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.
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 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.
A short presentation on this upcoming study was given at FPWR's 2019 Research Symposium and Family Conference. Watch this 7-minute video below.
Study Type: Interventional
Eligible Ages: 6-65 years
ClinicalTrials.Gov Id: NCT04257929
Duration: 11 week double blind, placebo controlled study, followed by optional open label extension
Lead Sponsor: Harmony Biosciences
Countries: United States
- Is able to provide voluntary, written informed consent (patient or parent[s]/legal guardian[s]) and, where applicable, voluntary, written assent (patient, as appropriate).
- 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.
- Male or female patients ages 6 to 65 years at the time of enrollment.
- 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Has a diagnosis of another genetic or chromosomal disorder as distinct from PWS.
- 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).
- Is unable/unwilling to wear the actigraph for 14 days during Screening.
- 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.
- 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.
- Does not agree to discontinue any prohibited medication or substance listed in the protocol.
- 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.
- Has a primary psychiatric diagnosis with current active symptoms of psychosis or schizophrenia.
- Has a diagnosis of end-stage renal disease (eGFR of <15 mL/minute/1.73 m2) or severe hepatic impairment (Child-Pugh C).
- 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.
- Has abnormal laboratory values at Screening that are clinically significant as determined by the Investigator.
- 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).
- 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.
- 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.
- 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).
- Has planned surgery during the Double-Blind Treatment Phase of the study; planned surgery is permitted during the OLE Phase.
- 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.
- Is receiving a medication known to prolong the QT interval.
- 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).
- 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.
- 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.
This study will be available at the following sites:
|Contact: Krystle Davis, Harmony Biosciences||Phone: email@example.com|