Clinical Research
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Efficacy and Safety of Pitolisant Hydrochloride in Prader-Willi Syndrome: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study

Trial ID
2023-508307-21-00
Protocol
HBS-101-CL-312
Sponsor
Harmony Biosciences LLC

Trial statistics

science
6
test molecules
location_city
24
research sites
public
10
countries
medical_information
1
disease
person_search
24
investigators
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10
vendors

Diseases & Conditions

Prader-Willi syndrome

Objectives

The primary objective of this study is to evaluate the **efficacy** of pitolisant in reducing the severity of excessive daytime sleepiness (EDS) in patients with Prader-Willi syndrome (PWS). This is clinically relevant as EDS significantly impacts the quality of life and daily functioning in individuals with PWS, and effective management could improve patient outcomes.

Secondary objectives include:

  • Assessing the impact of pitolisant on the severity of irritable and disruptive behaviors in patients with PWS.
  • Evaluating the effect of pitolisant on the overall severity of EDS in patients with PWS.
  • Further evaluating the impact of pitolisant on the overall severity of irritable and disruptive behaviors in patients with PWS.
  • Assessing the impact of pitolisant on the severity of hyperphagia in patients with PWS.
  • Further evaluating the impact of pitolisant on the severity of EDS in patients with PWS.
  • Evaluating the impact of pitolisant on the severity of behavioral problems in PWS, including social withdrawal, stereotypic behavior, hyperactivity/noncompliance, and inappropriate speech.
  • Evaluating the safety of pitolisant in patients with PWS.
  • Assessing the concentration of pitolisant in patients with PWS.

Participants

The clinical trial involves a total of **74 participants** diagnosed with **Prader-Willi syndrome** (PWS), a genetic disorder. The study population includes both male and female subjects aged 6 years and older. Participants were selected based on their ability to provide informed consent and a confirmed diagnosis of PWS through genetic testing. The trial includes individuals with a stable history of seizures and those on stable doses of certain medications, including hormone treatments and cannabidiol. Participants are required to maintain consistent medication regimens or undergo a washout period prior to the study. The trial population is considered vulnerable, necessitating the presence of a consistent caregiver to assist with study assessments. The study aims to evaluate the impact of pitolisant on the severity of excessive daytime sleepiness (EDS) in patients with PWS.

Plans and Procedures

The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of **pitolisant hydrochloride** in patients with **Prader-Willi syndrome** (PWS). The trial aims to assess the impact of pitolisant on the severity of excessive daytime sleepiness (EDS) in this patient population. The study will be conducted over an estimated period, with recruitment starting on November 19, 2024, and the trial expected to conclude by March 12, 2027.

Participants will be randomly assigned to receive either pitolisant or a placebo, with the treatment administered orally in tablet form. The trial will include several key visits: an initial screening visit to confirm eligibility, followed by a baseline visit to establish initial health metrics. Participants will then enter the double-blind treatment period, which will last for 11 weeks. During this period, regular follow-up visits will be scheduled to monitor the participants' health and response to the treatment. The primary endpoint will be the change in severity of EDS as measured by the PROMIS SRI T-score from baseline to the end of the double-blind treatment period on Day 77.

The expected length of participant involvement is approximately 11 weeks, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with the study protocol. The study will also include an open-label extension phase, allowing for further evaluation of long-term safety and efficacy. Secondary endpoints will assess changes in irritable and disruptive behaviors, hyperphagia, and other behavioral problems, as well as safety and pharmacokinetic parameters. The trial is not categorized as low intervention and is intended to support a US FDA marketing application for the indication of EDS in people with PWS.

Treatment

The clinical trial involves the administration of **pitolisant hydrochloride**, an experimental medication, under the product names **HBS-101** and **WAKIX**. Both products are formulated as tablets for **oral use**. The maximum daily dose of pitolisant hydrochloride is 44.5 mg, with a total maximum dose of 2928.1 mg for HBS-101 over a treatment period of 11 weeks, and 15699.6 mg for WAKIX over a treatment period of 52 weeks. The active substance, pitolisant hydrochloride, is of chemical origin and is provided by Harmony Biosciences LLC. The administration schedule requires monitoring to ensure participant compliance with the dosing regimen.

