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

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

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.

Feasibility, Necrotizing enterocolitis, Phase II, RCT, Randomized clinical trial, Remote ischemic conditioning
0179-0358
679-694
Ganji, Niloofar
b5764bf0-b10e-43ea-a691-668eafcefc62
Li, Bo
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Ahmad, Irfan
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Daneman, Alan
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Deshpande, Poorva
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Dhar, Vijay
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Eaton, Simon
68aa3fd1-4959-42a6-a26a-ddcd4695a37e
Faingold, Ricardo
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Gauda, Estelle B.
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Hall, Nigel
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el Helou, Salhab
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Kabeer, Mustafa H.
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Kim, Jae H.
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King, Alice
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Livingston, Michael H.
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Ng, Eugene
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Offringa, Martin
e5ed389e-fa7e-4349-9a42-29b6db45f205
Palleri, Elena
617a4fd1-106c-494d-be8e-2de236e01407
Walton, Mark
ec3799df-3d3b-44e8-818a-48cff3f888c0
Wesson, David E.
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Wester, Tomas
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Wijnen, Rene M.H.
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Willan, Andrew
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Yankanah, Rosanna
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Zozaya, Carlos
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Shah, Prakesh S.
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Pierro, Agostino
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Ganji, Niloofar
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Li, Bo
45f539bd-631c-4538-84d7-f43b7ffbcdbc
Ahmad, Irfan
df92dce8-f0ae-46c6-99ae-ad7fa72da45e
Daneman, Alan
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Deshpande, Poorva
7739c159-f14c-49f1-8406-43918079f814
Dhar, Vijay
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Eaton, Simon
68aa3fd1-4959-42a6-a26a-ddcd4695a37e
Faingold, Ricardo
bae155b0-874a-4b2b-8633-8effb44bf2dc
Gauda, Estelle B.
0150358e-b1e6-4ed4-b9d9-a786b989aa3e
Hall, Nigel
6919e8af-3890-42c1-98a7-c110791957cf
el Helou, Salhab
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Kabeer, Mustafa H.
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Kim, Jae H.
60eedd7e-5cbc-49c3-9d7d-eefbe85682db
King, Alice
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Livingston, Michael H.
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Ng, Eugene
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Offringa, Martin
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Palleri, Elena
617a4fd1-106c-494d-be8e-2de236e01407
Walton, Mark
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Wesson, David E.
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Wester, Tomas
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Wijnen, Rene M.H.
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Willan, Andrew
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Yankanah, Rosanna
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Zozaya, Carlos
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Shah, Prakesh S.
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Pierro, Agostino
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Ganji, Niloofar, Li, Bo, Ahmad, Irfan, Daneman, Alan, Deshpande, Poorva, Dhar, Vijay, Eaton, Simon, Faingold, Ricardo, Gauda, Estelle B., Hall, Nigel, el Helou, Salhab, Kabeer, Mustafa H., Kim, Jae H., King, Alice, Livingston, Michael H., Ng, Eugene, Offringa, Martin, Palleri, Elena, Walton, Mark, Wesson, David E., Wester, Tomas, Wijnen, Rene M.H., Willan, Andrew, Yankanah, Rosanna, Zozaya, Carlos, Shah, Prakesh S. and Pierro, Agostino (2022) Remote ischemic conditioning in necrotizing enterocolitis: study protocol of a multi‑center phase II feasibility randomized controlled trial. Pediatric Surgery International, 38, 679-694. (doi:10.1007/s00383-022-05095-1).

Record type: Article

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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More information

Accepted/In Press date: 2 February 2022
e-pub ahead of print date: 16 March 2022
Published date: 1 May 2022
Keywords: Feasibility, Necrotizing enterocolitis, Phase II, RCT, Randomized clinical trial, Remote ischemic conditioning

Identifiers

Local EPrints ID: 484542
URI: http://eprints.soton.ac.uk/id/eprint/484542
ISSN: 0179-0358
PURE UUID: fdc14663-4e85-4af9-b4f1-f2d12ddfe992
ORCID for Nigel Hall: ORCID iD orcid.org/0000-0001-8570-9374

Catalogue record

Date deposited: 16 Nov 2023 14:48
Last modified: 17 Mar 2024 03:24

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Contributors

Author: Niloofar Ganji
Author: Bo Li
Author: Irfan Ahmad
Author: Alan Daneman
Author: Poorva Deshpande
Author: Vijay Dhar
Author: Simon Eaton
Author: Ricardo Faingold
Author: Estelle B. Gauda
Author: Nigel Hall ORCID iD
Author: Salhab el Helou
Author: Mustafa H. Kabeer
Author: Jae H. Kim
Author: Alice King
Author: Michael H. Livingston
Author: Eugene Ng
Author: Martin Offringa
Author: Elena Palleri
Author: Mark Walton
Author: David E. Wesson
Author: Tomas Wester
Author: Rene M.H. Wijnen
Author: Andrew Willan
Author: Rosanna Yankanah
Author: Carlos Zozaya
Author: Prakesh S. Shah
Author: Agostino Pierro

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