HBS-101-CL-002

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 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 lower dose pitolisant, higher 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 as specified in the protocol. 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.

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/or 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. Demonstrates adequate sleep duration via patient sleep diary during Screening, defined as at least 8 hours of sleep per night for patients ages 6 to 442 ms for patients ages 0 to 439 ms for patients ages 10 to 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).

5. 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.

1. 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.

1. 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).

1. Has planned surgery during the Double-Blind Treatment Phase of the study; planned

surgery is permitted during the OLE Phase.

1. 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.

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

2. 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).

1. 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.

1. 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.

1. 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.