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

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Brief Title

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

Official 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

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 135 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 low dose pitolisant, high 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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Excessive Daytime Sleepiness

Secondary Outcome

 Excessive Daytime Sleepiness

Condition

Myotonic Dystrophy 1

Intervention

Pitolisant Oral Tablet

Study Arms / Comparison Groups

 High dose pitolisant
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

135

Start Date

June 28, 2021

Completion Date

October 2023

Primary Completion Date

September 2023

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) and patient medical records.

          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. Has a mean sleep latency of ≤25 minutes as determined by MWT score at the Baseline
             Visit (Visit 2).

          6. 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
                  or 14 days, whichever is longer, prior to randomization and agree to remain off
                  these treatments for the duration of the Double-Blind Treatment Phase of the
                  study.

          7. 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.

          8. Able to walk independently with or without an assistive device (e.g., cane, walker,
             orthoses allowed).

          9. 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.

         10. 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.

          2. Experiences <6 hours on average of sleep per night based on their sleep diary during
             Screening (patients need to record at least 7 consecutive nights 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 or 1 week, whichever
             is longer, 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.

          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/unexplained death, cardiac 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.

         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. Patients with
             implanted univentricular pacemakers that are used prophylactically to prevent
             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
             consistently 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; patients who undergo a washout of these medications of at
             least 5 half-lives or one week (whichever is longer) can be enrolled in the
             Double-Blind Treatment Phase of the study. Use of strong CYP2D6 inhibitors and strong
             CYP3A4 inducers is allowed during the OLE Phase; however, adjustment of pitolisant
             dose is required. Although not prohibited during the OLE Phase of the study, use of
             H1R antagonists should be avoided.

         24. Is unable to discontinue any medication known to prolong QTc interval.

         25. Is a known CYP2D6 poor metabolizer (PM).

         26. 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 week prior to study-related
             assessments).

         27. Has abnormal laboratory values at Screening that are clinically significant as
             determined by the Investigator.

         28. 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.

         29. 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).

         30. Has planned surgery during the Double-Blind Treatment Phase of the study; planned
             surgery is permitted during the OLE Phase.

         31. 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.

         32. 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.
      

Gender

All

Ages

18 Years - 65 Years

Accepts Healthy Volunteers

No

Contacts

, 7733836258, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04886518

Organization ID

HBS-101-CL-005


Responsible Party

Sponsor

Study Sponsor

Harmony Biosciences, LLC


Study Sponsor

, , 


Verification Date

May 2022