RIC-NEC Randomized Controlled Trial

NCT ID: NCT05279664

Last Updated: 2026-02-03

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 78 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-02-09
• Study Completion Date: 2026-03-18

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.

Detailed Description

Background: 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 resulting in mortality rates as high as 50%, reduced quality of life and long-term disabilities such as short bowel syndrome, poor growth, and neurodevelopmental delay. Experimentally, the investigators have discovered that intestinal and brain damage, as well as mortality following NEC, can be avoided by remote ischemic conditioning (RIC) in the early stage of the disease. Remote ischemic conditioning is a therapeutic maneuver involving brief cycles of non-lethal ischemia and reperfusion applied to a limb that protects distant organs (such as the intestine) from sustained ischemic damage. In the clinical setting, the cycles of ischemia and reperfusion can be administered by inflation and deflation of a blood pressure cuff, similar to routine blood pressure measurements. The investigators have also demonstrated that this non-invasive, simple, and easy-to-use maneuver consisting of inflation/deflation of a blood pressure cuff on the upper arm is safe in preterm human neonates with NEC.

Hypothesis and Objectives: The investigators hypothesize that a masked multi-center randomized controlled trial of RIC in neonates with early-stage NEC is feasible.

Study design: This is a Phase II multicenter, masked, randomized controlled feasibility trial consisting of two arms: RIC (intervention) and no RIC (control).

Study population: Preterm neonates with clinical and radiological evidence of early-stage NEC and receiving medical treatment.

Sample size/power of primary endpoint: In the 12 international collaborating centers, the investigators expect to randomize, in 30 months, 78 patients with NEC receiving medical treatment (39 per arm) which represents 40% of approached eligible neonates.

Conditions

Necrotizing Enterocolitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Control (Standard of care for NEC)

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.

Group Type: SHAM_COMPARATOR

Standard of Care for NEC

Intervention Type: OTHER

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

Intervention (RIC + standard of care for NEC)

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

Group Type: EXPERIMENTAL

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

Intervention Type: 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.

Interventions

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

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 Type: OTHER

Standard of Care for NEC

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

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

1. All gestational age at birth.

2. Current weight ≥600 g

3. 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).

4. NEC diagnosis established within the previous 24 hours.

Exclusion Criteria

1. 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

2. Previous episodes of NEC

3. Diagnosis of NEC established >24 hours ago

4. Major congenital heart disease which needs surgical repair

5. Antecedent limb ischemia/limb thrombotic events, occlusive arterial or venous thrombosis

6. Associated gastrointestinal anomalies including gastroschisis or congenital diaphragmatic hernia.

• Minimum Eligible Age: 0 Weeks
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Thrasher Research Fund

OTHER

Sponsor Role: collaborator

Mount Sinai Hospital, Canada

OTHER

Sponsor Role: collaborator

Sunnybrook Health Sciences Centre

OTHER

Sponsor Role: collaborator

McMaster Children's Hospital

OTHER

Sponsor Role: collaborator

Children's Hospital Medical Center, Cincinnati

OTHER

Sponsor Role: collaborator

Children's Hospital of Orange County

OTHER

Sponsor Role: collaborator

Karolinska University Hospital

OTHER

Sponsor Role: collaborator

Sophia Kindergeneeskunde

OTHER

Sponsor Role: collaborator

UCL Great Ormond Street Institute of Child Health

OTHER

Sponsor Role: collaborator

Hospital Universitario La Paz

OTHER

Sponsor Role: collaborator

University of Southampton

OTHER

Sponsor Role: collaborator

Xiamen Children's Hospital, Fujian of China

OTHER

Sponsor Role: collaborator

Shanghai Children's Hospital

OTHER

Sponsor Role: collaborator

The Hospital for Sick Children

OTHER

Sponsor Role: lead

Responsible Party

Agostino Pierro

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Agostino Pierro, OBE, MD

Role: PRINCIPAL_INVESTIGATOR

The Hospital for Sick Children

Locations

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Sunnybrook Health Sciences Center

Toronto, Ontario, Canada

Mount Sinai Hospital

Toronto, Ontario, Canada

The Hospital for Sick Children

Toronto, Ontario, Canada

Countries

United States; Canada

References

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.

Reference Type: BACKGROUND

PMID: 33009377 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 31704804 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26850908 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 30740215 (View on PubMed)

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

Reference Type: BACKGROUND

PMID: 21247316 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 32297539 (View on PubMed)

Other Identifiers

CTO 3802

Identifier Type: -

Identifier Source: org_study_id