Clinical trial NCT04886518
Conditions: Myotonic Dystrophy 1 Excessive Daytime Sleepiness
Sponsor: Harmony Biosciences Management, Inc.
Start date: 2021-06-28; Completion date: 2024-10-31
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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 Myotonic Dystrophy Type 1 ages 18 to 65 years.

The secondary objectives of this study are to assess the impact of pitolisant on fatigue, cognitive function and the burden of disease along with assessing the long-term safety and effectiveness of pitolisant in patients with Myotonic Dystrophy Type 1 ages 18 to 65 years.

Detailed description:
The study will consist of a Screening Period, an 11-week Double-Blind Treatment Phase (including a 3-week Titration Period and an 8-week Stable Dose Period), and an optional Open Label Extension (OLE) Phase. The OLE Phase will last approximately one year for each patient or until the Sponsor elects to terminate the study.

Approximately 30 patients ages 18 to 65 years who meet all eligibility criteria will be randomized at the Baseline Visit in a 1:1:1 ratio to lower dose pitolisant, higher dose pitolisant, or matching placebo. 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.

Following the 11-week Double-Blind Treatment Phase, eligible patients will be given the opportunity to participate in an optional OLE Phase. During the OLE Phase, all eligible patients will receive treatment with open-label pitolisant. Patients will first undergo a 3-week Titration Period to a maximum target dose, after which they will continue to take their dose of pitolisant once daily in the morning upon wakening until the end of the study. The patient's dose of pitolisant may be adjusted during the OLE phase.

Arms: arm 1: Double-Blind Treatment Phase:

Week 1: 8.9 mg pitolisant administered once daily in the morning; Week 2: 17.8 mg pitolisant administered once daily in the morning; Weeks 3 through 11: 35.6 mg pitolisant administered once daily in the morning. arm 2: Double-Blind Treatment Phase:

Week 1: 4.45 mg pitolisant administered once daily in the morning; Week 2: 8.9 mg pitolisant administered once daily in the morning; Weeks 3 through 11: 17.8 mg pitolisant administered once daily in the morning arm 3: Double-Blind Treatment Phase:

Week 1: Matching placebo tablets; Week 2: Matching placebo tablets; Weeks 3 through 11: Matching placebo tablets
Interventions: intervention 1: Pitolisant Oral Tablet intervention 2: Placebo oral tablet
Intervention descriptions: intervention 1: 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 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. intervention 2: Matching placebo tablets will be provided for each strength of active pitolisant film-coated tablets.

Protocol documents:
Prot_000.pdf: 
 
Official Title of Study: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
the Safety and Efficacy of Pitolisant on Excessive Daytime Sleepiness and Other Non-Muscular 
Symptoms in Patients with Myotonic Dystrophy Type 1, Followed by an Open-Label Extension  
 
NCT Number: NCT04886518 
 
Protocol Date (last revision date): July 18, 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-005 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Safety and Efficacy of Pitolisant on Excessive 
Daytime Sleepiness and Other Non-Muscular Symptoms in 
Patients with Myotonic Dystrophy Type 1, Followed by an 
Open-Label Extension 
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 
Medical Monitor: 
 
 
 
Operational Lead: 
 
 
Protocol Amendment: 
Effective Date: 
Amendment 5 
18JUL2023 
 
 
 


Protocol No: HBS-101-CL-005, Amendment 5 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
2 
Confidential 
SPONSOR SIGNATURE 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Safety and Efficacy of Pitolisant on Excessive Daytime 
Sleepiness and Other Non-Muscular Symptoms in Patients with 
Myotonic Dystrophy Type 1, Followed by an Open-Label Extension 
Protocol Number: 
HBS-101-CL-005 
This protocol Amendment 5 has been reviewed and approved by the Sponsor. 
Signatur
Date: 
 
Harmony Biosciences, LLC 
630 W. Germantown Pike, Suite 215 
Plymouth Meeting, PA 19462 
USA 
DocuSign Envelope ID: FB8A3DFE-2FB9-4341-8A1E-5CF7D3E22C89


Protocol No: HBS-101-CL-005, Amendment 5 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
 
 
3 
Confidential 
INVESTIGATOR AGREEMENT 
CLINICAL STUDY PROTOCOL: HBS-101-CL-005 
 
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and 
Efficacy of Pitolisant on Excessive Daytime Sleepiness and Other Non-Muscular Symptoms 
in Patients with Myotonic Dystrophy Type 1, 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-005 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 a Principal Investigator for 
review by you, your staff, and the applicable Institutional Review Board (IRB)/Ethics Committee 
(EC). 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-005, Amendment 5 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
 
 
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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-005 
PHASE OF DEVELOPMENT: 
2 
PROTOCOL TITLE: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Safety and Efficacy of Pitolisant on Excessive Daytime Sleepiness and Other Non-Muscular 
Symptoms in Patients with Myotonic Dystrophy Type 1, Followed by an Open-Label Extension 
NUMBER OF PLANNED SUBJECTS: 30 
STUDY SITES: Approximately 22 sites in the United States (US) and Canada 
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 myotonic dystrophy type 1 
(DM1) ages 18 to 65 years. 
Secondary Objectives 
The secondary objectives of this study are to assess: 
• 
the impact of pitolisant on fatigue in patients with DM1 
• 
the impact of pitolisant on selected domains of cognitive function in patients with DM1 
• 
investigator and patient impression of overall impact of pitolisant on burden of disease in 
patients with DM1 
• 
safety and effectiveness of pitolisant during long-term treatment (during the Open-Label 
Extension [OLE] Phase) 
METHODOLOGY: 
Double-Blind, Placebo-Controlled Treatment Phase: 
After completion of the Screening Period, eligible patients who agree to participate will be randomized 
in a 1:1:1 ratio to one of three treatment groups: lower dose pitolisant (17.8 mg), higher dose pitolisant 
(35.6 mg), or placebo. Study drug doses will be titrated during a 3-week period (Day 1 to 21): 
• 
Pitolisant lower dose 17.8 mg treatment group: Week 1 (Day 1-7), 4.45 mg; Week 2 
(Day 8-14), 8.9 mg; Week 3 (Day 15-21), 17.8 mg 
• 
Pitolisant higher dose 35.6 mg treatment group: Week 1 (Day 1-7), 8.9 mg; Week 2 
(Day 8-14), 17.8 mg; Week 3 (Day 15-21), 35.6 mg 
• 
Patients randomized to placebo will receive matching doses of placebo tablets over the 3-week 
Titration Period and during the Stable Dose Period. 
Adjustments to study drug dosing outside of the protocol-specified titration schedule are not allowed 
during the 11-week Double-Blind Treatment Phase. 
Efficacy assessments will be performed at the Baseline Visit (Day -1), Visit 4 (Day 49), and Visit 5 
(Day 77), with the exception of the optional Maintenance of Wakefulness Test (MWT), Cogstate 
Computerized Cognitive Battery Tests and Sustained Attention to Response Task (SART), which are 


Protocol No: HBS-101-CL-005, Amendment 5 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
 
 
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only to be performed at the Baseline and End of Treatment (EOT) study visits. At the end of the 
Double-Blind Treatment Phase (Day 77/Visit 5), patients who do not enter the optional OLE Phase will 
have two safety follow-up telephone contacts (TCs), one 15 (±3) days and another 30 (+3) days after 
the final dose of blinded treatment. 
Safety assessments will include electrocardiograms (ECGs; in triplicate) at Screening, Baseline, 
Day 22 (Visit 3), Day 49 (Visit 4), and Day 77 (Visit 5). In addition to ECG testing, Holter monitoring 
will be performed during Screening and at Visit 3 (Day 22). On those days when a Holter monitor is 
placed on the patient, the ECG data will be taken from the Holter monitor recording. Any clinically 
significant finding from Holter monitoring requires additional evaluation (including an unscheduled 
ECG). Adverse event (AE) and concomitant medication monitoring and Columbia-Suicide Severity 
Rating Scale (C-SSRS) assessment will be conducted at all visits whether on-site or by TC. Patients 
will receive TCs from the site on Days 8, 15, and 28. 
During the Double-Blind Treatment Phase, patients will undergo pharmacokinetic (PK) assessments at 
the study site on Day 22 (Visit 3) and at the end of the double-blind treatment on Day 77 (Visit 5). For 
on-site study visits with PK sampling, patients will be instructed to not take their study drug in the 
morning upon wakening; rather, study drug administration will be held until the patient is at the study 
site, and timing of dose administration will be based on the PK sampling schedule.  
Open-Label Extension Phase: 
For patients who elect to enter the OLE Phase of the study, eligibility criteria will be confirmed at the 
EOT Visit/Day 77 (Visit 5) in the Double-Blind Treatment Phase. Patients must complete the Double-
Blind Treatment Phase of the study to be eligible to participate in the optional OLE Phase of the study. 
All eligible patients who enter the OLE Phase will receive open-label pitolisant that will be titrated to a 
dose of 35.6 mg (or a maximum dose up to 35.6 mg based on Investigator assessment of tolerability): 
• 
Week 12 (Day 78-84), 8.9 mg 
• 
Week 13 (Day 85-91), 17.8 mg 
• 
Week 14 (Day 92-98), 35.6 mg 
After completion of the Titration Period in the OLE Phase, patients will continue to receive open-label 
pitolisant at 35.6 mg (or their maximum dose up to 35.6 mg based on Investigator assessment of 
tolerability) and will be instructed to take their study drug once daily in the morning upon wakening.  
Patients will receive TCs from the site on Day 85/Week 13 and Day 92/Week 14 during the OLE 
Titration Period to assess AEs (including cardiovascular [CV] symptoms and psychiatric events), and 
concomitant medication use, complete the C-SSRS and to confirm titration of pitolisant. On 
Day 99/Visit 6, patients will return to the site to complete safety and effectiveness assessments; 
24-hour Holter monitoring will be initiated at this visit (a clinically significant finding from Holter 
monitoring requires additional evaluation, including an unscheduled ECG). A telephone visit will occur 
3 months later on Day 189/Month 6 followed by an on-site study visit (Visit 7) 3 months later 
(Day 279/Month 9). Another telephone visit will occur 3 months later, on Day 369/Month 12. All 
patients who complete the study will have an End of Treatment (EOT) visit at Day 459/Month 15 
(Visit 8). If the patient withdraws from the study early or the study is terminated by the Sponsor, every 
effort should be made to conduct an EOT or Early Termination Visit. 
Study drug in a quantity sufficient for 3 months (i.e., 90 days) of once daily administration will be 
provided to eligible patients every 3 months (90 days) either via mail or at the on-site study visits; 
additional study drug may be dispensed between TCs and/or at on-site visits if necessary. 
At all on-site study visits (approximately every 6 months), safety assessments (including full physical 
examination, body weight, clinical laboratory assessments, 12-lead ECGs [in triplicate], vital signs, 
suicidality assessment [by C-SSRS]), and effectiveness assessments will be performed. If interim CV 
assessments are required at the discretion of the Investigator, patients will return to the study site for 
unscheduled visits that will include an ECG. Adverse events and concomitant medication use will be 


Protocol No: HBS-101-CL-005, Amendment 5 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
 
 
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monitored throughout treatment during all TCs and at all on-site study visits. The C-SSRS will also be 
completed during TCs by certified individuals. Patients who are treated in the OLE Phase will have 
two safety follow-up TCs with the study site 15 (±3) days and 30 (+3) days after their final dose of 
open-label pitolisant, which will include assessment for AEs (including CV symptoms or psychiatric 
events) and concomitant medication use. 
STUDY POPULATION:  
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. 
2. Has a diagnosis of DM1 confirmed by genetic testing (cytosine-thymine-guanine [CTG] repeat 
of >100) from the Screening Visit. 
3. Male or female patients ages 18 to 65 years at the time of enrollment. 
4. 
 
5. If on a wake-promoting treatment that could affect EDS (including stimulants, modafinil, and 
armodafinil): 
a. Must be on a stable dose for at least 2 months prior to Screening 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). 
b. If not on a stable dose for 2 months prior to Screening, washout for 5 half-lives prior to 
randomization and agree to remain off these treatments for the duration of the Double-
Blind Treatment Phase of the study. 
6. Washout of cannabidiol and tetrahydrocannabinol for 28 days prior to randomization and agree 
to remain off for the duration of the Double-Blind Treatment Phase of the study. 
7. Able to walk independently with or without an assistive device (e.g., cane, walker, orthoses 
allowed). 
8. A patient who is a female of child-bearing potential (FCBP) must have a negative serum 
pregnancy test at the Screening Visit and negative urine pregnancy test at the Baseline Visit 
and agree to remain abstinent or use an effective method of non-hormonal contraception to 
prevent pregnancy for the duration of the study and for 21 days after final dose of study drug. 
9. In the opinion of the Investigator, the patient is capable of understanding and complying with 
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 this study: 
1. Has a diagnosis of another genetic or chromosomal disorder that is distinct from DM1 and that 
is not being managed adequately in the opinion of the investigator.  
2. 
 
 


Protocol No: HBS-101-CL-005, Amendment 5 
 
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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 substances listed in the protocol 
(Section 5.7.2). 
5. 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. 
6. Participation in an interventional research study involving another investigational medication 
or device in the 28 days prior to enrollment; patients who undergo a washout of an 
investigational medication of at least 5 half-lives can 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. 
7. Has a primary diagnosis of severe psychiatric illness. 
8. Patients taking antidepressants who have not been on a stable dose of their antidepressant for at 
least 12 weeks prior to Screening; for patients on a stable dose of their antidepressant for at 
least 12 weeks prior to Screening, must agree to continue their stable dose for the duration of 
the Double-Blind Treatment Phase of the study. Dose adjustments will be permitted in the 
OLE Phase. In the Double-Blind Treatment Phase of the study, antidepressants that are strong 
CYP2D6 inhibitors are exclusionary (Section 5.7.2). 
9. Has a history of sleep-disordered breathing or another underlying sleep disorder that in the 
opinion of the Investigator is a main contributory factor to the patient’s EDS. 
10. Has a diagnosis of end-stage renal disease (ESRD; estimated glomerular filtration rate [eGFR] 
of <15 mL/minute/1.73 m2) or severe hepatic impairment (Child-Pugh C). 
11. 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.  
12. Has a family history of sudden cardiac death, unexplained death, or death from a primary 
dysrhythmia potentially associated with QT prolongation in any family member (i.e., first 
degree relative such as parent, sibling, or offspring). 
13. Has a history of unexplained syncope. 
14. Has a history of long corrected QT interval (QTc) syndrome or corrected QT interval using 
Fridericia’s formula (QTcF) >450 msec for males or >470 msec for females (QTcF = QT / 3√ 
RR) sustained atrial fibrillation (AF) or left ventricular ejection fraction <50%. 
15. Has a history of documented symptomatic arrhythmias (e.g., ECG, Holter monitor). 
16. Electrocardiogram abnormalities during a 10-second, 12-lead ECG at Screening of first-degree 
atrioventricular block (AVB; PR interval >220 msec), QRS >120 msec, heart rate (HR) 
<50 beats per minute (bpm), marked T-wave abnormalities, more than single atrial premature 


Protocol No: HBS-101-CL-005, Amendment 5 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
 
 
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complexes (APCs) or premature ventricular contractions (PVCs), left bundle branch block, or 
Brugada pattern type 1.  
 
Note: Patients with 1st degree AVB with a PR interval >220 msec who are treated 
prophylactically with an allowable implanted device are not excluded from the study. 
17. Based on Holter monitor, any episode of 3rd degree AVB, any prolonged episode of second 
degree AVB (>2 episodes during waking hours, >6 episodes during sleep), any prolonged 
episode of 2nd degree AVB (>10 seconds), any asystole longer than 3.5 seconds, any run of 
ventricular tachycardia (VT) >6 beats, frequent runs of non-sustained VT (>5/24 hour), 
>400 PVCs/24 hours, AF or paroxysmal AF, or frequent or complex atrial arrhythmias. 
18. Has history of New York Heart Association (NYHA) class III or class IV heart failure. 
19. Has an implanted defibrillator or implanted biventricular pacemaker.  
 
Note: Patients with implanted univentricular pacemakers that are used prophylactically to 
prevent or treat bradycardia or heart block may be included. 
20. Is receiving a medication known to prolong the QT interval. 
21. Has a history of clinically significant hypokalemia or hypomagnesemia that cannot be 
adequately controlled by supplementation. 
22. Has serum potassium or magnesium levels that are outside of the normal reference ranges and 
considered clinically significant at Screening. Patients with mild hyperkalemia that, in the 
opinion of the Investigator, does not pose an arrhythmia threat may be included. 
23. 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 receptor (H1R) 
antagonist (sedating antihistamine).  
 
Note: Patients who undergo a washout of these medications of at least 5 half-lives may be 
enrolled in the Double-Blind Treatment Phase of the study.  
Note: Use of strong CYP2D6 inhibitors and strong CYP3A4 inducers is allowed during the 
OLE Phase; however, adjustment of pitolisant dose is required (Section 3.1.2.2). Although not 
prohibited during the OLE Phase of the study, use of centrally acting or sedating H1R 
antagonists should be avoided.  
24. Is a known CYP2D6 poor metabolizer (PM). 
25. Regular use (more than twice per week) of any sleep-promoting treatments that could affect 
EDS and not willing to limit use to no more than twice per week during Screening and for the 
duration of the Double-Blind Treatment Phase of the study (use of sleep-promoting agents are 
not allowed within one day prior to study-related assessments). 
26. Has abnormal laboratory values at Screening that are clinically significant as determined by the 
Investigator.  


Protocol No: HBS-101-CL-005, Amendment 5 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
 
 
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27. Has initiated any new or change in allied health therapies or interventions that can interfere 
with the study outcomes within 28 days prior to randomization and that are prohibited during 
the Double-Blind Treatment Phase of the study, based on the Investigator’s judgment. 
28. Has a current or recent (within 1 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).  
29. Has planned surgery during the Double-Blind Treatment Phase of the study; planned surgery is 
permitted during the OLE Phase. 
30. Has a significant risk of committing suicide or suicidality 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 C-SSRS (Appendix C). 
31. Based on the judgment of the Investigator, is unsuitable for the study for any reason, including 
but not limited to an unstable or uncontrolled medical condition or one 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 will be provided as 4.45 mg and 17.8 mg tablets.  
Pitolisant will be administered orally as a single dose of lower dose pitolisant (17.8 mg) or higher dose 
pitolisant (35.6 mg) once daily in the morning upon wakening in the Double-Blind Treatment Phase, 
and 35.6 mg (or a maximum dose up to 35.6 mg based on Investigator assessment of tolerability) once 
daily in the morning upon wakening in the OLE Phase. 
REFERENCE THERAPY, DOSE, AND MODE OF ADMINISTRATION:  
Placebo will be provided as matching 4.45 mg and 17.8 mg tablets in the Double-Blind Treatment 
Phase, administered orally once daily in the morning upon wakening. 
DURATION OF TREATMENT:  
The duration of the study for each patient in the Double-Blind, Placebo-Controlled Phase of the study 
is expected to be approximately 20-21 weeks, including a maximum of 45 days of screening, 11 weeks 
of double-blind treatment (3-week Titration Period and 8-week Stable Dose Period) and two follow-up 
TCs for safety, the first 15 (±3) days and the second 30 (+3) days after final dose of study drug for 
patients who do not participate in the optional OLE Phase of the study.  
At the end of 11 weeks of double-blind treatment, eligible patients will be given the opportunity to 
enter the OLE Phase of the study. The OLE Phase of the study will end at Day 459/Month 15 (Visit 8) 
for each patient unless the patient withdraws from the study early or the Sponsor elects to terminate the 
study. 
STUDY ASSESSMENTS:  
Efficacy Assessments: 
Efficacy will be evaluated using the Daytime Sleepiness Scale (DSS), Fatigue Severity Scale (FSS), 
Cogstate Computerized Cognitive Battery Tests (Identification, Detection, and One Back), Myotonic 
Dystrophy Health Index (MDHI), ESS, CGI-S, PGI-S, SART, and MWT (for those patients who opt to 
have this assessment performed).  
During the Double-Blind Treatment Phase of the study, patients will undergo efficacy assessments 
(DSS, FSS, MDHI, ESS, CGI-S, and PGI-S) at Baseline (Visit 2; Day -1), Day 49 (Visit 4), and 
Day 77 (Visit 5).  The optional MWT will be assessed at Baseline (Visit 2, Day -3 to Day -1) and up to 


Protocol No: HBS-101-CL-005, Amendment 5 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
 
 
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3 days prior to Day 77 (Visit 5); the Cogstate Computerized Cognitive Battery Tests and SART will be 
performed at Baseline (Visit 2; Day -1) and at Day 77 (Visit 5). 
During the OLE Phase, clinical effectiveness will be assessed at all on-site study visits, which occur 
every 6 months, i.e., on Day 99/Month 3 (Visit 6), Day 279/Month 9 (Visit 7), Day 459/Month 15 
(Visit 8/EOT), using DSS, FSS, Cogstate Computerized Cognitive Battery Tests (Identification, 
Detection, and One Back), MDHI, ESS, CGI-S, and PGI-S. 
Safety Assessments: 
Safety will be assessed by monitoring and recording of all AEs from signing of the informed consent 
form (ICF) through the two safety follow-up TCs at 15 (±3) and 30 (+3) days after the final dose of 
study drug for the Double-Blind Treatment Phase (patients who do not enter the OLE), throughout the 
OLE Phase of the study by alternating TCs and on-site visits, and through two safety follow-up TCs 
(which will assess AEs including CV symptoms or psychiatric events and use of concomitant 
medications) at 15 (±3) and 30 (+3) days after the final dose of open-label pitolisant. Safety 
assessments also include assessment of suicide risk and suicidality (C-SSRS) during the Double-Blind 
Phase and OLE Phase of the study. 
In addition, 12-lead ECGs (in triplicate) and Holter monitoring will be performed during both the 
Double-Blind Phase and OLE Phase at time points specified in the Schedule of Assessments for each 
study phase. The ECG and Holter monitoring performed at Screening will determine whether an 
exclusionary CV issue is present and testing at later time points during the study is designed to detect 
any changes in CV parameters. Holter monitoring in the Double-Blind Phase and OLE Phase will be 
used to test for arrhythmias.   
Any QT prolongation or ECG finding deemed clinically significant by the Investigator at any time 
during the study will be checked against the requirements for discontinuation of study drug 
(Section 4.4.1) and a follow-up ECG should be scheduled. 
A core ECG laboratory will manage all ECG and Holter monitoring activities. All ECGs will be 
recorded in triplicate. All ECG and Holter data will be transmitted electronically to the core laboratory 
and will be promptly interpreted by trained cardiologists. Pre-specified ECG criteria for QT, QRS 
duration, AVB, and arrhythmias will trigger immediate notifications related to ECG and Holter 
monitoring abnormalities. Any ECG finding that demonstrates QT prolongation (i.e., QTcF >500 msec 
or an increase of >60 msec regardless of resultant QTc value) should be promptly addressed by the 
Investigator and will require discontinuation of study drug. In addition to a potential QT prolongation, 
the Medical Monitor should be consulted for PR >300 msec, QRS >140 msec, or any increase from 
baseline in PR or QRS greater than 50% or 40%, respectively. The Medical Monitor should also be 
consulted for any HR increase >65% over baseline or decrease >40% compared with baseline. The 
ECG should be repeated as soon as possible in the event of these clinically significant results; if done 
the next day, attempts should be made to perform the repeat ECG at the same time of day that the 
abnormal ECG was obtained. If the event persists or worsens, study drug will be interrupted for 
2-3 days and the ECG will be repeated on the third day. If the abnormality has resolved (i.e., return to 
baseline values), study drug dosing may resume at the same dose as administered before the 
interruption (or, in the OLE Phase, resumed with dose adjustment per the Investigator’s discretion). If 
the condition persists or worsens after study drug interruption (or after adjustment in the OLE Phase), 
treatment with study drug will be permanently discontinued and the subject will be referred to a 
cardiologist. In addition, in the event of an increase of >60 msec in QTc, study drug will be 
permanently discontinued, and the subject will be referred to a cardiologist. For all abnormal ECG or 
Holter monitoring findings considered clinically significant by the Investigator, a follow-up ECG 
should be performed within 24 hours and again 7 days later to ensure the abnormality is not worsening. 
These follow-up 12-lead ECGs may be performed locally. 
Measurement of laboratory parameters (hematology, serum chemistry, and urine values) and vital signs 
will be performed at every on-site visit in the Double-Blind Treatment Phase and OLE Phase of the 


Protocol No: HBS-101-CL-005, Amendment 5 
 
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Phase 2 Safety and Efficacy Study 
 
 
 
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Confidential 
study. Serum magnesium and potassium values will be monitored at on-site visits in both phases of the 
study, and patients will be administered supplements if the levels decrease by 20% or if the levels are 
in the low normal or below normal range. During the Double-Blind Treatment Phase, concomitant 
medications will be reviewed at every TC and on-site study visit; during the OLE Phase, concomitant 
medications will be reviewed every 3 months, either by phone call or at on-site study visits. During the 
OLE Phase, patients will be instructed to avoid strong metabolic inhibitors of CYP2D6 enzymes and 
strong inducers of CYP3A4 enzymes. If a patient begins taking a strong CYP2D6 inhibitor during the 
OLE Phase, the pitolisant dose is to be reduced by half. If a patient begins taking a strong CYP3A4 
inducer during the OLE Phase, assess for loss of efficacy of pitolisant and for patients stable on 
pitolisant 8.9 mg or 17.8 mg once daily, increase the dose of pitolisant to double the original daily dose 
(i.e., 17.8 mg or 35.6 mg, respectively) over 7 days. 
Full physical examinations will be performed at Screening and on Day 77 (Visit 5) in the Double-Blind 
Treatment Phase, and at every on-site visit during the OLE Phase.  
At the end of the Double-Blind Treatment Phase (Day 77/Visit 5), patients who do not enter the 
optional OLE Phase of the study will have two safety follow-up TCs from the study site to assess for 
AEs (including any CV symptoms and psychiatric events) and use of concomitant medications 15 (±3) 
days and 30 (+3) days after their final dose of blinded study drug. Patients in the OLE Phase will also 
have two safety follow-up TCs to assess for AEs (including any CV symptoms and psychiatric events) 
and use of concomitant medications 15 (±3) days and 30 (+3) days after the final dose of open-label 
treatment.  
Pharmacokinetic Assessments: 
During the Double-Blind Treatment Phase, blood samples will be collected to measure concentrations 
of pitolisant (and its major metabolite) on Day 22 (Visit 3) and Day 77 (Visit 5; end of blinded 
treatment) for trough and at the time of maximum concentration (tmax [3 hours ±30 minutes post dose]). 
Patients will be instructed to not take their dose of study drug in the morning upon wakening on the 
days of scheduled study visits that include PK sampling. 
Day 22 (Visit 3): At the study site, 12-lead ECGs (in triplicate) and a blood sample collection for PK 
analyses are to be performed before study drug is administered and at 3 hours (±30 minutes) after 
dosing. These ECGs must be performed prior to and within 15 minutes of the blood sample being 
collected for PK analysis. The time of study drug administration and the time of ECGs and blood 
sample collection for PK must be recorded. 
Day 77 (Visit 5): At the study site, 12-lead ECGs (in triplicate) and a blood sample collection for PK 
analyses are to be performed before study drug is administered and at 3 hours (±30 minutes) after 
dosing. These ECGs must be performed prior to and within 15 minutes of the blood sample being 
collected for PK analysis. The time of study drug administration and the time of ECGs and blood 
sample collection for PK must be recorded. 
Assessments associated with on-site study visits may be completed remotely or at an alternative 
location, under the oversight of the Investigator, as detailed in Section 6.5. 
STUDY ENDPOINTS: 
Efficacy Endpoints: 
Primary efficacy endpoint: 
• 
The primary efficacy endpoint is the change in DSS score from Baseline to Week 11 for 
pitolisant compared with placebo.  
Secondary efficacy endpoints are change from Baseline to Week 11 for pitolisant compared with 
placebo: 
• 
on the FSS 


Protocol No: HBS-101-CL-005, Amendment 5 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
 
 
12 
Confidential 
• 
in psychomotor function as measured by the Cogstate Detection Test 
• 
in attention as measured by the Cogstate Identification Test 
• 
in working memory as measured by the Cogstate One Back Test 
• 
on the MDHI 
• 
on the ESS 
• 
on the CGI-S (i.e., global assessment of overall severity of EDS as assessed by the 
clinician) 
• 
on the PGI-S, anchored to EDS 
• 
in attention as measured by SART 
Exploratory endpoint:  
For patients who complete the MWT assessments: 
• 
change in mean sleep latency (MSL) based on the MWT from Baseline to Week 11 for 
pitolisant compared with placebo 
Long-term effectiveness endpoints:  
• 
Changes from Baseline in DSS, FSS, Cogstate Detection Test, Cogstate Identification Test, 
Cogstate One Back Test, MDHI, ESS, CGI-S of EDS, and PGI-S of EDS during the OLE 
Phase of the study.  
Safety Endpoints: 
The incidence of AEs, changes in clinical laboratory test results and vital signs, 12-lead ECG results (in 
triplicate), Holter monitoring results, C-SSRS assessment, and physical examination findings will be 
evaluated. 
STATISTICAL METHODS:  
Determination of Sample Size:  
 
 
Efficacy Analyses:  
Summary statistics (mean, standard deviation [SD], median, minimum, maximum) for the primary 
efficacy endpoint will be reported for the change from the Baseline Visit to Week 11 for each of the 
treatment groups and for the active groups combined. The change from Baseline will be analyzed with 
mixed model repeated measures (MMRM). Fixed effects will be included for treatment visit, treatment 
× visit interaction, baseline value, and wake-promoting agent stratification factor. Least square means 
(LSMs), standard errors, and the LSM 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.  
A similar approach will be utilized for the OLE Phase effectiveness visits. Summary statistics will be 
reported for measures of effectiveness at each visit where it is collected.  


Protocol No: HBS-101-CL-005, Amendment 5 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
 
 
13 
Confidential 
Safety Analyses:  
All safety data will be tabulated or listed. Adverse events, ECG abnormalities, and other categorical 
outcomes will be summarized with counts and percentages. Continuous outcomes will be reported 
using summary statistics. 
Pharmacokinetic Analyses: Concentrations of pitolisant and its major metabolite will be assayed using 
a validated bioanalytical method and the concentrations will be reported in the clinical study report 
(CSR). Concentration-time data of pitolisant and BP1.3484 will be summarized using descriptive 
statistics. 
Interim Analysis: No interim analysis is planned. 
 


