RIC-NEC Randomized Controlled Trial

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Necrotizing Enterocolitis

Intervention / Treatment
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* Other: Remote ischemic conditioning (RIC) + Standard of Care for NEC
* Other: Standard of Care for NEC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Preterm neonates with gestational age at birth <33 weeks. Current weight ≥750 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 0 Weeks
Maximum Age: 33 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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 (4 minutes) followed by reperfusion (4 minutes) and a 5-minute gap before the next cycle of ischemia, 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.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention (RIC + standard of care for NEC)<br>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<br>* RIC will consist of 4 cycles of limb ischemia (4 min) followed by reperfusion (4 min) and a 5 minute-gap before the next cycle of ischemia, 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.<br>|
| Sham Comparator: Control (Standard of care for NEC)<br>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<br>* Neonates in this arm (i.e. the control arm) will receive standard of care for NEC.<br>|

What is the study measuring?
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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 of days patients receive inotropes | The number of days of administration of inotropes during the 90 days post-randomization will be recorded. | 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. | 3 months +/- 1 week | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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remote ischemic conditioning, prematurity