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

• ClinicalTrials.gov Identifier: NCT04886518
• Recruitment Status: Recruiting
• First Posted: May 14, 2021
• Last Update Posted: May 5, 2022
• Sponsor: Harmony Biosciences, LLC
• Information provided by (Responsible Party): Harmony Biosciences, LLC

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Myotonic Dystrophy 1; Excessive Daytime Sleepiness	Drug: Pitolisant Oral Tablet; Drug: Placebo oral tablet	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 135 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: June 28, 2021
• Estimated Primary Completion Date: September 2023
• Estimated Study Completion Date: October 2023

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: High dose pitolisant; 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.	Drug: Pitolisant Oral Tablet; 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.
Active Comparator: Low dose pitolisant; 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	Drug: Pitolisant Oral Tablet; 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.
Placebo Comparator: Placebo; Double-Blind Treatment Phase: Week 1: Matching placebo tablets; Week 2: Matching placebo tablets; Weeks 3 through 11: Matching placebo tablets	Drug: Placebo oral tablet; Matching placebo tablets will be provided for each strength of active pitolisant film-coated tablets.

Outcome Measures

Primary Outcome Measures :

1. Excessive Daytime Sleepiness [ Time Frame: Baseline to Week 11 ]

   Change in mean sleep latency based on the Maintenance of Wakefulness Test score from Baseline to Week 11 for pitolisant compared with placebo.

   An increase in mean sleep latency score on the Maintenance of Wakefulness Test represents an improvement in excessive daytime sleepiness.

Secondary Outcome Measures :

1. Excessive Daytime Sleepiness [ Time Frame: Baseline to Week 11 ]

   Change in Daytime Sleepiness Scale (DSS) score.

   The score of the DSS ranges from 0 to 15. A decrease in the DSS score represents an improvement in excessive daytime sleepiness.

2. Fatigue [ Time Frame: Baseline to Week 11 ]

   Change in Fatigue Severity Scale (FSS) score.

   The score of the FSS ranges from 0 to 63. A decrease in the FSS score represents an improvement in fatigue.

3. Psychomotor Function [ Time Frame: Baseline to Week 11 ]

   Change in Cogstate Detection Test.

   The Cogstate Detection Test is a computerized test. A faster speed represents an improvement in psychomotor test performance.

4. Attention [ Time Frame: Baseline to Week 11 ]

   Change in Cogstate Identification Test.

   The Cogstate Identification Test is a computerized test. A faster speed represents an improvement in attention test performance.

5. Working Memory [ Time Frame: Baseline to Week 11 ]

   Change in Cogstate One Back Test.

   The Cogstate One Back Test is a computerized test. A faster speed represents a better working memory test performance.

6. Burden of Disease (Myotonic Dystrophy Type 1) [ Time Frame: Baseline to Week 11 ]

   Change in Myotonic Dystrophy Health Index.

   The Myotonic Dystrophy Health Index score ranges from 0 to 100. A decrease in the Myotonic Dystrophy Health Index score represents an improvement in overall burden of disease.

7. Excessive Daytime Sleepiness [ Time Frame: Baseline to Week 11 ]

   Change in Epworth Sleepiness Scale (ESS) score.

   The score of the ESS ranges from 0 to 24. A decrease in the ESS score represents an improvement in excessive daytime sleepiness.

8. Excessive Daytime Sleepiness [ Time Frame: Baseline to Week 11 ]

   Change in Clinical Global Impression of Severity.

   The Clinical Global Impression of Severity is a four item scale that ranges from none to severe. An assessment of less severe symptoms represents an improvement in the clinician's perception of symptoms of excessive daytime sleepiness.

9. Excessive Daytime Sleepiness [ Time Frame: Baseline to Week 11 ]

   Change in Patient Global Impression of Severity.

   The Patient Global Impression of Severity is a four item scale that ranges from none to high. An assessment of less likelihood of falling asleep during daytime activities represents an improvement in the patient's perception of their excessive daytime sleepiness.

10. Sustained Attention [ Time Frame: Baseline to Week 11 ]

    Change in Sustained Attention to Response Task.

