A proof-of-concept study of pitolisant for excessive daytime sleepiness in patients with Prader-Willi syndrome

Abstract

Study objectives: The majority of patients with Prader-Willi syndrome experience excessive daytime sleepiness (EDS). This study evaluated the effects of pitolisant, a histamine 3 (H₃)-receptor antagonist/inverse agonist that promotes wakefulness, in patients with Prader-Willi syndrome and EDS.

Methods: In this phase 2, randomized, double-blind, placebo-controlled, proof-of-concept study, patients ages 6-65 years with a confirmed diagnosis of Prader-Willi syndrome with EDS were randomized 1:1:1 to receive lower-dose pitolisant (children/adolescents/adults, 8.9/13.35/17.8 mg), higher-dose pitolisant (children/adolescents/adults, 17.8/26.7/35.6 mg), or matching placebo for 11 weeks (3-week titration/8-week maintenance). The primary endpoint was change from baseline to week 11 in Epworth Sleepiness Scale for Children and Adolescents (parent/caregiver version) score. Other measures included the Caregiver Global Impression of Severity for EDS, Aberrant Behavior Checklist-Community, second edition, and Hyperphagia Questionnaire for Clinical Trials.

Results: Of 65 patients randomized and treated, 59 (90.8%) completed the double-blind phase. Least-squares (LS) mean improvement from baseline to week 11 in Epworth Sleepiness Scale for Children and Adolescents score was greater for higher-dose pitolisant (-5.0) vs placebo (-3.9; LS mean [standard error] difference, -1.1 [1.52]), but not for lower-dose pitolisant (-3.5) vs placebo (LS mean [standard error] difference, 0.5 [1.6]). The largest effect of pitolisant was seen in children (ages 6 to < 12 years; LS mean [standard error] difference for higher-dose pitolisant vs placebo, -3.5 [1.90]). Improvements were observed across other measures, especially in the higher-dose pitolisant group, including LS mean (standard error) change of -5.5 (1.2) on the irritability domain of the Aberrant Behavior Checklist-Community, second edition, and -3.1 (1.0) on the Hyperphagia Questionnaire for Clinical Trials. The most common adverse events in pitolisant-treated patients (doses pooled) were anxiety, irritability, and headache (11.9% each), consistent with the known safety profile of pitolisant.

Conclusions: Results of this proof-of-concept study support further evaluation of pitolisant in patients with Prader-Willi syndrome and EDS.

Clinical trial registration: Registry: ClinicalTrials.gov; Name: A Phase 2 Study to Evaluate the Safety and Efficacy of Pitolisant in Patients With Prader-Willi Syndrome, Followed by an Open Label Extension; URL: https://clinicaltrials.gov/study/NCT04257929; Identifier: NCT04257929.

Citation: Revana A, Bhattacharjee R, Miller JL, et al. A proof-of-concept study of pitolisant for excessive daytime sleepiness in patients with Prader-Willi syndrome. J Clin Sleep Med. 2025;21(11):1893-1902.

Keywords: H₃ histamine receptor antagonists; behavioral symptoms; excessive daytime sleepiness; histamine H₃ receptor; proof-of-concept study.

Figure 1. Study design.

Figure 2. Patient disposition (double-blind treatment phase).

*Six patients were randomized but did not receive the assigned treatment because they did not meet inclusion/exclusion criteria; †patient was diagnosed with/positive for COVID-19; ‡QTcF interval value of a single baseline ECG was > 442 ms (448 ms; mean of the triplicate was 428.3 ms and did not meet the exclusion criterion). AE = adverse event, DBT = double-blind treatment, ECG = electrocardiogram, QTcF = QT interval corrected for heart rate based on Fridericia’s formula.

Figure 3. ESS-CHAD (parent/caregiver version).

LS mean change from baseline to week 11 (A) in the overall population and (B) by age group (mITT population, unless otherwise indicated). *Based on a separate MMRM analysis with outlier excluded. ESS-CHAD scores range from 0–24, with higher scores indicating increased likelihood of excessive daytime sleepiness. ESS-CHAD = Epworth Sleepiness Scale for Children and Adolescents, LS = least-squares, mITT = modified intent-to-treat, MMRM = mixed model for repeated measures, SE = standard error, SEP = sensitivity efficacy population.