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

Necrotizing enterocolitis (NEC) is an acute and severe intestinal inflammation
of the small and/or large intestine. Due to the inflammation, the intestine is
not well supplied with blood (ischemia), and parts of the intestine can die
(necrosis). NEC mainly occurs in premature (premature) babies. NEC often
requires urgent abdominal surgery. NEC increases the risk of serious additional
problems (complications) and death.

The development of NEC is therefore related to reduced oxygen supply to the
gut. Recent researchers have shown that inflating and deflating a blood
pressure cuff in the arm or leg (similar to taking a blood pressure reading)
can protect a distant organ such as the gut during NEC. This treatment is
called remote ischemic conditioning (RIC). Many babies can develop serious
complications as a result of NEC, and our experiments indicate that RIC can
help these babies recover from NEC by improving the oxygen reaching the gut.
Previous studies have shown that RIC is safe and well tolerated in 15 small
infants with NEC at the Hospital for Sick Children (Toronto, Canada).

Primary Endpoint: Feasibility of including patients in the study, randomization
and delivery of the intervention.

To assess the primary endpoint, we will examine the probability that:
(1) a screened patient is eligible; (2) an eligible patient consents and is
randomized within 24 hours from diagnosis; (3) the RIC maneuver is masked from
healthcare workers (responsible nurse, neonatologist, surgeon) and
parents/caregivers; (4) a randomized patient receives allocated intervention;
(5) a randomized patient receives intervention within 24 hours from NEC
diagnosis; (6) a randomized patient is assessed for the NEC-related outcomes
which we have selected as potential elements of *primary composite outcome* of
the future Phase III trial.

Secondary Endpoints:
1. To determine the acceptability and accurate recordability of NEC outcome
measures to calculate sample size for the future Phase III randomized
controlled trial.
2. To determine the satisfaction of key trial stakeholders (parents and
healthcare workers) with the recruitment process and the intervention to
identify facilitators and barriers to participation in a future Phase III
trial.

Exploratory Endpoints:
1. Intestinal oxygenation by near-infrared spectroscopy (NIRS) at baseline
(before RIC) and continuously for 48 hours after RIC.
2. Intestinal perfusion by abdominal colour doppler ultrasonography at baseline
(before RIC) and 48 hours after RIC.

Phase II multicenter masked feasibility RCT, conducted at 12 academic centers
treating preterm neonates with medical necrotizing enterocolitis (NEC) in
Canada, United States, United Kingdom, Sweden, and The Netherlands.
We hypothesize that it is feasible to conduct a multicentre randomized trial to
evaluate remote ischemic conditioning (RIC) during the management of neonates
with medical NEC.
The intervention being tested in this study is RIC, a simple non-invasive
physical maneuver that involves the application of brief cycles of
ischemia-reperfusion to the neonate*s arm or leg, similar to routine blood
pressure measurement. This study will consist of two arms RIC (intervention)
and no RIC (control) to compare the RIC intervention to the standard of care.

An infant's participation in this study will last approximately 1 hour per day,
on two consecutive days, followed by 2 follow-up assessments, one at 1 month
and the other at 3 months after enrollment in the study.
All study activities during this period will be performed during the NICU
inpatient or outpatient setting.
The total duration of this study is 2.5 years and the results should be
available approximately 6 months after the last patient was recruited.

Patients randomized to the intervention arm will receive RIC as well as the
standard medical management for NEC. As determined in a previously completed
Phase I safety trial (Hospital for Sick Children), 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 research
nurse and/or fellow 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
(see above) connected to a monitor. During ischemia time, the cuff will be
inflated to a pressure of 15 mmHg above the child*s systolic pressure.

c. Safety of RIC in infants: RIC appears safe in human premature neonates with
NEC, as demonstrated in our Phase I safety and feasibility trial
(ClinicalTrials.gov: NCT03860701) by no adverse effects or complications due to
RIC. Muscle ischemia could lead to muscle necrosis and rhabdomyolysis. The most
severe potential complication of rhabdomyolysis is oliguric acute kidney injury
secondary to renal tubules obstruction with myoglobin affecting >50% of the
kidneys. RIC may also lead to damage to the limb peripheral nerves. RIC could
potentially lead to microhemorrhages (petechiae, ecchymosis, bruising). Also,
the presence of an inflated blood pressure cuff over a more extended than usual
period - blood pressure measurement - could lead to skin breakdown, especially
in this vulnerable population (neonates). RIC may also cause pain in the limb
receiving the RIC stimulus.