RIC in HIE: A Safety and Feasibility Trial

NCT ID: NCT05379218

Last Updated: 2024-03-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 32 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-01-17
• Study Completion Date: 2024-02-05

Brief Summary

Remote Ischemic Conditioning has never been studied in neonates with HIE. However, RIC has been studied in animal models of perinatal asphyxia and has shown encouraging results. In neonatal rats with HIE, RIC is associated with reduced sensory motor deficits compared to non-RIC, and repeated cycles in three consecutive days is superior to a single treatment. In piglets, four cycles of 10 minutes of bilateral hindlimb ischemia immediately after bilateral common carotid occlusion results in reduced cell death in the periventricular white matter and internal capsule. These preclinical studies support the hypothesis that RIC may be beneficial in infants with HIE.

Detailed Description

Hypoxic-ischemic encephalopathy (HIE) is a devastating condition in which newborn infants are deprived of oxygen in the peripartum period, resulting in brain injury. HIE is a leading cause of infant morbidity and mortality worldwide. Within the last 15 years, the introduction of hypothermia as a therapy for HIE has revolutionized our care of these vulnerable infants, but despite these improvements, nearly 50% of infants die or have major disability at 18 months. Therefore, there is a significant need to develop novel adjunctive therapies for HIE.

Remote ischemic conditioning (RIC) is a procedure that involves the application of brief cycles of non-lethal ischemia and reperfusion to a remote site, with the goal of protecting distant organs exposed to ischemic injury. RIC has been extensively studied in experimental models and applied clinically in adults, children, and neonates. In neonates, there have been trials exploring its potential role before cardiac surgery and necrotizing enterocolitis. Most of these studies performed up to 4 cycles of 5 minutes of ischemia in a single day and found RIC to be feasible and safe. Experimental studies suggest that RIC, acting through three inter-related mechanisms (neural, humoral, and systemic pathways) is associated with increased cerebral blood flow, decreased inflammation, and enhanced cell survival. RIC has been studied as a potential treatment in adult stroke, and while the evidence to date is inconclusive, preliminary data suggest that RIC may reduce the size and the severity of the stroke lesion, as well as improve cognitive outcomes.

RIC has been studied in animal models of perinatal asphyxia and has shown encouraging results. In neonatal rats with HIE, RIC is associated with reduced sensory motor deficits compared to non-RIC, and repeated cycles in three consecutive days is superior to a single treatment. In piglets, four cycles of 10 minutes of bilateral hindlimb ischemia immediately after bilateral common carotid occlusion results in reduced cell death in the periventricular white matter and internal capsule. These preclinical studies support the hypothesis that RIC may be beneficial in infants with HIE. In this proposal, we outline a carefully designed and conducted early phase study of RIC in neonates with HIE.

Conditions

Hypoxic-Ischemic Encephalopathy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

Intervention Arm - Remote Ischemic Conditioning

Remote Ischemic Conditioning

Group Type: EXPERIMENTAL

Remote Ischemic Conditioning

Intervention Type: DEVICE

Patients randomized to the RIC arm, cohorts of 4 consecutive patients will receive escalating therapy:

A. 4 consecutive patients will undergo 4 cycles of 3 minutes ischemia, followed by 5 minutes reperfusion, on Day 1 of therapeutic hypothermia B. Observing no safety events (see below) from patients in group A, 4 consecutive patients will undergo 4 cycles of 5 minutes ischemia, followed by 5 minutes reperfusion, on Day 1 of therapeutic hypothermia.

C. Observing no safety events from patients in group B, 4 consecutive patients will undergo 4 cycles of 5 minutes ischemia, followed by 5 minutes reperfusion, on Days 1 and 2 of therapeutic hypothermia.

D. Observing no safety events from patients in group C, 4 consecutive patients will undergo 4 cycles of 5 minutes ischemia, followed by 5 minutes reperfusion, on Days 1, 2, and 3 of therapeutic hypothermia.

All infants will have an extra 1ml of blood collected.

Control Arm - No Remote Ischemic Conditioning

No intervention. A blood pressure cuff will be placed on the infant's arm but will not be inflated.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Remote Ischemic Conditioning

Patients randomized to the RIC arm, cohorts of 4 consecutive patients will receive escalating therapy:

A. 4 consecutive patients will undergo 4 cycles of 3 minutes ischemia, followed by 5 minutes reperfusion, on Day 1 of therapeutic hypothermia B. Observing no safety events (see below) from patients in group A, 4 consecutive patients will undergo 4 cycles of 5 minutes ischemia, followed by 5 minutes reperfusion, on Day 1 of therapeutic hypothermia.

C. Observing no safety events from patients in group B, 4 consecutive patients will undergo 4 cycles of 5 minutes ischemia, followed by 5 minutes reperfusion, on Days 1 and 2 of therapeutic hypothermia.

D. Observing no safety events from patients in group C, 4 consecutive patients will undergo 4 cycles of 5 minutes ischemia, followed by 5 minutes reperfusion, on Days 1, 2, and 3 of therapeutic hypothermia.

All infants will have an extra 1ml of blood collected.

Intervention Type: DEVICE

Eligibility Criteria

Inclusion Criteria

• Qualifying for therapeutic hypothermia according to the primary care team based on the current SickKids HIE Protocol

Exclusion Criteria

• Gestational age <35 weeks
• Known central nervous system malformations
• Known chromosomal or genetic anomalies
• Confirmed or suspected inborn error of metabolism
• Parental decision for withdrawal of life-sustaining treatment ("comfort care"). If this decision is made after enrollment but before completion of RIC intervention, no further study-related intervention will be performed.
• Patients requiring significant hemodynamic support (two or more agents for blood pressure support, >0.05mcg/kg/min epinephrine infusion, or >0.1 mU/kg/min vasopressin) for the four hour period prior to RIC
• Patients requiring inhaled nitric oxide or fraction of inspired oxygen (FiO2) >50% for the four-hour period prior to RIC

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The Hospital for Sick Children

OTHER

Sponsor Role: lead

Responsible Party

Brian Kalish

Neonatologist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Brian Kalish, MD

Role: PRINCIPAL_INVESTIGATOR

The Hospital for Sick Children

Locations

The Hospital for Sick Children

Toronto, Ontario, Canada

Countries

Canada

Other Identifiers

1000077295

Identifier Type: -

Identifier Source: org_study_id