Protocol No: HBS-101-CL-005, Amendment 5 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
 
 
14  
Confidential 
SCHEDULE OF ASSESSMENTS, DOUBLE-BLIND TREATMENT PHASE 
Visit/TC 
Study Day 
Screening 
VISIT 1 
Day -45 
to -2 
 
Double-Blind Treatment Phase (11 Weeks) 
Safety 
F-Up 
TCf 
Unsch 
Visitsg 
 
Titration Perioda 
Weeks 1 to 3 
Day 1 to 21 
Stable Dose Periodb 
Weeks 4 to 11 
Day 22 to 77 
Baseline 
VISIT 2 
Day -3 to 
Day -1  
 
 
Day 1 
TC 1 
Day 8 
(±3 days) 
TC 2 
Day 15 
(±3 days) 
VISIT 3 
Day 22 
(±3 days) 
TC 3c 
Day 28 
(±3 days) 
VISIT 4 
Day 49 
(±3 days) 
EOTd/ETe 
VISIT 5 
Day 77 
(±3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Assess/confirm eligibility 
X 
X 
 
 
 
 
 
 
Xd 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test (FCBP)h 
X 
X 
 
 
 
X 
 
X 
X 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
 
X 
 
 
Physical examinationi 
X 
X 
 
 
 
X 
 
X 
X 
 
 
Body weight 
X 
X 
 
 
 
 
 
 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Vital signsj 
X 
X 
 
 
 
X 
 
X 
X 
 
 
Clinical laboratory tests 
X 
X 
 
 
 
X 
 
X 
X 
 
 
Genetic testing for DM1k 
X 
 
 
 
 
 
 
 
 
 
 
Holter monitoringl 
X 
 
 
 
 
X 
 
 
 
 
 
12-lead ECG (in triplicate)m 
X 
X 
 
 
 
X 
 
X 
X 
 
 
C-SSRS 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Blood sample for PK 
 
 
 
 
 
Xn 
 
 
Xo 
 
 
Adverse eventsp 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol No: HBS-101-CL-005, Amendment 5 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
 
 
15  
Confidential 
Visit/TC 
Study Day 
Screening 
VISIT 1 
Day -45 
to -2 
 
Double-Blind Treatment Phase (11 Weeks) 
Safety 
F-Up 
TCf 
Unsch 
Visitsg 
 
Titration Perioda 
Weeks 1 to 3 
Day 1 to 21 
Stable Dose Periodb 
Weeks 4 to 11 
Day 22 to 77 
Baseline 
VISIT 2 
Day -3 to 
Day -1  
 
 
Day 1 
TC 1 
Day 8 
(±3 days) 
TC 2 
Day 15 
(±3 days) 
VISIT 3 
Day 22 
(±3 days) 
TC 3c 
Day 28 
(±3 days) 
VISIT 4 
Day 49 
(±3 days) 
EOTd/ETe 
VISIT 5 
Day 77 
(±3 days) 
Dispense sleep diaryq 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
Xr 
 
 
 
 
 
 
 
 
 
Dispense study drug 
 
Xr 
 
 
 
X 
 
X 
Xs 
 
 
Dispense study drug dosing 
diaryt 
 
Xr 
 
 
 
 
 
 
 
 
 
Administer/Titrate Study 
drugu 
 
 
Xa 
X 
X 
X 
X 
X 
X 
 
 
Study drug 
compliance/accountability 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
MWT (optional)v 
 
X 
 
 
 
 
 
 
X 
 
 
DSS 
 
X 
 
 
 
 
 
X 
X 
 
 
FSS 
 
X 
 
 
 
 
 
X 
X 
 
 
Cogstate Detection 
Xw 
X 
 
 
 
 
 
 
X 
 
 
Cogstate Identification 
Xw 
X 
 
 
 
 
 
 
X 
 
 
Cogstate One Back 
Xw 
X 
 
 
 
 
 
 
X 
 
 
MDHI 
X 
X 
 
 
 
 
 
X 
X 
 
 
ESS 
 
X 
 
 
 
 
 
X 
X 
 
 
CGI-S  
Xx 
X 
 
 
 
 
 
X 
X 
 
 
PGI-S  
 
X 
 
 
 
 
 
X 
X 
 
 
SART 
Xy 
X 
 
 
 
 
 
 
X 
 
 
Abbreviations: AE = adverse event; CGI-S = Clinical Global Impression of Severity; C-SSRS = Columbia-Suicide Severity Rating Scale; DM1 =  myotonic dystrophy Type 1; 
DSS = Daytime Sleepiness Scale; ECG = electrocardiogram; EOT = end-of-treatment; ESS = Epworth Sleepiness Scale; ET = early termination; FCBP = female of childbearing 
potential; FSS = Fatigue Severity Scale; F-Up = follow-up; MDHI = Myotonic Dystrophy Health Index; MWT = Maintenance of Wakefulness Test; OLE = Open-Label 


Protocol No: HBS-101-CL-005, Amendment 5 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
 
 
16  
Confidential 
Extension; PGI-S = Patient Global Impression of Severity; PK = pharmacokinetics; SART = Sustained Attention to Response Task; TC = telephone contact; Unsch = 
unscheduled.  
 
a The 3-week Titration Period for the Double-Blind Treatment Phase will be from Day 1 to Day 21 (± 3 days); eligible patients will receive their first dose of study drug on Day 1, 
and study drug dose will be titrated on Days 8 and 15; all patients will be at their randomized dose of study drug by Day 15. Patients will receive TCs on Day 8 ±3 days (TC 1) 
and Day 15 ±3 days (TC 2) to assess for AEs (including inquiries regarding signs and symptoms of arrhythmia, and other cardiac manifestations [e.g., syncope], and psychiatric 
events [e.g., suicidality, compulsive behavior, anxiety]) and concomitant medication use, complete the C-SSRS, and review/confirm titration of study drug.  
b The 8-week Stable Dose Period for 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; Visit 5) at the study site; study drug compliance will be monitored by TC and at study visits as detailed in Section 5.5. The EOT (Week 11) optional MWT assessment 
should not be performed on the same day as the Visit 5 PK as patients will take their dose of study drug at the site after ECGs and pre-dose PK blood draw are done. The EOT 
(Week 11) optional MWT may be conducted up to 3 days in advance of Day 77; patients should take their dose of study drug on the morning of the scheduled Week 11 MWT 
assessment. 
c Patients will receive a TC from study site personnel on Day 28 (±3 days; TC 3) 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, complete the C-SSRS, and 
review/confirm study drug compliance. 
d 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 OLE study drug for 
titration at this visit on Day 77 (Section 5.4.2); eligibility criteria must be confirmed by reviewing the original eligibility criteria in Section 4.1.1 and Section 4.1.2 before a 
patient can participate in the OLE Phase.  
e Patients who prematurely discontinue study drug are required to undergo the ET Visit and all ET assessments (Section 7.2.5). Reasons for discontinuation must be recorded. 
f  Patients who do not enter the optional OLE Phase will receive Safety Follow-up TCs from the study site, 15 (±3) days and 30 (+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.  
g 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 7.5). 
h Serum pregnancy test is to be performed at Screening and a urine pregnancy test is to be performed at all other visits, as indicated. 
i Full physical examination is to be performed at the Screening Visit and Visit 5; an abbreviated physical examination is to be performed at Visits 2, 3 and 4 (Section 6.3.2). 
j 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. 
k Genetic testing will be provided by the Sponsor. The results from the genetic test done at Screening should be used for determination of eligibility. 
l A 24-hour Holter monitor will be placed at the Screening Visit and at Visit 3. A clinically significant finding from Holter monitoring requires additional evaluation (including an 
unscheduled ECG). On days when a Holter monitor is required (Screening Visit and Visit 3), it should be placed on the patient and the continuous recording started as the 
12-lead ECG (in triplicate) data are taken from the Holter monitor recording. 
m All 12-lead ECGs are to be performed in triplicate. Perform ECGs after the patient has been resting for at least 5 minutes. At Visits 2, 3, and 5, 12-lead ECGs are to be performed 
before study drug administration. Any clinically significant ECG value is to be promptly addressed by the Investigator in accordance with the protocol. 
n Patients will be instructed to record in their study diary the time of day that they take the study drug on the day before Visit 3. Patients will be instructed to not take their dose of 
study drug in the morning of Visit 3 (Day 22 ±3 days). Study drug administration will be at the study site and timing will be based on timing of the PK sampling schedule. The 
Holter monitor should be placed on the patient at the start of the day for Visit 3 and continuous recording started as the 12-lead ECG (in triplicate) data are taken from the Holter 
monitor recording. At the study site, 12-lead ECGs (in triplicate) and a blood sample collection for PK analyses are to be performed before study drug is administered. The 
12-lead ECGs should be done prior to and within 15 minutes of the pre-dose blood sample collection for PK analyses. The time of study drug administration and the time of ECG 
and blood sample collection for PK must be recorded. In addition, 12-lead ECGs and additional PK samples are to be collected at 3 hours (±30 minutes) after dosing. Similarly, 
the 12-lead ECG should be done prior to and within 15 minutes of the post-dose blood sample collection for PK analyses. The time of study drug administration and the time of 
ECG and blood sample collection for PK must be recorded. The total volume of blood collected is not to exceed the maximal allowable for adults of 10.5 mL/kg or 550 mL, 
whichever is smaller, over any 8-week period. 


Protocol No: HBS-101-CL-005, Amendment 5 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
 
 
17  
Confidential 
o Patients will be instructed to record in their study diary the time of day that they take study drug on the day before Visit 5. Patients will be instructed to not take their dose of 
study drug in the morning of Visit 5 (Day 77 ±3 days). Study drug administration will be at the study site and timing will be based on timing of the PK sampling schedule. At the 
study site, 12-lead ECGs (in triplicate) and a blood sample collection for PK analyses are to be performed before study drug is administered. The 12-lead ECGs should be done 
prior to and within 15 minutes of the pre-dose blood sample collection for PK analyses. The time of study drug administration and the time of ECG and blood sample collection 
for PK must be recorded. In addition, 12-lead ECGs and additional PK samples are to be collected at 3 hours (± 30 minutes) after dosing. Similarly, the 12-lead ECG should be 
done prior to and within 15 minutes of the post-dose blood sample collection for PK analyses. The time of study drug administration and the time of ECG and blood sample 
collection for PK must be recorded. The total volume of blood collected is not to exceed the maximal allowable for adults of 10.5 mL/kg or 550 mL, whichever is smaller, over 
any 8-week period. 
p All AEs regardless of seriousness, severity, or causality will be collected from the time the patient provides written informed consent through 30 days (+3 days) after final dose 
of study drug (Study Follow-up TCs, Section 7.4). 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.  
q Patients will be instructed to record what time they went to bed and what time they woke up in the sleep diary during Screening. Eligible patients must have an average of at least 
6 hours of sleep per night for at least 7 of 10 consecutive nights including 2 nights that fall on a weekend during Screening. The average should be taken from all days recorded 
in the patient’s sleep diary. 
r Randomization and dispensing of study drug and study diary will occur after all patient eligibility assessments are conducted, and patient is verified for enrollment. 
s Eligible patients who enter the OLE Phase will be dispensed OLE pitolisant for titration at Visit 5 (Day 77 ±3 days) and will be instructed to take their first dose of open-label 
pitolisant on the following day (Day 78 ±3 days). 
t Patients will be dispensed a study drug dosing diary at the Baseline Visit and will record the number of tablets administered daily (the study drug dosing diary will be used 
during the Double-Blind Treatment Phase of the study only). 
u Eligible patients will be instructed to take study drug once daily in the morning upon wakening starting the day after the Baseline Visit (Day 1); exceptions are on the mornings 
of Visits 3 and 5 when study drug administration will be at the study site (the timing of administration is based on the PK sampling schedule at these visits).  
v For patients enrolling after protocol Amendment 4 was implemented, the MWT is an optional assessment to be conducted only for those patients who provide written informed 
consent. These patients must return to the study site on the day before each scheduled MWT assessment (i.e., the day before the MWT Baseline Visit and the day before the EOT 
MWT assessment in the Double-Blind Treatment Phase [Visit 5]). The MWT baseline assessment may be performed up to 3 days prior to Day 1 to accommodate sleep 
laboratory scheduling and patient availability. If a patient enrolled prior to protocol Amendment 4 (i.e., had the MWT Baseline assessment) the MWT at Week 11 must be 
performed. For EOT (Week 11), patients should take their dose of study drug on the morning of the MWT assessment. The MWT should not be performed on the same day as 
the Visit 5 PK since patients will take their dose of study drug at the site after ECGs and the pre-dose PK blood draw are done. 
w 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. 
x The CGI-S at Screening is required to confirm eligibility for the study. 
y To familiarize patients with the SART, the test will be administered during Screening. 
 
Assessments associated with on-site study visits during the Double-Blind Treatment Phase may be completed remotely or at an alternative location, under the oversight of the 
Investigator, as detailed in Section 6.5. 


Protocol No: HBS-101-CL-005, Amendment 5 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
 
 
18  
Confidential 
SCHEDULE OF ASSESSMENTS, OPEN-LABEL EXTENSION PHASE 
 
3-Week Titration Perioda 
Day 78 to 98 
OLE Long-Term Dosing Periodb 
Day 99 to End of Study 
 
 
 
 
Week 12 
Week 13 
Week 14 
Week 15 
Months 6 and 12 
Month 9  
 
 
 
Visit/TC 
Study Day 
Day 78c 
(±3 days) 
TC 4 
Day 85 
(±3 days) 
TC 5 
Day 92 
(±3 days) 
VISIT 6 
Day 99 
(±3 days) 
Telephone Contactsd 
Days 189 (Month 6/TC 
6), 369 (Month 12/TC 7) 
(±7 days) 
VISIT 7 
Day 279/Month 9  
(±7 days) 
VISIT 8/ 
EOT 
(Day 459/ 
Month 15)/ 
ET Visite 
(±7 days) 
Safety 
F-Upf 
TC 
Unsch 
visitsg 
Urine pregnancy test 
(FCBP) 
 
 
 
X 
 
X 
X 
 
 
Urine drug screen 
 
 
 
X 
 
X 
 
 
 
Full physical examination 
 
 
 
X 
 
X 
X 
 
 
Body weight 
 
 
 
X 
 
X 
X 
 
 
Clinical laboratory tests 
 
 
 
X 
 
X 
X 
 
 
Vital signsh 
 
 
 
X 
 
X 
X 
 
 
12-lead ECG (in triplicate)i 
 
 
 
X 
 
X 
X 
 
 
Holter monitoringj 
 
 
 
X 
 
 
 
 
 
C-SSRS 
 
X 
X 
X 
X 
X 
X 
 
 
Dispense/confirm receipt of 
study drugk 
 
 
 
X 
X 
X 
 
 
 
Administer/Titrate study 
drugl 
Xa 
X b 
 
 
Study drug 
compliance/accountability 
 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsm 
 
X 
X 
X 
X 
X 
X 
X 
X 
DSS 
 
 
 
X 
 
X 
X 
 
 
FSS 
 
 
 
X 
 
X 
X 
 
 


Protocol No: HBS-101-CL-005, Amendment 5 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
 
 
19  
Confidential 
 
3-Week Titration Perioda 
Day 78 to 98 
OLE Long-Term Dosing Periodb 
Day 99 to End of Study 
 
 
 
 
Week 12 
Week 13 
Week 14 
Week 15 
Months 6 and 12 
Month 9  
 
 
 
Visit/TC 
Study Day 
Day 78c 
(±3 days) 
TC 4 
Day 85 
(±3 days) 
TC 5 
Day 92 
(±3 days) 
VISIT 6 
Day 99 
(±3 days) 
Telephone Contactsd 
Days 189 (Month 6/TC 
6), 369 (Month 12/TC 7) 
(±7 days) 
VISIT 7 
Day 279/Month 9  
(±7 days) 
VISIT 8/ 
EOT 
(Day 459/ 
Month 15)/ 
ET Visite 
(±7 days) 
Safety 
F-Upf 
TC 
Unsch 
visitsg 
Cogstate Detection 
 
 
 
X 
 
X 
X 
 
 
Cogstate Identification 
 
 
 
X 
 
X 
X 
 
 
Cogstate One Back 
 
 
 
X 
 
X 
X 
 
 
MDHI 
 
 
 
X 
 
X 
X 
 
 
ESS 
 
 
 
X 
 
X 
X 
 
 
CGI-S  
 
 
 
X 
 
X 
X 
 
 
PGI-S 
 
 
 
X 
 
X 
X 
 
 
Abbreviations: AE = adverse event; CGI-S = Clinical Global Impression of Severity; C-SSRS = Columbia-Suicide Severity Rating Scale; DM1 = myotonic dystrophy type 1; 
DSS = Daytime Sleepiness Scale; ECG = electrocardiogram; EOS = end of study; EOT = end of treatment; ESS = Epworth Sleepiness Scale; ET = early termination; 
FCBP = female of childbearing potential; FSS = Fatigue Severity Scale; F-Up = follow-up; MDHI = myotonic dystrophy health index; OLE = open-label extension; 
PGI-S = Patient Global Impression of Severity; TC = telephone contact; Unsch = unscheduled. 
 
a Eligible patients who enter the OLE Phase will begin a 3-week 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 in the Double-Blind Treatment Phase (Visit 5; Day 77 ±3 days) and will end on Day 98 (±3 days). All 
patients in the OLE Phase will receive open-label pitolisant and will be titrated to a dose of 35.6 mg (or a maximum dose up to 35.6 mg based on Investigator assessment of 
tolerability). The first day of open-label treatment is on Day 78 (±3 days); pitolisant dose will be titrated on Day 85 (±3 days) and again on Day 92 (±3 days). Patients will 
receive TCs on Days 85 and 92 (±3 days) 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, complete the C-SSRS, and to review/confirm titration of pitolisant 
dose. 
b At the end of the 3-week OLE Titration Period, patients will continue to take open-label pitolisant once daily in the morning upon wakening through the EOS (Long-Term 
Dosing Period). Adjustments to pitolisant dose are permitted as detailed in Section 3.1.2.2. The Open-Label Treatment Period for the OLE Phase will be from Day 99 (±3 days) 
until Day459/Month 15 (Visit 8; EOT) unless the patient withdraws from the study early or the Sponsor elects to terminate the study. 
c Day 78 (±3 days) is the first day of open-label pitolisant treatment; there is no visit or TC required on this day. Eligibility will be confirmed on Day 77/EOT Visit 5 in the 
Double-Blind Treatment Phase. 
d TCs will be 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, complete the C-SSRS, confirm the current dose of study drug and compliance with dosing, and 
confirm shipment/receipt of study drug sufficient for 3 months (i.e., 90 days) of once daily administration. 
e All patients will undergo an EOT Visit. Patients who prematurely discontinue study drug are required to undergo the ET Visit (Section 7.3.2.5). Reasons for discontinuation must 
be recorded. 


Protocol No: HBS-101-CL-005, Amendment 5 
 
Harmony Biosciences, LLC 
Phase 2 Safety and Efficacy Study 
 
 
 
20  
Confidential 
f All patients will receive Safety Follow-up TCs from the study site, 15 (±3) days and 30 (+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. 
g 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 7.5). 
h 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. 
i All 12-lead ECGs are to be performed in triplicate. Perform ECGs after the patient has been resting for at least 5 minutes. Any clinically significant ECG value is to be promptly 
addressed by the Investigator in accordance with the protocol. At Visit 6 (Day 99), the Holter monitor should be placed on the patient and continuous recording started, as the 
12-lead ECG (in triplicate) data are taken from the Holter monitor recording. 
j Patients will have a 24-hour Holter monitor placed at Day 99 (+3 days). A clinically significant Holter monitor value is to be promptly addressed by the Investigator in 
accordance with the protocol.   
k Study drug in a quantity sufficient for 3 months (i.e., 90 days) of once daily administration will be provided to eligible patients every 3 months (90 days) either via mail or at the 
on-site study visits; additional study drug may be dispensed between TCs and on-site visits, if necessary. 
l Eligible patients will take the first dose of open-label pitolisant on Day 78 (+3 days) and will be instructed to take study drug once daily in the morning upon wakening. 
m All AEs regardless of seriousness, severity, or causality will be collected from the time the patient provides written informed consent through 30 days (+3 days) after final dose 
of open-label pitolisant (Safety Follow-up TCs, Section 7.4). 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.  
 
Assessments associated with on-site study visits during the OLE Phase may be completed remotely or at an alternative location, under the oversight of the Investigator, as detailed 
in Section 6.5. 
 
 


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TABLE OF CONTENTS 
SPONSOR SIGNATURE ................................................................................................................2 
INVESTIGATOR AGREEMENT...................................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
SCHEDULE OF ASSESSMENTS, DOUBLE-BLIND TREATMENT PHASE .........................14 
SCHEDULE OF ASSESSMENTS, OPEN-LABEL EXTENSION PHASE ................................18 
TABLE OF CONTENTS ...............................................................................................................21 
LIST OF TABLES .........................................................................................................................27 
LIST OF FIGURES .......................................................................................................................27 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................................................28 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ........................................................31 
SUMMARY OF CHANGES, AMENDMENT 5 ..........................................................................32 
SUMMARY OF CHANGES, AMENDMENT 4 ..........................................................................34 
SUMMARY OF CHANGES, AMENDMENT 3 (ADMINISTRATIVE CHANGE) ..................37 
SUMMARY OF CHANGES, AMENDMENT 3 ..........................................................................39 
SUMMARY OF CHANGES, AMENDMENT 2 ..........................................................................41 
SUMMARY OF CHANGES, AMENDMENT 1 ..........................................................................42 
1. 
INTRODUCTION ......................................................................................................45 
1.1. 
Background Information and Study Rationale ...........................................................45 
1.2. 
Rationale for Study Design .........................................................................................47 
1.3. 
Dose Rationale ............................................................................................................48 
1.4. 
Potential Risks and Benefits .......................................................................................48 
2. 
STUDY OBJECTIVES ..............................................................................................50 
2.1. 
Primary Objective .......................................................................................................50 
2.2. 
Secondary Objectives .................................................................................................50 
3. 
INVESTIGATIONAL PLAN AND ENDPOINTS ....................................................51 
3.1. 
Description of the Study Design .................................................................................51 
3.1.1. 
Overall Study Design ..................................................................................................51 
3.1.1.1. 
Screening Period .........................................................................................................54 
3.1.1.2. 
Double-Blind Treatment Phase ...................................................................................54 
3.1.1.3. 
Open-Label Extension Phase ......................................................................................55 
3.1.2. 
Dose Adjustments .......................................................................................................57 


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Phase 2 Safety and Efficacy Study 
 
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3.1.2.1. 
Double-Blind Treatment Phase ...................................................................................57 
3.1.2.2. 
Open-Label Extension Phase ......................................................................................57 
3.1.3. 
Dose Interruptions ......................................................................................................58 
3.2. 
Study Endpoints ..........................................................................................................58 
3.2.1. 
Efficacy Endpoints ......................................................................................................58 
3.2.1.1. 
Double-Blind Treatment Phase ...................................................................................58 
3.2.1.2. 
Long-Term Effectiveness Endpoints ..........................................................................59 
3.2.2. 
Safety Endpoints .........................................................................................................59 
3.3. 
Study Duration ............................................................................................................59 
4. 
STUDY ENROLLMENT AND WITHDRAWAL ....................................................60 
4.1. 
Study Population .........................................................................................................60 
4.1.1. 
Inclusion Criteria ........................................................................................................60 
4.1.2. 
Exclusion Criteria .......................................................................................................60 
4.2. 
Method of Assigning Patients to Treatment Groups ..................................................63 
4.2.1. 
Procedures for Handling Randomized Subjects 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 .............................................................................64 
4.4.1. 
Patient Withdrawal .....................................................................................................64 
4.4.2. 
Temporary Withdrawal of Study Drug During the Open-Label Extension 
Phase ...........................................................................................................................65 
4.4.3. 
Procedures for Patient Follow-up ...............................................................................65 
4.4.4. 
Withdrawal of Consent for Contact ............................................................................66 
4.4.5. 
Patients Deemed Lost to Follow-up ...........................................................................66 
4.5. 
Patient Replacement ...................................................................................................66 
4.6. 
Study and Patient Completion ....................................................................................66 
4.6.1. 
Study Completion .......................................................................................................66 
4.6.2. 
Patient Completion .....................................................................................................66 
4.7. 
Screen Failures ............................................................................................................67 
5. 
STUDY TREATMENT ..............................................................................................68 
5.1. 
Description of Treatments ..........................................................................................68 
5.1.1. 
Pitolisant (Investigational Product) ............................................................................68 


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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 ...............69 
5.3. 
Storage ........................................................................................................................69 
5.4. 
Study Drug Administration.........................................................................................69 
5.4.1. 
Study Drug Administration During the Double-Blind Treatment Phase....................69 
5.4.2. 
Study Drug Administration During the Open-Label Extension Phase .......................69 
5.5. 
Study Drug Compliance .............................................................................................69 
5.6. 
Study Drug Accountability .........................................................................................70 
5.7. 
Prior and Concomitant Therapy ..................................................................................70 
5.7.1. 
Permitted Concomitant Medications ..........................................................................71 
5.7.2. 
Prohibited Medications ...............................................................................................71 
5.7.3. 
Medications Requiring Adjustment to the Dose of Pitolisant ....................................71 
6. 
STUDY PROCEDURES AND ASSESSMENTS......................................................73 
6.1. 
Medical History and Demographics ...........................................................................73 
6.1.1. 
Medical History ..........................................................................................................73 
6.1.2. 
Demographics .............................................................................................................73 
6.2. 
Efficacy Assessments .................................................................................................73 
6.2.1. 
Daytime Sleepiness Scale ...........................................................................................73 
6.2.2. 
Fatigue Severity Scale ................................................................................................73 
6.2.3. 
Cogstate Computerized Cognitive Battery Tests ........................................................74 
6.2.3.1. 
Cogstate Detection Test (Psychomotor Function) ......................................................74 
6.2.3.2. 
Cogstate Identification Test (Attention) .....................................................................74 
6.2.3.3. 
Cogstate One Back Test (Working Memory) .............................................................74 
6.2.4. 
Myotonic Dystrophy Health Index .............................................................................74 
6.2.5. 
Epworth Sleepiness Scale ...........................................................................................75 
6.2.6. 
Clinical Global Impression of Severity of Excessive Daytime Sleepiness ................75 
6.2.7. 
Patient Global Impression of Severity of Excessive Daytime Sleepiness ..................75 
6.2.8. 
Sustained Attention to Response Task .......................................................................76 
6.2.9. 
Maintenance of Wakefulness Test ..............................................................................76 
6.3. 
Safety Assessments .....................................................................................................76 
6.3.1. 
Adverse Events ...........................................................................................................76 


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Phase 2 Safety and Efficacy Study 
 
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6.3.2. 
Physical Examinations ................................................................................................76 
6.3.3. 
Vital Signs ..................................................................................................................77 
6.3.4. 
Holter Monitoring and 12-Lead Electrocardiograms .................................................77 
6.3.4.1. 
Holter Monitoring .......................................................................................................77 
6.3.4.2. 
12-Lead Electrocardiograms .......................................................................................78 
6.3.5. 
Clinical Laboratory Tests ...........................................................................................78 
6.3.6. 
Additional Safety Assessments...................................................................................80 
6.4. 
Pharmacokinetic Assessments ....................................................................................80 
6.5. 
Potential Use of Alternative Methods for Completing Study Assessments ...............80 
6.5.1. 
Assessments that may be Completed Remotely .........................................................81 
6.5.2. 
Assessments that may be Completed at the Patient’s Home ......................................81 
6.5.3. 
Other Considerations ..................................................................................................81 
7. 
TIMING OF PROCEDURES AND ASSESSMENTS ..............................................83 
7.1. 
Screening (Visit 1) ......................................................................................................83 
7.2. 
Double-Blind Treatment Phase (Day -1 to Day 77) ...................................................84 
7.2.1. 
Baseline Visit (Visit 2; Day -3 to Day -1) ..................................................................84 
7.2.2. 
Titration Period, Double-Blind Phase (Days -1 to 21) ...............................................85 
7.2.3. 
Telephone Contacts (TC 1 and TC 2) (Days 8 and 15 ±3 Days) ................................85 
7.2.4. 
Stable Dose Period, Double-Blind Phase (Days 22 to 77) .........................................85 
7.2.4.1. 
Visit 3 (Day 22 ±3 Days) ............................................................................................85 
7.2.4.2. 
Telephone Contact (TC 3) (Day 28 ±3 Days) ............................................................86 
7.2.4.3. 
Visit 4 (Day 49 ±3 Days) ............................................................................................86 
7.2.4.4. 
Visit 5 (Day 77 ±3 Days); End-of-Treatment in the Double-Blind Treatment 
Phase ...........................................................................................................................87 
7.2.5. 
Early Termination Visit for Double-Blind Treatment Phase ......................................89 
7.3. 
Open-Label Extension Phase (Day 78 to End-of-Treatment) .....................................89 
7.3.1. 
Titration Period; Open-Label Extension Phase (Days 78 to Day 98) .........................89 
7.3.2. 
Long-Term Dosing Period, Open-Label Extension Phase (Day 99 to End of 
Treatment) ...................................................................................................................89 
7.3.2.1. 
Visit 6 (Day 99 ±3 Days) ............................................................................................90 
7.3.2.2. 
Telephone Contacts; Day 189 (±7 Days; TC 6) and Day 369 (±7 days; TC 7)..........90 
7.3.2.3. 
Visit 7 (Day 279 [±7 Days]) .......................................................................................91 
7.3.2.4. 
Visit 8/End-of-Treatment Visit for the Open-Label Extension Phase ........................92 


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Phase 2 Safety and Efficacy Study 
 
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7.3.2.5. 
Early Termination Visit for the Open-Label Extension Phase ...................................92 
7.4. 
Safety Follow-Up Telephone Contacts .......................................................................92 
7.5. 
Unscheduled Visits and Assessments .........................................................................92 
8. 
SAFETY MONITORING AND REPORTING .........................................................94 
8.1. 
Definition of Safety Parameters..................................................................................94 
8.1.1. 
Definition of an Adverse Event ..................................................................................94 
8.1.2. 
Definition of a Serious Adverse Event .......................................................................95 
8.1.3. 
Definition of a Suspected Adverse Reaction ..............................................................95 
8.1.4. 
Definition of a Serious Suspected Adverse Reaction .................................................96 
8.1.5. 
Definition of Unanticipated Problems ........................................................................96 
8.2. 
Classification of Adverse Events ................................................................................96 
8.2.1. 
Severity of Adverse Events ........................................................................................96 
8.2.2. 
Relationship to Study Drug ........................................................................................96 
8.3. 
Time Period and Frequency for Adverse Event Assessment and Follow-up .............97 
8.3.1. 
Adverse Event and Serious Adverse Event Monitoring .............................................97 
8.3.2. 
Follow-up of Events ...................................................................................................97 
8.4. 
Reporting Procedures ..................................................................................................98 
8.4.1. 
Reporting Serious Adverse Events to the Sponsor .....................................................98 
8.4.2. 
Reporting Unanticipated Problems to the Sponsor .....................................................99 
8.4.3. 
Regulatory Reporting Requirements ..........................................................................99 
8.4.4. 
Pregnancy Reporting ................................................................................................100 
9. 
STATISTICAL CONSIDERATIONS .....................................................................101 
9.1. 
General Considerations .............................................................................................101 
9.1.1. 
Estimand ...................................................................................................................101 
9.1.2. 
Multiple Comparisons ..............................................................................................101 
9.1.3. 
Missing Data .............................................................................................................101 
9.2. 
Determination of Sample Size ..................................................................................101 
9.3. 
Analysis Populations ................................................................................................102 
9.3.1. 
Modified Intent-to-Treat Population .........................................................................102 
9.3.2. 
Double-Blind Safety Population ...............................................................................102 
9.3.3. 
Open-Label Safety Population ..................................................................................102 
9.3.4. 
Pharmacokinetic Population .....................................................................................102 
9.4. 
Statistical Analysis Methods.....................................................................................102 


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Phase 2 Safety and Efficacy Study 
 
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9.4.1. 
Disposition and Demographics .................................................................................102 
9.4.2. 
Efficacy Analysis ......................................................................................................103 
9.4.2.1. 
Double-Blind Treatment Phase .................................................................................103 
9.4.2.2. 
Open-Label Extension Analyses ...............................................................................103 
9.4.3. 
Safety Analysis .........................................................................................................103 
9.4.4. 
Pharmacokinetic Analyses ........................................................................................104 
9.5. 
Interim Analysis ........................................................................................................104 
10. 
QUALITY ASSURANCE AND QUALITY CONTROL .......................................105 
11. 
REGULATORY AND ETHICAL CONSIDERATIONS ........................................106 
11.1. 
Regulatory Authority Approval ................................................................................106 
11.2. 
Ethical Conduct of the Study ....................................................................................106 
11.3. 
Institutional Review Board/Ethics Committee Approval .........................................106 
11.4. 
Informed Consent Process ........................................................................................106 
11.5. 
Confidentiality ..........................................................................................................107 
12. 
STUDY ADMINISTRATION .................................................................................109 
12.1. 
Clinical Monitoring ..................................................................................................109 
12.2. 
Management of Protocol Amendments and Deviations ...........................................109 
12.2.1. 
Protocol Modification ...............................................................................................109 
12.2.2. 
Protocol Violations and Deviations ..........................................................................109 
12.3. 
Financial Disclosure .................................................................................................110 
12.4. 
Suspension or Termination of Study or Investigational Site ....................................110 
12.4.1. 
Suspension of Study .................................................................................................110 
12.4.2. 
Termination of Study or Investigational Site ............................................................110 
12.5. 
Publication and Information Disclosure Policy ........................................................110 
13. 
REFERENCE LIST ..................................................................................................112 
APPENDIX A. PATIENT SLEEP DIARY FOR SCREENING (EXAMPLE) .......................117 
APPENDIX B. PATIENT STUDY DRUG DOSING DIARY FOR DOUBLE-BLIND 
TREATMENT PHASE (EXAMPLE) ......................................................................118 
APPENDIX C. COLUMBIA-SUICIDE SEVERITY RATING SCALE-LIFETIME 
RECENT ...................................................................................................................122 
APPENDIX D. COLUMBIA-SUICIDE SEVERITY RATING SCALE-SINCE LAST 
CONTACT ...............................................................................................................125 


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Phase 2 Safety and Efficacy Study 
 
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APPENDIX E. EXAMPLES OF STRONG CYP2D6 INHIBITORS, STRONG 
CYP3A4 INDUCERS, MEDICATIONS THAT PROLONG QT 
INTERVAL, AND CENTRALLY ACTING H1R ANTAGONISTS ......................128 
APPENDIX F. DAYTIME SLEEPINESS SCALE (DSS) .......................................................129 
APPENDIX G. FATIGUE SEVERITY SCALE (FSS) ............................................................130 
APPENDIX H. MYOTONIC DYSTROPHY HEALTH INDEX (MDHI) ..............................131 
APPENDIX I. EPWORTH SLEEPINESS SCALE (ESS) .......................................................137 
APPENDIX J. CLINICAL GLOBAL IMPRESSION OF SEVERITY (CGI-S) FOR 
EXCESSIVE DAYTIME SLEEPINESS .................................................................138 
APPENDIX K. PATIENT GLOBAL IMPRESSION OF SEVERITY (PGI-S) FOR 
EXCESSIVE DAYTIME SLEEPINESS .................................................................139 
 
LIST OF TABLES 
Table 1: 
Summary of Changes for Amendment 5 ....................................................................32 
Table 2: 
Summary of Changes for Amendment 4 ....................................................................34 
Table 3: 
Summary of Changes for Amendment 3 ....................................................................39 
Table 4: 
Summary of Changes for Amendment 2 ....................................................................41 
Table 5: 
Summary of Changes for Amendment 1 ....................................................................42 
Table 6: 
Study Drug Dosing in the Double-Blind Treatment Phase ........................................54 
Table 7: 
Pitolisant Dosing in the Open-Label Extension Phase ...............................................56 
Table 8: 
Clinical Laboratory Tests ...........................................................................................79 
Table 9: 
Estimated Total Blood Draw Volumes on Pharmacokinetic Sampling Days ............80 
Table 10: Alternative Methods for Completing Study Assessments ..........................................81 
 
LIST OF FIGURES 
Figure 1: 
Overall Study Design ..................................................................................................52 
 


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Phase 2 Safety and Efficacy Study 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
AF 
Atrial fibrillation 
APC 
Atrial premature complex 
ASP 
Average sleep propensity 
AVB 
Atrioventricular block 
BiPAP 
Bilevel Positive Airway Pressure 
bpm 
Beats per minute 
CGI-S 
Clinical Global Impression of Severity  
cGCP 
Current Good Clinical Practice 
CNS 
Central nervous system 
COVID-19 
Coronavirus disease 2019 
CPAP 
Continuous Positive Airway Pressure 
CSF 
Cerebrospinal fluid 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CSR 
Clinical study report 
CTG 
Cytosine-thymine-guanine 
CUG 
Cytosine-uracil-guanine 
CV 
Cardiovascular 
CYP 
Cytochrome P450 
DM 
Myotonic dystrophy 
DM1 
Myotonic dystrophy type 1 
DMC 
Data Monitoring Committee 
DMPK 
Dystrophia myotonica protein kinase 
DNA 
Deoxyribonucleic acid 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
DSS 
Daytime Sleepiness Scale 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 


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Phase 2 Safety and Efficacy Study 
 
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EDS 
Excessive daytime sleepiness 
eGFR 
Estimated glomerular filtration rate 
EOT  
End-of-Treatment 
ESRD 
End-stage renal disease 
ESS 
Epworth Sleepiness Scale 
ET 
Early Termination 
EU 
European Union 
FCBP 
Female of child-bearing potential 
FDA 
Food and Drug Administration 
FSS 
Fatigue Severity Scale 
GCP 
Good Clinical Practice 
H1R 
Histamine 1 receptor 
H3R 
Histamine 3 receptor 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Heart rate 
HST 
Home Sleep Test 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ID 
Identification 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
LOE 
Lack of effect 
LSM 
Least square mean 
MAR 
Missing at random 
MDHI 
Myotonic Dystrophy Health Index 
mITT 
Modified intent-to-treat  
mRNA 
Messenger ribonucleic acid 
MSL 
Mean sleep latency 
MWT 
Maintenance of Wakefulness Test 
NINDS 
National Institute of Neurological Disorders and Stroke  


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NYHA 
New York Heart Association 
OLE 
Open-Label Extension 
PGI-S 
Patient Global Impression of Severity 
OSA 
Obstructive sleep apnea 
PK 
Pharmacokinetic 
PM 
Poor metabolizer 
PVC 
Premature ventricular contraction 
QTc 
Corrected QT interval 
QTcF 
Corrected QT interval using Fridericia’s formula 
RNA 
Ribonucleic acid 
RT 
Reaction time 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SART 
Sustained Attention to Response Task 
SD 
Standard deviation 
SOP 
Standard operating procedure 
SOREMP 
Sleep-onset rapid eye movement period 
TC 
Telephone contact 
TEAE 
Treatment-emergent adverse event 
tmax 
Time of maximum concentration 
US 
United States 
USP 
United States Pharmacopeia 
VT 
Ventricular tachycardia 
Note: Abbreviations used only in tables, figures, or an appendix are defined in the table or figure footnotes or the 
appendix. 
 
