Melatonin for Sleep in Children with Autism: Safety, Tolerability, and Dosing

描述（由申请人提供）：患有神经精神疾病的儿童，如自闭症谱系障碍（ASD），是失眠的高危人群，迫切需要对这一人群进行失眠的药物治疗。缺乏恢复性睡眠可能会加剧与ASD相关的致残行为。促进自闭症儿童睡眠的治疗可以改善这些行为，也可以增强父母应对这种疾病的能力，帮助他们的孩子克服残疾。我们的长期目标是确定补充褪黑激素是否能有效治疗自闭症儿童的失眠，以及使用褪黑激素治疗失眠是否能改善这些儿童的日间行为并减少父母的压力水平。虽然人们普遍认为褪黑素安全且耐受性良好，但褪黑素对ASD的疗效尚未在对照研究中得到证实，与剂量相关的治疗策略也存在很大差异。在进行将测试这些目标的III期随机临床试验（RCT）之前，需要解决关键的设计问题。这项初步临床试验拨款将允许我们设计一个有效的随机对照试验。本初步临床试验拨款的具体目的是：(1)优化补充褪黑激素对ASD儿童睡眠潜伏期的安全性、耐受性和影响的干预策略；(2)表征补充褪黑素的药代动力学特征；(3)试点一组行为和父母压力量表，为随机对照试验做准备。为了实现这些目标，我们将使用16周的可选滴定设计，对30名4-10岁的ASD儿童进行褪黑素（1- 9mg）补充治疗。这种设计允许家长在孩子对治疗有反应且没有显著不良事件发生的剂量下停止滴定。将对12名儿童进行药代动力学研究。我们将使用多导睡眠图和活动图来确定褪黑激素剂量对睡眠潜伏期的反应，这是一种有效的、非侵入性的睡眠开始和持续时间测量方法。不良事件也将被捕获。

DESCRIPTION (provided by applicant): Children with neuropsychiatric conditions, such as autism spectrum disorders (ASD), are at high risk for insomnia, and pharmacological treatments for insomnia in this population are acutely needed. Lack of restorative sleep may exacerbate disabling behaviors associated with ASD. Treatments that promote sleep in children with ASD may ameliorate these behaviors as well as strengthen the ability of parents to cope with this disorder and to assist their children in overcoming their disabilities. Our long-term objectives are to determine if supplemental melatonin is an effective treatment for insomnia in children with ASD and whether the use of melatonin to treat insomnia improves these children's daytime behaviors and reduces levels of parental stress. Although generally accepted as safe and well tolerated, melatonin's efficacy in ASD has not been proven in controlled studies, and treatment strategies related to dosage vary widely. Prior to carrying out a Phase III Randomized Clinical Trial (RCT) that will test these objectives, critical design issues need to be addressed. This proposed Preliminary Clinical Trials Grant will allow us to design an effective RCT. The Specific Aims of this Preliminary Clinical Trials Grant are to: (1) Optimize the intervention strategy for administering supplemental melatonin in relation to safety, tolerability, and effect on sleep latency in children with ASD; (2) Characterize the pharmacokinetic profile of supplemental melatonin; and (3) Pilot a group of behavioral and parental stress scales in preparation for an RCT. To achieve these aims, we will treat 30 children with ASD, ages 4-10, with supplemental melatonin (1-9 mg) using a 16-week optional titration design. This design allows parents to stop titration at a dose in which their children respond to treatment and at which no significant adverse events occur. A subset of 12 children will undergo pharmacokinetic studies. We will determine the response of melatonin dose on sleep latency using polysomnography and actigraphy, a validated and non-intrusive measure of sleep onset and duration. Adverse events will also be captured.