
any concerns or questions regarding the study conduct.  During monitoring visits, the following 
aspects of study conduct will be carefully reviewed:  patients’ informed consent/assent 
documents, patient recruitment procedures, patients’ compliance with study procedures, source-
data verification, drug source documents, and record retention. 
In the event monitoring of source data by monitors cannot be completed on site, monitoring of 
source data may be completed remotely.  
Each study site will maintain study documents and records as specified in ICH E6, Section 8 
(Essential Documents for the Conduct of a Clinical Trial) and as required by regulatory and 
institutional requirements.  These include, but are not limited to:  study protocol, eCRF, 
delegation of authority log, pharmacy dispensing records, drug accountability logs, AE reports, 
patient source data (original or certified copies), correspondence with health authorities and 
IRB/ECs, informed consent/assent forms, monitoring visit logs, laboratory certification or 
quality control procedures, and laboratory reference ranges.  Access to study documents and 
records will be strictly controlled (Section 11.5).  
Study records must be retained for at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  However, these 
documents should be retained for a longer period if required by applicable regulatory 
requirements or if agreed to in the Clinical Trial Agreement.  It is the responsibility of the 
Sponsor to inform the site as to when these documents no longer need to be retained. 
12.2. 
Management of Protocol Amendments and Deviations 
12.2.1. 
Protocol Modification 
The protocol cannot be modified except in a formal protocol amendment by the Sponsor. 
12.2.2. 
Protocol Violations and Deviations 
Protocol deviations are a change, divergence, or departure from the study design or procedures 
defined in this protocol.  An important protocol deviation is a deviation that may significantly 
impact the completeness, accuracy, and/or reliability of the study data or that may significantly 
affect a patient’s rights, safety, or well-being.  The Investigator will notify the IRB of any 
protocol deviations as required by IRB guidelines and site requirements.  Protocol deviations will 
be documented at the site and in the Sponsor files.  In the event of an important protocol 

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deviation, the site will notify the Sponsor or designee.  The Sponsor is responsible for notifying 
the regulatory authorities of any protocol deviations, as required. 
12.3. 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as required to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators are 
responsible for providing information on financial interests during the study and for 1 year after 
completion of the study. 
12.4. 
Suspension or Termination of Study or Investigational Site 
12.4.1. 
Suspension of Study 
The Sponsor may suspend or terminate the study, or part of the study, at any time for any reason.  
If the study is suspended or terminated, the Sponsor will ensure that applicable sites, regulatory 
agencies, and IRBs/ECs are notified as appropriate. 
12.4.2. 
Termination of Study or Investigational Site 
If the Sponsor, Investigator, or officials from regulatory agencies discover conditions arising 
during the study that indicate that the study should be halted or that a study site should be closed, 
this action may be taken after appropriate consultation between the Sponsor and Investigator(s).  
Reasons for terminating the study early or closing a site include, but are not limited to: 
• Discovery of an unexpected, significant, or unacceptable risk to the patients 
• Failure of the Investigator to comply with the protocol, cGCP regulations and 
guidelines, or local requirements 
• Insufficient adherence to protocol requirements or an unacceptably high rate of 
missing, erroneous, or improperly collected data 
• Data are not sufficiently complete and/or evaluable 
• Sponsor decision 
If the study is terminated early by the Sponsor, written notification documenting the reason for 
study termination will be provided to the Investigator and regulatory authorities.  The 
Investigator will promptly inform the IRB and provide the reason(s) for study termination. 
12.5. 
Publication and Information Disclosure Policy 
All information provided by the Sponsor and all data and information generated by the site as 
part of the study (other than a patient’s medical records) are the sole property of Harmony 
Biosciences, LLC.  
For clinical interventional studies in patients, Harmony Biosciences will post study results on 
websites such as https://clinicaltrials.gov/ and https://eudract.ema.europa.eu/ in accordance with 
FDA and EU reporting rules.  Regardless of study outcome, Harmony Biosciences commits to 
submit for publication results of its interventional clinical studies according to the prespecified 

