Niloofar Ganji1,2, Bo Li1, Irfan Ahmad3, Alan Daneman1, Poorva Deshpande4, Vijay Dhar3, Simon Eaton5, Ricardo Faingold1, Estelle B Gauda1, Nigel Hall6, Salhab El Helou7, Mustafa H Kabeer3, Jae H Kim8,9, Alice King10, Michael H Livingston7, Eugene Ng11, Martin Offringa1, Elena Palleri12, Mark Walton7, David E Wesson10, Tomas Wester12, Rene M H Wijnen13, Andrew Willan14, Rosanna Yankanah1, Carlos Zozaya15, Prakesh S Shah4, Agostino Pierro16,17. 1. The Hospital for Sick Children, University of Toronto, 1526-555 University Ave, Toronto, ON, M5G 1X8, Canada. 2. Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada. 3. Children's Hospital of Orange County, Orange County, CA, USA. 4. Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada. 5. The ULC Great Ormond, Street Institute of Child Health, London, UK. 6. Southampton Children's Hospital, Southampton, UK. 7. McMaster Children's Hospital, McMaster University, Hamilton, ON, Canada. 8. Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. 9. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA. 10. Texas Children's Hospital, Houston, USA. 11. Sunnybrook Health Sciences Center, University of Toronto, Toronto, ON, Canada. 12. Karolinska University Hospital, Stockholm, Sweden. 13. Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands. 14. Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. 15. La Paz University Hospital, Madrid, Spain. 16. The Hospital for Sick Children, University of Toronto, 1526-555 University Ave, Toronto, ON, M5G 1X8, Canada. agostino.pierro@sickkids.ca. 17. Department of Surgery, University of Toronto, Toronto, ON, Canada. agostino.pierro@sickkids.ca.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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