Remote ischemic conditioning in necrotizing enterocolitis: study protocol of a multi-center phase II feasibility randomized controlled trial

Abstract

PurposeRemote 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. MethodsRIC 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. ResultsWe 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. ConclusionsThe 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.

Necrotizing enterocolitis: current understanding of the prevention and management

“…RIC targets the intestinal microcirculation and by improving blood flow to the intestine, reduces the intestinal damage of experimental NEC and prolongs survival [ 68 ]. A phase II feasibility randomized controlled trial involving 12 centers in 6 countries is currently underway, to investigate the feasibility of RIC as a treatment for early-stage NEC in preterm neonates [ 69 ].…”

“…Evidence-based medicine has shown that currently, the most practical approaches to prevent NEC include optimizing maternal health care, reducing obstetric complications in mothers, and decreasing their risk of preterm birth [36]. Guiding the mother's diet and antibiotic use [17,35] Reducing obstetric complications in mothers [36] Abnormal colonization of intestinal bacteria and the microbiota Systematic use of probiotics [37,38] but is controversial [39, 40] Formula feeding and enteral nutrition Breast milk [41][42][43][44] Donor breast milk [45,46], but ethical issues need to be considered [47] Slow feeding patterns but risky [48] Infection and inflammation Interleukin 10 [51] Intra-intestinal strategies targeting TLR4 [52], such as amniotic fluid [53] and breast milk [54,55] Chondroitin sulfate [56] Local ischemia-hypoxia reperfusion Direct peritoneal resuscitation [59,60] Injury of the intestine PGE2 and its receptor PTGER4 [61] 1.5% glucose intraperitoneal infusion [62] Reducing feeding during transfusion [63] Screening congenital heart disease [64] Supplementation with arginine [65,66] Targeting HIF-1 and GLUT1 [67] Remote ischemic conditioning [68,69]…”

Prevention Strategies and Management of Necrotizing Enterocolitis

“…A Phase II Feasibility RCT [103] evaluating the effect of RIC on NEC is ongoing. RIC is a therapy where brief cycles of non-lethal ischemia and reperfusion to a limb results in protection from ischemic damage in distant organs.…”

Transcriptomic analysis of the effect of remote ischaemic conditioning in an animal model of necrotising enterocolitis

“…Therefore the processes within intestinal tissue which are important in the context of NEC, are not well understood and is the focus of our studies. There has already been a phase I trial on the use of RIC in human infants and the protocol for a phase II 9 , international study has been published. There is a direct pathway for translation to clinical practice.…”