RIC-NEC Randomized Controlled Trial

NCT05279664 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: CTO 3802
• Study Type: interventional
• Target: 78
• Locations: 2 countries
• Sites: 4

Brief Summary

Necrotizing enterocolitis (NEC) is a serious intestinal disease of preterm and term neonates which remains a major cause of intestinal failure, and an unsolved clinical challenge in pediatrics. While overall mortality of preterm infants continues to decrease due to improvements in general neonatal care, mortality caused by NEC remains high (up to 30-50%) and survivors suffer from reduced quality of life, and long-term disabilities such as debilitating complications of intestinal failure, poor growth and neurodevelopmental delay. Besides prevention, there have been hardly any innovations in the treatment of NEC which underwent trial evaluation. NEC pathogenesis is multifactorial, but bowel ischemia is known to play an essential role in the development of NEC. Remote ischemic conditioning (RIC) is a therapeutic maneuver that involves brief cycles of non-lethal ischemia and reperfusion applied to a limb, which protects distant organs (such as the intestine) from ischemic damage. The investigators have shown that in preclinical models of NEC, RIC effectively reduces intestinal damage and prolongs survival. The investigators have also demonstrated the safety of RIC in preterm neonates with NEC. Before the investigators can evaluate the effectiveness of RIC in treating neonates with NEC in a Phase III randomized clinical trial (RCT), a Phase II Feasibility RCT must be conducted to evaluate issues related to the enrollment and randomization of neonates, masking of the RIC intervention, and measurement of clinical outcomes. The investigators hypothesize that it is feasible to conduct a multicenter RCT to evaluate RIC during the management of neonates with medical NEC.

Conditions

Necrotizing Enterocolitis

Keywords

remote ischemic conditioning; prematurity

Outcome Measures

Primary Outcomes (5)

• The proportion (% total) of screened patients that are eligible for enrollment in the trial.

  The investigators will determine the proportion (% total) of screened patients who meet the inclusion criteria and do not meet the exclusion criteria and are therefore eligible for enrollment in this study.

  24 hours

• The proportion (% total) of eligible patients that give consent and are randomized.

  The investigators will determine the proportion (% total) of eligible patients for whom informed consent from parents/caregivers can be obtained and randomization can be completed within 24 hours from confirmed diagnosis of medical NEC by a neonatologist and pediatric surgeon.

  24 hours

• The proportion (% total) of randomized patients that receive allocated intervention.

  The investigators will determine the proportion (% total) of patients randomized to each study arm who successfully receive the intervention corresponding to that arm: RIC or no RIC.

  72 hours

• The proportion (% total) of randomized patients receiving masked allocated intervention.

  The investigators will determine the proportion (% total) of randomized patients that receive the allocated intervention (RIC or no RIC) successfully masked from the circle of care as well as parents/caregivers.

  72 hours

• The proportion (% total) of randomized patients assessed for NEC-related outcomes.

  The investigators will determine the proportion (% total) of randomized patients that are successfully assessed for the NEC-related outcomes (please see secondary outcomes 6-13 below).

  3 months +/- 1 week

Secondary Outcomes (8)

• Number of patients surviving without the development of intestinal perforation, necrosis or stricture.

  3 months +/- 1 week

• Timing and cause of death

  3 months +/- 1 week

• Number, type and times of abdominal operations performed.

  3 months +/- 1 week

• Number of patients receiving parenteral nutrition

  3 months +/- 1 week

• Number of patients developing severe neurological injury

  3 months +/- 1 week

Study Arms (2)

Intervention (RIC + standard of care for NEC)

EXPERIMENTAL

Neonates randomized to the intervention arm will receive RIC and will continue to receive the standard of care for NEC.

Other: Remote ischemic conditioning (RIC) + Standard of Care for NEC

Control (Standard of care for NEC)

SHAM COMPARATOR

Neonates randomized to the control arm will receive the standard of care for NEC. The research fellow or nurse responsible for performing RIC will be performing sham inflation/deflation of the blood pressure cuff connected to a dummy arm to mimic the noise of the cuff for neonates in the control arm.

Other: Standard of Care for NEC

Interventions

Standard of Care for NEC OTHER

Neonates in this arm (i.e. the control arm) will receive standard of care for NEC.

Control (Standard of care for NEC)

Remote ischemic conditioning (RIC) + Standard of Care for NEC OTHER

RIC will consist of 4 cycles of limb ischemia (5 min) followed by reperfusion (5 min), repeated on two consecutive days. An appropriately sized blood pressure cuff (covering 2/3 of the distance between the shoulder and the elbow) will be applied by a trained research fellow or nurse to an arm (or leg if the arm is not available because of medical reasons such as central line insertion). The systolic blood pressure will be measured before the first RIC cycle using a different cuff of same size connected to a monitor. During ischemia time, the cuff will be inflated to a pressure of 15 mmHg above the child's systolic pressure. Neonates in this arm will continue to receive standard of care for NEC.

Intervention (RIC + standard of care for NEC)

Eligibility Criteria

• Age: 0 Weeks+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• All gestational age at birth.
• Current weight ≥600 g
• Confirmed diagnosis of "medical" NEC based on the joint opinion of two attending experts in the field (two neonatologists or one neonatologist and one pediatric surgeon).
• NEC diagnosis established within the previous 24 hours.

