Inclusion Criteria

• Male or female patients 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.
• ESS-CHAD (parent/caregiver version) total score ≥ 12 at Screening and at Baseline.
• CaGI-S for EDS score ≥ 2 (moderate, severe, or very severe) at Screening and at Baseline.
• Experiences a mean of at least 8 hours of sleep per night for patients ages 6 to < 12 years, at least 7 hours per night for patients ages 12 to < 18 years, or at least 6 hours per night for patients ages ≥ 18 years based on sleep data collected during Screening (with recordings of at least 7 nights during a consecutive 10-day period during the 45-day Screening/Baseline Period; Section 8.1.4).
• 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 a 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 the 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 a 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 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. Permitted contraceptive methods are presented in Appendix 15.
• 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.

Exclusion Criteria

• Diagnosis of sleep apnea (OSA, CSA) that is not adequately controlled at the discretion of the Investigator.
• 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 5 half-lives (whichever is longer) of the investigational medication prior to Screening.
• Has a primary psychiatric diagnosis of psychosis or schizophrenia.
• Has a history of diagnosis of moderate hepatic impairment (Child-Pugh B) or severe hepatic impairment (Child-Pugh C).
• Has a history of diagnosis of moderate or severe renal impairment or ESRD (eGFR ≤ 59 mL/minute/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 ms (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 (Appendix 13 includes examples).
• 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 (Appendix 13 includes examples).
• 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 (Appendix 13 includes examples).
• Has a significant risk of committing suicide based on history, routine psychiatric examination, Investigator's judgment, or answering "yes" to any question on the C-SSRS at Screening or Baseline.
• 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 21 days after final dose of study drug.
• Patients deprived of liberty by administrative or judicial decision; patients under court protection, guardianship, curatorship, or family guardianship.
• Patients with a known hypersensitivity to the inactive ingredients of pitolisant or placebo tablets listed in Table 5.
• Based on the judgment of the Investigator, patient 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.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 2/20/2024. Questions regarding updates should be directed to the study team contact.