RIC-NEC Randomized Controlled Trial (RIC-NEC)

RIC-NEC Phase II Feasibility Randomized Controlled Trial: Remote Ischemic Conditioning in Necrotizing Enterocolitis

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.

Study Overview

• Status: Recruiting
• Conditions: Necrotizing Enterocolitis
• Intervention / Treatment: Other: Standard of Care for NEC; Other: Remote ischemic conditioning (RIC) + Standard of Care for 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.

• Study Type: Interventional
• Enrollment (Estimated): 78
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Agostino Pierro, OBE, MD, FRCS, FAAP; Phone Number: 309350 4168137654; Email: agostino.pierro@sickkids.ca
• Study Contact Backup: Name: Niloofar Ganji, BSc, MSc; Phone Number: 6478702781; Email: niloofar.ganji@sickkids.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X5
      • Recruiting
      • Mount Sinai Hospital
      • Contact: Poorva Desphande, MD; Email: poorva.deshpande@sinaihealth.ca
      • Principal Investigator: Poorva Desphande, MD
    • Toronto, Ontario, Canada, M5G1X8
      • Recruiting
      • The Hospital for Sick Children
      • Contact: Agostino Pierro, OBE, MD, FRCS(Engl), FRCS(Ed),; Phone Number: 416-813-7340; Email: agostino.pierro@sickkids.ca
      • Contact: Niloofar Ganji, MSc; Phone Number: 6478702781; Email: niloofar.ganji@sickkids.ca
      • Principal Investigator: Agostino Pierro, OBE, MD, FRCS(Engl), FRCS(Ed),
    • Toronto, Ontario, Canada, M4Y 3M5
      • Recruiting
      • Sunnybrook Health Sciences Center
      • Contact: Maher Shahroor, MD, RCPSC (SEAP); Phone Number: 687939 (416) 480-6100; Email: maher.shahroor@sunnybrook.ca
      • Principal Investigator: Maher Shahroor, MD, RCPSC (SEAP)
• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Recruiting
      • Cincinnati Children's Hospital Medical Center
      • Contact: David Russell, JD; Phone Number: 513-517-0282; Email: david.russell@cchmc.org
      • Principal Investigator: Jae Kim, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 7 months (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Preterm neonates with all gestational age at birth.
2. Current weight ≥750 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Other: 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.
Sham Comparator: 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.	Other: Standard of Care for NEC; Neonates in this arm (i.e. the control arm) will receive standard of care for NEC.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients surviving without the development of intestinal perforation, necrosis or stricture.	The investigators will determine the number of randomized patients who survive at 1 month and 3 months post-randomization without developing intestinal perforation, intestinal necrosis, or intestinal stricture.	3 months +/- 1 week
Timing and cause of death	The time, and if possible, the cause of death will be recorded during the 90 days post-randomization considering whether it was possible to determine if death was related to complications of NEC or to a disease process in other systems including cardiac, neurological, respiratory, renal, metabolic.	3 months +/- 1 week
Number, type and times of abdominal operations performed.	The number, time(s), and type(s) of abdominal operations (insertion of peritoneal drainage or laparotomy) performed during the 90 days post-randomization will be recorded.	3 months +/- 1 week
Number of patients receiving parenteral nutrition	The number of patients receiving parenteral nutrition during the 90 days post-randomization will be recorded as a measure of intestinal function.	3 months +/- 1 week
Number of patients developing severe neurological injury	Development of severe neurological injury will be assessed based on head ultrasound at 1-month and 3-months post-randomization and will be defined as the presence of intraventricular hemorrhage (IVH), ventricular enlargement, parenchymal echogenicity or periventricular leucomalacia (PVL).	3 months +/- 1 week
Number of patients developing chronic lung disease (CLD)	Development of chronic lung disease (CLD) during the 90 days post-randomization will be defined as respiratory support given at 36 weeks' postmenstrual age or at discharge (if earlier than 36 weeks' postmenstrual age) to level 2 neonatal intensive care unit (NICU) and classified in different degrees of severity from mild to moderate to severe CLD according to the criteria published in the Canadian Neonatal Network (CNN) Annual Report (2019).	3 months +/- 1 week
Number of patients developing severe retinopathy of prematurity (ROP)	During the 90 days post-randomization, the investigators will assess the development of Stage 3, 4 or 5 retinopathy of prematurity (ROP) as defined by the International Classification of ROP and/or those infants requiring treatment (laser or intraocular injection). ROP will be scored as the highest stage in either eye identified at any time.	3 months +/- 1 week
Survey of stakeholders' satisfaction	Satisfaction of key trial stakeholders (parents and healthcare workers) with the recruitment process, delivery and masking of the intervention will be evaluated by questionnaires, using a scale of 0-4. Higher scores indicate greater satisfaction and lower scores indicate less satisfaction.	1 month +/- 1 week

Collaborators and Investigators

• Sponsor: The Hospital for Sick Children
• Collaborators: Karolinska University Hospital; Sunnybrook Health Sciences Centre; University of Southampton; Children's Hospital Medical Center, Cincinnati; Mount Sinai Hospital, Canada; McMaster Children's Hospital; Children's Hospital of Orange County; Thrasher Research Fund; Hospital Universitario La Paz; Sophia Kindergeneeskunde; UCL Great Ormond Street Institute of Child Health
• Investigators: Principal Investigator: Agostino Pierro, OBE, MD, The Hospital for Sick Children

Publications and helpful links

General Publications

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

Study record dates

Study Major Dates

• Study Start (Actual): February 9, 2023
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): May 1, 2027

Study Registration Dates

• First Submitted: January 11, 2022
• First Submitted That Met QC Criteria: March 6, 2022
• First Posted (Actual): March 15, 2022

Study Record Updates

• Last Update Posted (Actual): January 10, 2024
• Last Update Submitted That Met QC Criteria: January 8, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: remote ischemic conditioning; prematurity
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Enterocolitis; Enterocolitis, Necrotizing
• Other Study ID Numbers: CTO 3802

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No