 
 
 
 


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Phase 2 Safety and Efficacy Study 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document History 
Effective Date 
Protocol Amendment 5 
18JUL2023 
Protocol Amendment 4 
15JUN2022 
Protocol Amendment 3, Administrative letter 
18JAN2022 
Protocol Amendment 3 
18NOV2021 
Protocol Amendment 2 
11AUG2021 
Protocol Amendment 1 
20MAR2021 
Original Protocol 
19DEC2020 
 


Protocol No: HBS-101-CL-005, Amendment 5 
 
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SUMMARY OF CHANGES, AMENDMENT 5  
Table 1 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.), and in the 
table of contents, list of abbreviations and definitions of terms, schedules of assessments, 
references, and synopsis are not listed.   
The protocol was primarily amended to revise the anticipated sample size from 78 to 30 patients 
and to revise the planned statistical analyses. 
Table 1: 
Summary of Changes for Amendment 5  
Section Number 
Section Title 
Description of Change 
Rationale 
Global 
Decreased the anticipated sample size from 78 to 
30 patients. 
Removed the Z-score (based on aggregation of 
the DSS and the MWT scores) as an exploratory 
endpoint. 
Sponsor decision. 
Revised the descriptors of the pitolisant 
treatment groups from 'low dose' (17.8 mg) and 
'high dose' (35.6 mg) to 'lower dose' and 'higher 
dose', respectively, because both doses are 
consistent with the FDA-approved prescribing 
information. 
Revised the primary efficacy endpoint to 
indicate that the change in DSS score (not 
change in mean DSS score) will be the primary 
efficacy endpoint. 
Clarification. 
Section 4.2  
Method of Assigning 
Patients to Treatment 
Groups 
Added stratification factor of concomitant use of 
wake-promoting agents. 
Clarification. 
Section 9.1.1  
Estimand 
 
Revised to indicate the mITT population will be 
the population used for the efficacy analyses; 
also retitled Section 9.3.1 to Modified Intent-to-
Treat Population. 
Clarification. 
Section 9.1.2  
Multiple Comparisons 
Revised to indicate all statistical analyses will be 
descriptive. 
Clarification. 
Section 9.1.3  
Missing Data 
Removed the sensitivity analyses for this 
exploratory study; also deleted Sensitivity 
Analyses section (previously Section 9.4.2.1.2). 
Sponsor decision. 
Section 9.3.5 (removed) 
MWT Population 
Removed the MWT population due to the 
limited number of patients (≤30 patients) with 
data for this measure (based on the change made 
in Amendment 4). 
Sponsor decision. 


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Phase 2 Safety and Efficacy Study 
 
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Section Number 
Section Title 
Description of Change 
Rationale 
Section 9.4.2.1.1  
Primary Efficacy Analysis 
Revised to indicate that change from Baseline 
will be analyzed by MMRM, not ANCOVA. 
Sponsor decision. 
Section 9.4.2.2  
Open-Label Extension 
Analysis 
Removed the specification of how the Open-
Label Extension Phase data will be summarized. 
Sponsor decision. 
Section 9.4.4  
Pharmacokinetic Analyses 
Revised to indicate concentration-time data will 
be summarized. 
Clarification. 
Section 12.3  
Financial Disclosure 
Revised to align with updated protocol template. 
Sponsor decision. 
ANCOVA = analysis of covariance; DSS = Daytime Sleepiness Scale; FDA = Food and Drug Administration; 
mITT = modified intent-to-treat population; MMRM = mixed model repeated measures; MWT = Maintenance of 
Wakefulness Test 
 


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Phase 2 Safety and Efficacy Study 
 
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SUMMARY OF CHANGES, AMENDMENT 4  
Table 2 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.), and in the 
table of contents, list of abbreviations and definitions of terms, schedules of assessment, and 
synopsis are not listed.   
The protocol was primarily amended to replace the Maintenance of Wakefulness Test (MWT) as 
the primary endpoint measure with the Daytime Sleepiness Scale (DSS); the MWT assessment 
was made optional for patients. 
Table 2: 
Summary of Changes for Amendment 4 
Section Number 
Section Title 
Description of Change 
Rationale 
Section 1.2  
Rationale for Study 
Design 
 
 
 
 
 
  
MWT assessment changed to optional. 
Sponsor decision.  
Section 2.2  
Secondary Objectives 
Inserted “selected domains” of cognitive function 
to reflect that not all domains of cognitive function 
will be assessed. 
Clarification.  
Section 3.1.1  
Overall Study Design 
Updated Figure 1 with the study design changes. 
Provided instructions for timing of PK, ECG, and 
MWT procedures. 
To align with other 
changes. 
Clarification. 
Section 3.1.1.1  
Screening Period 
Specified requirements for recording sleep per 
night in the sleep diary. 
Sponsor decision. 
Section 3.1.1.2  
Double-Blind Treatment 
Phase 
Updated text to reflect that the MWT assessment 
is now optional for which patients provide 
informed consent; provided timing for this 
assessment. 
Clarification based 
on MWT now being 
optional. 
Section 3.2.1.1.1  
Primary Efficacy 
Endpoint 
Replaced MWT with DSS as the primary endpoint 
measure. 
Sponsor decision. 
Section 3.2.1.1.2  
Secondary Efficacy 
Endpoints 
Removed the DSS and Z-score (based on 
aggregation of the DSS and the MWT scores) as 
secondary efficacy endpoints. 
Sponsor decision; to 
align with the 
endpoint change. 
Section 3.2.1.1.3  
Exploratory Endpoints 
Added new section to designate the MWT and 
related Z-score endpoints now as exploratory 
endpoints. 
Sponsor decision; to 
align with the 
endpoint change. 


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Phase 2 Safety and Efficacy Study 
 
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Section Number 
Section Title 
Description of Change 
Rationale 
Section 4.1.1  
Inclusion Criteria 
Inclusion Criterion #2: updated to specify that 
genetic testing is completed at the Screening Visit. 
Previous Inclusion Criterion #5: deleted as MWT 
is no longer required. 
Inclusion Criterion #5 (previously #6): removed 
the unnecessary washout period of 14 days. 
Clarification. 
 
To align with change 
to MWT. 
Clarification. 
Section 4.1.2  
Exclusion Criteria 
Exclusion Criterion #1: updated to specify another 
genetic disorder that is not adequately managed. 
Exclusion Criterion #2: updated to specify the 
requirements for recording sleep per night. 
Exclusion Criterion #6: updated the specified 
washout period for investigational medication. 
Exclusion Criterion #8: added that antidepressants 
that are strong CYP2D6 inhibitors are 
exclusionary. 
Exclusion Criterion #12: specified cardiac death as 
sudden cardiac death. 
Exclusion Criterion #16: updated to allow patients 
with 1st degree AVB with an implanted device. 
Exclusion Criterion #23: added that centrally 
acting H1R antagonists are sedating 
antihistamines; removed the unnecessary washout 
of one week. 
Previous Exclusion Criterion #24: deleted 
redundant criterion regarding medications 
prolonging the QT interval. 
Exclusion Criterion #25 (previously #24): updated 
prohibited use of sleep-promoting agents from one 
week to one day prior to study-related 
assessments. 
Clarification. 
 
Clarification. 
 
Clarification. 
 
Clarification. 
 
Clarification based 
on KOL and 
Investigator 
feedback. 
Clarification. 
 
Clarification. 
 
 
Clarification. 
 
 
Sponsor decision. 
Section 4.3  
Blinding 
Removed text regarding the DMC as there is no 
longer an interim analysis. 
Sponsor decision. 
Section 5.7.1  
Permitted Concomitant 
Medications 
Added that wake promoting agents prescribed to 
treat EDS are permitted, and the use of hypnotics 
is allowed up to 2 nights per week but not the 
night prior to any efficacy assessment.  
Sponsor decision. 
Section 5.7.2  
Prohibited Medications 
Removed the unnecessary reference to a washout 
of one week; added that centrally acting H1R 
antagonists are sedating antihistamines. 
Clarifications. 
Section 6.2  
Efficacy Assessments 
Moved the MWT sub-section to the end of the 
main section as it is now optional. 
To align with other 
changes. 


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Section Number 
Section Title 
Description of Change 
Rationale 
Section 6.3.4.1  
Holter Monitoring  
Added the timing for placing the Holter monitor, 
and that the ECG is taken from the Holter monitor 
recording; change made throughout the protocol. 
Clarification. 
Section 6.3.4.2  
12-Lead 
Electrocardiograms 
Specified timing of ECG assessments related to 
PK blood draws; change made throughout the 
protocol. 
Clarification. 
Section 6.3.5   
Clinical Laboratory Tests 
Added that wake promoting agents prescribed to 
treat EDS are permitted. 
Noted in Table 8 additional information regarding 
a urine drug screen that is positive for 
amphetamines. 
Clarification. 
Section 6.5.2  
Assessments that may be 
Completed at the 
Patient’s Home 
Added cross reference to Table 10 for other 
assessments that may be completed at the patient’s 
home.  
Clarification. 
Section 6.5.3  
Other Considerations 
Removed MWT as it is no longer the primary 
endpoint measure, and the assessment is now 
optional. 
To align with 
previous changes. 
Section 7.2.1  
Baseline Visit (Visit 2; 
Day -3 to Day -1) 
Removed requirement to complete the MWT as it 
is now optional and not part of the eligibility 
criteria. 
Added information regarding the optional MWT. 
Updated timing of patient receipt of study drug. 
To align with 
previous changes. 
 
Clarification. 
Section 7.2.4.1  
Visit 3 (Day 22 ±3 Days) 
Specified the timing for placement of the Holter 
monitor, collection of ECG data, and collection of 
blood for PK analyses. 
Updated text for patients’ receipt of study drug. 
Clarification. 
 
 
Clarification. 
Section 7.2.4.3  
Visit 4 (Day 49 ±3 Days) 
Updated text for patients’ receipt of study drug. 
Clarification. 
Section 7.2.4.4  
Visit 5 (Day 77 ±3 
Days); End-of-Treatment 
in the Double-Blind 
Treatment Phase 
Specified the timing for collection of ECG data 
relative to collection of blood for PK analyses. 
Added information regarding the optional MWT. 
Removed requirement for Holter monitoring for 
entering the OLE Phase of the study. 
Clarification. 
 
To align with 
previous changes. 
Sponsor decision. 
Section 7.2.5  
Early Termination Visit 
for Double-Blind 
Treatment Phase 
Specified that patients who discontinue from the 
Double-Blind Treatment Phase of the study prior 
to Day 77 may not enroll in the OLE Phase of the 
study. 
Sponsor decision. 
Section 9.1.1  
Estimand 
Specified the change in primary endpoint measure 
from MWT to DSS. 
Sponsor decision.  


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Section Number 
Section Title 
Description of Change 
Rationale 
Specified a treatment policy strategy will be 
utilized to address intercurrent events, with data 
analyzed as reported. 
Section 9.1.2  
Multiple Comparisons 
Specified DSS as the primary endpoint measure 
and how p-values will be reported for secondary 
and exploratory endpoints. 
To align with change 
to the primary 
endpoint measure. 
Section 9.1.3  
Missing Data 
Added text related to the primary analysis and for 
a sensitivity analysis utilizing an MI approach. 
Sponsor decision 
related to the 
statistical approach. 
Section 9.2  
Determination of Sample 
Size 
Specified details related to the change in sample 
size. 
To align with change 
to the primary 
endpoint measure. 
Section 9.3.5   
MWT Population 
Added section to define the MWT Population as 
not all patients will complete MWT assessments. 
To align with the 
decision to change 
the MWT assessment 
to optional and an 
exploratory endpoint. 
Section 9.4.2.1.1  
Primary Efficacy 
Analysis 
Removed text related to the blinded interim 
analysis. 
Sponsor decision. 
Section 9.4.2.1.2 
Sensitivity Analyses 
Specified four instead of three sensitivity analyses 
(added an ANCOVA model for data imputed 
using MI).  
Sponsor decision 
related to the 
statistical approach. 
Section 9.4.2.1.2  
Secondary Efficacy 
Analysis 
Removed text related to an interim analysis. 
Sponsor decision. 
Section 9.5  
Interim Analysis 
Removed text related to an interim analysis. 
Sponsor decision. 
Appendix E  
Updated the list of prohibited medications and 
added centrally acting to the H1R antagonist 
medication type. 
To provide additional 
information and 
clarity. 
ANCOVA = analysis of covariance; AVB = atrioventricular block; CYP = cytochrome P450; DMC = Data 
Monitoring Committee; DSS = Daytime Sleepiness Scale; ECG = electrocardiogram; EDS = excessive daytime 
sleepiness; H1R = histamine 1 receptor; MI = multiple imputation; MWT = Maintenance of Wakefulness Test; 
OLE = open-label extension; PK = pharmacokinetic 
 
SUMMARY OF CHANGES, AMENDMENT 3 (ADMINISTRATIVE 
CHANGE) 
Minor updates regarding timing of Holter monitoring at Visit 3 (Section 7.2.4.1) and removing 
reference to Holter monitoring at Visit 5 (Section 7.2.4.4) were made as an administrative 


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change to the protocol and were sent to Investigators in a letter dated 18 January 2022. These 
updates were for clarity and accuracy and have been incorporated in protocol Amendment 4. 


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SUMMARY OF CHANGES, AMENDMENT 3  
Table 3 describes the changes made in Amendment 3 of the protocol (dated 18 November 2021). 
Changes related to punctuation and formatting (i.e., changes in numbering, word order, location, 
etc.) in the table of contents, list of abbreviations and definitions of terms, and synopsis are not 
listed.   
The protocol was amended primarily to update the eligibility criterion for excessive daytime 
sleepiness (EDS); specifically, assessment via the Epworth Sleepiness Scale (ESS) was replaced 
with assessment via the CGI-S for EDS. 
Table 3: 
Summary of Changes for Amendment 3 
Section Number 
Section Title 
Description of Change 
Rationale 
Section 1.2  
Rationale for Study Design 
Added DSS as an assessment for evaluating 
sleepiness. 
Expert and Investigator 
feedback; Sponsor decision. 
Section 3.1.1.1  
Screening Period 
Specified that the 7 nights recorded in the 
sleep diary need to be consecutive nights. 
Removed reference to determination of 
AHI/RDI. 
Clarification. 
 
No longer required per 
Investigator feedback and 
Sponsor decision. 
Section 3.1.1.2  
Double-Blind Treatment 
Phase 
Removed reference to ESS at Baseline as a 
requirement to confirm eligibility for the 
study. 
To align with the change to 
eligibility criterion related to 
EDS. 
Section 3.2.1.1.2  
Secondary Efficacy 
Endpoints 
Added DSS as first in the list of secondary 
endpoints and moved ESS to below the 
MDHI. 
Replaced ESS with DSS in the z-score. 
Expert and Investigator 
feedback; Sponsor decision. 
 
To align with adding the 
DSS. 
Section 3.2.1.2  
Long-Term Effectiveness 
Endpoints 
Moved the ESS assessment to be listed after 
the MDHI assessment. 
For consistency with the 
double-blind phase of the 
study. 
Section 4.1.1  
Inclusion Criteria 
Updated the eligibility criterion for EDS from 
assessment via ESS to assessment via CGI-S. 
Investigator feedback related 
to ESS for this patient 
population; Sponsor decision 
to replace with CGI-S. 
Section 4.1.2  
Exclusion Criteria 
Exclusion Criterion #2: Specified that the 
minimum of 7 nights recorded in the sleep 
diary need to be consecutive nights. 
Exclusion Criterion #9: Combined with 
exclusion criterion #10 and removed 
requirement for determination of AHI/RDI. 
Exclusion Criterion #17: Removed second 
reference to non-sustained VT. 
Clarification. 
 
 
Investigator feedback and 
Sponsor decision to 
streamline criteria related to 
underlying sleep disorders. 
Corrected redundancy. 


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Phase 2 Safety and Efficacy Study 
 
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Section Number 
Section Title 
Description of Change 
Rationale 
Section 6.2  
Efficacy Assessments 
Added DSS with a description of the 
instrument (now Section 6.2.1). 
Reordered ESS to Section 6.2.5. 
Expert and Investigator 
feedback; Sponsor decision. 
For consistency. 
Section 6.2.5  
Epworth Sleepiness Scale 
Removed reference to the ESS being a self-
administered assessment. 
Investigator feedback. 
Section 6.5.3  
Other Considerations 
Table 10  
Added DSS to the list of assessments in 
Table 10 (Alternate Methods for Completing 
Study Assessments). 
For consistency. 
Section 7.1  
Screening (Visit 1) 
Removed the ESS from Screening. 
 
Added the CGI-S assessment as an evaluation 
done at Screening. 
Removed reference to determination of 
AHI/RDI. 
Expert and Investigator 
feedback. 
To align with the change to 
eligibility criterion for EDS. 
To align with the change to 
exclusion criteria #9 and #10. 
Section 7.2  
Double-Blind Treatment 
Phase (Day -1 to Day 77) 
Section 7.3  
Open-Label Extension 
Phase (Day 78 to End-of-
Treatment) 
Added DSS as the first efficacy assessment 
following MWT and moved ESS to occur 
after the MDHI for all on-site study visits 
(visits 4-7). 
Expert and Investigator 
feedback; Sponsor decision. 
Section 7.2.1  
Baseline Visit (Visit 2; 
Day -1 ± 2 Days) 
Removed reference to ESS at Baseline as a 
requirement to confirm eligibility for the 
study. 
To align with the change to 
eligibility criterion related to 
EDS. 
Section 8.4.1  
Reporting Serious Adverse 
Events to the Sponsor 
Removed reference to telephone notification 
for reporting SAEs. 
Clarification. 
Section 9.1.1  
Estimand 
 
 
 
Section 9.1.2  
Multiple Comparisons 
 
 
 
 
Section 9.1.3  
Missing Data 
 
 
 
 
Section 9.4.2.1.1  
Primary Efficacy Analysis 
 
 
 
 
 
 


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Section Number 
Section Title 
Description of Change 
Rationale 
Section 9.4.2.1.2 
Sensitivity Analyses 
 
 
 
 
CGI-S = Clinical Global Impression of Severity; EDS = excessive daytime sleepiness; ESS = Epworth Sleepiness 
Scale; DSS = Daytime Sleepiness Scale; MDHI = Myotonic Dystrophy Health Index; MWT = Maintenance of 
Wakefulness Test; SAE = serious adverse event; VT = ventricular tachycardia 
 
SUMMARY OF CHANGES, AMENDMENT 2  
Table 4 describes the changes made in Amendment 2 of the protocol (dated 11 August 2021). 
Changes related to punctuation and formatting (i.e., changes in numbering, word order, location, 
etc.) in the table of contents, list of abbreviations and definitions of terms, and synopsis are not 
listed.   
The protocol was amended based on the addition of sites in Canada. 
Table 4: 
Summary of Changes for Amendment 2 
Section Number 
Section Title 
Description of Change 
Rationale 
Section 1.2  
Rationale for Study Design 
Defined the end of the OLE Phase of the study 
for enrolled patients as Day 459/Month 15 
(Visit 8); change also made throughout the 
protocol. 
Sponsor decision. 
Section 3.1.1  
Overall Study Design 
Section 3.1.1.3  
Open-Label Extension 
Phase 
Defined the end of the OLE Phase of the study 
for enrolled patients as Day 459/Month 15 
(Visit 8);  
Updated Figure 1 (Overall Study Design) 
accordingly; 
Specified the day/month/visit for EOT. 
Sponsor decision; additional 
details for defining the end 
of the OLE Phase for 
patients made for clarity. 
Section 3.3  
Study Duration 
Updated based on defining the end of the OLE 
Phase for enrolled patients. 
Sponsor decision. 
Section 4.1  
Study Population 
Updated approximate number of sites from 16 
to 22 and added that the study will include sites 
in Canada. 
Sponsor decision. 
Section 4.1.2  
Exclusion Criteria 
Exclusion Criterion #9: Changed AHI/RDI 
exclusion from >10 to >15 (which reflects 
unmanaged OSA). 
Investigator feedback. 
Section 4.6.1  
Study Completion 
Section 4.6.2  
Patient Completion 
Defined the end of the OLE Phase of the study 
for enrolled patients; 
Defined completion for patients in the OLE 
Phase of the study. 
Sponsor decision; additional 
details for defining the end 
of the OLE Phase for 
patients made for clarity. 


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Section Number 
Section Title 
Description of Change 
Rationale 
Section 4.7  
Screen Failures 
Clarified the requirements for patients who re-
screen following screen failure. 
Clarification. 
Section 6.5  
Potential Use of Alternative 
Methods for Completing 
Study Assessments 
Updated section throughout to allow for 
specific assessments/procedures to be 
conducted remotely via telemedicine or at the 
patient’s home, no longer just due to 
restrictions related to COVID-19. 
Investigator feedback and 
Sponsor decision, to allow 
for greater flexibility and 
potentially decrease patient 
burden related to travel to 
the study site. 
Section 7.3  
Open-Label Extension 
Phase (Day 78 to End-of-
Treatment) 
Updated throughout section to define the end 
of the OLE Phase of the study for enrolled 
patients. 
Sponsor decision. 
Section 9.1.3  
Missing Data 
Section 9.4.2.1.1  
Primary Efficacy Analysis 
 
 
AHI = apnea hypoxia index; COVID-19 = coronavirus disease 2019; EOT = End-of-Treatment; OLE = open-label 
extension; OSA = obstructive sleep apnea; RDI = respiratory disturbance index 
 
SUMMARY OF CHANGES, AMENDMENT 1  
Table 5 describes the changes made in Amendment 1 of the protocol (dated 20 March 2021). 
Changes related to punctuation and formatting (i.e., changes in numbering, word order, location, 
etc.) in the table of contents, list of abbreviations and definitions of terms, and synopsis are not 
listed.   
   
Table 5: 
Summary of Changes for Amendment 1 
Section Number 
Section Title 
Description of Change 
Rationale 
Section 3.1.1.1  
Screening Period 
 
 
 
Section 3.1.1.2  
Double-Blind 
Treatment Phase 
Specified that both the Baseline ESS and MWT 
results are needed to confirm eligibility and the 
timing for these related to dispensing study drug. 
Clarification. 
Section 4.1  
Study Population 
 
 
 


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Phase 2 Safety and Efficacy Study 
 
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Section Number 
Section Title 
Description of Change 
Rationale 
Section 4.1.1  
Inclusion Criteria 
 
Inclusion Criterion #6: Updated to define 
parameters for patients on wake-promoting 
treatments that could affect EDS and moved use of 
sleep-promoting treatments to exclusion criteria. 
Inclusion Criterion #7: Restated serum potassium 
and magnesium levels as an exclusion criterion 
(#23); restated ability to ambulate as an inclusion 
criterion. 
 
 
Based on investigator 
feedback. 
 
 
For clarity, based on 
investigator feedback. 
Section 4.1.2  
Exclusion Criteria 
 
 
 
 
 
 
Exclusion Criterion #8: Added exclusion for 
patients not on a stable dose of their 
antidepressant(s). 
Exclusion Criterion #9: Updated AHI and RDI 
indices to >10 (from >5).  
Exclusion Criterion #10: Specified that sleep 
disordered breathing and hypoventilation is 
exclusionary if unmanaged. 
Exclusion Criterion #13: Specified family member 
as a first degree relative. 
Exclusion Criterion #16: Specified symptomatic 
arrhythmias as being documented. 
Exclusion Criterion #20: Added that patients with 
implanted univentricular pacemakers used 
prophylactically to prevent bradycardia or heart 
block are not excluded. 
Exclusion Criterion #22: Specified criteria for 
hypokalemia and hypomagnesemia. 
Exclusion Criterion #23: Restated potassium and 
magnesium levels as exclusionary, and specified 
parameters for when outside normal ranges. 
 
 
 
 
 
 
 
 
 
 
Based on investigator 
feedback. 
Based on investigator 
feedback. 
Based on investigator 
feedback. 
 
For clarity, based on 
investigator feedback. 
For clarity, based on 
investigator feedback. 
For clarity, based on 
investigator feedback. 
 
 
For clarity, based on 
investigator feedback. 
For clarity, based on 
investigator feedback. 
 
For clarity. 
 
 
 


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Phase 2 Safety and Efficacy Study 
 
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Section Number 
Section Title 
Description of Change 
Rationale 
Exclusion Criterion #33: Added reference to 
unstable or uncontrolled medical conditions as part 
of the Investigator’s judgement for exclusion. 
Section 7.1  
Screening (Visit 
1) 
 
 
Section 7.2.1  
Baseline Visit 
(Visit 2; Day -1 
±2 Days) 
Specified that both the ESS and MWT scores are 
required to confirm eligibility for the study; 
therefore, study drug will be dispensed the day 
following the MWT. 
Clarification. 
Section 7.2.4.3  
Visit 4 (Day 49 
±3 Days) 
 
 
 
Section 9.1.1  
Estimand 
Section 9.1.2  
Multiple 
Comparisons 
Section 9.1.3  
Missing Data 
Section 9.4.2.1.2 
Sensitivity 
Analyses 
 
 
 
Section 9.4.2.1.1  
Primary Efficacy 
Analysis 
 
 
 
 
Section 9.4.2.1.2  
Secondary 
Efficacy Analysis 
Provided text for this section, which was 
inadvertently missing in the original protocol. 
Correction. 
Section 9.5  
Interim Analysis 
 
 
 
 
AHI = apnea hypoxia index; ANCOVA = analysis of covariance; CGI-S = Clinical Global Impression of Severity; 
EDS = excessive daytime sleepiness; ESS = Epworth Sleepiness Scale; MWT = Maintenance of Wakefulness Test; 
PGI-S = Patient Global Impression of Severity; RDI = respiratory disturbance index 


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1. 
INTRODUCTION 
1.1. 
Background Information and Study Rationale 
Myotonic dystrophy type 1 (DM1) is a rare genetic disorder that is inherited in an autosomal 
dominant manner. The prevalence of DM1 ranges from 2.1 to 14.3 per 100,000 people 
worldwide (Laberge et al 2013), with approximately 40,000 people in the United States (US) 
with this disorder. More recently, the prevalence of DM1 in the US has been studied and results 
suggest that as many as 5 per 10,000 people in the US (140,000-150,000) have the genetic defect 
for DM1, with about 50% likely to be symptomatic, based on the number of repeats in the gene 
(i.e., >150), and the others possibly not being diagnosed (Johnson 2020). While often considered 
as primarily a neuromuscular disorder, DM1 is actually a multisystem disorder (Harper 2001). 
Hallmark signs of the disorder include myotonia, progressive muscular weakness, muscle 
atrophy, and smooth muscle involvement, but the disorder is also characterized by a wide variety 
of systemic clinical features, including cardiovascular (CV) conduction and other defects, 
gastrointestinal motility issues, sleep-disordered breathing, cataracts, endocrinopathies, and 
multiple abnormalities of the central nervous system (CNS), including excessive daytime 
sleepiness (EDS), fatigue and cognitive impairment (Heatwole et al 2012; Wenninger et al 2018; 
Turner and Hilton-Jones 2010). DM1 is also associated with significant incidence of obstructive 
sleep apnea (OSA) (Subramony et al 2020); however, despite compliance with the standard 
treatment of continuous positive airway pressure (CPAP), patients with DM1 often experience 
residual EDS (Gasa et al 2013; Pepin et al 2009). 
Myotonic dystrophy results from sequences of deoxyribonucleic acid (DNA) that are expanded 
abnormally, due to a repeat instability in a non-coding part of a gene. These genetic changes 
result in a disruption of the messenger ribonucleic acid (mRNA) metabolism, with the 
consequent formation of aberrant proteins that interfere with nuclear functions and leads to 
abnormal transcripts in other genes, thus explaining the multisystemic presentation in patients 
with DM1 (Tieleman et al 2010). The underlying cause of DM1 is a mutation in the dystrophia 
myotonica protein kinase (DMPK) gene, which encodes a serine/threonine kinase localized to 
both muscle and nervous tissue (Brook et al 1992). The gene mutation involves an unstable base 
triplet (cytosine-thymine-guanine [CTG]n) located in the 3’ untranslated region of the DMPK 
gene on the long arm of chromosome 19. In DM1, transcription of the CTG repeats generates 
cytosine-uracil-guanine (CUG) expansion ribonucleic acids (RNAs) that accumulate in cell 
nuclei and cause dysregulation of RNA binding proteins. The consequences of RNA binding 
protein dysregulation are disruption of alternative splicing, mRNA translation, and mRNA 
stability (Lee and Cooper 2009). The number of the (CTG)n repeats in the DMPK gene varies in 
the normal population from 3 to 30 units, but in patients with DM1 it varies from 100 up to 1500 
or more units (Perini et al 1999). The number of repeats tends to increase from one generation to 
the next (termed anticipation) and correlates with symptom severity and age of onset, such that 
the higher the repeat number the greater the severity of symptoms and the earlier the age of onset 
(Turner and Hilton-Jones 2014; De Antonio et al 2016; Wenninger et al 2018). Adult-onset DM1 
is the most common presentation of the disorder. 
Dauvilliers and Laberge (2012) noted that EDS is the most common non-muscular complaint in 
patients with DM1, and it is viewed by patients as a prominent and debilitating feature of the 
disorder (Laberge et al 2013). This was further validated in the PRISM-1 study, which reported a 


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Phase 2 Safety and Efficacy Study 
 
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prevalence of 87.9% for impaired sleep or daytime sleepiness in a population of patients with 
DM1, along with one of the highest average life impact scores reported in these patients (2.25 
[standard deviation (SD)=1.31], on a scale of 0-4 where a higher number represents a symptom 
that has a greater effect on a patient’s life), second only to fatigue, which had a score of 2.49 
(SD=1.22) (Heatwole et al 2012). In patients with DM1, EDS seems to be largely secondary to a 
dysfunction of brain/brainstem areas regulating sleep patterns, with lesser contributions from 
sleep fragmentation, sleep-related respiratory events, or periodic leg movements. Interestingly, 
daytime sleepiness appears to be dissociated from abnormalities in nocturnal breathing (van der 
Meché et al 1994); when sleep-disordered breathing was successfully treated in this patient 
population, the symptom of EDS persisted (Dauvilliers and Laberge 2012).  
Cheung et al (2018) have reported that significantly lower nadir oxygen (O2) saturation was 
found in patients with DM1 versus controls. Some patients with DM1 have also been observed to 
have sleep-onset rapid eye movement periods (SOREMPs) that resemble those observed in 
patients with narcolepsy (Park and Radtke 1995; Yu et al 2011; Bonanni et al 2018).   
Hypocretin (also known as orexin), a neuropeptide produced exclusively by neurons in the 
hypothalamus, is involved in maintaining wakefulness and regulating REM sleep (Teske and 
Mavanji 2012). Decreased cerebrospinal fluid (CSF) levels of this neuropeptide are observed in 
patients with narcolepsy and are an underlying cause of that sleep disorder (Nishino et al 2000; 
Peyron et al 2000; Thannickal et al 2000; Mignot et al 2002). Several studies have reported 
decreased levels of hypocretin in CSF from patients with DM1, but the results are inconsistent. 
Martinez-Rodriguez et al (2003) found decreased CSF orexin levels in patients with DM1, while 
Ciafaloni et al (2008) reported that CSF orexin levels in patients with DM1 were not different 
from the control group. Omori et al (2018) found that 7 of 17 patients with DM1 and associated 
EDS showed decreased CSF orexin levels, with significant differences in Epworth Sleepiness 
Scale (ESS) scores and mean sleep latency (MSL) between patients with DM1 with decreased 
CSF hypocretin (i.e., ≤200 pg/mL) versus normal controls (i.e., >200 pg/mL).  
Excessive daytime sleepiness is a symptom that is common among neurological and 
neuromuscular disorders, but whether the underlying cause of this symptom is similar across 
disease states remains unclear. However, evidence suggests that drugs effective in alleviating 
EDS in one disease state will be effective for this symptom in another disease state.  
Psychostimulant drugs (i.e., modafinil and methylphenidate) approved for the treatment of EDS 
in narcolepsy, which is characterized by a loss of CNS orexin (hypocretin), have been studied in 
patients with DM1. Modafinil, approved for the treatment of EDS associated with narcolepsy, 
has been used with equivocal success in patients with DM1 (Damian et al 2001; MacDonald et al 
2002; Talbot et al 2003; Wintzen et al 2007; Orlikowski et al 2009; West et al 2016) and, while 
Puymirat et al (2012) have shown benefit of methylphenidate for EDS in patients with DM1, this 
observation has not been independently replicated in another double-blind study. Additional well 
controlled, randomized trials are needed to establish the safety and efficacy of psychostimulants 
in the treatment regimen for patients with myotonic dystrophy (DM) (Annane et al 2006).  
Pitolisant (brand name WAKIX®) was approved in the European Union (EU) in March 2016 for 
the treatment of adults with narcolepsy with or without cataplexy and has since been approved in 
the US for the treatment of EDS or cataplexy in adult patients with narcolepsy.  