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plans for data analysis.  Wherever possible, Harmony Biosciences also plans to submit for 
publication the results of any nonclinical or technology studies while protecting any proprietary 
information. 
Any publication or presentation of the results of this study may only be made in compliance with 
the provisions outlined in the executed Clinical Trial Agreement.  Harmony has developed a 
policy for the publication of scientific and clinical data that follows the recommendations of the 
International Committee of Medical Journal Editors, the Consolidated Standards of Reporting 
Trials (CONSORT) group and Good Publication Practice.  A copy of this policy will be made 
available to the Investigator upon request. 
When the study is completed or prematurely terminated, the Sponsor or designee will ensure a 
Clinical Study Report is written in compliance with ICH E3 (Structure and Content of Clinical 
Study Reports) and submitted to the regulatory authorities, as required.  When required by 
applicable regulations, an Investigator signatory will be identified for the approval of the Clinical 
Study Report.  The Investigator will be provided reasonable access to statistical tables, listings, 
and figures, as well as relevant reports, and will have the opportunity to review the complete 
study results. 

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13. 
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APPENDIX A. MAXIMUM ALLOWABLE BLOOD DRAW VOLUMES 
This information is consistent with the National Institutes of Health (NIH) Pediatric Blood 
Volume for Research Guidelines (Howie 2011). 
PATIENT'S WEIGHT 
PATIENTS TOTAL 
VOLUME 
MAXIMUM mL IN ONE 
BLOOD DRAW 
Kg 
lbs 
mL 
2.5% of total blood volume 
1 
2.2 
100 
2.5 
2 
4.4 
200 
5 
3 
6.6 
240 
6 
4 
8.8 
320 
8 
5 
11 
400 
10 
6 
13.2 
480 
12 
7 
15.4 
560 
14 
8 
17.6 
640 
16 
9 
19.8 
720 
18 
10 
22 
800 
20 
11 thru 15 
24 thru 33 
880-1200 
22-30 
16 thru 20 
35 thru 44 
1280-1600 
32-40 
21 thru 25 
46 thru 55 
1680-2000 
42-50 
26 thru 30 
57 thru 66 
2080-2400 
52-60 
31 thru 35 
68 thru 77 
2480-2800 
62-70 
36 thru 40 
79 thru 88 
2880-3200 
72-80 
41 thru 45 
90 thru 99 
3280-3600 
82-90 
46 thru 50 
101 thru 110 
3680-4000 
92-100 
51 thru 55 
112 thru 121 
4080-4400 
102-110 
56 thru 60 
123 thru 132 
4480-4800 
112-120 
61 thru 65 
134 thru 143 
4880-5200 
122-130 
66 thru 70 
145 thru 154 
5280-5600 
132-140 
71 thru 75 
156 thru 165 
5680-6000 
142-150 
76 thru 80 
167 thru 176 
6080-6400 
152-160 
81 thru 85 
178 thru 187 
6480-6800 
162-170 
86 thru 90 
189 thru 198 
6880-7200 
172-180 
91 thru 95 
200 thru 209 
7280-7600 
182-190 
96 thru 100 
211 thru 220 
7680-8000 
192-200 
Chart based on blood volume of: 
1 to 2 kg 
100 mL/kg 
(pre-term infant) 
>2 kg 
80 mL/kg 
(term infant - adult) 

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Daily maximum: 3 mL/kg/day maximum.  If doing more than one draw per day, be careful to 
not exceed the one time maximum OR the daily maximum 3.0 mL/kg per day.   
The amount of blood that can be drawn in a 24-hour period is the same as the maximum amount 
column. 
Patients admitted for a solid organ transplant (pre-transplant) are expected to exceed this volume.  
For all other patients, physician approval is required if maximum volume is to be exceeded for a 
one-time draw or daily maximum. 
This information is similar to that used by the Committee on Clinical Investigations at Children's 
Hospital in Los Angeles, and at Baylor College of Medicine in Dallas, TX. 
Adapted by Seattle Children's Hospital Laboratory April 2012, Seattle, WA. 
Rev. 11/2018 

