Mekontso Dessap Armand, Ricard Jean-Damien, Contou Damien, Desnos Cyrielle, Decavèle Maxens, Sonneville Romain, Vivier Emmanuel, Terzi Nicolas, Callahan Jean-Christophe, Jochmans Sebastien, Leon Rusel, Carreira Serge, Nseir Saad, Chemouni Frank, Castelain Vincent, Paul Muriel, Benoist Jean-François, Audureau Etienne, Razazi Keyvan
Groupe de Recherche Clinique GR05 CARMAS, Université Paris Est Créteil, Institut Mondor de Recherche Biomédicale, INSERM, Créteil, France.
Service de Médecine Intensive Réanimation, Hôpitaux Universitaires Henri Mondor, Département Médico-Universitaire Médecine, AP-HP, Créteil, France.
Intensive Care Med. 2025 Jul 3. doi: 10.1007/s00134-025-08002-z.
To determine the dose of melatonin with an optimal pharmacokinetic profile and to test whether this dose reduces the prevalence of delirium in mechanically ventilated ICU patients as compared to placebo.
DEMEL, a multicenter adaptive phase 2b/3 randomized, placebo-controlled, double-blind trial included patients at 20 health centers in France from February 1st, 2019 through January 5th, 2021. Patients were randomized (1:1:1) to receive either placebo or low (0.3 mg) or high (3 mg) dose melatonin enterally at 9:00 p.m. for 14 consecutive nights or until death or ICU discharge, whichever came first. The interim primary endpoint (activity stage) was the percentage of patients who achieved an optimal melatonin pharmacokinetic profile 24 h after starting study treatment; the final primary endpoint (efficacy phase) was the percentage of patients who experienced delirium between randomization and day 14 (or until death or ICU discharge, whichever came first). Delirium was assessed twice daily using the Confusion Assessment Method for ICU.
We randomized 355 patients and included 334 in the primary analysis. At the preplanned analysis of the activity stage performed in 75 patients, the low-dose melatonin group had the highest rate of optimal pharmacokinetic profiles (12/24, 50%) when compared with the high-dose melatonin group (6/25, 24%) and the placebo group (0/26). Therefore, the Steering Committee recommended that the high-dose melatonin group be discontinued and that the low-dose melatonin group be selected to continue in the efficacy phase along with the placebo group. At the end of the efficacy stage, there was no difference in the final primary outcome of delirium incidence between the low-dose melatonin group and the placebo group: 80/147 (54.4%) vs 85/154 (55.2%), risk ratio, 0.986 [95% CI 0.803 to 1.211]; key secondary outcomes were also similar between groups. These included sleep quality, delirium-free, coma-free, and ventilator-free days at day 28; ICU and hospital length of stay; mortality at day 28, in the ICU, and in hospital; as well as long-term outcomes such as quality of life and postintensive care syndrome at day 90.
This randomized clinical trial found that the low-dose of melatonin (0.3 mg nightly) achieved a better pharmacokinetic profile than the high-dose (3 mg nightly), but did not change the incidence of delirium compared to placebo in mechanically ventilated critically-ill patients.
ClinicalTrial.gov website (NCT03524937).
确定具有最佳药代动力学特征的褪黑素剂量，并测试与安慰剂相比，该剂量是否能降低机械通气的重症监护病房（ICU）患者谵妄的发生率。
DEMEL是一项多中心适应性2b/3期随机、安慰剂对照、双盲试验，纳入了2019年2月1日至2021年1月5日期间法国20个医疗中心的患者。患者被随机分组（1:1:1），于晚上9点经肠内给予安慰剂或低剂量（0.3毫克）或高剂量（3毫克）褪黑素，连续14晚，或直至死亡或从ICU出院，以先发生者为准。中期主要终点（活性阶段）是开始研究治疗24小时后达到最佳褪黑素药代动力学特征的患者百分比；最终主要终点（疗效阶段）是随机分组至第14天（或直至死亡或ICU出院，以先发生者为准）期间发生谵妄的患者百分比。使用ICU谵妄评估方法每天对谵妄进行两次评估。
我们随机分配了355名患者，334名纳入主要分析。在对75名患者进行的活性阶段预先计划分析中，与高剂量褪黑素组（6/25，24%）和安慰剂组（0/26）相比，低剂量褪黑素组具有最佳药代动力学特征的比例最高（12/24，50%）。因此，指导委员会建议停止高剂量褪黑素组，并选择低剂量褪黑素组与安慰剂组一起进入疗效阶段。在疗效阶段结束时，低剂量褪黑素组和安慰剂组在谵妄发生率这一最终主要结局方面没有差异：80/147（54.4%）对85/154（55.2%），风险比为0.986 [95%置信区间0.803至1.211]；各组间关键次要结局也相似。这些包括第28天的睡眠质量、无谵妄、无昏迷和无呼吸机天数；ICU和住院时间；第28天、在ICU和住院期间的死亡率；以及长期结局，如第90天的生活质量和重症监护后综合征。
这项随机临床试验发现，低剂量褪黑素（每晚0.3毫克）比高剂量（每晚3毫克）具有更好的药代动力学特征，但与安慰剂相比，在机械通气的危重症患者中并未改变谵妄的发生率。
ClinicalTrial.gov网站（NCT03524937）。
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