In addition to the experimental medication, the study includes a **placebo** control. The placebo is presented as a white, round, plain, biconvex film-coated tablet, matching the appearance of the active medication tablets. The placebo tablets are available in two sizes: a 4.45 mg tablet with a diameter of 3.7 mm and a 17.8 mg tablet with a diameter of 7.5 mm. These placebo tablets are used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments.

Efficacy

The efficacy of the clinical trial will be assessed by evaluating the impact of **pitolisant hydrochloride** on the severity of excessive daytime sleepiness (EDS) in patients with Prader-Willi Syndrome (PWS). The primary endpoint for efficacy is the change in severity of EDS as measured by the PROMIS Sleep-Related Impairment (SRI) T-score from Baseline to the end of the Double-Blind Treatment Period, which is Day 77. Secondary endpoints include changes in the severity of irritable and disruptive behaviors, overall severity of EDS, and severity of hyperphagia, among others. These will be measured using various scales such as the ABC-C Irritability Domain score, CaGI-S for EDS score, CGI-S for EDS score, and HQ CT score in conjunction with the FSZQ score, all from Baseline to Day 77.

The efficacy parameters will be collected and analyzed at specific timepoints, with the primary and secondary endpoints being assessed at the end of the Double-Blind Treatment Period. The tools and instruments involved in these assessments include validated scales and questionnaires designed to measure the severity of EDS and related symptoms. The trial is structured to ensure that data collection is consistent and reliable, providing a comprehensive evaluation of the efficacy of pitolisant in managing symptoms associated with PWS.

Inclusion and Exclusion Criteria

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Inclusion Criteria

  • Male or female ages ≥6 years at the time of Screening.
  • Ability to provide voluntary, written informed consent (parent[s]/caregiver[s]/legal guardian[s]) and, where applicable, voluntary, written assent (patient, as appropriate).
  • A diagnosis of PWS confirmed by genetic testing and patient medical records. Genetic testing for PWS will be provided by the Sponsor if not confirmed based on the review of the patient’s medical records.
  • & 5. Patient meets criteria for EDS per questionnaires
  • Patient meets appropriate number of hours of sleep per night based on their age.
  • If taking nonprohibited chronically administered concomitant medication or supplements, patient must be on a stable dose for at least 30 days prior to Screening and agree to remain on that stable dose during the Double-Blind Treatment Period or agree to washout of these medications or supplements for at least 5 half-lives prior to Screening.
  • If taking hormone treatments (including growth hormone, testosterone, and estrogen supplements), patient must be on a stable dose of these medications for 30 days prior to Screening and during the Double-Blind Treatment Period; 20% variability in hormone dose is allowed.
  • If using cannabidiol and/or tetrahydrocannabinol, patient must be on a stable dose for 30 days prior to Screening and agree to continue on that stable dose for the duration of the Double-Blind Treatment Period of the study or agree to washout of this treatment for at least 5 half-lives prior to Screening.
  • If taking a strong CYP2D6 inhibitor, patient must be on a stable dose for at least 30 days prior to Screening and remain on that stable dose during the Double-Blind Treatment Period of the study or agree to washout of the medication for at least for 5 half-lives prior to Screening.
  • Patients with a history of seizures must have a stable seizure history (e.g., frequency and severity) for at least 6 months prior to Screening.
  • A patient who is an FCBP must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline 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. Patients using hormonal contraception must also use an alternative nonhormonal contraceptive method during treatment with pitolisant and for at least 21 days after discontinuing treatment. An FCBP is defined as a female who is post-menarcheal, has an intact uterus and at least 1 ovary, and is <1 year postmenopausal. Male patients who are not azoospermic (vasectomized or due to a medical cause) must agree to use a barrier method of contraception for the duration of the study and for 21 days after the final dose of study drug.
  • Has a consistent parent/caregiver (preferably the same person throughout the study) who is willing and able to complete the required study assessments.
  • In the opinion of the Investigator, the patient/parent(s)/caregiver(s)/legal guardian(s) are capable of understanding and complying with the requirements of the protocol and administration of oral study drug.
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Exclusion Criteria