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Pitolisant is a first-in-class, potent and highly selective histamine 3 receptor (H3R) 
antagonist/inverse agonist with a novel mechanism of action. It triggers long-lasting activation of 
histaminergic neurons in the brain, a neuronal system involved in the maintenance of 
wakefulness, attention, and cognition. Pitolisant binds to H3Rs and blocks the normal negative 
feedback mechanism for histamine release, resulting in increased release of this wake-promoting 
neurotransmitter. 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 (including dopamine, norepinephrine, serotonin, and acetylcholine) via 
heteroreceptors within those neuronal systems. Importantly, pitolisant does not increase 
dopamine release in the striatum, including the nucleus accumbens, which differentiates 
pitolisant from other wake-promoting agents that have abuse liability, such as psychostimulants.  
Pitolisant, unlike psychostimulants, is not a scheduled drug, and thus can potentially offer a 
better benefit/risk profile in comparison to other potential treatments for EDS associated with 
DM1. Pitolisant presents a novel approach to the management of EDS in patients with DM1, and 
based on its mechanism of action, could potentially impact the management of other non-
muscular symptoms, including fatigue and cognitive dysfunction. To date, no clinical studies 
have been conducted to evaluate pitolisant in patients with DM1. This Phase 2 study will 
evaluate the impact of pitolisant on non-muscular symptoms of DM1 in adults, with a focus on 
EDS, fatigue, cognitive function, and overall burden of disease.  
1.2. 
Rationale for Study Design 
This randomized, double-blind, placebo-controlled 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 non-muscular symptoms (including fatigue, cognitive function, and overall 
burden of disease) in patients with DM1 ages 18 to 65 years.  
In the randomized Double-Blind Treatment Phase, approximately 30 eligible patients ages 18 to 
65 years will be enrolled in the study and will be randomized in a 1:1:1 ratio. Investigators and 
patients will be blinded to treatment assignment, minimizing 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 Day 459/Month 15 
(Visit 8) unless the patient withdraws from the study early or 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. 
The primary efficacy endpoint in the study is the change in mean Daytime Sleepiness Scale 
(DSS) score from Baseline to Week 11 for pitolisant compared with placebo. A description of 
the DSS is provided in Section 6.2.1. Secondary efficacy endpoints will be evaluated using 
validated scales and measures. Change in sleepiness, fatigue, cognitive symptoms of DM1, and 
the overall burden of disease from the patient’s perspective will be evaluated using the DSS and 
ESS, the Fatigue Severity Scale (FSS), the Cogstate Computerized Cognitive Battery Tests and 
Sustained Attention to Response Task (SART), and the Myotonic Dystrophy Health Index 
(MDHI). Secondary efficacy endpoints of clinician-rated impression of the severity of the 
patient’s EDS and patient-rated impression of the severity of their EDS will be evaluated using 


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the global impression scales of Clinical Global Impression of Severity (CGI-S) and Patient 
Global Impression of Severity (PGI-S), respectively. Descriptions of the scales and measures 
used to evaluate the secondary endpoints are provided in Section 6.2.  
Patients with DM1 have an increased CV liability and risk of sudden death (Groh 2012). Cardiac 
manifestations of the disease present most commonly as arrhythmias or conduction disturbances 
(Lau et al 2015). Approximately 65% of patients have electrocardiogram (ECG) abnormalities, 
and specific ECG abnormalities have been noted as a sensitive predictor of sudden death, and 
thus may be useful for risk stratification in this population (Lau et al 2015; Sommerville et al 
2017). Specifically, risk of sudden death is significantly elevated in patients whose ECG shows 
atrial arrhythmia, PR interval >240 msec, QRS duration >120 msec, or advanced atrioventricular 
block (AVB) (Groh 2012). Therefore, in this Phase 2 study, the exclusion criteria will ensure the 
enrollment of patients with minimal conduction defects and low risk for clinically significant 
cardiac arrhythmias. Because pitolisant has the potential for QT prolongation, patients with 
potential for QT prolongation are excluded, as are patients who are known cytochrome P450 
(CYP) 2D6 poor metabolizers (PMs) (pitolisant exposure is 2- to 3-fold higher in CYP2D6 
PMs). In addition, patients’ CV status will be monitored clinically throughout the study using 
triplicate ECG assessments and Holter monitoring. This additional monitoring is warranted 
because up to 32% of patients with DM1 with a normal ECG may have arrhythmias and 
conduction abnormalities that are only detectable using arrhythmia monitoring (Merlevede et al 
2002).   
1.3. 
Dose Rationale 
Eligible patients (approximately 30 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. The proposed lower 
and higher doses of pitolisant for the Double-Blind Treatment Phase of the study are 17.8 mg 
and 35.6 mg, respectively, administered once daily in the morning upon wakening for 8 weeks 
following a 3-week titration period. In the OLE Phase, all patients will receive open-label 
pitolisant and will be titrated to a dose of 35.6 mg, or a maximum dose up to 35.6 mg based on 
Investigator assessment of tolerability. The pitolisant doses are the same as those that are 
approved by the Food and Drug Administration (FDA) for the narcolepsy indication. Dosing in 
both the Double-Blind Treatment Phase and OLE Phase of the study will include a 3-week 
titration period, which is consistent with the FDA-approved prescribing information for 
WAKIX® (pitolisant). 
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, OSA, 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 adverse events (TEAEs) in patients who received pitolisant in the Phase 2/3 studies 


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(N=1513) 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 is contraindicated in patients 
with severe hepatic impairment. Pitolisant is not recommended in patients with end-stage renal 
disease (ESRD). 
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 ESRD. To mitigate potential CV risks in this study, patients with potential for QT 
prolongation and patients who are known CYP2D6 PMs are excluded from participation and CV 
status of all patients will be monitored throughout the study using triplicate ECGs and Holter 
monitoring.  
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, ECG 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 DM1 ages 18 to 65 years. 
2.2. 
Secondary Objectives 
The secondary objectives of this study are to assess:  
• the impact of pitolisant on fatigue in patients with DM1 
• the impact of pitolisant on selected domains of cognitive function in patients with 
DM1 
• investigator and patient impression of overall impact of pitolisant on burden of 
disease in patients with DM1 
• safety and effectiveness of pitolisant during long-term treatment (during the OLE 
Phase) 
 


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3. 
INVESTIGATIONAL PLAN AND ENDPOINTS 
3.1. 
Description of the Study Design 
3.1.1. 
Overall Study Design 
This is an exploratory, randomized, double-blind, placebo-controlled, parallel-group study in 
adult patients (ages 18 to 65 years) with DM1, followed by an optional OLE Phase.  
The study will consist of a Screening Period (up to 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 continue until Day 459/Month 15 (Visit 8) for each 
patient unless the patient withdraws from the study early or the Sponsor elects to terminate the 
study. An overall schema of the study design is provided in Figure 1.  
After Screening, approximately 30 patients ages 18 to 65 years who meet all eligibility criteria 
will be randomized at the Baseline Visit in a 1:1:1 ratio to lower dose pitolisant (17.8 mg), 
higher dose pitolisant (35.6 mg), or matching placebo. In the Double-Blind Treatment Phase, 
patients will be titrated to their randomized stable dose of study drug during the 3-week Titration 
Period (Table 6). After completion of the 3-week Titration Period, patients will continue to take 
study drug at their randomized 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. Adjustments to study drug dosing outside of the protocol-specified 
titration schedule are not allowed during the 11-week Double-Blind Treatment Phase. 
Following the 11-week Double-Blind Treatment Phase, eligible patients will be given the 
opportunity to participate in an optional OLE Phase. During the OLE Phase, all eligible patients 
will receive treatment with open-label pitolisant and will be titrated during a 3-week Titration 
Period to a dose of 35.6 mg (or a maximum dose up to 35.6 mg based on Investigator assessment 
of tolerability) (Table 7). Adjustments to pitolisant dose are permitted during the OLE Phase; 
pitolisant dose can be adjusted (higher or lower) based on Investigator assessment of tolerability; 
the maximum dose allowed is 35.6 mg once daily. 
Safety, efficacy, and PK of pitolisant will be evaluated in the Double-Blind Treatment Phase 
(Section 3.1.1.2) and safety and effectiveness of pitolisant will be evaluated in the OLE Phase 
(Section 3.1.1.3). 
.


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Figure 1: 
Overall Study Design 
 
Abbreviations: AE = adverse event; BL = baseline; C-SSRS = Columbia-Suicide Severity Rating Scale; EOT = end-of-treatment; F-up = follow-up; MWT = Maintenance of 
Wakefulness Test; OLE = Open-Label Extension; PK = pharmacokinetics; TC = telephone contact; V = visit.  
 
a The Titration Period for the Double-Blind Treatment Phase will be from Days 1 to 21. Patients will receive their first dose of study drug on Day 1; study drug dose will be 
titrated on Day 8 and again on Day 15 (as appropriate based on randomized dose; Table 6); all patients will be at their final randomized dose by Day 15 of the Titration Period. 
b The 8-week Stable Dose Period for 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). Visit 5 (Day 77 ±3 days) is the EOT Visit for the Double-Blind Treatment Phase. The EOT (Week 11) MWT assessment should not be performed on the same day as 
the Visit 5 PK as patients will take their dose of study drug at the site after ECGs and the pre-dose PK blood draw are done. The EOT (Week 11) MWT may be conducted up to 
3 days in advance of Day 77; patients should take their dose of study drug on the morning of the scheduled Week 11 MWT assessment. Eligible patients who opt to enter the OLE 
Phase will be dispensed OLE study drug for titration at this visit. 
c The Titration Period for the OLE Phase will be from Days 78 to 98 (±3 days). Eligible patients will receive their first dose of open-label pitolisant on Day 78 and pitolisant dose 
will be titrated on Day 85 and again on Day 92 to a dose of 35.6 mg (or a maximum dose up to 35.6 mg based on Investigator assessment of tolerability). At the end of the 3-week 
Titration Period, patients will continue to take pitolisant 35.6 mg (or their maximum dose up to 35.6 mg based on Investigator assessment of tolerability) once daily in the morning 
upon wakening until the end of the study (Long-Term Dosing Period). During the OLE Phase, pitolisant dose can be adjusted (higher or lower) based on Investigator assessment of 
tolerability. The maximum pitolisant dose allowed in the study is 35.6 mg. 


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d In between the 6-monthly on-site study visits, patients will receive a TC from the study site approximately every 180 days (i.e., on Days 189 and 369) to record 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, complete C-SSRS, confirm the current dose of study drug and compliance with dosing, and confirm shipment/receipt of study drug sufficient for 
3 months (i.e., 90 days) of once daily administration.  
e All AEs regardless of seriousness, severity, or causality will be collected from the time the patient provides written informed consent through 30 days (+3 days) after final dose 
of study drug (Safety Follow-up TCs, Section 7.4). 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. 
f Patients who consent to the optional MWT must return to the study site on the day before the scheduled Baseline MWT assessment and the day before the scheduled EOT MWT 
assessment of the Double-Blind Treatment Phase. 


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3.1.1.1. 
Screening Period 
The Screening Period will be a maximum of 45 days. At the Screening Visit (Visit 1), after 
written informed consent is provided, patients will undergo screening assessments. Screening 
will include fitting of a 24-hour Holter monitor; a clinically significant finding from Holter 
monitoring will require additional evaluation including an unscheduled ECG (Section 6.3.4). 
Patients will be provided with a sleep diary (Appendix A) and will be asked to record their time 
to bed and time of wakening for at least 7 of 10 consecutive nights including 2 nights that fall on 
a weekend during Screening. Patients who meet all eligibility criteria will be enrolled in the 
study.  
3.1.1.2. 
Double-Blind Treatment Phase 
At the Baseline Visit (Day -3 to Day -1, Visit 2), after completion of all Baseline assessments, 
patients who continue to meet all eligibility criteria will be randomized at a 1:1:1 ratio to receive 
once daily treatment with lower dose pitolisant (17.8 mg), higher dose pitolisant (35.6 mg), or 
matching placebo in the Double-Blind Treatment Phase. Eligible patients will be dispensed study 
drug and instructed to take study drug once daily in the morning upon wakening in accordance 
with the schedule outlined in Table 6. Patients will be instructed to take their first dose of blinded 
study drug on the morning after they receive study drug from the site. Patients will be provided 
with a study drug dosing diary at the Baseline Visit and will be instructed to record the number 
of tablets administered (and from which bottle) daily. The study drug dosing diary will be used 
in the Double-Blind Treatment Phase only (an example of the study drug dosing diary is 
provided in Appendix B).  
Patients will be titrated during a 3-week Titration Period to their randomized dose of study drug 
as detailed in Table 6; study drug dose will be titrated on Day 8 and again on Day 15, with all 
patients at their randomized dose by Day 15. At the end of the 3-week Titration Period, patients 
will continue to take study drug (blinded pitolisant or placebo) in accordance with their 
randomized 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 6: 
Study Drug Dosing in the Double-Blind Treatment Phase 
 
Titration Period 
(3 Weeks) 
Stable Dose Period 
(8 Weeks) 
Treatment Groups  
Week 1 
(Days 1 - 7) 
Week 2 
(Days 8 - 14) 
Week 3 
(Days 15 - 21) 
Weeks 4 - 11 
(Days 22 - 77) 
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 
Note: Adjustments to study drug dosing outside of the protocol-specified titration schedule are not permitted during the Double-
Blind Treatment Phase. 
 
For patients enrolling after protocol Amendment 4 was implemented, the MWT is an optional 
assessment for which patients provide consent. Patients must return to the study site on the day 


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before each scheduled MWT assessment (i.e., the day before the MWT Baseline Visit and the 
day before the EOT MWT assessment of the Double-Blind Treatment Phase [Visit 5]). The 
MWT Baseline assessment may be performed up to 3 days prior to Day 1 to accommodate sleep 
laboratory scheduling and patient availability. If a patient enrolled prior to protocol 
Amendment 4 (i.e., had the MWT Baseline assessment) the MWT at Week 11 must be 
performed. For EOT (Week 11), patients should take their dose of study drug on the morning of 
the scheduled MWT assessment. The MWT should not be performed on the same day as the 
Visit 5 PK as patients will take their dose of study drug at the site after ECGs and the pre-dose 
PK blood draw are done. 
Adjustments to study drug dosing outside of the protocol-specified titration schedule are not 
permitted during the 11-week Double-Blind Treatment Phase; however, interruptions in study 
drug dosing may be allowed (e.g., for an adverse event [AE]) as detailed in Section 3.1.3. 
Patients will receive telephone contacts (TCs) from the study site on Days 8, 15, and 28 
(±3 days) (TCs 1, 2, and 3, respectively) 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, 
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 undergo safety and efficacy 
assessments at the study site on Days 22 (Visit 3), 49 (Visit 4), and 77 (Visit 5) (window for 
Visits 3, 4, and 5 is ±3 days). Blood sampling for PK assessments will be done at Days 22 (Visit 
3) and 77 (Visit 5). On Day 22 (Visit 3), safety assessments will include fitting of a Holter 
monitor; the patient will wear the monitor for 24 hours and the device will be returned to the 
study site via courier or directly to the site if the patient is able, as detailed in a separate 
instructional document. A clinically significant finding from Holter monitoring at any time 
during the study will require additional evaluation including an unscheduled ECG; further details 
on Holter monitoring at each visit are provided in Section 6.3.4.1. 
At the end of the Double-Blind Treatment Phase, eligible patients will be given the opportunity 
to enter an optional OLE Phase (Section 3.1.1.3). If a patient does not enter the OLE Phase, the 
patient will receive Safety Follow-up TCs from the study site 15 (±3) days and 30 (+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 
(Section 7.4).  
3.1.1.3. 
Open-Label Extension Phase 
Before patients can enter the OLE Phase of the study, eligibility criteria must be confirmed at 
Visit 5 (i.e., the End of Treatment [EOT] Visit 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). 
Regardless of the patient’s assigned randomization during the Double-Blind Treatment Phase, 
which will remain blinded at entry into the OLE Phase, all eligible patients who enter the OLE 
Phase will be titrated during a 3-week Titration Period to a dose of 35.6 mg open-label pitolisant 


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(or a maximum dose up to 35.6 mg based on Investigator assessment of tolerability), as detailed 
in Table 7. Eligible patients will be dispensed open-label pitolisant for titration at Visit 5 (Day 77 
±3 days) of the Double-Blind Treatment Phase and will take their first dose of open-label 
pitolisant the following morning upon wakening (Day 78 ±3 days). Pitolisant dose will be 
titrated on Day 85 (±3 days) and again on Day 92 (±3 days) (Table 7). At the end of the 3-week 
OLE Titration Period, patients will continue to take open-label pitolisant 35.6 mg (or their 
maximum dose up to 35.6 mg based on Investigator assessment of tolerability) once daily in the 
morning upon wakening through the end of the study (Long-Term Dosing Period).  
Adjustments to pitolisant dose are permitted in the OLE Phase; pitolisant dose can be adjusted 
(higher or lower) based on Investigator assessment of tolerability; the maximum dose allowed in 
the study is 35.6 mg. Details for pitolisant dose adjustments are provided in Section 3.1.2.2.  
Table 7: 
Pitolisant Dosing in the Open-Label Extension Phase 
 
Titration Perioda 
(3 Weeks) 
Long-Term Dosing Periodb 
 
Week 12 
(Days 78 - 84) 
Week 13 
(Days 85 - 91) 
Week 14 
(Days 92- 98) 
Weeks 15 (Day 99) to EOT 
Pitolisant dose 
8.9 mg 
17.8 mg 
35.6 mg 
35.6 mg 
Abbreviations: EOT = End-of-Treatment; OLE = Open-Label Extension. 
 
a Pitolisant dose will be titrated on Day 85 and again on Day 92. 
b After completion of the 3-week Titration Period, patients will continue to receive pitolisant 35.6 mg (or their maximum dose up 
to 35.6 mg based on Investigator assessment of tolerability). 
 
Note: Adjustments to study drug dosing after the protocol-specified titration period are permitted during the OLE Treatment 
Phase of the study, where the pitolisant dose can be adjusted (higher or lower) based on Investigator assessment of tolerability; 
the maximum pitolisant dose allowed in the study is 35.6 mg (Section 3.1.2.2) It is recommended that adjustments made during 
this time be to one of the three pre-specified doses of 35.6 mg, 17.8 mg, or 8.9 mg. If deemed necessary by the Investigator, 
alternative doses may be prescribed during the OLE Phase; however, the Investigator must first consult with the Medical 
Monitor. Dosing may be adjusted in increments of 4.45 mg. 
 
During the OLE Phase, patients will receive TCs from the study site on Days 85 and 92 
(±3 days) during the 3-week Titration Period 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, complete the C-SSRS, and review/confirm pitolisant dose titration. A clinically significant 
finding from Holter monitoring at any time during the study will require additional evaluation, 
including an unscheduled ECG (Section 6.3.4). 
At the end of the OLE Titration Period, patients will return to the study site for assessment of 
safety and effectiveness on Day 99 (±3 days; Visit 6); 24-hour Holter monitoring will be initiated 
at this visit (Section 6.3.4.1). The patient will wear the monitor for 24 hours and the device will 
be returned to the study site via courier or directly to the site if the patient is able, as detailed in a 
separate instructional document. A clinically significant finding from Holter monitoring at any 
time during the study will require additional evaluation, including an unscheduled ECG 
(Section 6.3.4). 


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A TC will occur 3 months after Visit 6 on Day 189/Month 6 followed by an on-site study visit 
(Visit 7) 3 months later (Day 279/Month 9). Another TC will occur 3 months later on 
Day 369/Month 12. All patients who complete the study will have an EOT visit at 
Day 459/Month 15 (Visit 8) unless the patient withdraws from the study early or the study is 
terminated by the Sponsor. A 3-month supply of study drug (i.e., sufficient for 90 days of once 
daily administration) will be provided to eligible patients every 3 months either via mail or at the 
on-site study visits; additional study drug may be dispensed between TCs and/or on-site visits if 
necessary. At all on-site study visits (approximately every 6 months), assessment of safety and 
effectiveness will be performed. If CV assessments are required at the discretion of the 
Investigator, patients will return to the study site for unscheduled visits that will include an ECG 
as detailed in Section 7.5. 
All patients will undergo an EOT Visit (Section 7.3.2.4). Patients will receive Safety Follow-up 
TCs from the study site 15 (±3) days and 30 (+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 (Section 7.4). 
3.1.2. 
Dose Adjustments 
3.1.2.1. 
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.   
3.1.2.2. 
Open-Label Extension Phase 
Adjustments in pitolisant dose are permitted in the OLE Phase. Pitolisant dose can be adjusted 
(higher or lower) based on Investigator assessment of tolerability. Decreases in pitolisant dose 
are permitted at any time at the discretion of the Investigator. For patients who are on less than 
the maximum dose of 35.6 mg pitolisant, dose increases are at the Investigator’s discretion in 
consultation with the Medical Monitor. Discussions and decisions regarding adjustments in 
pitolisant dose will occur over the telephone or during on-site study visits (either scheduled or 
unscheduled). Pitolisant doses may be adjusted (higher or lower). It is recommended that 
adjustments made during this time be to one of the three pre-specified doses of 35.6 mg, 
17.8 mg, or 8.9 mg. If deemed necessary by the Investigator, alternate doses may be prescribed 
during the OLE Phase; however, the Investigator must first consult with the Medical Monitor. 
Dosing may be adjusted in increments of 4.45 mg. The maximum permitted pitolisant dose in the 
study is 35.6 mg once daily. 
In the event a patient has clinically significant abnormal ECG results, study drug may need to be 
adjusted and/or interrupted as detailed in Section 4.4.2 and Section 6.3.4.2. 
In the event a patient develops moderate hepatic impairment (Child-Pugh B) or moderate or 
severe renal impairment during the OLE Phase of the study, the dose of pitolisant may need to be 
decreased by the Investigator in consultation with the Medical Monitor; a maximum daily dose 
of 17.8 mg is recommended in either situation. Patients who develop either ESRD (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). 


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If a patient begins taking a strong CYP2D6 inhibitor during the OLE Phase, pitolisant dose is to 
be reduced by one half (Section 5.7.3). 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 
of 35.6 mg; procedures for pitolisant dose increases must be followed, as outlined in this section. 
3.1.3. 
Dose Interruptions 
Every effort should be made to educate patients 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. Additionally, clinically significant ECG results 
may warrant interruption of study drug dosing as detailed in Section 4.4.2.  
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 greater than 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 and consider re-titrating the patient to the desired dose 
as detailed in Section 3.1.1.3. 
3.2. 
Study Endpoints 
3.2.1. 
Efficacy Endpoints 
Efficacy endpoints are to be assessed by comparison of patients treated with pitolisant versus 
patients who received placebo. 
3.2.1.1. 
Double-Blind Treatment Phase 
3.2.1.1.1. Primary Efficacy Endpoint 
The primary efficacy endpoint is the change in DSS score from Baseline to Week 11 for 
pitolisant compared with placebo. 
3.2.1.1.2. Secondary Efficacy Endpoints 
The secondary efficacy endpoints are change from Baseline to Week 11 for pitolisant compared 
with placebo: 
• on the FSS 
• in psychomotor function as measured by the Cogstate Detection Test 
• in attention as measured by the Cogstate Identification Test 
• in working memory as measured by the Cogstate One Back Test 
• on the MDHI 


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• on the ESS 
• on the CGI-S (i.e., global assessment of overall severity of EDS as assessed by the 
clinician) 
• on the PGI-S, anchored to EDS 
• in attention as measured by SART 
3.2.1.1.3. Exploratory Endpoint 
For patients who complete the MWT assessments: 
• change in MSL based on MWT from Baseline to Week 11 for pitolisant compared 
with placebo 
3.2.1.2. 
Long-Term Effectiveness Endpoints 
Long-term effectiveness endpoints for EDS, fatigue, cognitive function, and overall disease 
burden will be evaluated as measured by changes from baseline in DSS, FSS, Cogstate Detection 
Test, Cogstate Identification Test, Cogstate One Back Test, MDHI, ESS, CGI-S of EDS, and 
PGI-S of EDS during the OLE Phase of the study.  
3.2.2. 
Safety Endpoints 
Safety will be assessed by monitoring the incidence of AEs and changes in clinical laboratory 
test results, vital signs, 12-lead ECG results (in triplicate), Holter monitoring results, C-SSRS 
assessment, and physical examination findings 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 final patient enrolled reaches their Day 459/Month 15 (Visit 8/EOT) visit 
or 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 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 continue until the patient reaches Day 459/Month 15 (Visit 8) and then for an 
additional 30 days of safety follow-up. 


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4. 
STUDY ENROLLMENT AND WITHDRAWAL 
4.1. 
Study Population 
Approximately 30 patients with DM1 are planned to be enrolled in the study at approximately 
22 sites in the US and Canada. 
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. 
2. Has a diagnosis of DM1 confirmed by genetic testing (CTG repeat of >100) from the 
Screening Visit. 
3. Male or female patients ages 18 to 65 years at the time of enrollment. 
4.
 
 
5. If on a wake-promoting treatment that could affect EDS (including stimulants, modafinil, 
and armodafinil): 
a. Must be on a stable dose for at least 2 months prior to Screening 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). 
b. If not on a stable dose for 2 months prior to Screening, washout for 5 half-lives prior 
to randomization and agree to remain off these treatments for the duration of the 
Double-Blind Treatment Phase of the study. 
6. Washout of cannabidiol and tetrahydrocannabinol for 28 days prior to randomization and 
agree to remain off for the duration of the Double-Blind Treatment Phase of the study. 
7. Able to walk independently with or without an assistive device (e.g., cane, walker, 
orthoses allowed). 
8. A patient who is a female of child-bearing potential (FCBP) must have a negative serum 
pregnancy test at the Screening Visit and negative urine pregnancy test at the Baseline 
Visit and agree to remain abstinent or use an effective method of non-hormonal 
contraception to prevent pregnancy for the duration of the study and for 21 days after 
final dose of study drug. 
9. In the opinion of the Investigator, patient is capable of understanding and complying with 
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 that is distinct from DM1 
and that is not being managed adequately in the opinion of the Investigator.  


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2. 
 
 
 
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 substances listed in the 
protocol. 
5. 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. 
6. Participation in an interventional research study involving another investigational 
medication or device in the 28 days prior to enrollment; patients who undergo a washout 
of an investigational medication of at least 5 half-lives can 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. 
7. Has a primary diagnosis of severe psychiatric illness. 
8. Patients taking antidepressants who have not been on a stable dose of their antidepressant 
for at least 12 weeks prior to Screening; for patients on a stable dose of their 
antidepressant for at least 12 weeks prior to Screening, must agree to continue their stable 
dose for the duration of the Double-Blind Treatment Phase of the study. Dose 
adjustments will be permitted in the OLE Phase. In the Double-Blind Treatment Phase of 
the study, antidepressants that are strong CYP2D6 inhibitors are exclusionary 
(Section 5.7.2). 
9. Has a history of sleep-disordered breathing or another underlying sleep disorder that in 
the opinion of the Investigator is a main contributory factor to the patient’s EDS. 
10. Has a diagnosis of ESRD (eGFR of <15 mL/minute/1.73 m2) or severe hepatic 
impairment (Child-Pugh C). 
11. 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.  
12. Has a family history of sudden cardiac death, unexplained death, or death from a primary 
dysrhythmia potentially associated with QT prolongation in any family member (i.e., first 
degree relative such as parent, sibling, or offspring). 
13. Has a history of unexplained syncope. 
14. Has a history of long corrected QT interval (QTc) syndrome or corrected QT interval 
using Fridericia’s formula (QTcF) >450 msec for males or >470 msec for females 
(QTcF = QT / 3√ RR) sustained atrial fibrillation (AF) or left ventricular ejection fraction 
<50%. 


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15. Has a history of documented symptomatic arrhythmias (e.g., ECG, Holter monitor). 
16. Electrocardiogram abnormalities during a 10-second, 12-lead ECG at Screening of first 
degree AVB (PR interval >220 msec), QRS >120 msec, heart rate (HR) <50 beats per 
minute (bpm), marked T-wave abnormalities, more than single atrial premature 
complexes (APCs) or premature ventricular contractions (PVCs), left bundle branch 
block, or Brugada pattern type 1.  
 
Note: Patients with 1st degree AVB with a PR interval >220 msec, who are treated 
prophylactically with an allowable implanted device are not excluded from the study. 
17. Based on Holter monitor, any episode of 3rd degree AVB, any prolonged episode of 
second degree AVB (>2 episodes during waking hours, >6 episodes during sleep), any 
prolonged episode of 2nd degree AVB (>10 seconds), any asystole longer than 
3.5 seconds, any run of ventricular tachycardia (VT) >6 beats, frequent runs of 
non-sustained VT (>5/24 hour), >400 PVCs/24 hours, AF or paroxysmal AF, or frequent 
or complex atrial arrhythmias. 
18. Has history of New York Heart Association (NYHA) class III or class IV heart failure. 
19. Has an implanted defibrillator or implanted biventricular pacemaker.  
 
Note: Patients with implanted univentricular pacemakers that are used prophylactically to 
prevent or treat bradycardia or heart block may be included. 
20. Is receiving a medication known to prolong the QT interval. 
21. Has a history of clinically significant hypokalemia or hypomagnesemia that cannot be 
adequately controlled by supplementation. 
22. Has serum potassium or magnesium levels that are outside of the normal reference ranges 
and considered clinically significant at Screening. Patients with mild hyperkalemia that, 
in the opinion of the Investigator, does not pose an arrhythmia threat may be included. 
23. Is receiving a concomitant medication that is known to be a strong CYP2D6 inhibitor, a 
strong CYP3A4 inducer; or a centrally acting histamine 1 receptor (H1R) antagonist 
(sedating antihistamine).  
 
Note: Patients who undergo a washout of these medications of at least 5 half-lives may be 
enrolled in the Double-Blind Treatment Phase of the study.  
Note: Use of strong CYP2D6 inhibitors and strong CYP3A4 inducers is allowed during 
the OLE Phase; however, adjustment of pitolisant dose is required (Section 3.1.2.2). 
Although not prohibited during the OLE Phase of the study, use of centrally acting or 
sedating H1R antagonists should be avoided.  
24. Is a known CYP2D6 PM. 
25. Regular use (more than twice per week) of any sleep-promoting treatments that could 
affect EDS and not willing to limit use to no more than twice per week during Screening 
and for the duration of the Double-Blind Treatment Phase of the study (use of sleep-
promoting agents are not allowed within one day prior to study-related assessments). 


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26. Has abnormal laboratory values at Screening that are clinically significant as determined 
by the Investigator.  
27. Has initiated any new or change in allied health therapies or interventions that can 
interfere with the study outcomes within 28 days prior to randomization and that are 
prohibited during the Double-Blind Treatment Phase of the study, based on the 
Investigator’s judgment. 
28. Has a current or recent (within 1 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).  
29. Has planned surgery during the Double-Blind Treatment Phase of the study; planned 
surgery is permitted during the OLE Phase. 
30. Has a significant risk of committing suicide or suicidality 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 C-SSRS (Appendix C). 
31. Based on the judgment of the Investigator, is unsuitable for the study for any reason, 
including but not limited to an unstable or uncontrolled medical condition or one 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). 
Randomization will be stratified by concomitant use of wake-promoting agents. Medications that 
are considered wake-promoting agents are:   
• Solriamfetol/Sunosi 
• Modafinil/Provigil 
• Armodafinil/Nuvigil 
• Lisdexamfetamine dimesylate/Vyvanse 
• Dexmethylphenidate/Focalin 
• Methylphenidate/Adhansia, Aptensio, Concerta, Cotempla, Daytrana, Jornay, 
Metadate, Methylin, Quillichew, Quillivant, Ritalin 
• Amphetamine and amphetamine salts/Adderall, Adzenys, Desoxyn, Dexedrine, 
Dyanavel, Eveko, Mydayis, Procentra, Zenzedi 
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. 


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4.2.1. 
Procedures for Handling Randomized Subjects 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 the 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, 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.  
Blinding is not applicable in the OLE Phase of the study. 
4.3.1. 
Breaking the Blind 
The study blind should not be broken except for in medical emergencies when the appropriate 
medical management of the patient requires knowledge of the study drug they 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 the premature unblinding must be clearly documented. 
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 one determines that it is not in the patient’s best interest to 
continue participation. 
Possible reasons for early withdrawal include: 
• AE 
• Lack of effect (LOE) 
• Patient decision 
• Lost to follow-up 
• No longer meets eligibility criteria 
• Non-compliance with study protocol 
• Non-compliance with study treatment 


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• Other, with specific reason (e.g., pregnancy) 
Any ECG finding that demonstrates QT prolongation (i.e., QTcF >500 msec or an increase 
>60 msec regardless of resultant QTc value) should be promptly addressed by the Investigator 
and will require discontinuation of study drug. Other ECG abnormalities may require 
discontinuation of study drug based on Investigator discretion, in consultation with the Medical 
Monitor, as detailed in Section 6.3.4.2. 
Patients who develop ESRD (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. 
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 C-SSRS will be discontinued and will require further evaluation by the 
Investigator. 
The date and the 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 7.2.5 and Section 7.3.2.5). 
4.4.2. 
Temporary Withdrawal of Study Drug During the Open-Label Extension Phase 
As noted in Section 6.3.4.2, 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. 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. 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.  
4.4.3. 
Procedures for Patient Follow-up 
All patients who complete the Double-Blind Treatment Phase of the study are required to 
undergo the safety assessments outlined in the EOT Visit (Section 7.2.4.4). Patients who 
prematurely discontinue study drug during the Double-Blind Treatment Phase are required to 
undergo the safety assessments outlined in the ET Visit, and the reasons for discontinuation must 
be recorded (Section 7.2.5). Additionally, patients in the Double-Blind Treatment Phase who do 
not enter the OLE Phase will be contacted by telephone 15 (±3) days and 30 (+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 concomitant medication use (Safety 
Follow-up TCs; Section 7.4). 
All patients who complete the optional OLE Phase of the study are required to undergo the safety 
assessments outlined for the EOT Visit (Section 7.3.2.4). Patients who prematurely discontinue 
study drug during the OLE Phase are required to undergo the safety assessments outlined in the 


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ET Visit, and the reasons for discontinuation must be recorded (Section 7.3.2.5). Additionally, 
patients in the OLE Phase will be contacted by telephone 15 (±3) days and 30 (+3) days after 
taking the final dose of open-label pitolisant to assess 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 (Safety 
Follow up TCs; Section 7.4). 
Every effort should be made to educate patients 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 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 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 who are potentially lost to follow-up, 
including pursuing any alternative contact methods permitted by local regulations or agreed by 
the patient. All attempts to contact the patient will be documented in the patient’s eCRF and 
source notes. At a minimum, three documented attempts to contact the patient, including at least 
one certified letter, should be performed before a patient is deemed lost to follow-up.  
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 either the last patient completes the EOT Visit 
(Visit 8) after the final dose of open-label treatment or 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 study. The OLE Phase of the study is optional and patients who complete an 
EOT Visit (Visit 8, or earlier in the event the Sponsor terminates the study prior to a patient’s 
Visit 8) in the OLE Phase will be considered to have completed the study. 


