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
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This study evaluated the effects of pitolisant, a histamine 3 (H<sub>3</sub>)-receptor antagonist/inverse agonist that promotes wakefulness, in patients with PWS and EDS.</p><p><strong>Methods: </strong>In this phase 2, randomized, double-blind, placebo-controlled, proof-of-concept study, patients ages 6-65 years with a confirmed diagnosis of PWS 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 (ESS-CHAD; parent/caregiver version) score. Other measures included the Caregiver Global Impression of Severity for EDS, Aberrant Behavior Checklist-C (ABC-C), and Hyperphagia Questionnaire for Clinical Trials (HQ-CT).</p><p><strong>Results: </strong>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 ESS-CHAD score was greater for higher-dose pitolisant (-5.0) versus placebo (-3.9; LS mean [SE] difference, -1.1 [1.52]), but not for lower-dose pitolisant (-3.5) versus placebo (LS mean [SE] difference, 0.5 [1.6].The largest effect of pitolisant was seen in children (ages 6 to <12 years; LS mean [SE] difference for higher-dose pitolisant versus placebo, -3.5 [1.90]). Improvements were observed across other measures, especially in the higher-dose pitolisant group, including LS mean (SE) change of -5.5 (1.2) on the irritability domain of the ABC-C and -3.1 (1.0) on the HQ-CT. 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引用次数: 0
摘要
研究目的：大多数普瑞德-威利综合征（PWS）患者会出现白天嗜睡（EDS）。本研究评估了pitolisant对PWS和EDS患者的作用，pitolisant是一种组胺3 （H3）受体拮抗剂/逆激动剂，可促进清醒。方法：在这项随机、双盲、安慰剂对照、概念验证的2期研究中，年龄6-65岁确诊为PWS合并EDS的患者以1:1∶1的比例随机接受低剂量匹托利坦（儿童/青少年/成人，8.9/13.35/17.8 mg）、高剂量匹托利坦（儿童/青少年/成人，17.8/26.7/35.6 mg）或匹配安慰剂治疗11周（3周滴定/8周维持）。主要终点是儿童和青少年Epworth嗜睡量表(ESS-CHAD；父母/照顾者版本)得分。其他测量包括照顾者对EDS严重程度的总体印象、异常行为清单- c （ABC-C）和临床试验贪食问卷（HQ-CT）。结果：65例患者中，59例（90.8%）完成了双盲期。从基线到第11周，最小二乘（LS）平均改善的ESS-CHAD评分，高剂量吡托抗药（-5.0）比安慰剂（-3.9）更大；LS平均[SE]差异为-1.1[1.52])，但低剂量匹立抗药与安慰剂的LS平均[SE]差异为-3.5 （LS平均[SE]差异为0.5[1.6]）。结论：这项概念验证性研究的结果支持进一步评估pitolisant在PWS和EDS患者中的作用。临床试验注册：注册：ClinicalTrials.gov；标识符:NCT04257929。
A proof-of-concept study of pitolisant for excessive daytime sleepiness in patients with Prader-Willi syndrome.
Study objectives: The majority of patients with Prader-Willi syndrome (PWS) 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 PWS 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 PWS 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 (ESS-CHAD; parent/caregiver version) score. Other measures included the Caregiver Global Impression of Severity for EDS, Aberrant Behavior Checklist-C (ABC-C), and Hyperphagia Questionnaire for Clinical Trials (HQ-CT).
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 ESS-CHAD score was greater for higher-dose pitolisant (-5.0) versus placebo (-3.9; LS mean [SE] difference, -1.1 [1.52]), but not for lower-dose pitolisant (-3.5) versus placebo (LS mean [SE] difference, 0.5 [1.6].The largest effect of pitolisant was seen in children (ages 6 to <12 years; LS mean [SE] difference for higher-dose pitolisant versus placebo, -3.5 [1.90]). Improvements were observed across other measures, especially in the higher-dose pitolisant group, including LS mean (SE) change of -5.5 (1.2) on the irritability domain of the ABC-C and -3.1 (1.0) on the HQ-CT. The most common AEs 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 PWS and EDS.
期刊介绍：
Journal of Clinical Sleep Medicine focuses on clinical sleep medicine. Its emphasis is publication of papers with direct applicability and/or relevance to the clinical practice of sleep medicine. This includes clinical trials, clinical reviews, clinical commentary and debate, medical economic/practice perspectives, case series and novel/interesting case reports. In addition, the journal will publish proceedings from conferences, workshops and symposia sponsored by the American Academy of Sleep Medicine or other organizations related to improving the practice of sleep medicine.
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