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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called remote ischemic conditioning (RIC) for babies with necrotizing enterocolitis (NEC), a serious intestinal disease affecting newborns. RIC involves applying brief, non-harmful pressure to a limb to protect the intestines from damage. The study aims to determine if this method can be used effectively and safely alongside standard NEC care. Babies diagnosed with NEC in the last 24 hours and weighing at least 600 grams may qualify for this trial. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to important findings.

Will I have to stop taking my current medications?

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

What prior data suggests that remote ischemic conditioning is safe for neonates with NEC?

Research has shown that remote ischemic conditioning (RIC) is safe for premature babies with necrotizing enterocolitis (NEC). Earlier studies found that RIC did not harm these small and delicate infants. This treatment briefly and safely reduces blood flow to a limb, protecting other organs, like the intestines, from damage. Tests in animal studies, such as with baby mice, also found that RIC did not harm the intestines or affect their function. These findings support that RIC is well-tolerated in both human and animal studies. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for NEC?

Unlike the standard care for necrotizing enterocolitis (NEC), which typically involves antibiotics and, in severe cases, surgery, remote ischemic conditioning (RIC) offers a unique approach. RIC works by intermittently inflating and deflating a blood pressure cuff to induce brief, controlled periods of reduced blood flow, which can potentially trigger the body's protective responses. Researchers are excited about RIC because it targets the body's natural defense mechanisms without introducing new drugs or invasive procedures, offering a promising complementary treatment that might reduce the severity of NEC in newborns.

What evidence suggests that remote ischemic conditioning is effective for necrotizing enterocolitis?

This trial will compare remote ischemic conditioning (RIC) with standard care for necrotizing enterocolitis (NEC). Research has shown that RIC might help treat NEC by protecting the intestines from harm. Early studies have indicated that RIC is promising in maintaining blood flow in the intestines and reducing damage. Studies have also demonstrated that using RIC in premature babies with NEC is safe and does not cause harmful side effects. While more research is needed, early results suggest RIC could offer a new way to manage NEC in babies. ^{1 2 6 7 8}

Who Is on the Research Team?

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

Principal Investigator

The Hospital for Sick Children

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

Citations

1. nature.com nature.com/articles/s41467-020-18750-9

Remote ischemic conditioning counteracts the intestinal ... However, the effectiveness of RIC against NEC is unknown. To address this gap, we aimed to determine the efficacy and mechanism of action of RIC ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1055858623000598

Remote Ischemic Conditioning in Necrotizing Enterocolitis We have demonstrated, in a Phase I safety study that RIC in preterm infants with NEC was safe and produced no adverse complications30. We are ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9763186/

Remote ischaemic conditioning in necrotising enterocolitis Remote ischaemic conditioning (RIC) improves the outcome of experimental necrotising enterocolitis (NEC) by preserving intestinal microcirculation.

4. ric-necrct.org ric-necrct.org/

RIC-NEC RCT This study aims to determine whether it is safe and feasible to give RIC to babies with NEC, within 24 hours of confirmed diagnosis of NEC by a neonatologist ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35294595/

study protocol of a multi-center phase II feasibility ... In the early stage of experimental NEC, RIC decreased intestinal injury and prolonged survival by counteracting the derangements in intestinal ...

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0022346824008807

Remote Ischemic Conditioning (RIC) Decreases the ... The purpose of this study is to investigate the use of RIC for the prevention and treatment of NEC in a large animal model.

7. thrasherresearch.org thrasherresearch.org/grant/01041?lang=eng

RIC-NEC Phase II Feasibility Randomized Controlled Trial RIC has also been shown to be safe in preterm infants with NEC, producing no adverse complications. GAP: Our plan is to translate these exciting data into ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35940871/

Remote ischaemic conditioning in necrotising enterocolitis Remote ischaemic conditioning (RIC) improves the outcome of experimental necrotising enterocolitis (NEC) by preserving intestinal microcirculation.