Clinical trial NCT05379218: RIC in HIE: A Safety and Feasibility Trial
Official title: Remote Ischemic Conditioning in Hypoxic-Ischemic Encephalopathy: A Safety and Feasibility Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Hypoxic-Ischemic Encephalopathy
Keywords: Hypoxic-Ischemic Encephalopathy
Lead sponsor: The Hospital for Sick Children
Sponsor class: OTHER
First posted: 2022-05-18
Enrollment: 32
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

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

Primary outcomes:
measure: RIC cycles administered as planned (Y/N)
timeFrame: 72 hours
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
timeFrame: 72 hours
Secondary outcomes:
measure: Number of patients with cutaneous injury
timeFrame: 24 hours
measure: Number of patients with transient and persistent pain defined as a premature infant pain profile (PIPP) score >7
timeFrame: 24 hours
Other outcomes:
measure: aEEG
timeFrame: 4 hours
measure: Biomarkers
timeFrame: 72 hours
measure: MRI including diffusion-weighted imaging and spectroscopy
timeFrame: 7 days
measure: Number of patients with cognitive, motor, and/or language impairment at 18-24 months corrected age defined as < 85 (impairment) and <70 (severe impairment) on the Bayley Scales of Infant and Toddler Development (3rd edition)
timeFrame: 18-24 months
measure: Number of patients with deafness or hearing impairment on decibel scale at 18-24 months corrected age
timeFrame: 18-24 months
measure: Number of patients with blindness or visual impairment on visual acuity scale at 18-24 months corrected age
timeFrame: 18-24 months
Locations:
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
Study officials:
affiliation: The Hospital for Sick Children
name: Brian Kalish, MD
role: PRINCIPAL_INVESTIGATOR
References: