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A Phase 2 Study to Evaluate the Safety and Efficacy of Pitolisant in Patients With Prader-Willi Syndrome, Followed by an Open Label Extension

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04257929
Recruitment Status : Not yet recruiting
First Posted : February 6, 2020
Last Update Posted : October 20, 2020
Sponsor:
Information provided by (Responsible Party):
Harmony Biosciences, LLC

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 Prader Willi syndrome (PWS) ages 6 to 65 years.

Condition or disease Intervention/treatment Phase
Prader-Willi Syndrome Drug: Pitolisant oral tablets 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 be multi-year in duration and will continue until either pitolisant is approved for patients with PWS or the Sponsor elects to terminate the study.

Approximately 60 patients ages 6 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 and will undergo titration during a 3-week Titration Period to a maximum target dose based on their age. At the end of the 3-week Titration Period, patients will continue to take their target dose of pitolisant once daily in the morning upon wakening until the end of the study.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate the Safety and Efficacy of Pitolisant in Patients With Prader-Willi Syndrome, Followed by an Open Label Extension
Estimated Study Start Date : December 2020
Estimated Primary Completion Date : May 2022
Estimated Study Completion Date : June 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Low dose pitolisant

Pediatric patients (6 to less than 12 years of age) 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: 8.9 mg pitolisant administered once daily in the morning.

Adolescent patients (12 to less than 18 years of age) 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: 13.35 mg pitolisant administered once daily in the morning.

Adult patients (18 to 65 years of age) 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 tablets

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: High dose pitolisant

Pediatric patients (6 to less than 12 years of age) 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.

Adolescent patients (12 to less than 18 years of age) 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: 26.7 mg pitolisant administered once daily in the morning.

Adult patients (18 to 65 years of age) 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 tablets

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

Pediatric patients (6 to less than 12 years of age) Double-Blind Treatment Phase:

Week 1: Matching placebo tablets; Week 2: Matching placebo tablets; Weeks 3 through 11: Matching placebo tablets

Adolescent patients (12 to less than 18 years of age) Double-Blind Treatment Phase:

Week 1: Matching placebo tablets; Week 2: Matching placebo tablets; Weeks 3 through 11: Matching placebo tablets

Adult patients (18 to 65 years of age) 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.




Primary Outcome Measures :
  1. Excessive Daytime Sleepiness [ Time Frame: Baseline to Week 11 ]
    Change in Mean Sleep Latency Test


Secondary Outcome Measures :
  1. Excessive Daytime Sleepiness [ Time Frame: Baseline to Week 11 ]
    Change in Caregiver Global Impression of Severity for Excessive Daytime Sleepiness

  2. Clinical Symptoms [ Time Frame: Baseline to Week 11 ]
    Change in Clinician Global Impression of Severity for clinical status related to PWS

  3. Behavior [ Time Frame: Baseline to Week 11 ]
    Change in Aberrant Behavior Checklist, Second Edition

  4. Behavioral and cognitive rigidity [ Time Frame: Baseline to Week 11 ]
    Change in Montefiore-Einstein Rigidity Scale-Revised for Research Studies in PWS (MERS-R-PWS)

  5. Psychomotor Function [ Time Frame: Baseline to Week 11 ]
    Change in Cogstate Detection Test

  6. Attention [ Time Frame: Baseline to Week 11 ]
    Change in Cogstate Identification Test

  7. Working Memory [ Time Frame: Baseline to Week 11 ]
    Change in Cogstate One Back Test

  8. Caregiver Burden [ Time Frame: Baseline to Week 11 ]
    Change in 22-Item Zarit Burden Interview


Other Outcome Measures:
  1. Excessive Daytime Sleepiness [ Time Frame: Baseline to Week 11 ]
    Change in Epworth Sleepiness Scale for Children and Adolescents - Parent/Caregiver version

  2. Total Sleep Time [ Time Frame: Baseline to Week 11 ]
    Change in Total Sleep Time as measured by actigraphy

  3. Sleep Efficiency [ Time Frame: Baseline to Week 11 ]
    Change in Sleep Efficiency calculated based on actigraphy

  4. Time out of bed [ Time Frame: Baseline to Week 11 ]
    Change in Immobile Minutes during Time out of Bed as measured by actigraphy

  5. Hyperphagia [ Time Frame: Baseline to Week 11 ]
    Change in total score of the Hyperphagia Questionnaire for Clinical Trials in conjunction with the Food Safety Zone Questionnaire (FSZQ)

  6. Ghrelin levels [ Time Frame: Baseline to Week 11 ]
    Change in acylated and unacylated ghrelin levels



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   6 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Is able to provide voluntary, written informed consent (patient or parent[s]/legal guardian[s]) and, where applicable, voluntary, written assent (patient, as appropriate).
  2. Has a diagnosis of PWS confirmed by genetic testing and patient medical records. Genetic testing will be provided by the Sponsor, if not confirmed based on the review of the patient's medical records.
  3. Male or female patients ages 6 to 65 years at the time of enrollment.
  4. Has EDS as defined by MSLT <8 minutes that is not a direct result of inadequate sleep hygiene or other medical disorder (Screening/Baseline MSLT only).
  5. If taking hormone treatments (including growth hormone, testosterone, and estrogen supplements) and/or allowed chronic concomitant medication or supplements, patient must be on a stable dose of these medications for 3 months prior to randomization and for the duration of the Double-Blind Treatment Phase of the study; 10% variability in hormone dose is allowed.
  6. If taking metabolic treatments that could affect appetite (including metformin), patient must be on a stable dose of these medications for 21 days prior to randomization and for the duration of the Double-Blind Treatment Phase of the study.
  7. Washout of any wake-promoting treatments that could affect EDS (including stimulants, modafinil, and armodafinil) for at least 3 days prior to screening actigraphy monitoring, and prohibited for the duration of screening following actigraphy monitoring and the Double-Blind Treatment Phase of the study. Patients who are chronically administered sedating medications for management of behavioral manifestations (e.g., hypnotics, benzodiazepines, antipsychotics, alpha agonists, anticholinergics, and antidepressants) must be on stable doses for at least 4 weeks prior to screening actigraphy monitoring and remain stable during the Double-Blind Treatment Phase of the study.
  8. Washout of cannabidiol and tetrahydrocannabinol for 28 days prior to randomization and prohibited for the duration of the Double-Blind Treatment Phase of the study.
  9. Washout of weight-loss medications, oxytocin, or carbetocin during the 28 days prior to randomization and prohibited for the duration of the Double-Blind Treatment Phase of the study.
  10. A patient who is a female of child-bearing potential (FCBP) must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Baseline Visit and agree to remain abstinent or use an effective method of nonhormonal contraception to prevent pregnancy for the duration of the study and for 21 days after final dose of study drug.
  11. Has a consistent caregiver (preferably the same person throughout the Double-Blind Treatment Phase of the study) who is willing and able to complete the required assessments.
  12. In the opinion of the Investigator, patient/parent(s)/legal guardian(s) is capable of understanding and complying with the requirements of the protocol and administration of oral study drug.

Exclusion Criteria:

  1. Has a diagnosis of another genetic or chromosomal disorder as distinct from PWS.
  2. Experiences a mean TST of <8 hours (patients 6 to <18 years) or <6 hours (patients 18 years and older) as measured by actigraphy; patients must have a minimum of 7 scoreable nights from the 14 nights of actigraphy data (all scoreable nights are to be used to calculate mean TST).
  3. Is unable/unwilling to wear the actigraph for 14 days during Screening.
  4. Has untreated OSA or is unresponsive to treatment for OSA, has other relevant underlying sleep disorders, or experiences ODI >10 on pulse oximetry and/or <8 hours for patients 6 to <18 years or <6 hours for patients 18 years and older of sleep during the PSG conducted prior to the Screening/Baseline MSLT.
  5. 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.
  6. Does not agree to discontinue any prohibited medication or substance listed in the protocol.
  7. Participation in an interventional research study involving another investigational medication or device in the 28 days prior to enrollment and for the duration of the Double-Blind Treatment Phase of the study; 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.
  8. Has a primary psychiatric diagnosis with current active symptoms of psychosis or schizophrenia.
  9. Has a diagnosis of end-stage renal disease (eGFR of <15 mL/minute/1.73 m2) or severe hepatic impairment (Child-Pugh C).
  10. 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.
  11. Has abnormal laboratory values at Screening that are clinically significant as determined by the Investigator.
  12. Has a known history of long QT syndrome or any significant history of a serious abnormality of the ECG (e.g., recent myocardial infarction, clinically significant arrhythmia) or QT interval corrected for heart rate according to Fridericia's formula (QTcF) >442 ms for patients ages 0 to <10 years and >439 ms for patients ages 10 to <20 years, regardless of gender, and >450 ms for male patients and >470 ms for female patients ages 20 to 65 years (ECG QTcF = QT/3√ RR) (Mason et al 2007).
  13. 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.
  14. 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.
  15. Has a current or recent (within one year) history of a substance use disorder or dependence disorder, including alcohol and caffeine use disorders as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V).
  16. Has planned surgery during the Double-Blind Treatment Phase of the study; planned surgery is permitted during the OLE Phase.
  17. Is receiving a concomitant medication that is known to be a strong CYP2D6 inhibitor, a strong CYP3A4 inducer, or a centrally acting H1 receptor antagonist; patients who 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 (Section 5.7.3). Although not prohibited during the OLE Phase of the study, use of H1 receptor antagonists should be avoided.
  18. Is receiving a medication known to prolong the QT interval.
  19. Has a significant risk of committing suicide based on history, routine psychiatric examination, Investigator's judgment, or who has an answer of "yes" on any question other than questions 1 to 3 on the Very Young Child/Cognitively Impaired-Lifetime Recent Columbia Suicide Severity Rating Scale (C SSRS) (Appendix L).
  20. Has a history of seizures that have recently (within 6 months) been treated with antiepileptic medications that are strong CYP3A4 inducers. Patients with a history of seizures must have a stable seizure history (e.g., frequency and severity) for at least 3 months prior to enrollment.
  21. Based on the judgment of the Investigator, is unsuitable for the study for any reason, including but not limited to unstable medical conditions (including psychiatric and neurological conditions) or a medical condition that might interfere with the conduct of the study, confound interpretation of study results, pose a health risk to the patient, or compromise the integrity of the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04257929


Contacts
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Contact: Krystle Davis, MS 3128471289 clinicaltrials@harmonybiosciences.com
Contact: Eric D Bauer 3128471288 clinicaltrials@harmonybiosciences.com

Sponsors and Collaborators
Harmony Biosciences, LLC
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Responsible Party: Harmony Biosciences, LLC
ClinicalTrials.gov Identifier: NCT04257929    
Other Study ID Numbers: HBS-101-CL-002
First Posted: February 6, 2020    Key Record Dates
Last Update Posted: October 20, 2020
Last Verified: July 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Harmony Biosciences, LLC:
PWS
Additional relevant MeSH terms:
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Prader-Willi Syndrome
Syndrome
Disease
Pathologic Processes
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Abnormalities, Multiple
Congenital Abnormalities
Chromosome Disorders
Genetic Diseases, Inborn
Obesity
Overnutrition
Nutrition Disorders