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Study Objectives: <p>The majority of patients with Prader-Willi syndrome experience excessive daytime sleepiness (EDS). This study evaluated the effects of pitolisant, a histamine 3 (H<sub>3</sub>)-receptor antagonist/inverse agonist that promotes wakefulness, in patients with Prader-Willi syndrome and EDS.</p> Methods: <p>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.</p> Results: <p>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 &lt; 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.</p> Conclusions: <p>Results of this proof-of-concept study support further evaluation of pitolisant in patients with Prader-Willi syndrome and EDS.</p> <p><b>Clinical Trial Registration:</b> 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: <a href="https://clinicaltrials.gov/study/NCT04257929">https://clinicaltrials.gov/study/NCT04257929</a>; Identifier: NCT04257929.</p> Citation: <p>Revana A, Bhattacharjee R, Miller JL, et&#xa0;al. A proof-of-concept study of pitolisant for excessive daytime sleepiness in patients with Prader-Willi syndrome. <i>J Clin Sleep Med</i>. 2025;21(11):1893–1902.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月1日

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  • Amee Revana,
  • Rakesh Bhattacharjee,
  • Jennifer L. Miller,
  • Aaron Chidekel,
  • Priya Khanna,
  • Sarayu Ratnam,
  • Grant Runyan,
  • Eric Bauer,
  • Krystle Davis Rapchak,
  • David Seiden,
  • Kumar Budur,
  • Jeffrey M. Dayno

摘要

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.