The Hospital for Sick Children, University of Toronto, 1526-555 University Ave, Toronto, ON, M5G 1X8, Canada.
Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
Pediatr Surg Int. 2022 May;38(5):679-694. doi: 10.1007/s00383-022-05095-1. Epub 2022 Mar 16.
Remote ischemic conditioning (RIC) is a maneuver involving brief cycles of ischemia reperfusion in an individual's limb. In the early stage of experimental NEC, RIC decreased intestinal injury and prolonged survival by counteracting the derangements in intestinal microcirculation. A single-center phase I study demonstrated that the performance of RIC was safe in neonates with NEC. The aim of this phase II RCT was to evaluate the safety and feasibility of RIC, to identify challenges in recruitment, retainment, and to inform a phase III RCT to evaluate efficacy.
RIC will be performed by trained research personnel and will consist of four cycles of limb ischemia (4-min via cuff inflation) followed by reperfusion (4-min via cuff deflation), repeated on two consecutive days post randomization. The primary endpoint of this RCT is feasibility and acceptability of recruiting and randomizing neonates within 24 h from NEC diagnosis as well as masking and completing the RIC intervention.
We created a novel international consortium for this trial and created a consensus on the diagnostic criteria for NEC and protocol for the trial. The phase II multicenter-masked feasibility RCT will be conducted at 12 centers in Canada, USA, Sweden, The Netherlands, UK, and Spain. The inclusion criteria are: gestational age < 33 weeks, weight ≥ 750 g, NEC receiving medical treatment, and diagnosis established within previous 24 h. Neonates will be randomized to RIC (intervention) or no-RIC (control) and will continue to receive standard management of NEC. We expect to recruit and randomize 40% of eligible patients in the collaborating centers (78 patients; 39/arm) in 30 months. Bayesian methods will be used to combine uninformative prior distributions with the corresponding observed proportions from this trial to determine posterior distributions for parameters of feasibility.
The newly established NEC consortium has generated novel data on NEC diagnosis and defined the feasibility parameters for the introduction of a novel treatment in NEC. This phase II RCT will inform a future phase III RCT to evaluate the efficacy and safety of RIC in early-stage NEC.
远程缺血预处理（RIC）是一种涉及个体肢体短暂缺血再灌注循环的操作。在实验性 NEC 的早期阶段，RIC 通过逆转肠道微循环的紊乱来减少肠道损伤并延长生存时间。一项单中心 I 期研究表明，RIC 在患有 NEC 的新生儿中表现安全。这项 II 期 RCT 的目的是评估 RIC 的安全性和可行性，确定招募、保留方面的挑战，并为评估疗效的 III 期 RCT 提供信息。
RIC 将由经过培训的研究人员进行，包括在随机分组后的连续两天内进行 4 个周期的肢体缺血（通过袖带充气 4 分钟），随后再进行再灌注（通过袖带放气 4 分钟）。该 RCT 的主要终点是在 NEC 诊断后 24 小时内招募和随机分组新生儿的可行性和可接受性，以及对 RIC 干预进行盲法和完成。
我们为此试验创建了一个新的国际联盟，并就 NEC 的诊断标准和试验方案达成了共识。这项 II 期多中心盲法可行性 RCT 将在加拿大、美国、瑞典、荷兰、英国和西班牙的 12 个中心进行。纳入标准为：胎龄<33 周，体重≥750g，正在接受 NEC 治疗，并且在之前 24 小时内确诊。新生儿将被随机分配到 RIC（干预）或无-RIC（对照）组，并继续接受 NEC 的标准治疗。我们预计在 30 个月内从合作中心招募和随机分配 40%的合格患者（78 例；每组 39 例）。贝叶斯方法将用于将无信息的先验分布与来自该试验的相应观察到的比例相结合，以确定可行性参数的后验分布。
新成立的 NEC 联盟已就 NEC 诊断生成了新数据，并确定了引入 NEC 新治疗方法的可行性参数。这项 II 期 RCT 将为评估早期 NEC 中 RIC 的疗效和安全性的未来 III 期 RCT 提供信息。