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4.7. 
Screen Failures 
Patients who fail to meet the eligibility criteria should not receive study drug.  
Patients who do not meet the eligibility criteria at the Screening/Baseline Visit will be 
screen-failed without receiving study drug but may be rescreened 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 the IRT system. If the patient is out of the initial 
45-day screening window, all screening procedures must be repeated except for the genetic test 
confirming DM1. 
In the event a patient does not meet the 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, unless otherwise specified (Section 7.2.4.1 and Section 7.2.4.4). 
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 
diameter. 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 
diameter. 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 
The Double-Blind Treatment kit will consist of three boxes, one box for the Titration Period 
(titration sub-kit; contains three smaller boxes, one for each week) 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).  
The kit for the Double-Blind Treatment Phase will contain: 
• Titration sub-kit: 
− Week 1 – 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 
− Week 2 – 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 
− Week 3 – 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 


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• Stable dosing sub-kits: 
− Weeks 4 through 7 – 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 
− Weeks 8 through 11 – 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 
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 7. Study drug for the OLE 
Phase will be provided to patients as individual bottles for both the OLE Titration Period and the 
OLE Long-Term Dosing Period. 
Open-label pitolisant for Day 78 through the EOT 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 is 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 6. Patients will be instructed to record in the study drug dosing section of the study 
diary the number of tablets taken from each bottle daily; the time of study drug dosing will be 
recorded in the diary on the day prior to Visits 3 and 5. 
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 7. 
5.5. 
Study Drug Compliance 
Patients will be instructed to return all used and unused bottles of study drug at each on-site 
study visit.  


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Study drug compliance during the Double-Blind Treatment Phase of the study will be monitored 
by reviewing the patient study drug dosing diary in conjunction with the Investigator or designee 
conducting tablet counts based on the returned study drug. The patient’s study drug dosing diary 
will be reconciled with tablet counts, and any discrepancies investigated and documented. 
During TCs, compliance will be monitored by confirming the current dose of study drug being 
taken by the patient. 
Study drug compliance during the OLE Phase will be monitored during on-site visits by 
conducting tablet counts based on the returned study drug. During the OLE TCs, compliance will 
be monitored by confirming the current dose of study drug being taken by the patient as well as 
shipment/receipt of study drug in a quantity sufficient for 3 months (i.e., 90 days) of once daily 
administration. 
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] Good Clinical Practice [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 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 and the second Safety 
Follow-Up TC (30 +3 days after final dose of study drug, Section 7.4) 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 on 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. 
Except for the prohibited medications specified in Section 5.7.2, patients will be allowed to 
continue medications for the treatment of DM or other comorbidities as currently prescribed by 
their physicians. Wake-promoting agents including mixed amphetamine salts such as Vyvanse 
(lisdexamfetamine dimesylate), Adderall (amphetamine and dextroamphetamine) and similar 
agents that are prescribed to treat EDS are permitted. The use of hypnotics is allowed up to 
2 nights per week, but they are not allowed the night prior to any efficacy assessment. 
For concomitant medications administered due to an AE/serious adverse event (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. 
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 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 H1R 
antagonists (sedating antihistamines) that cross the blood-brain barrier may reduce the 
effectiveness of pitolisant. Concomitant use of centrally acting or sedating H1R antagonists is not 
permitted during the Double-Blind Treatment Phase of the study (requires a washout of 5 half-
lives 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 or sedating H1R antagonists, strong CYP2D6 inhibitors, strong 
CYP3A4 inducers, and medications that may prolong the QT interval are provided in 
Appendix E. 
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 response should be monitored, and pitolisant 


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dose may need to be increased. Pitolisant dose may only be increased up to the 
maximum permitted dose of 35.6 mg daily. 
Procedures for pitolisant dose adjustments in the OLE Phase are provided in Section 3.1.2.2. 


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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 Open-Label Extension 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 
DM1 will be obtained via review of the patient’s medical records; genetic testing will be 
performed during Screening to confirm CTG repeat of >100. 
6.1.2. 
Demographics 
Demographic information collected will include date of birth, sex, race, and ethnicity. In 
addition, a patient’s current employment status will be recorded in the eCRF. 
6.2. 
Efficacy Assessments 
Patients will be assessed for efficacy using validated scales, assessments, and questionnaires. 
Various symptoms of DM1 will be evaluated, including those related to EDS, fatigue, and 
cognitive functioning. The order of administering efficacy assessments is: DSS, FSS, Cogstate 
Detection Test, Cogstate Identification Test, Cogstate One-back Test, MDHI, ESS, PGI-S, and 
SART. The CGI-S will be assessed by the Investigator. The optional MWT will occur based on 
scheduling with the study site’s sleep lab. 
6.2.1. 
Daytime Sleepiness Scale 
The DSS is a questionnaire in which patients are asked to assess five items with scores of 
never (0), seldom (1), often (2), and always (3), one of which is scored in the reverse order. The 
DSS score can vary from 0 to 15 and the higher the score, the higher the degree of sleepiness. It 
was developed and validated in patients with DM1 in three sub-groups: early adult-onset (onset 
of symptoms from 11-20 years old), adult (onset of symptoms from 21-40 years old) and mild 
(onset of symptoms at >40 years old). The instrument has demonstrated construct (factorial) 
validity (Laberge et al 2004), convergent and discriminant validity (Laberge et al 2009; Laberge 
and Dauvilliers 2010) and responsiveness (Laberge et al 2022). The DSS is provided in 
Appendix F. 
6.2.2. 
Fatigue Severity Scale 
The FSS is a 9 item Patient Reported Outcome assessment that covers physical, social, and 
cognitive effects of fatigue such as function, work, and motivation (Krupp et al 1989). The 
9 items are summed and then averaged to produce a global score. Each item has seven choices 
from strongly disagree to strongly agree (1-7), and the recall period is the past week. The FSS 
takes approximately 2-3 minutes to complete. It has demonstrated content, construct, and 


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criterion validity and has demonstrated the ability to detect change (Hewlett et al 2011). The FSS 
has been used to evaluate fatigue in patients with DM (Hermans et al 2013; Laberge et al 2009). 
The FSS is provided in Appendix G. 
6.2.3. 
Cogstate Computerized Cognitive Battery Tests 
Cognition will be assessed using the Cogstate Computerized Cognitive Battery Tests, 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. Patients will undergo two short training sessions to become familiar 
with the test.  
6.2.3.1. 
Cogstate Detection Test (Psychomotor Function) 
The Cogstate Detection Test is a computerized measure of psychomotor function and uses a 
validated simple reaction time (RT) paradigm with playing card-like stimuli displayed on a 
computer 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. 
6.2.3.2. 
Cogstate Identification Test (Attention)  
The Cogstate Identification Test is a computerized measure of visual attention and uses a 
validated choice RT 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. 
6.2.3.3. 
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 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. 
6.2.4. 
Myotonic Dystrophy Health Index 
The MDHI is a disease-specific, patient-reported outcome measure for DM1. This instrument has 
been validated in a manner consistent with the FDA guidance on patient reported outcomes and 
is designed to accurately reflect the overall burden of disease from the patient’s perspective. It 


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focuses on the major symptoms experienced by patients with DM1 and prioritizes them by their 
relative importance to patients. It is scored on a scale of 0-100, with a higher score representing a 
higher burden of disease; subscales within the instrument are weighted so that certain themes, 
including sleep, fatigue, and cognitive impairment, have greater impact on the overall score. 
(Heatwole et al 2014 and Heatwole et al 2016). Overall, the MDHI is optimally suited to detect 
small but clinically relevant changes in several key areas of DM health over the course of a 
treatment trial and has been recognized by the DM working group of National Institute of 
Neurological Disorders and Stroke (NINDS) as one of the key assessments that should be used in 
clinical trials of patients with DM1 (NINDS 2014). The MDHI addresses several areas of health 
relevant to the condition. The tool consists of multiple symptom-related questions grouped into 
several themes including fatigue, sleep, and cognitive impairment. Subscales of the MDHI 
measure patients’ perception of their health as it relates to mobility, upper extremity function, 
ability to do activities, fatigue, pain, gastrointestinal issues, vision, communication, sleep, 
emotional issues, cognitive impairment, social satisfaction, social performance, myotonia, 
breathing, swallowing, and hearing. The MDHI is provided in Appendix H. 
6.2.5. 
Epworth Sleepiness Scale 
The ESS is a questionnaire with eight questions in which respondents are asked to rate, on a 4-
point scale (0-3), their usual chances of dozing or falling asleep while engaged in eight different 
activities. The questionnaire is a validated measure with high specificity and sensitivity for 
assessing subjective sleepiness in narcolepsy (Johns 1991). It has been deemed appropriate for 
the assessment of EDS in patients with DM1 by the NINDS and is recommended for use in this 
population (NINDS 2014). The total ESS score (sum of 8 item scores) can range from 0 to 24; 
the total score gives an estimate of the person’s ‘average sleep propensity’ (ASP), across a wide 
range of activities in their daily lives. The higher the ESS score, the higher that person’s ASP in 
daily life or their ‘daytime sleepiness’. The ESS is provided in Appendix I. 
6.2.6. 
Clinical Global Impression of Severity of Excessive Daytime Sleepiness   
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, Week 11/EOT in 
the Double-Blind Treatment Phase, and at each on-site study visit in the OLE Phase, the 
Investigator will rate his/her impression of the severity of the patient’s current overall clinical 
status related to EDS relative to the Investigator’s experience with this patient population, based 
on observed and reported symptoms and function. The CGI-S asks the clinician one question: 
“Considering your total clinical experience with this particular population, please rate the 
patient’s overall severity of EDS at this time”. The responses for this investigator-completed 
scale range from “none” to “severe”. The CGI-S is provided in Appendix J. 
6.2.7. 
Patient Global Impression of Severity of Excessive Daytime Sleepiness  
The PGI-S is a one-item, 4-point Likert rating scale completed by the patient to rate their overall 
impression of their EDS. At Baseline, Week 11/EOT in the Double-Blind Treatment Phase, and 
at each on-site study visit during the OLE Phase, patients will be asked to rate their impression of 
the overall severity of their symptoms of EDS over the past week, based on the impact EDS has 
on the patient’s ability to function during the day. The PGI-S of EDS asks the patient to rate their 
likelihood of falling asleep during daytime activities over the past week. The responses for the 


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patient-completed scale range from “none” to “high” The PGI-S for EDS is provided in 
Appendix K. 
6.2.8. 
Sustained Attention to Response Task  
The SART is a measure of sustained attention, which is the ability to focus on an activity or 
stimulus over a long period of time, or to direct focus and cognitive ability on specific stimuli. It 
is a computer-based go/no-go task that requires participants to withhold behavioral response to a 
single, infrequent target presented amongst a background of frequent non-targets. Both accuracy 
and response speed, quantified as RT, are important. The SART was developed to investigate 
lapses of sustained attention in individuals with neurological impairment. It also proved to be a 
useful tool to investigate sustained attention in a number of other clinical conditions including 
sleep disorders (van Schie et al 2012). Validation of the SART was done in patients with 
narcolepsy and is based on a comparison between patients with narcolepsy and healthy controls 
(Fronczek et al 2006). The SART is also considered a useful tool to measure treatment efficacy 
in narcolepsy (van der Heide et al 2015).  
6.2.9. 
Maintenance of Wakefulness Test 
The MWT, a daytime polysomnographic procedure for the evaluation of daytime 
somnolence/wakefulness, is used to assess an individual’s ability to stay awake while resisting 
the pressure to fall asleep. It is used clinically in disorders with excessive somnolence such as 
narcolepsy and sleep apnea syndrome (Browman et al 1983; Browman et al 1986; Poceta et al 
1992; Sangal et al 1992a). The MWT evaluates the magnitude of sleepiness in relationship to the 
underlying wakefulness system’s functioning. It has also been utilized to examine treatment 
efficacy (Sangal et al 1992b). When conducting the MWT, patients are administered four 
40-minute sessions at 2-hour intervals according to the validated standard (Doghramji et al 
1997), with the initial session beginning two hours after wakening. 
6.3. 
Safety Assessments 
6.3.1. 
Adverse Events 
All AEs, regardless of causality or seriousness, will be collected from the time the patient 
provides written informed consent through 30 days after the final dose of study drug (Safety 
Follow-up TC, Section 7.4). 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, Holter monitoring, 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. 
6.3.2. 
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 


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CV, respiratory, gastrointestinal, neurological, dermatological, and musculoskeletal systems. 
Abbreviated physical examinations will be performed based on patient-reported symptoms.  
Height and weight will be measured using standardized methods. Height will be recorded at 
Screening. Body weight will be recorded at Screening (Visit 1), Baseline (Visit 2), EOT 
(Visit 5), and all on-site study visits during the OLE Phase, as detailed in Section 7. 
6.3.3. 
Vital Signs 
Vital signs will include blood pressure, HR, 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. 
6.3.4. 
Holter Monitoring and 12-Lead Electrocardiograms 
Holter monitoring and triplicate 12-lead ECGs will be performed at Screening and during the 
Double-Blind Treatment Phase and OLE Phase of the study as detailed in Section 7. The Holter 
monitoring performed at Screening and the ECGs performed at Screening and Baseline will 
determine whether an exclusionary CV issue is present, and assessment at later time points 
during the study is designed to detect any changes in CV parameters and to detect the 
development of arrhythmias.  
A core ECG laboratory will manage all ECG and Holter monitoring activities, including 
standardization and training of the technical staff at all study sites in proper electrode placement, 
operation of the hardware, and management of patients during testing. Electrocardiogram and 
Holter monitoring data will be transmitted electronically to the core laboratory and will be 
promptly interpreted by trained cardiologists. Pre-specified criteria for QT, QRS duration, AVB, 
and arrhythmias will trigger immediate notifications.  
6.3.4.1. 
Holter Monitoring 
Holter monitoring will be performed during Screening (Visit 1) and Visit 3 (Day 22) during the 
Double-Blind Treatment Phase. Patients will be fitted with a Holter monitor, which they will 
wear for 24 hours before returning the device to the study site via courier or directly to the site if 
able, as detailed in a separate instructional document.  
In the OLE Phase, to monitor for arrhythmias at the time patients have reached their 35.6 mg 
dose of pitolisant, Holter monitoring (24-hour) will be initiated at the end of the OLE Titration 
Period at Visit 6 (Day 99).  
For all abnormal Holter monitor findings considered clinically significant by the Investigator, 
additional evaluation, including an unscheduled ECG, is required (the ECG can be performed 
locally); abnormal findings on follow-up ECGs should be addressed as detailed in 
Section 6.3.4.2. 
The Holter monitor must be placed on the patient and continuous recording started as the ECG 
data will be taken from the Holter monitor recording. 


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6.3.4.2. 
12-Lead Electrocardiograms 
Triplicate 12-lead ECGs will be obtained for all patients at every on-site study visit as detailed in 
Section 7. Patients should be resting for at least 5 minutes before each 12-lead ECG is 
performed. At Visit 3 and Visit 5, triplicate 12-lead ECGs will be performed with every blood 
sample collected for PK analyses, as detailed in Section 7.2.4.1 and Section 7.2.4.4, respectively. 
The ECGs should be done prior to and within 15 minutes of the blood draw for PK analyses. 
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 and sent to the Investigator for assessment; the Investigator will submit all 
ECGs done locally to the central ECG vendor. 
The following ECG abnormalities should be promptly addressed by the Investigator and will 
require discontinuation of study drug (Section 4.4.1):  
• Any ECG finding that demonstrates QT prolongation (i.e., QTcF >500 msec or an 
increase >60 msec) regardless of resultant QTc value  
In addition to a potential QT prolongation, the Medical Monitor should be consulted for: 
• PR interval >300 msec, QRS duration >140 msec, or any increase from baseline in 
PR or QRS greater than 50% or 40%, respectively 
• HR increase >65% over baseline or decrease >40% compared with baseline  
In the event of these clinically significant abnormal PR interval, QRS duration, or HR ECG 
results, the ECG should be repeated as soon as possible and if done the next day, attempts should 
be made to perform the repeat ECG at the same time of day that the abnormal ECG was 
obtained. If the event persists or worsens, study drug may be interrupted for 2 to 3 days and the 
ECG will be repeated on the third day. If the abnormality has improved, study drug dosing may 
resume. If the condition persists or worsens after the study drug interruption, the Investigator, in 
consultation with the Medical Monitor, will decide whether treatment should be permanently 
discontinued. 
6.3.5. 
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 8. Samples for clinical 
laboratory tests (serum chemistry and hematology) will be collected as outlined in Section 7. 
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.  
Patients will be administered supplements if their serum magnesium and/or potassium values 
decrease by 20% compared with Baseline or if the levels are in the low normal or below normal 
range. 


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The total volume of blood collected is not to exceed the maximal allowable for adults of 
10.5 mL/kg or 550 mL, whichever is smaller, over any 8-week period (NIH 2009). 
Table 8: 
Clinical Laboratory Tests 
Urine Drug Screen 
-Barbiturates 
-Cocaine metabolites 
-Opiates 
-Tetrahydrocannabinol 
-Cannabidiol 
-Phencyclidine 
-Methadone 
-Amphetamines/Stimulants  
-Hypnotics  
Urinalysis 
-Specific gravity 
-pH 
-Blood 
-Glucose 
-Protein 
-Leukocyte esterase 
-Ketones 
-Bilirubin 
-Nitrites 
-Casts 
-Crystals 
-Erythrocytes 
-Renal tubular epithelial cells 
-WBCs 
-Bacteria 
Pregnancy Screen (FCBP only) 
-Serum (at Screening only) 
-Urine (as scheduled after screening) 
Serum Chemistry 
-Albumin 
-Alkaline phosphatase 
-Alanine aminotransferase 
-Aspartate aminotransferase 
-Blood urea nitrogen 
-Calcium 
-Chloride 
-Creatinine 
-Creatine kinase 
-Glucose 
-High-density lipoprotein 
-Low-density lipoprotein 
-Magnesiuma 
-Phosphorus 
-Potassiuma 
-Sodium 
-Total bilirubin 
-Direct bilirubin 
-Total cholesterol 
-Total protein 
-Triglycerides 
-Uric acid 
 
Hematology 
-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 Patients will be administered supplements if serum magnesium and/or potassium levels decrease by 20% 
compared with Baseline, or if the levels are in the low normal or below normal range. 
 
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 Open-Label Extension Phase.  
NOTE: Wake-promoting agents including mixed amphetamine salts such as Vyvanse (lisdexamfetamine 
dimesylate), Adderall (amphetamine and dextroamphetamine) and similar agents that are prescribed to treat EDS are 
permitted. Mexilitene may cause a positive urine drug screen for amphetamine. In the event a urine drug screen is 
positive for amphetamines, consult with the Medical Monitor before screen failing the patient. Hypnotics are 
permitted during the study (Section 5.7.1). 
 


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6.3.6. 
Additional Safety Assessments 
Suicide Risk/Suicidality 
Suicide risk and suicidality at Screening will be assessed through the use of the Lifetime Recent 
C-SSRS (Appendix C). After Screening, suicidality will be evaluated at study visits and TCs 
through use of the Since Last Contact C-SSRS (Appendix D). 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). 
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. 
6.4. 
Pharmacokinetic Assessments 
Blood samples for determination of pitolisant and its major metabolite concentrations (trough 
and at the time of maximum concentration [tmax (3 hours ±30 minutes post dose)]) will be 
collected during the Stable Dose Period of the Double-Blind Treatment Phase (Visits 3 and 5), as 
detailed in Section 7.2.4.1 and Section 7.2.4.4, respectively. Triplicate 12-lead ECGs will be 
performed before each PK sample collection. At Visit 3, the Holter monitor should be placed on 
the patient and continuous recording started as the 12-lead ECG (in triplicate) data are taken 
from the Holter monitor recording. 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 9. The total 
volume of blood collected is not to exceed the maximal allowable for adults of 10.5 mL/kg or 
550 mL, whichever is smaller, over any 8-week period (NIH 2009). 
Detailed instructions on PK sample collection, processing, storage, and shipping procedures are 
provided in the Laboratory Manual. 
Table 9: 
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 5 (Day 77 ±3 days) 
4 
5 
4 
13 
PK = pharmacokinetics 
Note: Serum chemistry and hematology parameters are listed in Table 8. 
 
6.5. 
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 10).  


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6.5.1. 
Assessments that may be Completed Remotely 
Specific safety assessments including the assessment of AEs, the review of concomitant 
medications, and administration of the C-SSRS may be completed by the Investigator and/or site 
staff remotely using telemedicine technology. 
Specific efficacy assessments including administration of the DSS, FSS, MDHI, ESS, CGI-S, 
and PGI-S 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. 
6.5.2. 
Assessments that may be Completed at the Patient’s Home 
The following assessments may be completed by a home healthcare professional at the patient’s 
home under the guidance and supervision of the Investigator:  
• Vital signs 
• Abbreviated physical examination 
• 12-lead ECG (in triplicate) 
• Laboratory assessments  
• Other assessments including Holter monitoring and study drug accountability 
(Table 10) 
Visit 3 PK samples may be collected at the next on-site study visit or at an unscheduled visit if 
not able to be collected earlier. 
6.5.3. 
Other Considerations 
The Cogstate Computerized Cognitive Battery Tests, SART, and optional MWT, which are to be 
completed at the Baseline Visit (Visit 2) and EOT Visit (Visit 5) cannot be completed remotely; 
therefore, these assessments are required to be completed at the site. Every effort should be made 
for the Visit 2/Baseline and Visit 5/EOT to be completed at the study site according to the study 
schedule. 
If patients do not attend an on-site study visit, study drug may be sent to patients per the study 
site’s SOPs. 
Table 10: 
Alternative Methods for Completing Study Assessments 
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  
Informed Consent 
X 
 
 
Pregnancy Test (FCBP) 
 
X 
 
Urine Drug Screen 
 
X 
 


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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  
Abbreviated Physical 
Examination 
 
X 
 
Vital Signs 
 
X 
 
12-Lead ECG (in 
triplicate) 
 
X 
 
Holter Monitoringa 
 
X 
 
DSS, FSS, MDHI, ESS, 
CGI-S, PGI-S 
X 
 
 
Cogstate Detection, 
Identification, One Back  
 
 
X 
SART 
 
 
X 
Clinical Laboratory Tests 
 
X 
 
Blood Sample for PK 
 
 
X 
Adverse Events 
X 
X 
 
Concomitant Medications 
X 
X 
 
C-SSRS 
X 
 
 
Dispense Study Drug 
X 
 
 
Study Drug Compliance 
X 
 
 
Study Drug Accountability 
X 
X 
 
a When an ECG is also required, Holter monitor should be placed on the patient and continuous recording started as the ECG 
data are taken from the Holter monitor recording. 
 
CGI-S = Clinical Global Impression of Severity; C-SSRS = Columbia-Suicide Severity Rating Scale; DSS = Daytime Sleepiness 
Scale; ECG = electrocardiogram; ESS = Epworth Sleepiness Scale; FCBP = female of child-bearing potential; FSS = Fatigue 
Severity Scale; MDHI = Myotonic Dystrophy Health Index; MWT = Maintenance of Wakefulness Test; PGI-S = Patient Global 
Impression of Severity PK = pharmacokinetic(s); SART = Sustained Attention to Response Task 
 


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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, patients will undergo 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.  
Patients will be provided with a sleep diary (Appendix A) and 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) 
• Serum pregnancy test (FCBP only)  
• Urine drug screen (Table 8) 
• Full physical examination (Section 6.3.2) 
• Body weight and height (Section 6.3.2)  
• Vital signs (Section 6.3.3) 
• Clinical laboratory tests (serum chemistry, hematology, urinalysis; Table 8) 
• Genetic testing 
• 24-hour Holter monitoring (Section 6.3.4.1) 
• 12-lead ECG (in triplicate) (Section 6.3.4.2) 
• AEs (since providing written informed consent) 
• Concomitant medications (since providing written informed consent) 
• Risk of suicide/suicidality (C-SSRS Lifetime Recent; Appendix C) 
• Cogstate Detection Test training (Section 6.2.3.1) 
• Cogstate Identification Test training (Section 6.2.3.2) 
• Cogstate One Back Test training (Section 6.2.3.3) 
• MDHI (Section 6.2.4) 
• CGI-S for EDS (Section 6.2.6) 
• SART training (Section 6.2.8) 


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Patients who fail screening for any reason can be rescreened once at the discretion of the 
Investigator. 
7.2. 
Double-Blind Treatment Phase (Day -1 to Day 77) 
Section 3.1.1.2 provides details on study drug dosing during the 11-week Double-Blind 
Treatment Phase of the study. 
7.2.1. 
Baseline Visit (Visit 2; Day -3 to Day -1)  
The following assessments will be performed on Day -1:  
• Review of inclusion/exclusion criteria (patients must meet all eligibility criteria) 
(Section 4.1) 
• Medical history update (Section 6.1.1) 
• Urine pregnancy test (FCBP only)  
• Urine drug screen (Table 8) 
• Abbreviated physical examination (Section 6.3.2) 
• Body weight (Section 6.3.2) 
• Vital signs (Section 6.3.3) 
• Clinical laboratory tests (serum chemistry, hematology, urinalysis; Table 8) 
• 12-Lead ECG (in triplicate) (Section 6.3.4.2) 
• Review of AEs (since providing written informed consent) 
• Review of concomitant medications (since providing written informed consent) 
• C-SSRS (Since Last Update; Appendix D) 
• Optional MWT (Section 6.2.9) (to be performed only for those patients who provide 
written informed consent and are successfully scheduled for this assessment; these 
patients must return to the study site before the scheduled MWT); the MWT Baseline 
assessment may be performed up to 3 days in advance of Day 1 
• DSS (Section 6.2.1) 
• FSS (Section 6.2.2) 
• Cogstate Detection Test (Section 6.2.3.1) 
• Cogstate Identification Test (Section 6.2.3.2) 
• Cogstate One Back Test (Section 6.2.3.3) 
• MDHI (Section 6.2.4) 
• ESS (Section 6.2.5) 
• CGI-S of EDS (Section 6.2.6)  
• PGI-S of EDS (Section 6.2.7) 


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• SART (Section 6.2.8) 
Patients who meet all eligibility criteria at the Baseline Visit will be randomized at a 1:1:1 ratio 
to receive treatment with lower dose pitolisant, higher dose pitolisant, or matching placebo as 
detailed in Section 3.1.1.2.  
Eligible patients will be dispensed a study drug dosing diary and study drug sub-kit for titration 
for Week 1 through Week 3; patients will be instructed to take study drug once daily in the 
morning upon wakening and to record daily the date and number of tablets of study drug taken 
(Section 5.4.1 and Appendix B). 
Patients will receive study drug after completion of Day -1 assessments and will be instructed to 
take their first dose of study drug on the morning after they receive their study drug from the site 
(i.e., the first day of study drug dosing is Day 1). 
Patients will be instructed to bring the study drug dosing diary and all used and unused bottles of 
study drug with them to all on-site study visits. The study drug dosing diary will be completed 
only during the Double-Blind Treatment Phase of the study.  
7.2.2. 
Titration Period, Double-Blind Phase (Days -1 to 21) 
Eligible patients will be titrated to their randomized dose during a 3-week Titration Period. First 
day of blinded treatment will be on the day following the Baseline Visit (Day 1) and study drug 
dose will be titrated on Day 8 and again on Day 15; all patients will be at their randomized dose 
of study drug by Day 15 (Table 6). 
7.2.3. 
Telephone Contacts (TC 1 and TC 2) (Days 8 and 15 ±3 Days) 
After completion of the Baseline Visit (Day -1), no additional on-site study visits are scheduled 
during the Titration Period in the Double-Blind Treatment Phase. Patients 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 (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, complete the C-SSRS, and review/confirm titration of 
study drug dose. 
7.2.4. 
Stable Dose Period, Double-Blind Phase (Days 22 to 77) 
Patients will continue to take study drug at their randomized dose during the Stable Dose Period 
in the Double-Blind Treatment Phase and will return to the study site on Days 22, 49, and 77 
(±3 days; Visits 3, 4, and 5, respectively) for safety and efficacy assessments. Pharmacokinetic 
assessments will be performed on Visits 3 and 5. Patients will be contacted by the study site by 
telephone on Day 28 (±3 days; TC 3). The last dose of blinded treatment is on Day 77 ±3 days 
(Visit 5; EOT Visit in the Double-Blind Treatment Phase). 
7.2.4.1. 
Visit 3 (Day 22 ±3 Days)  
To accommodate PK sample collection at Visit 3, patients will be instructed to not take their 
daily dose of study drug before arriving at the study site; patients will bring their study drug and 
study diary with them to the study visit (time of study drug administration on the day before 
Visit 3 should be recorded in the study diary).  


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Study drug administration will be at the study site and timing will be based on timing of the PK 
sampling and 12-lead ECGs. 
12-lead ECGs and blood sample collection for PK analyses:  
• Holter monitor should be placed on the patient and continuous recording started as 
ECG data are taken from the Holter recording. 
• 12-lead ECGs (in triplicate) and a blood sample collection for PK analyses will be 
performed before study drug is administered (the time of the ECG and blood sample 
collection for PK must be recorded). The ECGs should be done prior to and within 
15 minutes of the pre-dose blood sample collection for PK analyses. 
• After the 12-lead ECGs and PK sample collection are completed, patients will be 
administered study drug (the time of study drug administration must be recorded). 
• Additional 12-lead ECGs and blood sample collection for PK analyses will be 
performed at 3 hours (±30 minutes) after dosing (the time of each ECG and blood 
sample collection for PK must be recorded). The ECGs should be done prior to and 
within 15 minutes of the post-dose blood sample collection for PK analyses. 
The following assessments will also be performed at Visit 3: 
• Urine pregnancy test (FCBP only)  
• Abbreviated physical examination (Section 6.3.2) 
• Vital signs (Section 6.3.3) 
• Clinical laboratory tests (serum chemistry, hematology, urinalysis) (Table 8) 
• Review of AEs  
• Review of concomitant medications  
• C-SSRS (Since Last Update; Appendix D) 
• Review study drug compliance/accountability (Section 5.5 and Section 5.6) 
• 24-hour Holter monitoring  
Patients will be dispensed study drug in a sub-kit for Week 4 through Week 7. 
7.2.4.2. 
Telephone Contact (TC 3) (Day 28 ±3 Days) 
Patients will be contacted by the study site by telephone on Day 28 (±3 days; TC 3) 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, complete the C-SSRS, and confirm compliance with 
administration of study drug. 
7.2.4.3. 
Visit 4 (Day 49 ±3 Days) 
The following assessments will be performed at Visit 4: 
• Urine pregnancy test (FCBP only)  


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• Abbreviated physical examination (Section 6.3.2) 
• Vital signs (Section 6.3.3) 
• Clinical laboratory tests (serum chemistry, hematology, urinalysis) (Table 8) 
• 12-Lead ECG (in triplicate) (Section 6.3.4.2) 
• Review AEs  
• Review concomitant medications  
• C-SSRS (Since Last Update; Appendix D) 
• DSS (Section 6.2.1) 
• FSS (Section 6.2.2) 
• MDHI (Section 6.2.4) 
• ESS (Section 6.2.5) 
• CGI-S of EDS (Section 6.2.6) 
• PGI-S of EDS (Section 6.2.7) 
Patients will be dispensed study drug in a sub-kit for Week 8 through Week 11. 
7.2.4.4. 
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.  
To accommodate PK sample collection at Visit 5, patients will be instructed to not take their 
daily dose of study drug before arriving at the study site; patients will bring their study drug and 
study diary with them to the study visit (time of study drug administration on the day before 
Visit 5 should be recorded in the study diary).  
Study drug administration will be at the study site and timing will be based on timing of the PK 
sampling and 12-lead ECGs. 
12-lead ECGs and blood sample collection for PK analyses:  
• 12-lead ECGs (in triplicate) and a blood sample collection for PK analyses will be 
performed before study drug is administered (the time of the ECG and blood sample 
collection for PK must be recorded). 
• After the 12-lead ECGs and PK sample collection are completed, patients will be 
administered study drug (the time of study drug administration must be recorded). 
• Additional 12-lead ECGs and blood sample collection for PK analyses will be 
performed at 3 hours (±30 minutes) after dosing (the time of each ECG and blood 
sample collection for PK must be recorded). The 12-lead ECGs should be conducted 
prior to and within 15 minutes of blood sample collection for PK analyses. 
The following assessments will also be performed at Visit 5: 
• Urine pregnancy test (FCBP only)  


Protocol No: HBS-101-CL-005, Amendment 5 
 
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Phase 2 Safety and Efficacy Study 
 
 
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• Urine drug screen (Table 8) 
• Full physical examination (Section 6.3.2) 
• Body weight (Section 6.3.2) 
• Vital signs (Section 6.3.3) 
• Clinical laboratory tests (serum chemistry, hematology, urinalysis) (Table 8) 
• Review of AEs 
• Review of concomitant medications 
• C-SSRS (Since Last Update; Appendix D) 
• Optional MWT (Section 6.2.9) 
− If a patient enrolled prior to protocol Amendment 4 (i.e., had MWT Baseline 
assessment) the MWT at Week 11 must be performed.  
− If a patient enrolled after protocol Amendment 4 was implemented, this is an 
optional assessment, to be conducted only for those patients who provide written 
informed consent. 
− The EOT (Week 11) MWT assessment should not be performed on the same day 
as the Visit 5 PK as patients will take their dose of study drug at the site after 
ECGs and the pre-dose PK blood draw are done. The EOT (Week 11) MWT may 
be conducted up to 3 days in advance of Day 77; patients should take their dose of 
study drug on the morning of the scheduled Week 11 MWT assessment.  
• DSS (Section 6.2.1) 
• FSS (Section 6.2.2) 
• Cogstate Detection Test (Section 6.2.3.1) 
• Cogstate Identification Test (Section 6.2.3.2) 
• Cogstate One Back Test (Section 6.2.3.3) 
• MDHI (Section 6.2.4) 
• ESS (Section 6.2.5) 
• CGI-S of EDS (Section 6.2.6) 
• PGI-S of EDS (Section 6.2.7)  
• SART (Section 6.2.8) 
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 OLE pitolisant for titration 
(Section 5.4.2); 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). 


