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

1. Has a diagnosis of another genetic or chromosomal disorder distinct from PWS.

2. Has untreated obstructive sleep apnea (OSA) or is at high risk for OSA based on medical history and clinical assessment; or, has another relevant underlying sleep disorder that in the opinion of the Investigator is the primary contributing factor to the patient's EDS.

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 substance listed in the protocol.

5. 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, unless the Investigator consults with the Medical Monitor and obtains written approval for the patient to enroll; patients who complete a washout of an investigational medication of at least 5 half-lives or 14 days (whichever is longer) may 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.

6. Has a primary psychiatric diagnosis with current active symptoms of psychosis or schizophrenia.

7. Has a diagnosis of end-stage renal disease (estimated glomerular filtration rate \[eGFR\] of \<15 mL/minute/1.73 m²) or severe hepatic impairment (Child-Pugh C).

8. 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.

9. Has abnormal laboratory values at Screening that are clinically significant as determined by the Investigator.

10. Has a known history of long QT syndrome or any significant history of a serious abnormality of the electrocardiogram (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).

11. 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.

12. If receiving any new or initiating a change in allied health therapies or interventions for symptoms of PWS, must be on a stable course of therapy for at least 28 days prior to randomization.

13. 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).

14. Has planned surgery during the Double-Blind Treatment Phase of the study; planned surgery is permitted during the OLE Phase.

15. 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 (H1) receptor antagonist; patients who complete a washout of these medications of at least 5 half-lives or 14 days (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 H1 receptor antagonists should be avoided.

16. Is receiving a medication known to prolong the QT interval.

17. Has a significant risk of committing suicide based on history, routine psychiatric examination, Investigator's judgment, or 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).

18. 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 6 months prior to enrollment.

19. 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.

20. 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.

What this study is about