  • Diagnosis of sleep apnea (OSA, CSA) that is not adequately controlled at the discretion of the Investigator.
  • Has a diagnosis of hypersomnia due to another sleep/medical disorder.
  • Has previously taken pitolisant.
  • Participation in an interventional research study involving another investigational medication, device, or behavioral treatment within 30 days or within 5 half-lives (whichever is longer) of the investigational medication prior to Screening.
  • Has a primary psychiatric diagnosis of ps5. Has a primary psychiatric diagnosis of psychosis or schizophrenia.ychosis or schizophrenia.
  • Has a history of moderate hepatic impairment (Child-Pugh Class B) or severe hepatic impairment (Child-Pugh C).
  • Has a history of eGFR <60 mL/min/1.73 m2.
  • 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).
  • Has a QTcF with a mean value of >450 msec (QTcF=QT/3√ RR) at Screening based on the mean of triplicate 12-lead ECGs.
  • 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.
  • Has a current or recent (within 1 year) history of a substance use disorder or dependence disorder as defined in the DSM-V.
  • Has surgery planned during the Double-Blind Treatment Period of the study.
  • Is receiving a concomitant medication that is known to be a centrally acting H1R antagonist; patients who complete a washout for at least 5 half-lives prior to Screening are eligible.
  • Is receiving a concomitant medication that is known to be a strong CYP3A4 inducer; patients who complete a washout for at least 5 half-lives prior to Screening are eligible.
  • Is receiving a concomitant medication that is known to prolong the QT interval; patients who complete a washout for at least 5 half-lives prior to Screening are eligible.
  • Has a significant risk of committing suicide based on history, routine psychiatric examination, Investigator’s judgment, or answering "yes" to question 4 or 5 on the C-SSRS at Screening or Baseline, or with any suicidal behavior within the last 12 months before Screening.
  • 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 and for 7 days after final dose of study drug.
  • Has been deprived of liberty by administrative or judicial decision.
  • Has a known hypersensitivity to the inactive ingredients of pitolisant or placebo tablets.
  • Based on the judgment of the Investigator, is unsuitable for the study for any reason, including but not limited to unstable or uncontrolled 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.

Trial Status by Country

Country Status Start of Recruitment Planned Patients
Belgium BelgiumRecruiting19 Nov 20242
Czechia CzechiaNot Recruiting19 Nov 20248
Denmark DenmarkRecruiting19 Nov 20244
France FranceRecruiting19 Nov 20246
Germany GermanyRecruiting19 Nov 20244
Italy ItalyRecruiting19 Nov 202414
Poland PolandRecruiting19 Nov 20245
Romania RomaniaRecruiting19 Nov 202410
Spain SpainRecruiting19 Nov 202410
Sweden SwedenRecruiting19 Nov 20244

Sites & Investigators

Investigational Products

Details about the medicinal products being studied in this clinical trial.

Product Name Role in Trial Formulation Administration Max Daily Dose Treatment Duration EU MP Number
HBS-101
TestTABLETORAL USE44.511PRD11317303
White, round, plain, biconvex film-coated tablet. Matching 4.45 mg tablet is 3.7 mm in diameter.
PlaceboN/A———N/A
White, round, plain, biconvex film-coated tablet. matching 17.8 mg tablet is 7.5 mm in diameter.
PlaceboN/A———N/A
WAKIX
TestTABLETORAL USE44.552PRD11608444
HBS-101
TestTABLETORAL USE44.511PRD11317304
WAKIX
TestTABLETORAL USE44.552PRD11608443

Conditions Studied in This Trial