Remote Ischemic Conditioning for Necrotizing Enterocolitis

(RIC-NEC Trial)

Recruiting at 3 trial locations

Overseen By Niloofar Ganji, BSc, MSc

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: The Hospital for Sick Children

Disqualifiers: Surgical NEC, Previous NEC, Heart disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 72 hours

78 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial protocol does not specify whether participants must stop taking their current medications.

What data supports the effectiveness of the treatment Remote Ischemic Conditioning (RIC) for necrotizing enterocolitis (NEC)?

Research shows that Remote Ischemic Conditioning (RIC) can improve blood flow in the intestines and reduce damage in experimental models of necrotizing enterocolitis (NEC), a serious intestinal condition in newborns. Studies have demonstrated that RIC is safe in preterm infants and can decrease intestinal injury and prolong survival in early-stage NEC. ^{1 2 3 4 5}

Is remote ischemic conditioning (RIC) safe for humans?

Research indicates that remote ischemic conditioning (RIC) is safe for preterm infants with necrotizing enterocolitis (NEC), as demonstrated in a phase I safety study. ^{1 2 3 4 5}

How is the treatment Remote Ischemic Conditioning (RIC) different from other treatments for necrotizing enterocolitis (NEC)?

Remote Ischemic Conditioning (RIC) is unique because it involves brief cycles of reduced blood flow and restoration in a limb, which helps protect the intestines by improving blood flow and reducing inflammation. Unlike other treatments, RIC is non-invasive and activates the body's natural protective mechanisms to reduce intestinal damage in NEC. ^{1 2 3 4 5}

Research Team

Agostino Pierro, OBE, MD, FRCS(Engl), FRCS(Ed),

Principal Investigator

The Hospital for Sick Children

Eligibility Criteria

This trial is for preterm babies born before 33 weeks of gestation, currently weighing at least 750 grams, and diagnosed with 'medical' NEC by two experts within the last day. It's not specified who can't join.

Inclusion Criteria

My NEC diagnosis was confirmed by two expert doctors.

You were diagnosed with NEC (Necrotizing Enterocolitis) within the last 24 hours.

My current weight is at least 750 grams.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

24 hours

Treatment

Participants receive either RIC intervention or standard care for NEC

72 hours

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

Outcome Assessment

Assessment of NEC-related outcomes and other secondary measures

3 months

Treatment Details

Interventions

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

Trial Overview The study tests if adding Remote Ischemic Conditioning (RIC) to standard care improves outcomes in neonates with NEC compared to standard care alone. RIC involves cycles of controlled blood flow interruption to a limb.

Participant Groups

Group I: Intervention (RIC + standard of care for NEC) Experimental Treatment 1 Intervention

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

Group II: Control (Standard of care for NEC) Placebo Group 1 Intervention

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.

Remote ischemic conditioning (RIC) is already approved in Canada, United States, European Union, China for the following indications:

Approved in Canada as Remote ischemic conditioning for:

• Necrotizing enterocolitis (NEC)

Approved in United States as Remote ischemic conditioning for:

• Necrotizing enterocolitis (NEC)

Approved in European Union as Remote ischemic conditioning for:

• Necrotizing enterocolitis (NEC)

Approved in China as Remote ischemic conditioning for:

• Necrotizing enterocolitis (NEC)

Who Is Running the Clinical Trial?

