Children's Sleep Medicine, Evelina London Children's Hospital, Guy's and St Thomas', London.
Neurim Pharmaceuticals Ltd, Tel Aviv, Israel.
J Am Acad Child Adolesc Psychiatry. 2017 Nov;56(11):948-957.e4. doi: 10.1016/j.jaac.2017.09.414. Epub 2017 Sep 19.
To assess the efficacy and safety of novel pediatric-appropriate, prolonged-release melatonin minitablets (PedPRM) versus placebo for insomnia in children and adolescents with autism spectrum disorder (ASD), with or without attention-deficit/hyperactivity disorder (ADHD) comorbidity, and neurogenetic disorders (NGD).
A total of 125 children and adolescents (2-17.5 years of age; 96.8% ASD, 3.2% Smith-Magenis syndrome [SMS]) whose sleep failed to improve on behavioral intervention alone were randomized (1:1 ratio), double-blind, to receive PedPRM (2 mg escalated to 5 mg) or placebo for 13 weeks. Sleep measures included the validated caregivers' Sleep and Nap Diary (SND) and Composite Sleep Disturbance Index (CSDI). The a priori primary endpoint was SND-reported total sleep time (TST) after 13 weeks of treatment.
The study met the primary endpoint: after 13 weeks of double-blind treatment, participants slept on average 57.5 minutes longer at night with PedPRM compared to 9.14 minutes with placebo (adjusted mean treatment difference PedPRM-placebo -32.43 minutes; p = .034). Sleep latency (SL) decreased by 39.6 minutes on average with PedPRM and 12.5 minutes with placebo (adjusted mean treatment difference -25.30 minutes; p = .011) without causing earlier wakeup time. The rate of participants attaining clinically meaningful responses in TST and/or SL was significantly higher with PedPRM than with placebo (68.9% versus 39.3% respectively; p = .001) corresponding to a number needed to treat (NNT) of 3.38. Overall sleep disturbance (CSDI) tended to decrease. PedPRM was generally safe; somnolence was more commonly reported with PedPRM than placebo.
PedPRM was efficacious and safe for treatment of insomnia in children and adolescents with ASD with/without ADHD and NGD. The acceptability of this pediatric formulation in a population who usually experience significant difficulties in swallowing was remarkably high. Clinical trial registration information-Efficacy and Safety of Circadin in the Treatment of Sleep Disturbances in Children With Neurodevelopment Disabilities; http://clinicaltrials.gov/; NCT01906866.
评估新型儿科长效褪黑素迷你片（PedPRM）与安慰剂治疗自闭症谱系障碍（ASD）儿童和青少年失眠的疗效和安全性，这些儿童和青少年伴有或不伴有注意力缺陷/多动障碍（ADHD）共病和神经发育障碍（NGD）。
共有 125 名儿童和青少年（2-17.5 岁；96.8%为 ASD，3.2%为 Smith-Magenis 综合征[SMS]）单独接受行为干预后睡眠无改善，被随机（1:1 比例）、双盲分组，接受 PedPRM（2mg 递增至 5mg）或安慰剂治疗 13 周。睡眠测量包括经过验证的照顾者睡眠和打盹日记（SND）和综合睡眠障碍指数（CSDI）。主要预先设定的终点是 13 周治疗后 SND 报告的总睡眠时间（TST）。
研究达到了主要终点：经过 13 周的双盲治疗，与安慰剂相比，参与者在夜间平均多睡 57.5 分钟（调整后的平均治疗差异 PedPRM-安慰剂-32.43 分钟；p=0.034）。褪黑素组的睡眠潜伏期（SL）平均下降 39.6 分钟，而安慰剂组下降 12.5 分钟（调整后的平均治疗差异-25.3 分钟；p=0.011），但不会导致提前醒来。与安慰剂相比，接受 PedPRM 的参与者在 TST 和/或 SL 方面达到临床有意义的反应的比例明显更高（分别为 68.9%和 39.3%；p=0.001），相应的治疗需要数（NNT）为 3.38。总体睡眠障碍（CSDI）有下降趋势。PedPRM 总体上是安全的；与安慰剂相比，服用 PedPRM 后更常出现嗜睡。
PedPRM 治疗自闭症谱系障碍儿童和青少年失眠症（伴有或不伴有 ADHD 和 NGD）有效且安全。这种儿科制剂在吞咽困难发生率高的人群中具有极高的可接受性。临床试验注册信息-治疗神经发育障碍儿童睡眠障碍的 Circadin 疗效和安全性；http://clinicaltrials.gov/；NCT01906866。