    The Sustained Attention to Response Task is a computerized test. A decrease in total error score represents an improvement in vigilance.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Contacts

Contact: Ann Adee; 7733836258; clinicaltrials@harmonybiosciences.com

Contact: Michelle Manuel; 8479034610; clinicaltrials@harmonybiosciences.com

Locations

United States, California

UCI Center for Clinical Research; Recruiting

Irvine, California, United States, 92697

Contact: Susan Tieng stieng@hs.uci.edu

Principal Investigator: Tahseen Mozaffar, MD

United States, Colorado

University of Colorado School of Medicine; Recruiting

Aurora, Colorado, United States, 80045

Contact: Haley Simpson 303-724-4644 NeuroResearch@CUAnschutz.edu

Contact: Brenna Baines brenna.baines@cuanschutz.edu

Principal Investigator: Matthew Wicklund, MD

United States, Florida

University of Florida; Recruiting

Gainesville, Florida, United States, 32611

Contact: Julie Segura julie.segura@neurology.ufl.edu

Principal Investigator: Sub Subramony, MD

University of South Florida; Recruiting

Tampa, Florida, United States, 33612

Contact: Jessica Shaw 813-974-9413 jessshaw@usf.edu

Principal Investigator: Tuan Vu, MD

United States, Georgia

Rare Disease Research; Recruiting

Atlanta, Georgia, United States, 30329

Contact: Genevieve Wilson 678-883-6897 Genevieve.Wilson@RareDiseaseResearch.com

Principal Investigator: Han C Phan, MD

United States, Indiana

Indiana University; Recruiting

Indianapolis, Indiana, United States, 46202

Contact: Lauren Perrey, RN, BSN 317-963-7505 lperrey@iupui.edu

Principal Investigator: Laurie Gutmann, MD, FAAN

United States, Kansas

University of Kansas Medical Center; Recruiting

Kansas City, Kansas, United States, 66160

Contact: Katie Roath kroath@kumc.edu

Principal Investigator: Jeffrey Statland, MD

United States, Maryland

Kennedy Krieger Institute Center for Genetic Muscle Disorders; Recruiting

Baltimore, Maryland, United States, 21205

Contact: Sharanya Suresh 443-923-3832 suresh@kennedykrieger.org

Principal Investigator: Doris Leung, MD, PhD

United States, Massachusetts

Massachusetts General Hospital; Recruiting

Boston, Massachusetts, United States, 02114

Contact: Melina Durson bdurson@bwh.harvard.edu

Principal Investigator: Paloma Gonzalez-Perez, MD

United States, Minnesota

University of Minnesota; Not yet recruiting

Minneapolis, Minnesota, United States, 55455

Contact: Natalya Alassy burla019@umn.edu

Principal Investigator: Peter Karachunski, MD

United States, New York

University of Rochester Medical Center; Recruiting

Rochester, New York, United States, 14642

Contact: Elizabeth Luebbe Elizabeth_Luebbe@URMC.Rochester.edu

Principal Investigator: Johanna Hamel, MD

United States, North Carolina

Wake Forest; Recruiting

Winston-Salem, North Carolina, United States, 27157

Contact: Carolina Burgos 336-713-2603 caguilar@wakehealth.edu

Principal Investigator: Araya Puwanant, MD

United States, Pennsylvania

University of Pennsylvania; Recruiting

Philadelphia, Pennsylvania, United States, 19104

Contact: Pranali Ravikumar, MS 215-615-0550 Pranali.Ravikumar@pennmedicine.upenn.edu

Principal Investigator: Lauren Elman, MD

United States, Washington

University of Washington; Not yet recruiting

Seattle, Washington, United States, 98195

Contact: Leo Wang, MD, PhD

Principal Investigator: Leo Wang, MD, PhD

Sponsors and Collaborators

Harmony Biosciences, LLC

More Information

• Responsible Party: Harmony Biosciences, LLC
• ClinicalTrials.gov Identifier: NCT04886518
• Other Study ID Numbers: HBS-101-CL-005
• First Posted: May 14, 2021
• Last Update Posted: May 5, 2022
• Last Verified: May 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Myotonic Dystrophy; Disorders of Excessive Somnolence; Sleepiness; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Myotonic Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Mental Disorders