Clinical trial NCT05279664: RIC-NEC Randomized Controlled Trial
Official title: RIC-NEC Phase II Feasibility Randomized Controlled Trial: Remote Ischemic Conditioning in Necrotizing Enterocolitis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Necrotizing Enterocolitis
Keywords: remote ischemic conditioning
prematurity
Lead sponsor: The Hospital for Sick Children
Sponsor class: OTHER
Collaborators: name: Thrasher Research Fund
name: Mount Sinai Hospital, Canada
name: Sunnybrook Health Sciences Centre
name: McMaster Children's Hospital
name: Children's Hospital Medical Center, Cincinnati
name: Children's Hospital of Orange County
name: Karolinska University Hospital
name: Sophia Kindergeneeskunde
name: UCL Great Ormond Street Institute of Child Health
name: Hospital Universitario La Paz
name: University of Southampton
First posted: 2022-03-15
Enrollment: 78
Sex: ALL
Minimum age (years): 0
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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 (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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: The proportion (% total) of screened patients that are eligible for enrollment in the trial.
timeFrame: 24 hours
measure: The proportion (% total) of eligible patients that give consent and are randomized.
timeFrame: 24 hours
measure: The proportion (% total) of randomized patients that receive allocated intervention.
timeFrame: 72 hours
measure: The proportion (% total) of randomized patients receiving masked allocated intervention.
timeFrame: 72 hours
measure: The proportion (% total) of randomized patients assessed for NEC-related outcomes.
timeFrame: 3 months +/- 1 week
Secondary outcomes:
measure: Number of patients surviving without the development of intestinal perforation, necrosis or stricture.
timeFrame: 3 months +/- 1 week
measure: Timing and cause of death
timeFrame: 3 months +/- 1 week
measure: Number, type and times of abdominal operations performed.
timeFrame: 3 months +/- 1 week
measure: Number of patients receiving parenteral nutrition
timeFrame: 3 months +/- 1 week
measure: Number of patients developing severe neurological injury
timeFrame: 3 months +/- 1 week
measure: Number of patients developing chronic lung disease (CLD)
timeFrame: 3 months +/- 1 week
measure: Number of patients developing severe retinopathy of prematurity (ROP)
timeFrame: 3 months +/- 1 week
measure: Survey of stakeholders' satisfaction
timeFrame: 1 month +/- 1 week
Other outcomes:
Locations:
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Center
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
Study officials:
affiliation: The Hospital for Sick Children
name: Agostino Pierro, OBE, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med. 2011 Jan 20;364(3):255-64. doi: 10.1056/NEJMra1005408. No abstract available.
citation: 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.