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APPENDIX B. STUDY DIARY: PATIENT PITOLISANT STUDY DRUG 
DOSING AND SLEEP DIARY  
 
 

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Appendix C. 
EXAMPLES OF STRONG CYP2D6 INHIBITORS, 
STRONG CYP3A4 INDUCERS, MEDICATIONS THAT 
PROLONG QT INTERVAL, AND CENTRALLY ACTING 
H1 RECEPTOR ANTAGONISTS  
 
Medication Type 
Examples 
Strong CYP2D6 inhibitors 
paroxetine, fluoxetine, bupropion, quinidine, terbinafine 
Strong CYP3A4 inducers 
rifampin, carbamazepine, phenytoin, apalutamide, St John’s 
wort, enzalutamide, mitotane 
Medications that prolong QT interval  
Class 1A antiarrhythmics: quinidine, procainamide, 
disopyramide; 
Class 3 antiarrhythmics: amiodarone, sotalol, dofetilide 
Antipsychotics: ziprasidone, chlorpromazine, thioridazine, 
haloperidol 
Antibiotics: moxifloxacin, ciprofloxacin, erythromycin, 
ketoconazole 
H1 receptor antagonists 
pheniramine maleate, diphenhydramine, promethazine (anti-
histamines) imipramine, clomipramine, mirtazapine (tri or 
tetracyclic antidepressants  
CYP = cytochrome P450 
 
 
 

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Appendix D. 
EPWORTH SLEEPINESS SCALE FOR CHILDREN AND 
ADOLESCENTS (ESS-CHAD [PARENT/CAREGIVER 
VERSION]) 
 
 

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Appendix E. 
CAREGIVER GLOBAL IMPRESSIONS OF SEVERITY 
(CaGI-S) FOR EXCESSIVE DAYTIME SLEEPINESS 
 
Please choose the response below that best describes your child’s (care recipient’s) likelihood of 
falling asleep during daytime activities over the past week: 
□ 0 = Not at all  
□ 1 = Slight likelihood 
□ 2 = Moderate likelihood 
□ 3 = High likelihood  
□ 4 = Very high likelihood 
 

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APPENDIX F. CLINICAL GLOBAL IMPRESSION OF SEVERITY OF 
OVERALL CLINICAL STATUS 
 
Considering your total clinical experience with this particular population, please rate the 
patient’s condition at this time.  Check one: 
□ 1 = Normal  
□ 2 = Mildly symptomatic 
□ 3 = Moderately symptomatic 
□ 4 = Severely symptomatic 
 
 

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APPENDIX G. ABERRANT BEHAVIOR CHECKLIST-COMMUNITY, 
SECOND EDITION (ABC-C) 
 
 
 

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APPENDIX H. MONTEFIORE-EINSTEIN RIGIDITY SCALE – REVISED 
FOR RESEARCH STUDIES IN PWS (MERS-R-PWS) 
 
 

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APPENDIX I. 22-ITEM ZARIT BURDEN INTERVIEW (ZBI-22) 
 
 

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APPENDIX J. HYPERPHAGIA QUESTIONNAIRE FOR CLINICAL 
TRIALS (HQ-CT) 
 
 
Source: McCandless SE, Yanovski JA, Mille J, et al. Effects of MetAP2 inhibition on hyperphagia and body weight 
in Prader-Willi syndrome: a randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2017; 
19(12):1751-61. 
 
 
 

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APPENDIX K. FOOD SAFE ZONE QUESTIONNAIRE (FSZQ) 
 
 
 

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Appendix L. 
COLUMBIA-SUICIDE SEVERITY RATING SCALE 
(C-SSRS) VERY YOUNG CHILD/COGNITIVELY 
IMPAIRED-LIFETIME RECENT 
 
 
 

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APPENDIX M. COLUMBIA-SUICIDE SEVERITY RATING SCALE 
(C-SSRS) VERY YOUNG CHILD/COGNITIVELY 
IMPAIRED-SINCE LAST CONTACT 
 
 
 
 
 

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APPENDIX N. ANXIETY, DEPRESSION, AND MOOD SCALE (ADAMS)