You may not qualify if:

• Indication for surgery in the joint opinion of the attending neonatologist and pediatric surgeon (i.e. surgical NEC). This diagnosis is based on the presence of pneumoperitoneum in the abdominal radiograph and/or failure of medical treatment for NEC
• Previous episodes of NEC
• Diagnosis of NEC established \>24 hours ago
• Major congenital heart disease which needs surgical repair
• Antecedent limb ischemia/limb thrombotic events, occlusive arterial or venous thrombosis
• Associated gastrointestinal anomalies including gastroschisis or congenital diaphragmatic hernia.

Sponsors & Collaborators

• The Hospital for Sick Children: lead
• Thrasher Research Fund: collaborator
• Mount Sinai Hospital, Canada: collaborator
• Sunnybrook Health Sciences Centre: collaborator
• McMaster Children's Hospital: collaborator
• Children's Hospital Medical Center, Cincinnati: collaborator
• Children's Hospital of Orange County: collaborator
• Karolinska University Hospital: collaborator
• Sophia Kindergeneeskunde: collaborator
• Hospital Universitario La Paz: collaborator
• University of Southampton: collaborator
• Xiamen Children's Hospital, Fujian of China: collaborator
• Shanghai Children's Hospital: collaborator
• UCL Great Ormond Street Institute of Child Health: collaborator

Study Sites (4)

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Sunnybrook Health Sciences Center

Toronto, Ontario, M4Y 3M5, Canada

Location

Mount Sinai Hospital

Toronto, Ontario, M5G 1X5, Canada

Location

The Hospital for Sick Children

Toronto, Ontario, M5G1X8, Canada

Location

Related Publications (6)

• Koike Y, Li B, Ganji N, Zhu H, Miyake H, Chen Y, Lee C, Janssen Lok M, Zozaya C, Lau E, Lee D, Chusilp S, Zhang Z, Yamoto M, Wu RY, Inoue M, Uchida K, Kusunoki M, Delgado-Olguin P, Mertens L, Daneman A, Eaton S, Sherman PM, Pierro A. Remote ischemic conditioning counteracts the intestinal damage of necrotizing enterocolitis by improving intestinal microcirculation. Nat Commun. 2020 Oct 2;11(1):4950. doi: 10.1038/s41467-020-18750-9.

  PMID: 33009377 BACKGROUND

• Chen Y, Koike Y, Chi L, Ahmed A, Miyake H, Li B, Lee C, Delgado-Olguin P, Pierro A. Formula feeding and immature gut microcirculation promote intestinal hypoxia, leading to necrotizing enterocolitis. Dis Model Mech. 2019 Dec 9;12(12):dmm040998. doi: 10.1242/dmm.040998.

  PMID: 31704804 BACKGROUND

• Chen Y, Chang KT, Lian DW, Lu H, Roy S, Laksmi NK, Low Y, Krishnaswamy G, Pierro A, Ong CC. The role of ischemia in necrotizing enterocolitis. J Pediatr Surg. 2016 Aug;51(8):1255-61. doi: 10.1016/j.jpedsurg.2015.12.015. Epub 2016 Jan 8.

  PMID: 26850908 BACKGROUND

• Alganabi M, Lee C, Bindi E, Li B, Pierro A. Recent advances in understanding necrotizing enterocolitis. F1000Res. 2019 Jan 25;8:F1000 Faculty Rev-107. doi: 10.12688/f1000research.17228.1. eCollection 2019.

  PMID: 30740215 BACKGROUND

• Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med. 2011 Jan 20;364(3):255-64. doi: 10.1056/NEJMra1005408. No abstract available.

  PMID: 21247316 BACKGROUND

• Willan AR, Thabane L. Bayesian methods for pilot studies. Clin Trials. 2020 Aug;17(4):414-419. doi: 10.1177/1740774520914306. Epub 2020 Apr 16.

  PMID: 32297539 BACKGROUND

MeSH Terms

Conditions

Enterocolitis, Necrotizing; Premature Birth

Interventions

Standard of Care

Condition Hierarchy (Ancestors)

Enterocolitis; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Study Officials

• Agostino Pierro, OBE, MD

  The Hospital for Sick Children

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: RIC will be masked from the local team of healthcare workers and parents/caregivers. A trained research fellow/nurse not involved in the circle of care will perform, behind a portable sliding medical privacy screen, inflation/deflation of the cuff (RIC intervention) or sham inflation/deflation of the cuff connected to a dummy neonatal arm to mimic the noise of cuff inflation (control). Both limbs (receiving and not receiving RIC) will be blinded from the circle of care and parents/caregivers. During the RIC procedure, the research fellow/nurse will monitor the oxygen saturation of the limb receiving RIC via pulse oximetry. The circle of care will continue to monitor the neonate's clinical parameters on the cardiopulmonary monitor on the other side of the privacy screen.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: The intervention used in this study is remote ischemic conditioning (RIC). Patients randomized to the intervention arm will receive RIC as well as the standard medical management for NEC. RIC will consist of 4 cycles of limb ischemia (5 minutes) followed by reperfusion (5 minutes), repeated on two consecutive days. An appropriately sized blood pressure cuff (covering 2/3 of the distance between the shoulder and the elbow) will be applied by a trained research fellow or nurse to an arm (or leg if the arm is not available because of medical reasons such as central line insertion). The systolic blood pressure will be measured before the first RIC cycle using a different cuff of the same size connected to a monitor. During ischemia time, the cuff will be inflated to a pressure of 15 mmHg above the child's systolic pressure.

Study Record Dates

• First Submitted: January 11, 2022
• First Posted: March 15, 2022
• Study Start: February 9, 2023
• Primary Completion: December 20, 2025
• Study Completion: March 18, 2026
• Last Updated: February 3, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

CA (3); US (1)