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Patients who do not enter the OLE Phase will receive Safety Follow-up TCs from the study site 
15 (± 3) days and 30 (+3) days after last dose of blinded treatment, as outlined in Section 7.4. 
7.2.5. 
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 7.2.4.4). 
Patients who discontinue from the Double-Blind Treatment Phase prior to Day 77 may not enroll 
in the OLE Phase of the study. 
7.3. 
Open-Label Extension Phase (Day 78 to End-of-Treatment) 
Eligible patients who enter the OLE Phase of the study will begin a 3-week titration period after 
completion of the Double-Blind Treatment Phase. The Titration Period for the OLE will start on 
Day 78 (±3 days) and will end on Day 98 (±3 days); the Long-Term Dosing Period will start on 
Day 99 (±3 days) and will end at Day 459/Month 15 (EOT; Visit 8) for each patient unless the 
patient withdraws from the study early or the Sponsor elects to terminate the study.  
Section 3.1.1.3 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) 
based on Investigator assessment of tolerability as outlined in Section 3.1.2.2. 
7.3.1. 
Titration Period; Open-Label Extension Phase (Days 78 to Day 98) 
Patients will be titrated to a 35.6 mg dose of open-label pitolisant during the 3-week Titration 
Period as detailed in Table 7. Patients will receive their first dose on Day 78 (±3 days); pitolisant 
dose will be titrated on Day 85 (±3 days) and again on Day 92 (±3 days), with patients reaching a 
dose of 35.6 mg (or a maximum dose up to 35.6 mg based on Investigator assessment of 
tolerability) by Day 92; dose adjustments are permitted (Section 3.1.2.2).  
No study visits are scheduled during the OLE Titration Period. Patients will be contacted by the 
study site by telephone on Days 85 and 92 (±3 days; TCs 4 and 5, respectively) 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, complete the C-SSRS, and review/confirm titration of 
study drug. 
7.3.2. 
Long-Term Dosing Period, Open-Label Extension Phase (Day 99 to End of 
Treatment) 
Patients will continue to take open-label pitolisant (35.6 mg or their maximum dose up to 
35.6 mg based on Investigator assessment of tolerability) during the OLE Long-Term Dosing 
Period as detailed in Table 7, with dosing adjustments permitted as described in Section 3.1.2.2.  
The Long-Term Dosing Period will begin on Day 99 (±3 days); patients will have an on-site 
study visit on that day (Visit 6; Section 7.3.2.1) followed by alternating follow-up TCs to assess 
safety (Section 7.3.2.2) and on-site study visits approximately every 3 months (90 days ±7 days) 
to assess safety and effectiveness (Section 7.3.2.3). This pattern of alternating TCs and on-site 


Protocol No: HBS-101-CL-005, Amendment 5 
 
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Phase 2 Safety and Efficacy Study 
 
 
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study visits will be repeated until Day 459/Month 15 (Visit 8) unless the patient withdraws from 
the study early or the Sponsor elects to terminate the study. 
7.3.2.1. 
Visit 6 (Day 99 ±3 Days)  
Patients will return to the study site on Day 99 (±3 days); the following assessments will be 
performed: 
• Urine pregnancy test (FCBP only)  
• Urine drug screen (Table 8) 
• Full physical examination (Section 6.3.2) 
• Body weight (Section 6.3.2) 
• Clinical laboratory tests (serum chemistry, hematology, urinalysis) (Table 8) 
• Vital signs (Section 6.3.3) 
• 12-lead ECG (in triplicate) (Section 6.3.4.2) 
• 24-hour Holter monitoring (Section 6.3.4.1) 
• Review of AEs 
• Review of concomitant medications 
• C-SSRS (Since Last Update; Appendix D) 
• DSS (Section 6.2.1) 
• FSS (Section 6.2.2) 
• Cogstate Detection Test (Section 6.2.3.1) 
• Cogstate Identification Test (Section 6.2.3.2) 
• Cogstate One Back Test (Section 6.2.3.3) 
• MDHI (Section 6.2.4) 
• ESS (Section 6.2.5) 
• CGI-S of EDS (Section 6.2.6) 
• PGI-S of EDS (Section 6.2.7) 
• 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 this visit. 
7.3.2.2. 
Telephone Contacts; Day 189 (±7 Days; TC 6) and Day 369 (±7 days; TC 7) 
Patients will receive a TC from the study site on Day 189 (±7 days) and approximately 6 months 
later (Day 369 ±7 days) unless the patient withdraws from the study early or the Sponsor elects 
to terminate the study.  


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The following will be recorded at each TC: 
• Review AEs 
• Review concomitant medications 
• C-SSRS (Since Last Update; Appendix D)  
• Confirm shipment/receipt of the next 3-month (90-day) supply of study drug  
• Review study drug compliance/accountability (Section 5.5 and Section 5.6) 
Additional unscheduled TCs may be conducted as needed to discuss potential dose changes, 
arrange for shipment of additional study drug, if necessary, report AEs, or to complete other 
assessments if clinically indicated in the opinion of the Investigator. 
7.3.2.3. 
Visit 7 (Day 279 [±7 Days]) 
Patients will undergo the following assessments at on-site study visits:  
• Urine pregnancy test (FCBP only)  
• Urine drug screen (Table 8) 
• Full physical examination (Section 6.3.2) 
• Body weight (Section 6.3.2) 
• Clinical laboratory tests (serum chemistry, hematology, urinalysis) (Table 8) 
• Vital signs (Section 6.3.3) 
• 12-lead ECG (in triplicate) (Section 6.3.4.2) 
• Review of AEs  
• Review of concomitant medications 
• C-SSRS (Since Last Update; Appendix D) 
• DSS (Section 6.2.1) 
• FSS (Section 6.2.2) 
• Cogstate Detection Test (Section 6.2.3.1) 
• Cogstate Identification Test (Section 6.2.3.2) 
• Cogstate One Back Test (Section 6.2.3.3) 
• MDHI (Section 6.2.4) 
• ESS (Section 6.2.5) 
• CGI-S of EDS (Section 6.2.6) 
• PGI-S of EDS (Section 6.2.7) 
• Review study drug compliance/accountability (Section 5.5 and Section 5.6) 


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Patients will be dispensed study drug in a quantity sufficient for 3 months (i.e., 90 days) of once 
daily administration at this visit. 
7.3.2.4. 
Visit 8/End-of-Treatment Visit for the Open-Label Extension Phase 
Patients are to undergo an EOT Visit (Visit 8) 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 7, which is a 6-month on-site study visit (Section 7.3.2.3). 
7.3.2.5. 
Early Termination Visit for the Open-Label Extension Phase 
Every effort should be made to perform the ET Visit 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 7, which is a 6-month on-site study visit (Section 7.3.2.3). 
7.4. 
Safety Follow-Up Telephone Contacts  
Patients in the Double-Blind Treatment Phase who do not enter the optional OLE Phase will 
receive a TC from the study site 15 (±3) days and 30 (+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 concomitant medication use.  
Patients in the OLE Phase will receive a TC from the study site 15 (±3) days and 30 (+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 concomitant medication use.  
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. 
7.5. 
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 a minimum, the following assessments are to be performed at unscheduled on-site study 
visits: 
• Abbreviated physical examination (Section 6.3.2) 
• Vital signs (Section 6.3.3) 
• Review of AEs 
• Review of concomitant medications 
• Review of study drug compliance/accountability (Section 5.5 and Section 5.6) 


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At a minimum, the following assessments are to be performed at unscheduled visits conducted 
by telephone: 
• Review of AEs 
• Review of concomitant medications 
• Review of study drug compliance/accountability (Section 5.5 and Section 5.6) 
Other assessments (e.g., 12-lead ECGs, clinical laboratory tests, urine pregnancy test, C-SSRS) 
may be completed based on the reason for the unscheduled visit and at the Investigator’s 
discretion. Unscheduled visits for clinically significant Holter monitoring results require a 
12-lead ECG (in triplicate) to be performed as detailed in Section 6.3.4. 


Protocol No: HBS-101-CL-005, Amendment 5 
 
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Phase 2 Safety and Efficacy Study 
 
 
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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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Phase 2 Safety and Efficacy 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 
the AE was caused by the study drug. 


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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 provides written informed consent through 30 (+3) days after final dose of study drug 
(Safety Follow-up TCs, Section 7.4).  
For patients who receive study drug in the Double-Blind Treatment 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 
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All AEs and SAEs will be followed after the last scheduled study visit until the event resolves, 
the condition stabilizes, or the event is otherwise explained or judged by the Investigator to be no 
longer clinically significant (unless the patient is lost to follow-up or the patient 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, he/she must notify the Sponsor within 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 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 


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other identifying information not collected in the patient’s eCRF) is to be redacted from copies 
of the patient’s medical records. 
In rare circumstances and in the absence of e-mail capacity, a copy of the SAE reporting form 
may be sent to the Sponsor by overnight mail. Initial notification via telephone does not replace 
the need for the Investigator to complete the SAE information in the eCRF within the timeframes 
outlined. 
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 


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appropriate project contact for SAE receipt is essential so that serious suspected adverse 
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 
e-mailing 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, 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. 
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 DSS score from Baseline to Week 11 
for pitolisant compared with placebo. The primary comparison of interest will be higher dose 
pitolisant compared with placebo. 
The target population is all patients in the modified intent-to-treat (mITT) population with DM1 
as defined by the inclusion/exclusion criteria. 
A treatment policy strategy will be utilized to address intercurrent events. Data will be analyzed 
as reported; no special data handling or imputation will be applied to account for intercurrent 
events such as use of concomitant medications, halting treatment, or study discontinuation.  
The population-level summary will be the least-square means from the primary endpoint model 
(Section 9.4.2.1.1). 
9.1.2. 
Multiple Comparisons 
The DSS will be the primary endpoint measure. All statistical analyses will be purely descriptive.  
9.1.3. 
Missing Data 
Every effort will be made to retain patients in the study; however, patients are free 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 early termination visit for completion of assessments (Schedule of Assessments, 
Double-Blind Treatment Phase).  
9.2. 
Determination of Sample Size 
 
 
 


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9.3. 
Analysis Populations 
The safety analyses will be conducted on the safety population. The mITT 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. 
Modified Intent-to-Treat Population 
The mITT 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. 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. Patients will be analyzed according to treatment 
received in the Double-Blind Treatment Phase (identical to the group they are reported under for 
the double-blind safety), active arms pooled, and overall. 
9.3.4. 
Pharmacokinetic Population 
The PK population will include all patients who received at least one dose of study drug and 
have calculable concentrations of pitolisant and/or its major metabolite 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 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 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. 


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Demographics and baseline characteristics will be reported for the efficacy, double-blind safety, 
open-label safety, and PK 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 that enter the OLE Phase. 
9.4.2. 
Efficacy Analysis 
9.4.2.1. 
Double-Blind Treatment Phase 
Double-Blind analyses will be completed once all patients have completed (or discontinued) the 
Double-Blind Treatment Phase of the study, and the associated data are frozen and unblinding is 
completed; patients may still be ongoing in the OLE Phase of the study at the time Double-Blind 
analyses are performed. 
9.4.2.1.1. Primary Efficacy Analysis 
Summary statistics (mean, SD, median, minimum, maximum) for the primary efficacy endpoint 
will be reported for the change from the Baseline Visit to Week 11 for each of the treatment 
groups and for the active groups combined. The change from Baseline will be analyzed with 
mixed model repeated measures (MMRM). Fixed effects will be included for treatment, baseline 
value, treatment visit, treatment × visit interaction, and wake-promoting agent stratification 
factor. Least square means (LSMs), standard errors, and the LSM 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. 
9.4.2.1.2. Secondary Efficacy Analysis 
Analysis of the secondary efficacy endpoints will utilize parallel methodology to that used for 
the primary efficacy analysis, adjusted as appropriate for distributions and collection time points. 
Full details will be provided in the SAP. 
9.4.2.2. 
Open-Label Extension Analyses 
Summary statistics will be reported for the measures of effectiveness at each visit where it is 
collected.  
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 tabulated or listed. No formal statistics will be performed for 
the safety analysis. 
Adverse events that occur between the time written informed consent is provided and the start of 
study drug administration will be considered pretreatment AEs. Adverse events that start during 
or after study drug administration, or AEs with an onset prior to study drug administration that 
worsen after study drug administration will be considered TEAEs. 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. 
Adverse events will be summarized with counts and percentages.  


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Laboratory parameters will be summarized. 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 in and out of the normal range as well as by visit. Laboratory parameters will also be 
summarized by visit. 
The change from Baseline to each visit for vital sign variables will be summarized. Abnormal 
vital sign values will be flagged and listed. ECG and Holter monitor abnormalities, cardiac 
arrhythmias and other categorical outcomes will be summarized with counts and percentages. 
Continuous outcomes will be reported using summary statistics. Results of C-SSRS will be 
listed. 
9.4.4. 
Pharmacokinetic Analyses 
Concentrations of pitolisant and its major metabolite will be assayed using a validated 
bioanalytical method. Trough and tmax (3 hours [±30 minutes] post dose) concentrations will be 
reported in the CSR. Concentration-time data of pitolisant and BP1.3484 will be summarized 
using descriptive statistics. 
9.5. 
Interim Analysis 
No interim analysis is planned. 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/Ethics Committee Approval  
The Investigator or the Sponsor is responsible for submitting the following documents to the 
IRBs/ECs for review and, if applicable, approval: study protocol, ICF, 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 ICF 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 Process 
All references to “patient” in this section refer to the study patient or his/her legally authorized 
representative. 
The Sponsor (or its designee) will provide Investigators with an ICF for this study. Investigators 
may adapt the information to suit the needs of their institution, if necessary, but it must reflect 
the required elements of informed consent specified in 21 CFR Part 50.25. The final ICF must be 
accepted by the Sponsor and approved by the IRB/EC. Investigators must provide the Sponsor 
with an unsigned copy of the final ICF 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 ICF, the Sponsor will provide 
Investigators with a revised ICF.  
Prior to participating in any study-related procedure, each patient must sign and date an 
IRB/EC-approved ICF written in a language the patient can understand. The ICF should be as 


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nontechnical as practical and understandable to the patient. The ICF 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 ICF details the requirements of the participant and the fact that they 
are free to withdraw at any time without giving a reason and without prejudice to their further 
medical care. Before informed consent 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 ICF will be stored in the Investigator’s site file and made available for 
review by the Sponsor. Documentation of the informed consent discussion must be noted in the 
patient’s case history. All patients will receive a copy of their signed and dated ICF. 
If the ICF is revised during the study and requires the patient to be re-consented, informed 
consent will be obtained in the same manner as for the original ICF. 
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 identification 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 
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 


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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 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, e-mails, 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 documents, 
patient recruitment procedures, patients’ compliance with the 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 due to potential 
restrictions related to the COVID-19 pandemic, 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, 
ICFs, 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 


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be documented at the site and in the Sponsor files. In the event of an important protocol 
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 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 course of 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 


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submit for publication results of its interventional clinical studies according to the prespecified 
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 
CSR is written in compliance with ICH E3 (Structure and Content of Clinical Study Reports) and 
submitted to the regulatory authorities, as required. Where required by applicable regulations, an 
Investigator signatory will be identified for the approval of the CSR. 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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Yu H, Laberge L, Jaussent I, et al. Daytime sleepiness and REM sleep characteristics in 
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APPENDIX A. PATIENT SLEEP DIARY FOR SCREENING (EXAMPLE) 
 


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APPENDIX B. PATIENT STUDY DRUG DOSING DIARY FOR DOUBLE-
BLIND TREATMENT PHASE (EXAMPLE) 
 


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APPENDIX C. COLUMBIA-SUICIDE SEVERITY RATING SCALE-
LIFETIME RECENT  
 


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APPENDIX D. COLUMBIA-SUICIDE SEVERITY RATING SCALE-
SINCE LAST CONTACT 
 


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APPENDIX E. EXAMPLES OF STRONG CYP2D6 INHIBITORS, 
STRONG CYP3A4 INDUCERS, MEDICATIONS THAT 
PROLONG QT INTERVAL, AND CENTRALLY ACTING 
H1R 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 
Centrally acting H1R antagonists  
(sedating or lipophilic H1R antagonists) 
pheniramine maleate, diphenhydramine, promethazine (anti-
histamines) imipramine, clomipramine, mirtazapine (tri or 
tetracyclic antidepressants)  
CYP = cytochrome P450; H1R = histamine 1 receptor 
 


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APPENDIX F. DAYTIME SLEEPINESS SCALE (DSS) 
 


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APPENDIX G. FATIGUE SEVERITY SCALE (FSS) 
 


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APPENDIX H. MYOTONIC DYSTROPHY HEALTH INDEX (MDHI) 
 
 
 
 


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APPENDIX I. EPWORTH SLEEPINESS SCALE (ESS) 
 
 


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APPENDIX J. CLINICAL GLOBAL IMPRESSION OF SEVERITY 
(CGI-S) FOR EXCESSIVE DAYTIME SLEEPINESS   
 
 
 
  
 
 
 
 
 


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APPENDIX K. PATIENT GLOBAL IMPRESSION OF SEVERITY (PGI-S) 
FOR EXCESSIVE DAYTIME SLEEPINESS 
 
  
 
 
 
  
 
 
  
 
 

SAP_001.pdf: 
 
Official Title of Study: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
the Safety and Efficacy of Pitolisant on Excessive Daytime Sleepiness and Other Non-Muscular 
Symptoms in Patients with Myotonic Dystrophy Type 1, Followed by an Open-Label Extension  
 
NCT Number: NCT04886518 
 
SAP Date (last revision date): November 3, 2023 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
Version Date: 03Nov2023 
Sponsor: Harmony Biosciences, LLC 
 
Protocol No: HBS-101-CL-005 
 
PRA-QMS-02745 8.0 
Page 1 of 42 
Strictly Confidential.  © 2023, ICON Clinical Research.  All rights reserved. 
 
Statistical Analysis Plan (SAP) 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Safety and Efficacy of Pitolisant on Excessive 
Daytime Sleepiness and Other Non-Muscular Symptoms in 
Patients with Myotonic Dystrophy Type 1, Followed by an 
Open-Label Extension 
Protocol Version No./Date: 
Protocol Amendment 5 / 18Jul2023 
CRF Version No./Date: 
Version 4.0 / 09May2023 
SAP Version No./Date: 
Version 3.0 / 03Nov2023 
 
1 Approvals 
Sponsor 
Sponsor Name: 
Harmony Biosciences, LLC 
Representative/ Title: 
 
 
 
Signature /Date: 
 
 
 
 
 
 
 
ICON 
Biostatistician / Title: 
 
Signature /Date: 
 
 
 
 
 
 
 
 
 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
Version Date: 03Nov2023 
Sponsor: Harmony Biosciences, LLC 
 
Protocol No: HBS-101-CL-005 
 
PRA-QMS-02745 8.0 
Page 2 of 42 
Strictly Confidential.  © 2023, ICON Clinical Research.  All rights reserved. 
 
2 Change History 
The table below details changes from the prior approved version of the statistical analysis plan (SAP). 
Version/Date 
Change Log 
1.0 / 27-Apr-2021 
Created as new 
2.0 /03Nov2023 
Section 6.0: Updated the protocol version and the change of CRO name. 
Section 6.1: Added justification to indicate that treatment is summarized by total 
treatment in the Open-Label Extension Phase of the study. 
Section 8.1: Updated the section to match changes in the protocol to the duration of  
(i.e. to define the end of the Open-Label Extension Phase of the study).  
Section 8.2:  
• 
Removed sample size and statistical power estimation. 
• 
Updated the section to match changes in the protocol to the sample size 
considerations. 
Section 8.3: Added stratification factor in the randomization. 
Section 9.1:  
• 
Updated the section to match changes in the protocol to the primary efficacy 
endpoint. 
• 
Removed Z-score (aggregation of Daytime Sleepiness Scale [DSS] and 
Mean Sleep Latency [MSL]) endpoint  
Section 9.2.1:  
• Updated visit window in the Double-Blind Treatment Phase to be identical 
across assessments. 
• Updated visit window schedule for the Open-Label Extension Phase (last visit 
is now visit 8 / Month 15). 
• Updated Visit label to include the visit number and study day/month.  
• Added rules for revising study day, if there is a re-start in dose escalation in 
the Double-Blind Treatment Phase. 
Section 10.0: Clarified the analysis population and treatment group for the Open-
Label Extension Phase. 
Section 10.3: Updated details on how the patients will be summarized. 
Section 10.4: Revised PK population definition to match the protocol. 
Section 10.5: Removed Maintenance of Wakefulness Test (MWT) population  
Section 11.0: Updated the section to match changes in the protocol. 
Section 11.1.1: Revised to add screen failure details and patient disposition with 
respect to treatment and study during the Open-Label Extension Phase. 
Section 11.1.2: Clarified summary for Double-Blind Treatment Phase and overall for 
the OLE Phase.  
Section 11.1.3: Clarified that the failed inclusion/exclusion criteria for randomized 
patients will be listed. 
Section 11.2.3: Removed summary for the seizure history, as it is not required. 
Section 11.3.3: New added section to provide details on identifying wake-promoting 
agents. 
Section 11.4: Clarified that wake-promoting agents at randomization will also be 
derived from the database.  
 
Added stratification factor to inferential model. In addition, minor reorganization to 
section numbering to accommodate revisions to match changes in the protocol. 
Section 11.4.1:  


 
 
Statistical Analysis Plan (SAP) 
 
 
 
Version Date: 03Nov2023 
Sponsor: Harmony Biosciences, LLC 
 
Protocol No: HBS-101-CL-005 
 
PRA-QMS-02745 8.0 
Page 3 of 42 
Strictly Confidential.  © 2023, ICON Clinical Research.  All rights reserved. 
 
• 
Updated the section to match changes in the protocol. 
• 
Replaced Analysis of Covariance (ANCOVA) with Mixed Model Repeated 
Measures (MMRM) for primary endpoint analysis method 
Section 11.4.1.1: Updated pooling strategy to clarify the pooled active groups. 
Section 11.4.3: Removed analysis of site effect in statistical models for study 
endpoint analysis. 
Section 11.4.3.1.2: Removed multiple imputation (MI) and sensitivity analyses 
Section 11.6.1: Included summary by system organ and class and preferred term for 
all adverse events and all serious adverse events. 
Section 11.6.3: Added details on imputation of results reported as “<xx” or “>xx”. 
Section 11.6.4: Added vital sign reference ranges and shift table summary. Removed 
abnormal criteria and associated summary. 
Appendix 4: Added stratification factor in SAS code examples. 
 
 
 


 
 
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3 Table of Contents 
1 
Approvals .............................................................................................................................................. 1 
2 
Change History...................................................................................................................................... 2 
3 
Table of Contents .................................................................................................................................. 4 
4 
Purpose ................................................................................................................................................. 6 
5 
Scope .................................................................................................................................................... 6 
6 
Introduction ............................................................................................................................................ 6 
6.1 
Changes from Protocol............................................................................................................. 6 
7 
Study Objectives ................................................................................................................................... 7 
7.1 
Primary Objectives ................................................................................................................... 7 
7.2 
Secondary Objectives .............................................................................................................. 7 
8 
Study Design ......................................................................................................................................... 7 
8.1 
General Design ........................................................................................................................ 7 
8.2 
Study and  Patient Completion ................................................................................................. 8 
8.3 
Sample Size Considerations .................................................................................................. 11 
8.4 
Randomization ....................................................................................................................... 11 
9 
Study Endpoints, Conventions and Derivations .................................................................................. 12 
9.1 
Endpoints ............................................................................................................................... 12 
9.2 
Study Day Windows ............................................................................................................... 13 
9.2.1 
Visit Window .......................................................................................................................... 13 
9.2.2 
Data Selection for Multiple Results ....................................................................................... 14 
9.3 
Baseline .................................................................................................................................. 15 
9.4 
Double-Blind and OLE Analyses Reporting ........................................................................... 15 
10 
Analysis Sets ....................................................................................................................................... 15 
10.1 
Modified Intent-to-Treat Population ........................................................................................ 16 
10.2 
Double-Blind Safety Population ............................................................................................. 16 
10.3 
Open-Label Safety Population ............................................................................................... 16 
10.4 
Pharmacokinetic Population ................................................................................................... 16 
11 
Statistical Methods .............................................................................................................................. 16 
11.1 
Patient Disposition .................................................................................................................. 16 
11.1.1 
Disposition ............................................................................................................................. 16 
11.1.2 
Important Protocol Deviations ............................................................................................... 17 
11.1.3 
Inclusion and Exclusion Criteria ............................................................................................ 17 
11.2 
Demographic and Baseline Characteristics ........................................................................... 17 
11.2.1 
Demographics ....................................................................................................................... 17 
11.2.2 
Medical History ...................................................................................................................... 17 
11.2.3 
Seizure History ...................................................................................................................... 18 
11.2.4 
Myotonic Dystrophy Type 1 History ...................................................................................... 18 
11.3 
Treatments ............................................................................................................................. 18 
11.3.1 
Prior, Concomitant and Prohibited Medications .................................................................... 18 
11.3.2 
Prohibited and Restricted Concomitant Medications ............................................................ 18 
11.3.3 
Wake-Promoting Agents ....................................................................................................... 19 
11.3.4 
Extent of Study Drug Exposure ............................................................................................. 19 
11.4 
Efficacy Analyses ................................................................................................................... 20 
11.4.1 
Double-Blind Treatment Phase ............................................................................................. 21 
11.4.2 
Primary Efficacy Analysis ...................................................................................................... 24 
11.4.3 
Secondary Efficacy Analyses ................................................................................................ 24 
11.4.4 
Open-Label Extension Efficacy Analyses ............................................................................. 29 
11.5 
PK Analyses ........................................................................................................................... 29 
11.6 
Safety Analyses ...................................................................................................................... 29 
11.6.1 
Adverse Events ..................................................................................................................... 29 
11.6.2 
Seizure Disorder ................................................................................................................... 31 
11.6.3 
Clinical Laboratory Evaluations ............................................................................................. 31 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
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11.6.4 
Vital Signs ............................................................................................................................. 31 
11.6.5 
Physical Examinations .......................................................................................................... 32 
11.6.6 
12-Lead Electrocardiograms ................................................................................................. 32 
11.6.7 
Holter Monitoring ................................................................................................................... 33 
11.6.8 
Columbia-Suicide Severity Rating Scale (C-SSRS) ............................................................. 33 
12 
References .......................................................................................................................................... 34 
13 
Appendix 1 Glossary of Abbreviations ................................................................................................ 35 
14 
Appendix 5 Adverse Event Start/Stop Date Imputation ...................................................................... 37 
15 
Appendix 2 Prior and Concomitant Medication Start/Stop Date Imputation ....................................... 38 
16 
Appendix 3 Example of Prohibited Medications .................................................................................. 39 
17 
Appendix 4 SAS Sample Code ........................................................................................................... 40 
18 
Appendix 6 Clinical Laboratory Tests ................................................................................................. 41 
 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
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4 Purpose 
The Statistical Analysis Plan (SAP) describes the statistical methods to be used during the analyses and 
reporting of data collected under Harmony Biosciences, LLC, Protocol HBS-101-CL-005. 
5 Scope 
The SAP outlines the following: 
• 
Study Objectives 
• 
Study Design 
• 
Endpoints 
• 
Applicable Study Definitions 
• 
Statistical Methods 
6 Introduction 
This SAP should be read in conjunction with the study protocol Amendment 5 dated 18 July 2023 and 
electronic case report form (eCRF) v4.0 dated 09May2023. Any changes to the protocol or eCRF may 
necessitate updates to the SAP. 
The SAP Version 1 was approved on 28 April 2021. This SAP Amendment 1 (Version 2.0) will include 
changes to the protocol through protocol Amendment 5. Final approval of the SAP by Harmony 
Biosciences, LLC and ICON will occur prior to the database entry lock and unblinding of the database for 
the analyses of the Double-Blind Treatment Phase of the study. 
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. 
6.1 Changes from Protocol 
The Intent-to-Treat Population referenced in protocol Amendment 4 is referred to as the modified Intent-to-
Treat Population (mITT) in the SAP; the definition remains same.  
For the Open-Label Extension (OLE) Phase reporting, all patients will be analyzed as a single group, which 
will be labelled “Total”. All patients will be titrated during a 3-week Titration Period to a dose of 35.6 mg 
pitolisant (or a maximum dose up to 35.6 mg based on Investigator assessment of tolerability). Additional 
changes from protocol Amendment 4 include: 
• 
Removed sample size and statistical power calculation 
• 
Removed Z-score (aggregation of Daytime Sleepiness Scale [DSS] and Mean Sleep Latency 
[MSL]) endpoint  
• 
Removed Maintenance of Wakefulness Test (MWT) population  
• 
Replaced Analysis of Covariance (ANCOVA) with Mixed Model Repeated Measures (MMRM) for 
primary endpoint analysis method 
• 
Removed analysis of site effect in statistical models for study endpoint analysis 
• 
Removed multiple imputation (MI) and sensitivity analyses 
 


 
 
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7 Study Objectives 
7.1 Primary Objectives 
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 myotonic dystrophy type 1 (DM1) ages 18 
to 65 years. 
7.2 Secondary Objectives 
The secondary objectives of this study are to assess:  
• 
The impact of pitolisant on fatigue in patients with DM1 
• 
The impact of pitolisant on selected domains of cognitive function in patients with DM1 
• 
Investigator and patient impression of overall impact of pitolisant on burden of disease in patients 
with DM1 
• 
Safety and effectiveness of pitolisant during long-term treatment (during the OLE Phase) 
8 Study Design 
8.1 General Design 
This is a randomized, Double-Blind, placebo-controlled, parallel-group study in adult patients (ages 18 to 
65 years) with DM1, followed by an optional OLE Phase.  
The study will consist of a Screening Period (up to 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 continue until Day 459/Month 15/Visit 8 for each patient, unless the patient withdraws from 
the study early or the Sponsor elects to terminate the study. An overall schema of the study design is 
provided in Figure 1.  
After Screening, approximately 30 patients ages 18 to 65 years who meet all eligibility criteria will be 
randomized at the Baseline Visit in a 1:1:1 ratio to lower dose pitolisant (17.8 mg), higher dose pitolisant 
(35.6 mg), or matching placebo. In the Double-Blind Treatment Phase, patients will be titrated to their 
randomized stable dose of study drug during the 3-week Titration Period (Table 1). After completion of the 
3-week Titration Period, patients will continue to take study drug at their randomized 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. Adjustments to study drug dosing outside of the 
protocol-specified titration schedule are not allowed during the 11-week Double-Blind Treatment Phase. 
Following the 11-week Double-Blind Treatment Phase, eligible patients will be given the opportunity to 
participate in an optional OLE Phase. During the OLE Phase, all eligible patients will receive treatment with 
open-label pitolisant and will be titrated during a 3-week Titration Period to a dose of 35.6 mg (or a maximum 
dose up to 35.6 mg based on Investigator assessment of tolerability) (Table 2). Adjustments to pitolisant 
dose are permitted during the OLE Phase; pitolisant dose can be adjusted (higher or lower) based on 
Investigator assessment of tolerability; the maximum dose allowed is 35.6 mg once daily. 
The COVID-19 (Coronavirus Disease 2019) pandemic has had a major impact on the conduct of clinical 
trials worldwide, including restrictions on travel, dislocation of clinical trial subjects, and the need of many 
health care facilities to handle an influx of patients with COVID-19. Recognizing the impact of COVID-19 
on clinical trials, the National Institutes of Health (NIH) and the U.S. Food and Drug Administration (FDA) 
released guidance to provide general considerations to assist sponsors in assuring the safety of trial 
participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to trial integrity 


 
 
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for the duration of the COVID-19 public health emergency. Details of analyses of data collected regarding 
the impact of COVID-19 on this study are included within the applicable sections. 
8.2 Study and  Patient Completion 
• 
Patients who completed the DBT Phase are patients who completed treatment 
during the DBT Phase and entered the OLE Phase and or patients who completed 
treatment during the DBT Phase and did not enter in the OLE Phase. 
• 
Patients who completed the study drug who discontinued study drug during the DBT 
Phase and continued to meet the eligibility criteria for the study. 
 
