背景:发作性睡病是一种终生疾病,其特征是白天过度嗜睡和猝倒,通常出现在童年或青春期。沥青,一种选择性组胺H3受体反向激动剂,在欧洲和美国已被批准用于患有或不患有猝倒的发作性睡病的成年人,具有良好的安全性。这项3期研究旨在评估pitolisant在伴有或不伴有猝倒的发作性睡病儿童中的安全性和有效性。
方法:对于这种双盲,随机化,安慰剂对照,多中心研究,我们在5个国家的11个睡眠中心招募了6-17岁有或没有猝倒的发作性睡病患者(意大利,法国,荷兰,俄罗斯,和芬兰)。要求参与者的儿科日间嗜睡量表评分为15分或更高,并且在招募前至少14天未接受过精神兴奋剂;需要抗癌症药(包括羟丁酸钠)的参与者需要至少1个月的稳定剂量。在筛选结束时,参与者被随机分配以2:1的比例接受pitolisant或安慰剂治疗。研究中心对随机化进行分层,并使用交互式网络响应系统分配治疗。经过4周的筛查期,包括2周的基线期,患者进入为期4周的个人向上滴定方案,从每天5毫克到每天最多40毫克的pitolisant或安慰剂;治疗以稳定剂量进行4周,随后是1周的安慰剂期。对于主要分析,我们使用Ullanlinna发作性睡病量表(UNS)总分从基线到整个分析集中双盲期结束的变化来评估pitolisant与安慰剂的比较,定义为所有随机分配的患者,这些患者接受至少一次剂量的治疗,并且具有至少一个基线UNS值.UNS总分的下降反映了白天过度嗜睡和猝倒的减少。在安全性人群中评估所有不良事件,定义为服用至少一剂研究药物的所有参与者.开放标签的后续行动正在进行中。这项研究在ClinicalTrials.gov注册,NCT02611687。
结果:在2016年6月6日至2021年4月3日之间,我们筛选了115名参与者,随机分配了110名参与者(平均年龄12·9[SD3·0]岁,61[55%]男性,90例[82%]猝倒;72例分配给pitolisant,38例分配给安慰剂);107例(70例接受pitolisant,37例接受安慰剂)完成了双盲期。从基线到双盲期结束的UNS总分的平均校正差异在pitolisant组为-6·3(SE1·1),在安慰剂组为-2·6(1·4)(最小二乘平均差-3·7;95%CI-6·4至-1·0,p=0·007)。pitolisant组72例患者中的22例(31%)和安慰剂组38例患者中的13例(34%)报告了治疗引起的不良事件。两组中最常见的不良事件(影响≥5%的患者)是头痛(pitolisant组14[19%],安慰剂组3[8%])和失眠(pitolisant组5[7%],安慰剂组1[3%])。
结论:Pitolisant治疗可改善儿童发作性睡病症状,尽管在我们的研究开始时,UNS在发作性睡病儿童中的应用尚未得到验证.安全性与成人报告相似,但需要进一步研究以确认长期安全性。
背景:Bioprojet。
Narcolepsy is a life-long disorder characterised by excessive daytime sleepiness and cataplexy, often arising in childhood or adolescence. Pitolisant, a selective histamine H3 receptor inverse agonist, has been approved in Europe and USA for adults with narcolepsy with or without cataplexy, with a favourable safety profile. This phase 3
study aimed to assess the safety and efficacy of pitolisant in children with narcolepsy with or without cataplexy.
For this double-blind, randomised, placebo-controlled, multisite
study, we recruited patients aged 6-17 years with narcolepsy with or without cataplexy in 11 sleep centres in five countries (Italy, France, Netherlands, Russia, and Finland). Participants were required to have a Pediatric Daytime Sleepiness Scale score of 15 or greater and to have not received psychostimulants for at least 14 days before enrolment; participants who needed anticataplectics (including sodium oxybate) were required to have been on a stable dose for at least 1 month. Participants were randomly assigned to treatment with pitolisant or placebo in a 2:1 ratio at the end of screening. Randomisation was stratified by
study centre and treatment was allocated using an interactive web response system. After a 4-week screening period including a 2-week baseline period, patients entered in a 4-week individual up-titration scheme from 5 mg a day to a maximum of 40 mg a day of pitolisant or placebo; treatment was administered at a stable dose for 4 weeks, followed by a 1-week placebo period. For the primary analysis, we assessed pitolisant versus placebo using change in the Ullanlinna Narcolepsy Scale (UNS) total score from baseline to the end of double-blind period in the full analysis set, defined as all randomly allocated patients who received at least one dose of treatment and who had at least one baseline UNS value. A decrease in the UNS total score reflects a reduction in both excessive daytime sleepiness and cataplexy. All adverse events were assessed in the safety population, defined as all participants who took at least one dose of study medication. An open-label follow-up is ongoing. This
study is registered at ClinicalTrials.gov, NCT02611687.
Between June 6, 2016, and April 3, 2021, we screened 115 participants and 110 were randomly assigned (mean age 12·9 [SD 3·0] years, 61 [55%] male, and 90 [82%] with cataplexy; 72 assigned to pitolisant and 38 to placebo); 107 (70 receiving pitolisant and 37 receiving placebo) completed the double-blind period. The mean adjusted difference in UNS total score from baseline to the end of the double-blind period was -6·3 (SE 1·1) in the pitolisant group and -2·6 (1·4) in the placebo group (least squares mean difference -3·7; 95% CI -6·4 to -1·0, p=0·007). Treatment-emergent adverse events were reported in 22 (31%) of 72 patients in the pitolisant group and 13 (34%) of 38 patients in the placebo group. The most frequently reported adverse events (affecting ≥5% of patients) in either group were headache (14 [19%] in the pitolisant group and three [8%] in the placebo group) and insomnia (five [7%] in the pitolisant group and one [3%] in the placebo group).
Pitolisant treatment resulted in an improvement in narcolepsy symptoms in children, although the UNS was not validated for use in children with narcolepsy when our
study began. The safety profile was similar to that reported in adults but further studies are needed to confirm long-term safety.
Bioprojet.