Safety and Efficacy of Pitolisant on Excessive Daytime Sleepiness and Other Non-Muscular Symptoms in Patients With Myotonic Dystrophy Type 1

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.

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.

Eligibility Criteria:
Inclusion Criteria:

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. Has a Clinical Global Impression of Severity (CGI-S) assessment of moderate or severe for overall severity of EDS at Screening.
5. If on a wake-promoting treatment that could affect EDS (including stimulants, modafinil, and armodafinil):

   1. 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).
   2. 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:

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. Experiences \<6 hours on average of sleep per night based on their sleep diary during Screening (patients need to record at least 7 of 10 consecutive nights including 2 nights that fall on a weekend in their sleep diary during Screening).
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.
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 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. 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.
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 Columbia-Suicide Severity Rating Scale.
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.