 
 


 
 
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Figure 1: 
Overall Study Design 
 
Abbreviations: AE = adverse event; BL = baseline; C-SSRS = Columbia-Suicide Severity Rating Scale; EOT = end-of-treatment; F-up = follow-up; MWT = Maintenance of Wakefulness 
Test; OLE = Open-Label Extension; PK = pharmacokinetics; TC = telephone contact; V = visit.  
 
a The Titration Period for the Double-Blind Treatment Phase will be from Days 1 to 21. Patients will receive their first dose of study drug on Day 1; study drug dose will be titrated on 
Day 8 and again on Day 15 (as appropriate based on randomized dose; Table 1); all patients will be at their final randomized dose by Day 15 of the Titration Period. 
b The 8-week Stable Dose Period for 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). Visit 5 (Day 77 ±3 days) is the EOT Visit for the Double-Blind Treatment Phase. The EOT (Week 11) MWT assessment should not be performed on the same day as the 
Visit 5 PK as patients will take their dose of study drug at the site after ECGs and the pre-dose PK blood draw are done. The EOT (Week 11) MWT may be conducted up to 3 days in 
advance of Day 77; patients should take their dose of study drug on the morning of the scheduled Week 11 MWT assessment. Eligible patients who opt to enter the OLE Phase will 
be dispensed OLE study drug for titration at this visit. 
c The Titration Period for the OLE Phase will be from Days 78 to 98 (±3 days). Eligible patients will receive their first dose of open-label pitolisant on Day 78 and pitolisant dose will be 
titrated on Day 85 and again on Day 92 to a dose of 35.6 mg (or a maximum dose up to 35.6 mg based on Investigator assessment of tolerability). At the end of the 3-week Titration 
Period, patients will continue to take pitolisant 35.6 mg (or their maximum dose up to 35.6 mg based on Investigator assessment of tolerability) once daily in the morning upon 
wakening until the end of the study (Long-Term Dosing Period). During the OLE Phase, pitolisant dose can be adjusted (higher or lower) based on Investigator assessment of 
tolerability. The maximum pitolisant dose allowed in the study is 35.6 mg. 
d In between the 6-monthly on-site study visits, patients will receive a TC from the study site approximately every 180 days (i.e., on Days 189 and 369) to record 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 


 
 
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concomitant medication use, complete C-SSRS, confirm the current dose of study drug and compliance with dosing, and confirm shipment/receipt of study drug sufficient for 3 
months (i.e., 90 days) of once daily administration.  
e All AEs regardless of seriousness, severity, or causality will be collected from the time the patient provides written informed consent through 30 days (+3 days) after final dose of 
study drug (Safety Follow-up TCs, Protocol Section 7.4). 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. 
f Patients who consent to the optional MWT must return to the study site on the day before the scheduled Baseline MWT assessment and the day before the scheduled EOT MWT 
assessment of the Double-Blind Treatment Phase. 
 


 
 
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Table 1: Study Drug Dosing in the Double-Blind Treatment Phase  
 
Titration Period 
(3 Weeks) 
Stable Dose Period 
(8 Weeks) 
Treatment Groups  
Week 1 
(Days 1 - 7) 
Week 2 
(Days 8 - 14) 
Week 3 
(Days 15 - 21) 
Weeks 4 - 11 
(Days 22 - 77) 
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 
Note: Adjustments to study drug dosing outside of the protocol-specified titration schedule are not permitted during the Double-Blind 
Treatment Phase. 
 
Table 2: Pitolisant Dosing in the OLE Phase  
 
Titration Perioda 
(3 Weeks) 
Long-Term Dosing Periodb 
 
Week 12 
(Days 78 - 84) 
Week 13 
(Days 85 - 91) 
Week 14 
(Days 92- 98) 
Weeks 15 (Day 99) to EOT 
Pitolisant dose 
8.9 mg 
17.8 mg 
35.6 mg 
35.6 mg 
Abbreviations: EOT = End-of-Treatment; OLE = Open-Label Extension. 
a Pitolisant dose will be titrated on Day 85 and again on Day 92. 
b After completion of the 3-week Titration Period, patients will continue to receive pitolisant 35.6 mg (or their maximum dose up to 
35.6 mg based on Investigator assessment of tolerability). 
 
Note: Adjustments to study drug dosing after the protocol-specified titration period are permitted during the OLE 
Treatment Phase of the study, where the pitolisant dose can be adjusted (higher or lower) based on Investigator 
assessment of tolerability; the maximum pitolisant dose allowed in the study is 35.6 mg (Protocol Section 3.1.2.2) It is 
recommended that adjustments made during this time be to one of the three pre-specified doses of 35.6 mg, 
17.8 mg, or 8.9 mg. If deemed necessary by the Investigator, alternative doses may be prescribed during the OLE 
Phase; however, the Investigator must first consult with the Medical Monitor. Dosing may be adjusted in increments 
of 4.45 mg. 
 
8.3 Sample Size Considerations 
 
 
 
8.4 Randomization 
After Screening, approximately 30 patients ages 18 to 65 years who meet all eligibility criteria will be 
randomized at the Baseline Visit in a 1:1:1 ratio via an interactive response technology (IRT) to lower dose 
pitolisant, higher dose pitolisant, or matching placebo. The randomization will be stratified by concomitant 
use of wake-promoting agents (Yes/No). 
Enrolled patients will be allocated a unique identification number in a sequential order; blocks will be 
dynamically assigned to each stratification level to balance the randomization within each stratification level. 
Following randomization, Harmony Biosciences will provide all study drug in a packed and labelled kit, and 
the IRT will identify the kit number to be dispensed to the patient according to the treatment assigned in the 
randomization schedule. 


 
 
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9 Study Endpoints, Conventions and Derivations 
9.1 Endpoints 
Table 3 and Table 4 list the objectives and the assessments being used for the respective endpoints in the 
study. 
Table 3: Double-Blind Treatment Phase Objectives and Endpoints 
DOUBLE-BLIND TREATMENT PHASE 
Primary Objective 
Primary Endpoint 
To evaluate the safety and efficacy of pitolisant 
compared with placebo in treating EDS in 
patients with DM1. 
The change in Daytime Sleepiness Scale (DSS) score from 
Baseline to Week 11 (Visit 5) for pitolisant compared with placebo. 
Secondary Objectives 
Secondary Endpoints 
To assess the impact of pitolisant on fatigue in 
patients with DM1. 
The change in Fatigue Severity Scale (FSS) score from Baseline to 
Week 11 (Visit 5) for pitolisant compared with placebo.  
To assess the impact of pitolisant on selected 
domains of cognitive function in patients with 
DM1. 
The change from Baseline to Week 11 (Visit 5) for pitolisant 
compared with placebo assessment of Cogstate Computerized 
Cognitive Battery Tests in:  
• 
Identification (Attention), SART (attention), Detection 
(Psychomotor Function), and One Back (Working Memory). 
To assess the impact of pitolisant on EDS in 
patients with DM1. 
The change in Epworth Sleepiness Scale (ESS) score from Baseline 
to Week 11 (Visit 5) for pitolisant compared with placebo. 
To assess investigator and patient impression of 
overall impact of pitolisant on burden of disease 
in patients with DM1. 
The change in score from Baseline to Week 11 (Visit 5) for pitolisant 
compared with placebo in:  
• 
Clinical Global Impression of Severity (CGI-S) for EDS  
• 
Patient Global Impression of Severity (PGI-S) for EDS 
• 
Myotonic Dystrophy Health Index (MDHI)  
Exploratory Objectives 
Exploratory Endpoints 
To assess the impact of pitolisant on EDS 
in patients with DM1.  
• 
The change in MSL based on MWT from Baseline to Week 11 
for pitolisant compared with placebo. 
Safety 
Safety Endpoints 
To assess the safety and tolerability of pitolisant 
• 
Adverse Events (AEs) 
• 
Clinical laboratory test results 
• 
Vital signs 
• 
12-lead electrocardiogram (ECG) 
• 
Holter monitoring 
• 
C-SSRS assessment  
• 
Physical examinations 
Abbreviations: CGI-S = Clinical Global Impression of Severity; C-SSRS = Columbia-Suicide Severity Rating Scale; DM1 = Myotonic dystrophy 
type 1; DSS = Daytime Sleepiness Scale; ECG = electrocardiogram; EDS = Excessive Daytime Sleepiness; ESS = Epworth Sleepiness Scale; 
FSS = Fatigue Severity Scale; MDHI = Myotonic Dystrophy Health Index; MSL = Mean Sleep Latency; MWT = Maintenance of Wakefulness 
Test.; PGI-S = Patient Global Impression of Severity;  SART = Sustained Attention to Response Task 
 


 
 
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Table 4: Open-Label Extension Phase Objectives and Endpoints 
OPEN LABEL EXTENSION PHASE 
Objectives 
Efficacy Endpoints 
To assess effectiveness of pitolisant during 
long-term treatment (during the OLE Phase). 
• 
Changes from Baseline in: 
o 
DSS 
o 
ESS 
o 
FSS  
o 
Cogstate Detection Test, Cogstate SART,  
Cogstate Identification Test, and Cogstate 
One Back Test 
o 
MDHI 
o 
CGI-S of EDS  
o 
PGI-S of EDS 
Safety 
Safety Endpoints 
To assess the safety and tolerability of pitolisant  
o 
AEs 
o 
Clinical labs 
o 
Vital signs 
o 
12-lead ECG 
o 
Holter monitoring 
o 
Suicidality  
o 
Physical examinations 
Abbreviations: AE = Adverse Event; CGI-S = Clinical Global Impression of Severity; DSS = Daytime Sleepiness Scale; ECG = 
Electrocardiogram; EDS = Excessive Daytime Sleepiness; ESS = Epworth Sleepiness Scale; FSS = Fatigue Severity Scale; MDHI 
= Myotonic Dystrophy Health Index; OLE = Open-Label Extension; PGI-S = Patient Global Impression of Severity, SART = 
Sustained Attention to Response Task.   
 
9.2 Study Day Windows 
For each patient there will be a screening period, a Double-Blind Treatment Phase, and an optional OLE 
Phase. 
The study day for data collected after the first dose of study drug will be calculated as visit/assessment 
date – first dose date + 1. For data collected prior to first dose, the study day will be calculated as 
visit/assessment date – first dose date. The first dose date refers to the date the study drug was taken for 
the first time, i.e., at the beginning of the Double-Blind Treatment Phase. 
9.2.1 Visit Window 
The visit window and pharmacokinetic (PK) draw window appear in Table 5 and Table 6, respectively. 
Unless otherwise stated the endpoints will be analyzed and reported using the analysis visits.  
Analysis visit windows will be derived for the Double-Blind Treatment Phase and used for the analyses. For 
C-SSRS, no analysis window will be applied; data will be reported using the nominal visit. No summary will 
be created for C-SSRS data, which will be included in a listing only. Therefore, no analysis windowing will 
be applied on C-SSRS data. 
During the Double-Blind Treatment Phase, if a patient stopped taking treatment in the first week of the study 
(i.e., stopped treatment within 7 days of the date of first dose) for a reason other than an adverse event and 
then re-started study treatment more than 14 days after the treatment interruption, the analysis visit window 


 
 
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for post-baseline visits will be derived using the date the patient re-started their study treatment (i.e., the 
visit window will not be based on date of first dose for that patient). 
For the OLE Phase, nominal visit will be used.  
Table 5: Analysis Visit Window and Target Day 
Phase 
Protocol Visit 
Analysis Visit 
Target Day 
Analysis Visit 
Window Lower Limit 
Analysis Visit 
Window Upper Limit 
Screening 
Visit 1 
Baseline 
-1 
- inf 
1 
Visit 2 
Double-
Blind 
Visit 3 
Visit 3 (Day 22) 
22 
2 
35 
Visit 4 
Visit 4 (Day 49) 
49 
36 
63 
Visit 5 
Visit 5 (Day 77) 
77 
64 
Treatment Phase 
Completiona   
OLE 
Visit 6 
Visit 6 (Day 99) 
99 
maximum of (92, 
Treatment Phase 
Completion) 
129 
Visit 7 
Visit 7 (Month 9) 
279 
130 
309 
Visit 8 
Visit 8 (Month 15) 
459 
310 
489 
Abbreviations: OLE = Open-Label Extension. 
aIn the Double-Blind Treatment Phase, if the patient did not enter the OLE Phase, the upper limit of the visit window should be the 
date of the end of the completion of the treatment phase as collection in the CRF; if the patient entered the OLE Phase, the upper 
limit of the visit window should be the first dose of study drug intake in the OLE. 
 
Table 6: PK Draw Timing 
Phase 
Visit 
Target Day 
Timepoints 
Double-Blind 
Visit 3 
Day 22 
• 
Pre-dose 
• 
3 hours (±30 minutes) post-dose 
Visit 5 
Day 77 
• 
Pre-dose 
• 
3 hours (±30 minutes) post-dose 
 
9.2.2 Data Selection for Multiple Results 
Double-Blind Treatment Phase: For post-baseline assessments, if there are multiple non-missing results 
within the same analysis window (including scheduled and unscheduled results), then the non-missing 
result that is closest to the target date will be used in the analyses; if more than one result is equally close, 
the result that is after the target date of the assessment will be used. If necessary, time of the assessment 
(if collected) will be used to determine the record to be selected.  
OLE Phase: Assessments performed at nominal visits will be used in the analyses/summaries. 
Unscheduled assessments will only be used to determine worst, lowest and/or highest results post-baseline 
where applicable. 
Twelve-lead ECGs will be collected in triplicate at each nominal visit as prespecified in the protocol. The 
mean value of the triplicate (or duplicate) at each nominal visit will be derived. The rules defined above for 
the post-baseline assessments and for the baseline (section 9.3) will be applied to determine which mean 
values will be summarized. For the overall interpretation, the worst interpretation across the triplicate (or 
duplicate) for each given nominal visit will be selected first, and then the rules defined above for the post-
baseline assessments and for the baseline (section 9.3) will be applied to determine the results to be 
summarized. 


 
 
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9.3 Baseline 
For the Double-Blind Treatment Phase, Baseline is defined as the last non-missing record or measure 
collected prior to the study drug administration. For the OLE phase, Baseline will be identical to the 
Double-Blind Treatment Phase (i.e., the last non-missing record or measure collected prior to study drug 
administration).   
9.4 Double-Blind and OLE Analyses Reporting 
The data collected for the Double-Blind Treatment Phase and the OLE Phase are included in the same 
database.  
A data cut will be performed at the end of the Double-Blind Treatment Phase and another one will be 
performed at the end of the OLE Phase. The date of first dose in the OLE Phase will be used to determine 
if a patient entered the OLE Phase. A data cut-off will be applied to the datasets and only data related to 
the Double-Blind Treatment Phase will be reported: 
• 
Baseline and baseline characteristics. 
• 
Visits performed in the Double-Blind Treatment Phase, up to and including Visit 5 (Week 11) for 
patients who entered the OLE Phase, and up to the safety follow-up visits for patients who opt out 
of the OLE Phase. 
• 
For patients who entered the OLE Phase, any adverse event (AE) or medication that started up to 
and including the last dose of study drug in the Double-Blind Treatment Phase. For this patient 
group a (any AE or medication that started after and up to 30 days after the last dose of study drug 
in the Double-Blind Treatment Phase will be reported in separate listings, i.e., they will be excluded 
from the Double-Blind Treatment Phase summary tables). 
• 
For patients who opt out of the OLE Phase, all AEs and medications reported through the final 30-
day safety follow-up telephone contact will be reported as part of the Double-Blind Treatment 
Phase. 
The date of first dose in the OLE Phase will be kept in the datasets to determine if the patient has entered 
the OLE Phase. 
OLE Phase: 
For reporting the OLE analyses, no data cut-off will be applied to the datasets. Only data related to the OLE 
Phase will be reported: 
• 
Demographics and baseline characteristics for patients who received at least one dose of study 
drug within the OLE Phase 
• 
Baseline safety and efficacy data (section 9.3) 
• 
Safety and efficacy reported during the OLE Phase 
• 
AEs and concomitant medications started on or after the 1st dose of OLE study drug intake 
10 Analysis Sets 
For the Double-Blind Treatment Phase: Safety analyses will be conducted for the safety population. The 
mITT population will be used for the primary efficacy analysis. The PK population will be used for PK 
analyses. Patients will be analyzed according to their randomized treatment for efficacy assessments and 
according to the actual treatment received for safety assessments. 
For the OLE Phase: The open-label safety population will be used.   


 
 
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10.1 Modified Intent-to-Treat Population 
The mITT 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 during the Double-Blind Treatment Phase. 
This population will be used to summarize the primary, secondary, and other efficacy data. Patients will be 
analyzed according to their randomized treatment.  
10.2 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 their treatment received. In the case of mis-
dosing, patients will be counted at the highest dose they received in the Double-Blind Treatment Phase.  
10.3 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.  
10.4 Pharmacokinetic Population 
The PK population will include all patients who received at least one dose of study drug and have calculable 
concentrations of pitolisant available for analysis.  
11 Statistical Methods 
All analyses will use SAS version 9.4 or higher.  
Categorical variables will be summarized using counts and percentages based on the specified population 
total. Percentages will be rounded to one decimal place, except 100% will be displayed without any decimal 
places and percentages will not be displayed for zero counts.  
Continuous data will be summarized using non-missing observations (n, mean, SD, median, minimum, and 
maximum). The minimum and maximum values will be displayed to the same level of precision as the raw 
value. Mean, and median will be rounded to 1 decimal place greater than precision of the original value. 
The SD will be rounded to 2 decimal places greater than precision of the original value. Confidence intervals 
(CI), least squares (LS) means, and standard error (SE) will be provided as appropriate. CIs, LS means will 
be presented with a precision similar to mean and SEs will be presented with a precision similar to SD. 
This is an exploratory study. Except for the analysis of the SART endpoint (using Kruskal Wallis test and 
for which the p-value will be reported), no formal statistical hypothesis testing (including the generation of 
p-values) is planned for other study endpoints. For these endpoints, the p-values will be included in 
supporting statistical appendix. 
All listings will be displayed by treatment arm (where applicable), patient identifier and date of assessment. 
Age, sex, and race will be presented. 
11.1 Patient Disposition 
11.1.1 Disposition 
For the Double-Blind Treatment Phase, the number and percentage of patients screened, enrolled, 
completing the Double-Blind Treatment Phase, discontinuing from the Double-Blind Treatment Phase, and 
enrolled in OLE will be summarized, together with a breakdown of the corresponding reasons for withdrawal 
from study drug and from the study. Also, the number and percentage of patients included in each analysis 
set will be summarized. 


 
 
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The number of patients who screen failed and the reason for screen failure will be tabulated. A supportive 
data listing will be provided for the screen failure patients and will include the reason for screen failure and 
the list of inclusion/exclusion criteria failed.   
For the OLE Phase, the number and percentage of patients enrolled in the OLE Phase, completing the OLE 
Phase, discontinuing treatment and/or from the OLE Phase and the reasons for discontinuation from the 
treatment and/or the OLE Phase will be summarized. 
Patient disposition data will be presented in a data listing for Double-Blind safety and open-label safety 
populations. 
11.1.2 Important Protocol Deviations 
The number and percentage of patients with important protocol deviations (PD) by category will be 
summarized by treatment arm, active arms pooled, and overall for the Double-Blind Treatment Phase and 
total for the OLE Phase.  
Important PDs will be listed. All COVID-19 related PDs will be listed separately. 
11.1.3 Inclusion and Exclusion Criteria 
Failed inclusion and exclusion criteria for the randomized patients will be presented in a data listing. 
11.2 Demographic and Baseline Characteristics 
11.2.1 Demographics 
Baseline data will be summarized for continuous and categorical variables as applicable. 
The following demographic and baseline characteristics will be summarized: 
• 
Sex (female, male) 
• 
Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander 
• 
Ethnicity (Hispanic or Latino, not Hispanic or Latino, Not Reported, Unknown) 
• 
Age (years), as continuous variable  
• 
Height at baseline (cm) 
• 
Weight at baseline (kg) 
• 
Body mass index at baseline (kg/m2) defined as Weight (kg)/[Height (m)]2 
• 
Women of child-bearing potential  
At the time of the Double-Blind Treatment Phase database entry lock, the above information will be 
tabulated by treatment arm and overall using the mITT and the Double-Blind safety populations. At the time 
of OLE Phase database lock, the above information will be tabulated by using the OLE Safety Population. 
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. 
Demographic information will be presented in a data listing. No statistical testing will be performed on the 
demographic data. 
11.2.2 Medical History 
A complete medical history will be obtained at Screening to ensure patients qualify for the study and will be 
updated at the Baseline Visit if needed.  
Medical history will be summarized by treatment arm for all patients in the safety population. Medical history 
data will be coded using the Medical Dictionary for Regulatory Activities (MedDRA); the version used will 


 
 
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be included in the tables and listings footnotes and summarized by system organ class and preferred term. 
Medical history data will be presented in a data listing. 
11.2.3 Seizure History 
Seizure history will be obtained at Screening and will be updated at the Baseline Visit if needed.  
For patients in the safety population, in those patients with a history of a seizure disorder, the following 
aspects of their seizure history will be summarized.  
• 
Total number of patients with a history of seizure disorder 
• 
Whether there has been any change in seizure activity in the past 3 months (prior to the study) 
• 
Type of seizure disorder 
• 
Average weekly seizure frequency 
• 
Average seizure duration in seconds 
Seizure history data will be presented in a data listing. 
11.2.4 Myotonic Dystrophy Type 1 History 
Confirmation of a patient’s diagnosis of DM1 will be obtained via review of the patient’s medical records 
and genetic testing will be performed during Screening to confirm cytosine-thymine-guanine (CTG) repeat 
of ≥100. Number of repeats will be summarized and listed. Age at diagnosis of DM1 will be tabulated.  
Age at diagnosis of DM1 (years) = (date of diagnosis – date of birth)/365.25 
The date of diagnosis of DM1 will be presented in the baseline characteristics listing. 
11.3 Treatments 
11.3.1 Prior, Concomitant and Prohibited Medications 
Medications stopped prior to the first dose of study drug will be classified as prior medication. Medications 
started with or after the first dose of study drug will be classified as concomitant. Medications started before 
the first dose of study drug and stopped after the first dose of study drug will be classified as both prior and 
concomitant.  
Medications will be categorized by medication group and subgroup according to World Health Organization 
(WHO) drug dictionary (the version used will be included in the tables and listings footnotes). Refer to the 
Coding Conventions document for this study. 
Missing or partial medication start/stop date will be imputed as described in Appendix 2. A conservative 
approach will be used when flagging medications.  
Prior, concomitant, and prohibited medications will be summarized for the safety populations. All 
medications will be listed. 
11.3.2 Prohibited and Restricted Concomitant 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.  
Use of strong cytochrome P450 (CYP) 2D6 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 of these medications is required prior to enrollment and initiating study drug. These 
medications (examples are listed in Appendix 3) are allowed during the OLE Phase of the study, but 
adjustments to the dose of pitolisant is required.  


 
 
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Pitolisant increases the levels of histamine in the brain; therefore, centrally acting H1R (histamine 
1 receptor) antagonists (sedating antihistamines) that cross the blood-brain barrier may reduce the 
effectiveness of pitolisant. Concomitant use of centrally acting or sedating H1R antagonists is not permitted 
during the Double-Blind Treatment Phase of the study (requires a washout of 5 half-lives 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. 
Prohibited medications taken in the study will be reported and summarized with the protocol deviations.  
Prior and concomitant medications will be summarized based on the number and percentage of patients 
using each medication along with the number and percentage of patients using at least one medication within 
each medication group and subgroup. 
For patients who opt to continue in the OLE Phase of the study, only medications started on or before the 
last dose in the Double-Blind Treatment Phase will be included in the summaries for the Double-Blind 
Treatment Phase. Medications started after the last dose and up to 30 days after the last dose of treatment 
in the Double-Blind Treatment Phase will be included in a separate listing in the Double-Blind Treatment 
Phase and also summarized in the OLE Phase.  
11.3.3 Wake-Promoting Agents 
Randomization is stratified by concomitant use of wake-promoting agents (Yes/No). Medications that are 
considered wake-promoting agents are:   
• 
Solriamfetol/Sunosi 
• 
Modafinil/Provigil 
• 
Armodafinil/Nuvigil 
• 
Lisdexamfetamine Dimesylate/Vyvanse 
• 
Dexmethylphenidate/Focalin 
• 
Methylphenidate/Adhansia, Aptensio, Concerta, Cotempla, Daytrana, Jornay, Metadate, Methylin, 
Quillichew, Quillivant, Ritalin 
• 
Amphetamine and Amphetamine Salts/Adderall, Adzenys, Desoxyn, Dexedrine, Dyanavel, Eveko, 
Mydayis, Procentra, Zenzedi 
The EDC stratification is based on review of these medications prior to randomization (i.e., to identify 
patients who were taking wake-promoting agents). 
The identification of patients who were on wake-promoting agents at the time of randomization, based on 
review of the medications collected in EDC, will be done prior to database lock and study unblinding for the 
Double-Blind Phase. 
The medical monitor will review the list of medications prior to unblinding of the study for the Double-Blind 
Treatment Phase to finalize a list of medications considered wake-promoting agents. The finalized list will 
be used to determine if the patients were taking wake-promoting agents at the time of randomization. 
If the start and/or stop dates are partial/missing, the imputations rules defined in Appendix 2 will be used to 
determine if the medication was taken at the time of the first dose of study drug. If it is not possible to 
determine if the medication was taken at the time of the first dose of study drug, it will be assumed that the 
medication was not concomitant.  
Number (%) of patients on a wake-promoting agents will be tabulated and summarized. 
11.3.4 Extent of Study Drug Exposure 
The descriptive statistics will be provided by treatment group for the Double-Blind Treatment Phase 
analyses and by treatment group received during the Double-Blind Treatment Phase and total for the OLE 
Phase analyses.  


 
 
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11.3.4.1 
Double-Blind Treatment Phase 
The duration of exposure to study drug, number of days dose is taken and compliance (during the stable 
dose period) with study drug dosing will be summarized for the Double-Blind safety population. In addition, 
the number of tablets taken (i.e., returned - dispensed) will be listed for the titration phase and the stable 
dose phase in the Double-Blind Treatment Phase. 
Study drug accountability including bottle number and number of dispensed and returned tablets will be 
listed. Study drug not returned will be assumed to have been taken. 
Percentage of patients meeting study drug compliance during the stable-dose period will be summarized 
in the following categories: <80%, ≥80% to ≤120%, and >120%. Major non-compliance is defined as 
compliance <80% or compliance >120%. 
Duration of exposure: Date of last dose in the Double-Blind Treatment Phase – date of first dose in the 
Double-Blind Treatment Phase + 1. 
Number of days with at least one dose (tablet) taken: Duration of exposure in the Double-Blind 
Treatment Phase – number of days with missed doses in the Double-Blind Treatment Phase. 
Study Drug Compliance (stable-dose period): The start date of the stable dose period is the date of Visit 3 
(Day 22), and the end of the stable dose period is the last dose date in the Double-Blind Treatment Phase; 
during that period each patient should take 2 tablets each morning; i.e., compliance is the number of tablets 
taken during that period (i.e., sum of the tablets dispensed minus the sum of the tablets returned) divided 
by (2 times the number of days in the period [date of last dose – dispensed date at Visit 3 + 1]).   
11.3.4.2 
OLE Phase 
The duration of exposure to study drug will be summarized for the OLE safety population. Study drug 
accountability and number of dispensed and returned tablets will be listed. 
Duration of exposure: Date of last dose in the OLE Phase – date of first dose in the OLE Phase + 1, 
In addition, the following measures of changes in planned dose will be summarized for the OLE safety 
population: 
• 
Planned average daily dose: sum of the daily dose x for the duration of intake divided by the 
duration (end date minus start date + 1) of exposure; 
• 
Number and percentage of patients with at least one dose adjustment per reason (AE, dosing error, 
rechallenge, insufficient effectiveness, change in dose assignment criteria and other); 
• 
Number and percentage of patients with one dose adjustment, with 2 dose adjustments and with > 
2 dose adjustments due to any reason; 
• 
Number and percentage of patients with one dose adjustment, with 2 dose adjustments and with > 
2 dose adjustments due to AE; 
• 
Number and percentage of patients with one dose adjustment, with 2 dose adjustments and with > 
2 dose adjustments due to rechallenge; 
• 
Number and percentage of patients with one dose adjustment, with 2 dose adjustments and with > 
2 dose adjustments due to insufficient effectiveness. 
11.4 Efficacy Analyses 
For the inferential analysis, the stratification factor of wake-promoting agents (Yes/No) will be based on the 
stratification factor derived in the EDC. If there is more than 10% difference between the stratification factor 
recorded in IRT versus the stratification factor derived from the prior and concomitant in the EDC(see 
section 11.3.3), the primary analysis will be repeated using the stratification factor reported in the IRT.  
 


 
 
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11.4.1 Double-Blind Treatment Phase 
All efficacy analyses will be performed on the mITT Population. The analysis approaches for the efficacy 
endpoints at Visit 5 are detailed in Table 7. Similar analyses (where applicable) for efficacy endpoints 
collected at Visit 4 will be conducted as well.  


 
 
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Table 7: Double-Blind Inferential Analyses Strategy  
Endpoint 
Primary/ 
Secondary/ 
Exploratory 
Inference 
model 
Comparisons of interest 
CFB in DSS score at Week 11 (Visit 5) 
Primary 
MMRM 
Higher dose vs. Placebo; Lower dose vs. Placebo; Pooled active vs. Placebo 
CFB in ESS score at Week 11 (Visit 5) 
Secondary 
MMRM 
Higher dose vs. Placebo; Lower dose vs. Placebo; Pooled active vs. Placebo 
CFB in FSS score at Week 11 (Visit 5) 
Secondary 
MMRM 
Higher dose vs. Placebo; Lower dose vs. Placebo; Pooled active vs. Placebo 
CFB in Cogstate Detection Test score 
at Week 11 (Visit 5) 
Secondary 
ANCOVA 
Higher dose vs. Placebo; Lower dose vs. Placebo; Pooled active vs. Placebo 
CFB in Cogstate Identification Test 
score at Week 11 (Visit 5) 
Secondary 
ANCOVA 
Higher dose vs. Placebo; Lower dose vs. Placebo; Pooled active vs. Placebo 
CFB in Cogstate One Back Test score 
at Week 11 (Visit 5) 
Secondary 
ANCOVA 
Higher dose vs. Placebo; Lower dose vs. Placebo; Pooled active vs. Placebo 
CFB in MDHI total Score at Week 11 
(Visit 5) 
Secondary 
MMRM 
Higher dose vs. Placebo; Lower dose vs. Placebo; Pooled active vs. Placebo 
CFB in CGI-S score at Week 11 (Visit 
5) 
Secondary 
MMRM 
Higher dose vs. Placebo; Lower dose vs. Placebo; Pooled active vs. Placebo 
CFB in PGI-S score at Week 11 (Visit 
5) 
Secondary 
MMRM 
Higher dose vs. Placebo; Lower dose vs. Placebo; Pooled active vs. Placebo 
CFB in SART go score at 
Week 11 (Visit 5) 
Secondary 
Kruskal-
Wallis 
Higher dose vs. Placebo; Lower dose vs. Placebo; Pooled active vs. Placebo 
CFB in SART no-go score at Week 11 
(Visit 5) 
Secondary 
Kruskal-
Wallis 
Higher dose vs. Placebo; Lower dose vs. Placebo; Pooled active vs. Placebo 
CFB in SART total score at 
Week 11 (Visit 5) 
Secondary 
Kruskal-
Wallis 
Higher dose vs. Placebo; Lower dose vs. Placebo; Pooled active vs. Placebo 


 
 
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Endpoint 
Primary/ 
Secondary/ 
Exploratory 
Inference 
model 
Comparisons of interest 
CFB in MSL at Week 11 (Visit 5) 
Exploratory 
ANCOVA 
Higher dose vs. Placebo; Lower dose vs. Placebo; Pooled active vs. Placebo 
Abbreviations: ANCOVA = Analysis of Covariance; CGI-S = Clinical Global Impression of Severity; CFB = Change from Baseline; DSS = Daytime Sleepiness Scale; ESS = Epworth 
Sleepiness Scale; FSS = Fatigue Severity Scale; MDHI = Myotonic Dystrophy Health Index; MSL = Mean Sleep Latency; PGI-S = Patient Global Impression of Severity. 
 
 


 
 
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11.4.2 Primary Efficacy Analysis 
11.4.2.1.1 Daytime Sleepiness Scale (DSS) 
The DSS is a questionnaire in which patients are asked to assess five items with scores of never (0), seldom 
(1), often (2), and always (3). The DSS score is the sum of the answers to questions 1 to 4 plus the reversed 
score to question 5 (i.e., minus the score for question 5). If at least one question is not answered, the score 
will be set to missing. 
The DSS score can vary from 0 to 15 and the higher the score, the higher the degree of sleepiness. The 
questionnaire was developed and validated in patients with DM1 in three subgroups: early adult-onset 
(onset of symptoms from 11-20 years old), adult (onset of symptoms from 21-40 years old) and mild (onset 
of symptoms at >40 years old). The instrument has demonstrated construct (factorial) validity (Laberge et 
al 2004), convergent and discriminant validity (Laberge et al 2009; Laberge and Dauvilliers 2010) and 
responsiveness (Laberge et al 2021). 
A descriptive summary of DSS (mean, SD, median, minimum, maximum) for the absolute values and 
change from Baseline to Week 7 and to Week 11 will be presented by treatment group and for the active 
groups combined. If the termination visit occurs after the Week 7 Double-Blind visit, the early termination 
data will be windowed to Week 11 regardless of the discontinuation reason. 
The change from Baseline to Week 11 will be analyzed using a Mixed Model Repeated Measures (MMRM) 
approach. Fixed effects will be included for treatment, visit, treatment*visit interaction, baseline value, and 
stratification factor. An unstructured covariance structure will be utilized; in case of failure to converge, 
covariance structures TOEPH (Heterogeneous Toeplitz), ARH(1) (Heterogeneous auto-regressive 1), and 
VC (Variance Components) will be tested in the order specified. Least Square means, standard errors, and 
the LS mean differences (each treatment versus placebo and the pooled active groups versus placebo) at 
each visit will be reported. All estimates will be generated from a single model, i.e., the pooled active 
estimates will be created via model contrasts. 
If there is more than a 10% difference between the stratification factor recorded in IRT versus the 
stratification factor derived from the prior and concomitant in the EDC, the MMRM analysis will be repeated 
using the stratification factor reported in IRT. 
11.4.3 Secondary Efficacy Analyses 
Descriptive summary (mean, SD, median, minimum, maximum) of each of the secondary endpoints will be 
provided for absolute values and for change from baseline. All summaries will be presented by treatment 
group and for the active groups combined. 
11.4.3.1.1 Fatigue Severity Scale (FSS) 
The FSS is a 9 item patient reported outcome assessment that covers physical, social, and cognitive effects 
of fatigue such as function, work, and motivation (Krupp et al 1989 and Hewlett et al 2011). The 9 items are 
summed and then averaged (i.e., divided by 9) to produce a global score. Each item has seven choices 
from strongly disagree to strongly agree (1-7), and the recall period is the past week. The higher the score, 
the more severe the fatigue is and the more it affects the person's activities. 
If the number of missing items is <4, the FSS total score is derived as the mean of the non-missing items; 
if 4 or more items are missing, the total score is set to missing (Rosa 2014). 
Early termination visits will be summarized and analyzed under Week 7 or Week 11 (depending on which 
visit they are closest to, see section 9.2 on visit window) regardless of the discontinuation reason. 
A descriptive summary of the FSS absolute values and change from Baseline to Week 7 and to Week 11 
will be reported by treatment group and for the active groups combined.  