The Hospital for Sick Children

Lead Sponsor

Trials

724

Recruited

6,969,000+

UCL Great Ormond Street Institute of Child Health

Collaborator

Trials

4

Recruited

1,300+

McMaster Children's Hospital

Collaborator

Trials

43

Recruited

19,900+

UCL Great Ormond Street Institute of Child Health

Collaborator

Trials

5

Recruited

1,300+

Children's Hospital Medical Center, Cincinnati

Collaborator

Trials

844

Recruited

6,566,000+

Hospital Universitario La Paz

Collaborator

Trials

127

Recruited

37,900+

Children's Hospital of Orange County

Collaborator

Trials

38

Recruited

5,700+

Sophia Kindergeneeskunde

Collaborator

Trials

2

Recruited

1,500+

Karolinska University Hospital

Collaborator

Trials

509

Recruited

1,319,000+

Sunnybrook Health Sciences Centre

Collaborator

Trials

693

Recruited

1,569,000+

Findings from Research

Remote ischaemic conditioning (RIC) was found to be feasible and safe for use in 15 preterm infants with suspected or confirmed necrotising enterocolitis (NEC), with all infants showing normal perfusion recovery after the procedure.

The study established a protocol involving four cycles of limb ischaemia lasting 4 minutes, followed by reperfusion, which can inform future randomized controlled trials to evaluate the efficacy of RIC in this vulnerable population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Remote ischaemic conditioning in necrotising enterocolitis: a phase I feasibility and safety study. Zozaya, C., Ganji, N., Li, B., et al.[2022]

Remote ischemic conditioning (RIC) is a safe intervention for neonates with necrotizing enterocolitis (NEC), showing promise in reducing intestinal injury and improving survival based on earlier studies.

This phase II randomized controlled trial aims to assess the feasibility of recruiting and randomizing neonates for RIC treatment across 12 international centers, with plans to include 78 patients over 30 months, setting the stage for a future phase III trial to evaluate RIC's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Remote ischemic conditioning in necrotizing enterocolitis: study protocol of a multi-center phase II feasibility randomized controlled trial. Ganji, N., Li, B., Ahmad, I., et al.[2022]

Remote ischaemic conditioning (RIC) significantly reduced the extent of intestinal injury in a rat model of ischaemia-reperfusion injury, decreasing macroscopic injury from 100% to 58% and improving microscopic injury scores.

RIC also lowered neutrophil activation, as indicated by reduced myeloperoxidase activity, suggesting it may be a promising therapeutic approach for treating intestinal diseases like necrotising enterocolitis in newborns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Remote Ischaemic Pre-Conditioning Reduces Intestinal Ischaemia Reperfusion Injury in a Newborn Rat. Jones, IH., Tao, D., Vagdama, B., et al.[2023]

Remote ischemic conditioning (RIC) is a promising non-invasive treatment that protects the intestines of premature infants from damage caused by necrotizing enterocolitis (NEC) by improving blood flow and activating protective signaling pathways.

A Phase I safety study has shown that RIC is safe for use in preterm infants with NEC, and a Phase II randomized controlled trial is currently underway to further evaluate its feasibility as a treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Remote ischemic conditioning in necrotizing enterocolitis. Ganji, N., Biouss, G., Sabbatini, S., et al.[2023]

In a study using a mouse model of necrotizing enterocolitis (NEC), remote ischemic conditioning (RIC) significantly reduced pro-inflammatory cytokines and increased anti-inflammatory cytokines, suggesting it can help manage inflammation associated with NEC.

RIC also reversed the imbalance of Treg and Th17 cells in NEC mice, indicating its potential as a non-invasive treatment to modulate immune responses in this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Remote ischemic conditioning causes CD4 T cells shift towards reduced cell-mediated inflammation. Alganabi, M., Biouss, G., Ganji, N., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Remote ischaemic conditioning in necrotising enterocolitis: a phase I feasibility and safety study. [2022]

2. Germany pubmed.ncbi.nlm.nih.gov

Remote ischemic conditioning in necrotizing enterocolitis: study protocol of a multi-center phase II feasibility randomized controlled trial. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Remote Ischaemic Pre-Conditioning Reduces Intestinal Ischaemia Reperfusion Injury in a Newborn Rat. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Remote ischemic conditioning in necrotizing enterocolitis. [2023]

5. Germany pubmed.ncbi.nlm.nih.gov

Remote ischemic conditioning causes CD4 T cells shift towards reduced cell-mediated inflammation. [2022]