This was a prospective, randomized, double-blind, single-center placebo-controlled trial to assess the efficacy and safety of melatonin as an add-on treatment for infantile epileptic spasms syndrome (IESS). Participants aged 3 months to 2 years with a primary diagnosis of IESS were recruited and assigned to two groups in a 1:1 ratio. Both treatment groups received a combination of adrenocorticotrophic hormone (ACTH) and magnesium sulfate (MgSO₄) for 2 weeks, and the treatment group also received melatonin (3 mg) between 20:00 and 21:00 daily, 0.5–1 h before bedtime. The study's primary endpoint was the average reduction rate in spasm frequency assessed by seizure diaries. Secondary endpoints included assessment of the response rate, EEG hypsarrhythmia (Kramer score), and psychomotor development (Denver Developmental Screening Test, DDST). Sleep quality was assessed by using the Brief Infant Sleep Questionnaire (BISQ), the Infant Sleep Assessment Scale (ISAS), and actigraphy. Safety parameters were also evaluated. Statistical analyses were conducted on intention-to-treat and per-protocol populations. The trial is registered at Clinicaltrials.gov (ChiCTR2000036208). Out of 119 screened patients, 70 were randomized and 66 completed treatments. In the intention-to-treat population, there were no significant differences in the average percentage reduction of spasm frequency (median [interquartile range, IQR: Q3–Q1], 100% [46.7%] vs. 66.7% [55.3%], p = .288), the 3-day response rate (51.4% vs. 37.1%, p = .229), the 28-day response rate (42.9% vs. 28.6%, p = .212), EEG Kramer scores (2 [3.5] vs. 2 [3], p = .853), or DDST comprehensive months (5 [2.5] vs. 6 [6], p = .239) between the melatonin (n = 35) and placebo (n = 35) groups. However, caregivers reported improved sleep quality after melatonin treatment, with 85.7% reporting regular sleep compared to 42.9% with placebo (42.9%, p < .001). The melatonin group had lower ISAS scores in 4–11-month-old patients compared to the placebo (mean ± SD, 29.3 ± 4.4 vs. 35.2 ± 5.9, p < .001). Moreover, the median (IQR) value of sleep-onset latency was shortened by 6.0 (24.5) min after melatonin treatment, while that in the placebo group was extended by 3.0 (22.0) min (p = .030). The serum melatonin (6:00 h) level (pg/mL) of the children in the melatonin group after treatment was significantly higher than in the placebo group (median [IQR], 84.8 [142] vs. 17.5 [37.6], p < .001). No adverse effects related to melatonin were observed in the study, and there were no significant differences in adverse effects between the melatonin and placebo groups. Although not statistically significant, the results of this randomized clinical trial proved that melatonin supplementation, as an add-on treatment, can improve spasm control rate in the treatment of IESS. For IESS children treated with ACTH, the addition of melatonin was found to improve sleep quality, shorten sleep onset latency, and increase blood melatonin levels. Moreover, it was observed to be a safe treatment option.

中文翻译：

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褪黑激素补充剂作为婴儿癫痫痉挛综合征附加治疗的安全性和有效性：一项随机、安慰剂对照、双盲试验

这是一项前瞻性、随机、双盲、单中心安慰剂对照试验，旨在评估褪黑激素作为婴儿癫痫痉挛综合征 (IESS) 附加治疗的有效性和安全性。招募年龄为 3 个月至 2 岁、初步诊断为 IESS 的参与者，并按 1:1 的比例分配到两组。两个治疗组均接受促肾上腺皮质激素 (ACTH) 和硫酸镁 (MgSO ₄ ) 联合治疗 2 周，治疗组还在每天 20:00 至 21:00、睡前 0.5-1 小时期间接受褪黑激素 (3 mg) 。该研究的主要终点是通过癫痫日记评估的痉挛频率的平均降低率。次要终点包括反应率、脑电图高度心律失常（克莱默评分）和精神运动发育（丹佛发育筛查测试，DDST）的评估。睡眠质量通过婴儿睡眠简短问卷 (BISQ)、婴儿睡眠评估量表 (ISAS) 和体动记录仪进行评估。还评估了安全参数。对意向治疗和符合方案的人群进行了统计分析。该试验已在 ClinicalTrials.gov 上注册 (ChiCTR2000036208)。在 119 名筛查患者中，70 名患者被随机分配，66 名患者完成治疗。在意向治疗人群中，痉挛频率的平均减少百分比没有显着差异（中位数[四分位数范围，IQR：Q3–Q1]，100% [46.7%] vs. 66.7% [55.3%]，p  = .288）、3 天缓解率（51.4% vs. 37.1%，p  = .229）、28 天缓解率（42.9% vs. 28.6%，p  = .212）、EEG Kramer 评分（ 褪黑素 ( n  = 35) 和安慰剂( n ) 之间的2 [3.5] 与 2 [3]，p  = .853) 或 DDST 综合个月 (5 [2.5] 与 6 [6]，p = .239)  = 35) 组。然而，护理人员报告说，褪黑激素治疗后睡眠质量得到改善，其中 85.7% 的护理人员报告睡眠规律，而安慰剂组的这一比例为 42.9% (42.9%，p  < .001)。与安慰剂相比，褪黑激素组 4-11 个月大患者的 ISAS 评分较低（平均值 ± 标准差，29.3 ± 4.4 对比 35.2 ± 5.9，p  < .001）。此外，褪黑素治疗后入睡潜伏期的中位 (IQR) 值缩短了 6.0 (24.5) 分钟，而安慰剂组则延长了 3.0 (22.0) 分钟 ( p  = .030)。褪黑素组儿童治疗后血清褪黑素（6:00 h）水平（pg/mL）显着高于安慰剂组（中位[IQR]，84.8[142] vs. 17.5[37.6]，p < .001)。研究中没有观察到与褪黑激素相关的不良反应，并且褪黑激素组和安慰剂组之间的不良反应没有显着差异。虽然没有统计学意义，但这项随机临床试验的结果证明，补充褪黑激素作为附加治疗，可以提高 IESS 治疗中的痉挛控制率。对于接受 ACTH 治疗的 IESS 儿童，添加褪黑激素被发现可以改善睡眠质量、缩短入睡潜伏期并提高血液褪黑激素水平。此外，据观察，这是一种安全的治疗选择。