 
 
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The change from Baseline will be analyzed using a Mixed Model Repeated Measures (MMRM) approach. 
Fixed effects will be included for treatment, visit, treatment*visit interaction, baseline value, and wake-
promoting agents stratification factor. An unstructured covariance structure will be utilized; in case of failure 
to converge, covariance structures TOEPH (Heterogeneous Toeplitz), ARH(1) (Heterogeneous auto-
regressive 1), and VC (Variance Components) will be tested in the order specified. Least Square means, 
standard errors, and the LS mean differences (each treatment versus placebo and the pooled active groups 
versus placebo) at each visit will be reported. All estimates will be generated from a single model, i.e., the 
pooled active estimates will be created via model contrasts.  
11.4.3.1.2 Cogstate Detection Test 
The Cogstate detection test is a computerized measure of psychomotor function and uses a validated 
simple reaction time (890-) paradigm with playing card-like stimuli displayed on a computer 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 
RTs for correct responses). Decreasing scores represent improved test performance. 
Early termination visits will be summarized and analyzed under Week 11 (see section 9.2 for details on the 
visit window) regardless of the discontinuation reason.  
A descriptive summary of Cogstate detection test for the absolute values and change from Baseline to 
Week 11 will be reported by treatment group and for the active groups combined.  
In addition, similarly to the primary endpoint (see section 11.4.2.1.1) but without the multiple imputations, 
the change from Baseline will be analyzed with an ANCOVA. Fixed effects will be included for treatment, 
Baseline value, and stratification factor. LS means, SEs, and the LS mean differences (each treatment 
versus placebo and the pooled active groups versus placebo) will be reported. All estimates will be 
generated from a single model, i.e., the pooled active estimates will be created via model contrasts. The 
effect size (magnitude of the differences between treatment groups and placebo) will also be provided. 
The analysis of the Detection Test will be performed by Cogstate; more details are provided in the Cogstate 
SAP. 
11.4.3.1.3 Cogstate Identification Test 
The Cogstate Identification Test is a computerized measure of visual attention and uses a validated choice 
RT 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 RTs for correct responses). Decreasing scores 
represent improved test performance. 
Early termination visits will be summarized and analyzed under Week 11 (see section 9.2 for details on the 
visit window) regardless of the discontinuation reason.   
The same summaries and analyses as performed for Cogstate detection test will be repeated for the 
Cogstate identification test endpoint. Further details on the summaries and inferential analyses are provided 
in section 11.4.3.1.2. 
The analysis of the Identification Test will be performed by Cogstate; more details are provided in the 
Cogstate SAP. 
11.4.3.1.4 Cogstate One Back Test 
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 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 


 
 
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by pressing the “yes” or “no” key. The software measures the speed and accuracy of each response (mean 
of the log10-transformed RTs for correct responses). Decreasing scores represent improved test 
performance. 
Early termination visits will be summarized and analyzed under Week 11 (see section 9.2 for details on the 
visit window) regardless of the discontinuation reason.   
The same summaries and analyses as performed for Cogstate detection test will be repeated for the 
Cogstate on back test endpoint. Further details on the summaries and inferential analyses are provided in 
section 11.4.3.1.2. 
The analysis of the One Back Test will be performed by Cogstate; more details are provided in the Cogstate 
SAP. 
11.4.3.1.5 Myotonic Dystrophy Health Index (MDHI) 
The MDHI is a disease-specific, patient-reported outcome measure for DM1. It focuses on the major 
symptoms experienced by patients with DM1. The tool consists of multiple symptom-related questions 
grouped into several themes including fatigue, sleep, and cognitive impairment. 
Subscales of the MDHI measure patients’ perception of their health as it relates to mobility, upper extremity 
function, ability to do activities, fatigue, pain, gastrointestinal issues, vision, communication, sleep, 
emotional issues, cognitive impairment, social satisfaction, social performance, myotonia, breathing, 
swallowing, and hearing.  
Each subscale score is a weighted average of its components; the prevalence of each symptom and theme 
(prevalence scores), and their importance to patients (impact scores) form the basis of the weights. The 
total score is a weighted average of the subscales where the weights are based on the population impact 
scores. The subscales and total scores have been validated independently (Heatwole et al 2014 and 
Heatwole et al 2016), and are scored on a scale of 0-100, with a higher score representing a higher burden 
of disease.  
The questionnaires will be scored centrally (University of Rochester, Rochester, NY) and the total score 
and sub-scores will be provided for analysis.  
Early termination visits will be summarized and analyzed under Week 7 or Week 11 (depending on which 
visit they are closest to, see section 9.2 on visit window) regardless of the discontinuation reason. 
A descriptive summary of the MDHI total score, the fatigue sub-score, the sleep sub-score, and the 
cognitive impairment sub-score of the absolute values and change from Baseline to Week 7 and to Week 11 
will be reported by treatment group and for the active groups combined.  
The change from Baseline MDHI total score will be analyzed using a Mixed Model Repeated Measures 
(MMRM) approach. Fixed effects will be included for treatment, visit, treatment*visit interaction, baseline 
value, and wake-promoting agents stratification factor. An unstructured covariance structure will be 
utilized.; in case of failure to converge, covariance structures TOEPH (Heterogeneous Toeplitz), ARH(1) 
(Heterogeneous auto-regressive 1), and VC (Variance Components) will be tested in the order specified. 
Least Square means, standard errors, and the LS mean differences (each treatment versus placebo and 
the pooled active groups versus placebo) at each visit will be reported. All estimates will be generated 
from a single model, i.e., the pooled active estimates will be created via model contrasts.  
11.4.3.1.6 Epworth Sleepiness Scale (ESS) 
The ESS is a questionnaire with eight questions in which respondents are asked to rate, on a 4-point scale 
(0-3), their usual chances of dozing or falling asleep while engaged in eight different activities. The 
questionnaire is a validated measure with high specificity and sensitivity for assessing subjective sleepiness 
in narcolepsy (Johns 1991).  
The total ESS score (sum of 8 item scores) can range from 0 to 24; the total score gives an estimate of the 
person’s ‘average sleep propensity’ (ASP), across a wide range of activities in their daily lives. The higher 


 
 
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the ESS score, the higher that person’s ASP in daily life or their ‘daytime sleepiness’ (Hirshkowitz 2017). If 
one or more item’s score is missing, the ESS score will be invalid and not be derived.  
• 
0-5: Lower Normal Daytime Sleepiness 
• 
6-10: Higher Normal Daytime Sleepiness 
• 
11-12: Mild Excessive Daytime Sleepiness 
• 
13-15: Moderate Excessive Daytime Sleepiness 
• 
16-24: Severe Excessive Daytime Sleepiness 
A descriptive summary of ESS for the absolute values and change from Baseline to Week 7 and to Week 11 
will be reported by treatment group and for the active groups combined. In addition, frequency count and 
percentage of the ESS score at each visit versus Baseline category will be provided by way of shift tables. 
Early termination visits will be summarized under Week 7 or Week 11 (depending on which visit they are 
closest to, see section 9.2 on visit window) regardless of the discontinuation reason. 
 
The change from Baseline will be analyzed using a Mixed Model Repeated Measures (MMRM) approach. 
Fixed effects will be included for treatment, visit, treatment*visit interaction, baseline value, and wake-
promoting agents stratification factor. An unstructured covariance structure will be utilized.; in case of failure 
to converge, covariance structures TOEPH (Heterogeneous Toeplitz), ARH(1) (Heterogeneous auto-
regressive 1), and VC (Variance Components) will be tested in the order specified. Least Square means, 
standard errors, and the LS mean differences (each treatment versus placebo and the pooled active groups 
versus placebo) at each visit will be reported. All estimates will be generated from a single model, i.e., the 
pooled active estimates will be created via model contrasts.  
11.4.3.1.7 Clinical Global Impression of Severity (CGI-S) of Excessive Daytime Sleepiness 
(EDS) 
 
 
 
  
 
  
 
  
 
 
Numerical values in parentheses were assigned in the datasets. Early termination visits will be summarized 
and analyzed under Week 7 or Week 11 (depending on which visit they are closest to, see section 9.2 on 
visit window) regardless of the discontinuation reason. 
A descriptive summary of CGI-S for the absolute values and change from Baseline to Week 7 and to 
Week 11 will be presented by treatment group and for the active groups combined. In addition, frequency 
count and percentage of the CGI-S score at each visit versus baseline category will be provided using a 
shift table.  
The change from Baseline will be analyzed using a Mixed Model Repeated Measures (MMRM) approach. 
Fixed effects will be included for treatment, visit, treatment*visit interaction, baseline value, and wake-
promoting agents stratification factor. An unstructured covariance structure will be utilized; in case of failure 
to converge, covariance structures TOEPH (Heterogeneous Toeplitz), ARH(1) (Heterogeneous auto-
regressive 1), and VC (Variance Components) will be tested in the order specified. Least Square means, 
standard errors, and the LS mean differences (each treatment versus placebo and the pooled active groups 
versus placebo) at each visit will be reported. All estimates will be generated from a single model, i.e., the 
pooled active estimates will be created via model contrasts. 


 
 
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11.4.3.1.8 Patient Global Impression of Severity (PGI-S) of Excessive Daytime Sleepiness 
(EDS) 
 
 
 
  
 
  
 
  
 
 
Numerical values in parentheses were assigned in the datasets. The same summaries and analyses 
performed for CGI-S will be repeated for the PGI-S endpoint. Further details on the summaries and 
inferential analyses are provided in section 11.4.3.1.7. 
11.4.3.1.9 Mean Sleep Latency 
The MWT, a daytime polysomnographic procedure for the evaluation of daytime somnolence/wakefulness, 
is used to assess an individual’s ability to stay awake while resisting the pressure to fall asleep. The MWT 
evaluates the magnitude of sleepiness in relationship to the underlying wakefulness system’s functioning. 
For the MWT, patients will be administered four 40-minute sessions at 2-hour intervals according to the 
validated standard (Doghramji et al 1997), with the initial session beginning two hours after wakening. 
The session will end if the patient falls asleep, or if more than 40 minutes elapse without the patient falling 
asleep. The sleep latency, or the time it takes to fall asleep, will be recorded.  
Analysis of the MWT will be based on the average MSL computed from the four sessions. 
A descriptive summary of MSL for the absolute values and change from Baseline to Visit 5 will be reported 
by treatment group and for the active groups combined. If the termination visit occurs after the Visit4 Double-
Blind visit, the early termination data will be windowed to Visit 5 regardless of the discontinuation reason. 
The change from Baseline to Visit 5 will be analyzed using an ANCOVA model with fixed effect terms for 
treatment, baseline value, and wake-promoting agents stratification factor. Least Square means, standard 
errors, and the LS mean differences (each treatment versus placebo and the pooled active groups versus 
placebo) will be reported. All estimates will be generated from a single model, i.e., the pooled active 
estimates will be created via model contrasts. 
11.4.3.1.10 
Sustained Attention to Response Task (SART) 
The SART is a measure of sustained attention, which is the ability to focus on an activity or stimulus over 
a long period of time, or to direct focus and cognitive ability on specific stimuli. It is a computer-based go/no-
go task that requires participants to withhold behavioral response to a single, infrequent target presented 
amongst a background of frequent non-targets. Both accuracy and response speed, quantified as response 
time, are important. The total, go, and no-go scores will be summarized and analyzed. The total score is 
the sum of the go score and no-go score. 
Early termination visits will be summarized and analyzed under Visit 5 (see section 9.2) regardless of the 
discontinuation reason. The actual values and change from Baseline of the go, no-go and total score will 
be summarized using descriptive statistics.  
In addition, it is assumed that the change from Baseline in SART parameters are not normally distributed. 
For the difference between lower dose pitolisant and placebo, the difference between higher dose pitolisant 
and placebo, and the difference between pooled pitolisant and placebo, p-values will be generated and 
reported. Early termination visits will be summarized and analyzed under Visit 5 regardless of the 
discontinuation status. 


 
 
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11.4.4 Open-Label Extension Efficacy Analyses 
The OLE efficacy parameters are:  
• 
DSS 
• 
ESS 
• 
FSS  
• 
Cogstate (Detection Test, Identification Test, One Back Test) 
• 
MDHI Total score and sub-scores of sleep, fatigue and cognitive impairment 
• 
CGI-S for EDS  
• 
PGI-S for EDS 
Actual and change from Baseline results in the OLE Phase will be summarized by using descriptive 
statistics at each open-label visit. Results will be tabulated by total. In addition, shift tables from baseline to 
each of the OLE visits will be provided for DSS, ESS, CGI-S and PGI-S.  
11.5 PK Analyses 
Concentration-time data of pitolisant and BP1.3484 will be summarized using descriptive statistics (number 
of observations, number of results less than the lower limit of quantification, SD, geometric mean, geometric 
SD, coefficient of variation [%], median, minimum, and maximum) based on the PK population in the 
Double-Blind Treatment Phase by randomized treatment group (lower dose and higher dose only). For 
summarization, plasma concentrations below the quantifiable limit (BLQ) will be set to zero.  
Concentration will be listed.  
11.6 Safety Analyses 
Safety analyses will be provided 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 analyses. 
For the Double-Blind Treatment Phase, summaries will be presented by treatment arms. For the OLE 
Phase, results will be tabulated by treatment received during the Double-Blind Treatment Phase (including 
active arms pooled) and overall.  
11.6.1 Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  
A treatment-emergent AE (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. 
For the OLE Phase, any AE starting on or after the first dose of OLE treatment will be considered treatment 
emergent. 
A serious AE (SAE) is defined as any AE that results in any of the following outcomes: death, is life-
threatening, results in inpatient hospitalization or prolongation of existing hospitalization, results in a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal activities of daily 
living or is a congenital anomaly/birth defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered SAEs 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.  


 
 
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An AE’s relationship to study treatment will be evaluated by the Investigator. The following relationships will 
be collected in eCRF: definitely related, probably related, possibly related, unlikely related, or not related. 
AEs that are evaluated as definitely, probably, or possibly related (or with missing relationship) will be 
considered treatment-related AEs for summary purposes.  
The severity of AEs will be classified by the Investigator as mild, moderate, or severe. If the severity is 
missing, the AE will be assumed to be severe. 
An overall TEAE summary will be generated presenting the frequency and percentage of patients and the 
number of AEs for the following:  
• 
Any TEAE  
• 
Any treatment-related TEAE  
• 
Any severe TEAE  
• 
Any treatment-related severe TEAE  
• 
Any serious TEAE   
• 
Any treatment-related serious TAE  
• 
Any TEAE leading to study discontinuation 
• 
Any TEAE leading to discontinuation of investigational product (IP) 
• 
Any TEAE leading to interruption of IP 
• 
Any TEAE leading to death  
All AEs will be coded using MedDRA; the version used will be included in the tables and listings footnotes.  
The TEAEs will also be summarized by system organ class (SOC) and preferred term (PT), by severity and 
relationship to study treatment.  
The TEAE summary tables will be sorted by SOC and PT. SOCs will be displayed in descending order of 
overall frequency in the pooled pitolisant group and then alphabetically. PTs will be displayed in descending 
order of overall frequency and then alphabetically within SOC. A patient with 2 or more events within the 
same PT of summarization will be counted only once in that level using the most severe incident or most 
related incident. Percentages will be based on the number of patients in the safety population. The following 
summaries by SOC and PT will be provided: 
• 
TEAE 
• 
Treatment-related TEAE  
• 
TEAE by maximum severity 
• 
Serious TEAE 
• 
Treatment-related serious TEAE 
• 
TEAE leading to discontinuation of IP 
• 
TEAE leading to interruption of IP 
• 
TEAE leading to death 
Finally, a summary of all AEs and all SAEs by SOC and PT will be provided. 
All AEs will be presented in a data listing. Separate data listings will be generated for treatment related 
AEs, SAEs, and AEs leading to study discontinuation. 
For patients who opt to continue in the OLE Phase of the study, only AEs started on or before the last dose 
of the Double-Blind Treatment Phase will be included in the summaries for the Double-Blind Treatment 
Phase. AEs started after the last dose of treatment and up to 30 days after the last dose of treatment in the 
Double-Blind Treatment Phase will be included in a separate listing and summarized in the OLE Phase 
reporting.  
For clinicaltrials.gov and other registries, the following will be produced in XML format. 


 
 
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1. All-Cause Mortality: *§ A table of all anticipated and unanticipated deaths due to any cause, with 
the number and frequency of such events by arm or comparison group of the clinical study. 
2. Serious Treatment-Emergent Adverse Events: * A table of all serious adverse events, grouped by 
System Organ Class, with the number and frequency of such events by arm or comparison group 
of the clinical study.  
3. Other (Not Including Serious) Treatment-Emergent Adverse Events: * A table of anticipated and 
unanticipated events (not included in the serious adverse event table) that exceed a frequency 
threshold (for example, 5 percent) within any arm of the clinical study, grouped by organ system, 
with the number and frequency of such events by arm or comparison group of the clinical study. 
XML schema are here: https://prsinfo.clinicaltrials.gov/RRSUploadSchema.xsd 
11.6.2 Seizure Disorder 
A summary of 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 presented. Patients who 
experience worsening of their seizure disorder will be withdrawn from the study. 
A summary table of seizure will be sorted by SOC and PT. All seizure data will be presented in a data 
listing.  
11.6.3 Clinical Laboratory Evaluations 
Laboratory parameters will be summarized for Double-Blind safety population and OLE safety population. 
Laboratory data (hematology, serum chemistry, and urinalysis) will be converted to the International System 
of Units (SI) units for reporting and processing purposes. Absolute values and changes from Baseline at 
each visit will be presented descriptively. Results reported as “<xx” or “>xx” will be imputed to “xx” for 
calculating the summary statistics. 
Hematology, serum chemistry, and urinalysis will be summarized using descriptive statistics for numerical 
data and numbers and percentages for categorical data at each scheduled assessment. Numerical 
hematology, chemistry, and urinalysis results will be summarized using change from Baseline as well.  
All clinical laboratory test results will be presented in data listings. Laboratory values that are outside of the 
normal reference range will be flagged in the data listings.  
Urine drug screen will be listed only. 
11.6.4 Vital Signs 
Vital signs will include blood pressure, heart rate, respiratory rate, , and body temperature. Patients will be 
resting for at least 5 minutes before taking vital signs.  
Vital signs results and corresponding change from study baseline values will be summarized at each visit 
using descriptive statistics by treatment group.  
The reference ranges for the vitals are included in Table 8 and will be used to categorize the assessments 
by Normal, High, or Low. The lowest and highest post-baseline results will be compared with that at the 
study baseline, and the "shifts” from study baseline will be summarized using the number and percentage 
of patients in each shift category by treatment group. 
All vital signs measurements will be presented in a data listing; height will be presented within the 
demographic listing. 


 
 
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Table 8: Vital Signs Reference Ranges   
Parameter 
Low 
High 
Normal 
Systolic Blood Pressure (mmHg) 
< 80 
> 130 
80 - 130 
Diastolic Blood Pressure (mmHg) 
< 60 
> 90 
60 - 90 
Heart Rate (beat per minutes) 
< 60 
> 100 
60 - 100 
Respiration Rate (breath per minutes) 
< 12 
> 20 
12 - 20 
Temperature (°C) 
< 36.6 
> 37.3 
36.6 -- 37.3 
 
11.6.5 Physical Examinations 
Physical examination will include an evaluation of the head and neck as well as cardiovascular, respiratory, 
gastrointestinal, neurological, dermatological, and musculoskeletal systems (SoA for DBT phase and SoA 
for OLE phase in the protocol Amendment 5). Abbreviated physical examinations will be performed based 
on patient-reported symptoms (SoA for DBT phase and SoA for OLE phase in the protocol Amendment 5).  
Physical examination data will be presented in a data listing. 
11.6.6 12-Lead Electrocardiograms  
Triplicate 12-lead ECGs will be obtained after the patient has been resting for at least 5 minutes. For 
clinically significant ECG findings, a follow-up ECG should be performed within 24 hours and again 7 days 
later to ensure that the abnormality is not worsening. Follow-up 12-lead ECGs may be performed locally 
and sent to the Investigator for assessment; the Investigator will submit all ECGs done locally to the central 
ECG vendor. 
A core ECG laboratory will manage all ECG monitoring activities. All ECG results along with the 
investigator’s interpretation, including the average of triplicate measurements at each timepoint, will be 
presented in data listings.  
QT values will be presented with the implementation of corrections (i.e., Fridericia’s) as defined in 
International Council for Harmonisation (ICH) Guidelines E14 by the following categories:   
Absolute QT interval corrected for heart rate based on Fridericia’s formula (QTcF) interval prolongation: 
• 
QTcF interval <450 ms 
• 
QTcF interval 450-480 ms 
• 
QTcF interval 480-500 ms  
• 
QTcF interval >500 ms 
Change from baseline in QTcF interval: 
• 
QTcF interval increases from baseline 30-60 ms  
• 
QTcF interval increases from baseline >60 ms 
In addition, potential QT prolongations will be categorized as: 
• 
PR interval >300 msec 
• 
QRS duration >140 msec 
• 
PR interval increase from baseline >50% 
• 
QRS duration increase from baseline >40% 


 
 
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• 
HR increase >65% from baseline 
• 
HR decrease >40% from baseline 
The actual values and change from baseline values at each time point will be summarized for the safety 
populations. The overall interpretation will also be summarized by timepoint as well as the worst post-
baseline.  
The average of the triplicates at each timepoint will be used in the summaries as defined in Section 9.2.  
11.6.7 Holter Monitoring 
Patients will be fitted with a Holter monitor, which they will wear for 24 hours before returning the device 
and for all abnormal Holter monitor findings considered clinically significant by the Investigator, additional 
evaluation, including an unscheduled ECG, is required. 
A core ECG laboratory will manage all Holter monitoring activities. All Holter results will be presented in 
data listings.  
The actual values and change from baseline values at each time point will be summarized for the safety 
populations. Abnormalities will be summarized by frequency count and percentages.  
11.6.8 Columbia-Suicide Severity Rating Scale (C-SSRS)   
The Columbia-Suicide Severity Rating Scale (C-SSRS) scale is composed of 11 items answered Yes or 
No. The C-SSRS also includes a suicidal ideation intensity rating from 1 (least severe) to 5 (most severe).  
Results of the C-SSRS will be provided in data listings only.  
 
 


 
 
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12 References 
Doghramji K, Mitler MM, Sangal RB, et al. A normative study of the Maintenance of Wakefulness Test 
(MWT). Electroencephalogr Clin Neurophysiol. 1997; 103:554-62. 
Heatwole C, Bode R, Johnson N, et al. Myotonic dystrophy health index: initial evaluation of a disease 
specific outcome measure. Muscle and Nerve. 2014; 49(6):906-14. 
Heatwole C, Bode R, Johnson NE, et al. Myotonic Dystrophy Health Index: Correlations with clinical tests 
and patient function. Muscle and Nerve. 2016; 53(2):183-90. 
Hewlett S, Dures E, Almeida C. Measures of Fatigue. Arthritis Care and Research. 2011; 63(S11):S263-
86. 
Hirshkowitz M and Sharafkhaneh A. Evaluating Sleepiness. in Kryger M, Roth T and Dement WC. 
Principles and Practice of Sleep Medicine. 6th Ed. Elsevier, Philadelphia, 2017. P 1652. 
Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep. 1991; 
14(6):540-5. 
Krupp LB, LaRocca NG, Muir-Nash J, et al. The Fatigue Severity Scale: application to patients with multiple 
sclerosis and systemic lupus erythematosus. Arch Neurol. 1989; 46:1121-23. 
Laberge L, Bégin P, Montplaisir J, et al. Sleep complaints in patients with myotonic dystrophy. J Sleep 
Res. 2004; 13:95-100.  
Laberge L and Dauvilliers Y. Myotonic dystrophy and sleepiness in Thorpy M. and Billiard M. (Eds). 
Sleepiness: Causes, Consequences and Treatment. Cambridge University Press; 2010: 316-26.  
Laberge L, Dauvilliers Y, Bégin P, et al. Fatigue and daytime sleepiness in patients with myotonic 
dystrophy type 1: To lump or split? Neuromuscular Disorders 2009; 19:397-402.  
Laberge L, Gallais B, Auclair J, et al. Responsiveness of Daytime Sleepiness and Fatigue Scales in 
Myotonic Dystrophy Type 1. Can J Neurol Sci. 2021; 20:1-4. 
SAS Institute Inc. 2015. SAS 9.4 Procedures Guide. 5th ed. Cary, NC: SAS Institute Inc.  
Rosa, K., Fu, M., Gilles, L. et al. Validation of the Fatigue Severity Scale in chronic hepatitis C. Health Qual 
Life Outcomes. 2014; 12:90. https://doi.org/10.1186/1477-7525-12-90. 
 
 


 
 
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13 Appendix 1 Glossary of Abbreviations 
Glossary of Abbreviations:  
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
ASP 
Average sleep propensity 
BLQ 
Below the Quantifiable Limit 
bpm 
Beat per minutes 
CGI-S 
Clinical Global Impression of Severity 
CI 
Confidence Interval 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTG 
Cytosine-thymine-guanine 
CYP 
Cytochrome P450 
DBT 
Double-Blind Treatment 
DM1 
Myotonic dystrophy type 1 
DSS 
Daytime Sleepiness Scale 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDS 
Excessive daytime sleepiness 
EOT  
End of Treatment 
ESS 
Epworth Sleepiness Scale 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FSS 
Fatigue Severity Scale 
GCP 
Good Clinical Practice 
H1 
Histamine 1  
ICH 
International Council for Harmonisation 
IP 
Investigational product 
IRT 
Interactive Response Technology 
LOE 
Lack of efficacy 
LS 
Least square 
MDHI 
Myotonic Dystrophy Health Index 
MedDRA 
Medical Dictionary for Regulatory Activities 


 
 
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Glossary of Abbreviations:  
mITT 
Modified Intent-to-Treat 
MMRM 
Mixed effect model repeated measures 
MSL 
Mean sleep latency 
MWT 
Maintenance of Wakefulness Test 
NIH 
National Institutes of Health  
OLE 
Open-Label Extension 
PD 
Protocol deviations 
PGI-S 
Patient Global Impression of Severity 
PK 
Pharmacokinetic(s) 
PT 
Preferred term 
QTcF 
QT interval corrected for heart rate based on Fridericia’s formula 
RT 
Reaction time 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SART 
Sustained Attention to Response Task 
SD 
Standard deviation 
SE 
Standard error 
SI 
International System of Units 
SoA 
Schedule of Assessment 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
WHO 
World Health Organization 
 
 
 


 
 
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14 Appendix 5 Adverse Event Start/Stop Date Imputation 
 
Imputation Rules for Partial Dates (D = day, M = month, Y = year) 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date for 
AEs 
D 
M and Y same as M and Y of first dose of 
study drug 
Date of first dose of study drug 
M and/or Y not same as date of first 
dose of study drug 
First day of month 
D and M 
Y same as Y of first dose of study 
drug 
Date of first dose of study drug 
Y prior to Y of first dose of study drug but 
same as Y of screening date 
Date of screening date 
D, M, Y 
None - date completely missing 
Date of first dose of study drug 
Stop date for 
AEs 
D 
M and Y same as M and Y of last dose 
of study drug 
Date of last dose of study drug 
M and/or Y not same as date of last 
dose of study drug 
Use last day of month 
D and M 
Y same as Y of last dose of study drug 
Date of last dose of study drug 
Y not same as Y of last dose of study 
drug 
Use Dec 31 
D, M, Y 
None - date completely missing 
No imputation, but assume 
ongoing 
Note: In all cases, if an estimated start date is after a complete stop date, use the first day of the stop date month. 
Similarly, if the estimated stop date is before a complete or imputed start date, use the last day of the start day month. 
 
 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
Version Date: 03Nov2023 
Sponsor: Harmony Biosciences, LLC 
 
Protocol No: HBS-101-CL-005 
 
PRA-QMS-02745 8.0 
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15 
Appendix 2 Prior and Concomitant Medication Start/Stop Date 
Imputation 
Imputation Rules for Partial Dates (D = day, M = month, Y = year) 
Parameter 
 
Missing 
Additional Conditions 
Imputation 
Start date for 
con meds 
D only 
M and Y same as M and Y of first dose 
of study drug 
Date of first dose of study 
drug 
M and/or Y not same as date of first dose 
of study drug 
First day of month 
M and D 
Y same as Y of first dose of study 
drug 
Date of first dose of study drug 
Y not same as Y of first dose of study drug Use Jan 01 of Y 
M, D, and Y 
None - date completely missing 
Day prior to date of first dose of 
study drug 
Stop date for 
con meds 
D only 
M and Y same as M and Y of last dose of 
study drug 
Date of last dose of study drug 
M and/or Y not same as date of last 
dose of study drug 
Last day of month 
M and D 
Y same as Y of last dose of study drug 
Date of last dose of study 
drug 
Y not same as Y of last dose of study drug Use Dec 31 of Y 
M, D, and Y 
None - date completely missing and 
NOT ongoing 
Date of last dose of study drug 
Note: In all cases, if an estimated start date is after a complete stop date, use the first day of the stop date month. 
Similarly, if the estimated stop date is before a complete or imputed start date, use the last day of the start day month. 
 
 
 
 
 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
Version Date: 03Nov2023 
Sponsor: Harmony Biosciences, LLC 
 
Protocol No: HBS-101-CL-005 
 
PRA-QMS-02745 8.0 
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16 
Appendix 3 Example of Prohibited Medications 
Examples of strong CYP2D6 Inhibitors, strong CYP3A4 Inducers, Medications that prolongQT Interval, 
And Centrally Acting H1R Antagonists. 
 
Medicaiton Type 
Example 
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  
Centrally acting H1 receptor 
antagonists (sedating or 
lipophilic H1R antagonists) 
pheniramine maleate, diphenhydramine, promethazine (anti-histamines) 
imipramine, clomipramine, mirtazapine (tri or tetracyclic antidepressants).  
CYP = cytochrome P450; H1R = histamine 1 receptor 
 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
Version Date: 03Nov2023 
Sponsor: Harmony Biosciences, LLC 
 
Protocol No: HBS-101-CL-005 
 
PRA-QMS-02745 8.0 
 
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17 Appendix 4 SAS Sample Code 
 
Below are some examples of code for inferential statistics described in the SAP. 
ANCOVA:  
   proc mixed data=datain; 
      class trtpn wkprag; 
      model chg = base trtpn wkprag / solution; 
      lsmeans trtpn / cl stderr pdiff cov; 
      estimate ‘pooled vs placeco’ 0.5 0.5 -1 / cl; 
      ods output diffs = lsdiffs lsmeans = lsm solutionf = parms; 
run; 
 
 
MMRM: 
 proc mixed data=datain; 
     class subjid trtpn avisitn wkprag; 
     model chg = base trtpn avisitn trtpn*avisitn wkprag/ ddfm=KenwardRoger; 
     repeated visit / subject = subjid type = UN; 
     lsmeans trtpn / cl stderr pdiff cov; 
     estimate ‘pooled vs placeco’ 0.5 0.5 -1 / cl; 
     ods output diffs = lsdiffs lsmeans = lsm solutionf = parms; 
run; 
 
Kruskal-Wallis Test: 
proc npar1way data=datain wilcoxon dscf;  
    class trtpn; 
    var chg; 
run; 
 
 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
Version Date: 03Nov2023 
Sponsor: Harmony Biosciences, LLC 
 
Protocol No: HBS-101-CL-005 
 
PRA-QMS-02745 8.0 
 
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18 Appendix 6 Clinical Laboratory Tests 
 
Urine Drug Screen 
Barbiturates 
Cocaine metabolites 
Opiates 
Tetrahydrocannabinol 
Cannabidiol 
Phencyclidine 
Methadone 
Amphetamines/Stimulants 
Hypnotics 
Urinalysis 
Specific gravity 
pH 
Blood 
Glucose 
Protein 
Leukocyte esterase 
Ketones 
Bilirubin 
Nitrites 
Casts 
Crystals 
Erythrocytes 
Renal tubular epithelial cells 
WBCs 
Bacteria 
Pregnancy Screen (FCBP only) 
Serum (at Screening only 
Urine (as scheduled after screening) 
Serum Chemistry 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Blood urea nitrogen 
Calcium 
Chloride 
Creatinine 
Creatine kinase 
Glucose 
High-density lipoprotein 
Low-density lipoprotein 
Magensiuma 
Phosphorus 
Potassiuma 
Sodium 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Total protein 
Triglycerides 
Uric acid 
Hematology 
Complete blood count, including platelet count and WBC count with differential 
Hemoglobin 
Hematocrit 
HbA1c 
Abbreviations: FCBP = female of child-bearing potential; HbA1c = hemoglobin A1c; WBC = white blood cell 
aPatients will be administered supplements if serum magnesium and/or potassium levels decrease by 20% compared with Baseline, or if the levels are in the low normal or below 
normal range. 
 
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.  


 
 
Statistical Analysis Plan (SAP) 
 
 
 
Version Date: 03Nov2023 
Sponsor: Harmony Biosciences, LLC 
 
Protocol No: HBS-101-CL-005 
 
PRA-QMS-02745 8.0 
 
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NOTE: Wake-promoting agents including mixed amphetamine salts such as Vyvanse (lisdexamfetamine mesylate), Adderall (amphetamine and 
dextroamphetamine) and similar agents that are prescribed to treat EDS are permitted. Mexilitene may cause a positive urine drug screen for 
amphetamine. In the event a urine drug screen is positive for amphetamines, consult with the Medical Monitor before screen failing the patient. 
Hypnotics are permitted during the study.