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

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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.

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Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

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Authors and Affiliations

  1. The Hospital for Sick Children, University of Toronto, 1526-555 University Ave, Toronto, ON, M5G 1X8, Canada

    Niloofar Ganji, Bo Li, Alan Daneman, Ricardo Faingold, Estelle B. Gauda, Martin Offringa, Rosanna Yankanah & Agostino Pierro

  2. Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada

    Niloofar Ganji

  3. Children’s Hospital of Orange County, Orange County, CA, USA

    Irfan Ahmad, Vijay Dhar & Mustafa H. Kabeer

  4. Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada

    Poorva Deshpande & Prakesh S. Shah

  5. The ULC Great Ormond, Street Institute of Child Health, London, UK

    Simon Eaton

  6. Southampton Children’s Hospital, Southampton, UK

    Nigel Hall

  7. McMaster Children’s Hospital, McMaster University, Hamilton, ON, Canada

    Salhab el Helou, Michael H. Livingston & Mark Walton

  8. Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Jae H. Kim

  9. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Jae H. Kim

  10. Texas Children’s Hospital, Houston, USA

    Alice King & David E. Wesson

  11. Sunnybrook Health Sciences Center, University of Toronto, Toronto, ON, Canada

    Eugene Ng

  12. Karolinska University Hospital, Stockholm, Sweden

    Elena Palleri & Tomas Wester

  13. Erasmus MC Sophia Children’s Hospital, Rotterdam, The Netherlands

    Rene M. H. Wijnen

  14. Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada

    Andrew Willan

  15. La Paz University Hospital, Madrid, Spain

    Carlos Zozaya

  16. Department of Surgery, University of Toronto, Toronto, ON, Canada

    Agostino Pierro

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  1. Niloofar Ganji
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Ganji, N., Li, B., Ahmad, I. et al. Remote ischemic conditioning in necrotizing enterocolitis: study protocol of a multi-center phase II feasibility randomized controlled trial. Pediatr Surg Int 38, 679–694 (2022). https://doi.org/10.1007/s00383-022-05095-1

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  • DOI: https://doi.org/10.1007/s00383-022-05095-1

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