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RIC in HIE: A Safety and Feasibility Trial

Primary Purpose

Hypoxic-Ischemic Encephalopathy

Status
Recruiting
Phase
Not Applicable
Locations
Canada
Study Type
Interventional
Intervention
Remote Ischemic Conditioning
Sponsored by
The Hospital for Sick Children
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Hypoxic-Ischemic Encephalopathy focused on measuring Hypoxic-Ischemic Encephalopathy

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • The Hospital for Sick ChildrenRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Intervention Arm - Remote Ischemic Conditioning

Control Arm - No Remote Ischemic Conditioning

Arm Description

Remote Ischemic Conditioning

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

Outcomes

Primary Outcome Measures

RIC cycles administered as planned (Y/N)
Designated RIC cycles are administered as planned (dichotomous variable)
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Frequency of limb ischemia, incidence of RIC interruption and rescue intervention, incidence of subcutaneous fat necrosis, incidence of acute kidney injury, mortality

Secondary Outcome Measures

Number of patients with cutaneous injury
New-onset of skin breakdown, bruising, ecchymosis or petechiae, within 24 hours after the end of the maneuver (comparing to the previous baseline assessment)
Number of patients with transient and persistent pain defined as a premature infant pain profile (PIPP) score >7
Pain measured by PIPP score > 7 will be considered as an episode of pain. A patient will be considered to have persistent pain if PIPP score is higher than the baseline score 6 hours after the maneuver.

Full Information

First Posted
November 25, 2021
Last Updated
October 18, 2022
Sponsor
The Hospital for Sick Children
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1. Study Identification

Unique Protocol Identification Number
NCT05379218
Brief Title
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

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Recruiting
Study Start Date
January 17, 2022 (Actual)
Primary Completion Date
August 31, 2023 (Anticipated)
Study Completion Date
December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
The Hospital for Sick Children

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypoxic-Ischemic Encephalopathy
Keywords
Hypoxic-Ischemic Encephalopathy

7. Study Design

Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
32 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Intervention Arm - Remote Ischemic Conditioning
Arm Type
Experimental
Arm Description
Remote Ischemic Conditioning
Arm Title
Control Arm - No Remote Ischemic Conditioning
Arm Type
No Intervention
Arm Description
No intervention. A blood pressure cuff will be placed on the infant's arm but will not be inflated.
Intervention Type
Device
Intervention Name(s)
Remote Ischemic Conditioning
Intervention Description
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.
Primary Outcome Measure Information:
Title
RIC cycles administered as planned (Y/N)
Description
Designated RIC cycles are administered as planned (dichotomous variable)
Time Frame
72 hours
Title
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Description
Frequency of limb ischemia, incidence of RIC interruption and rescue intervention, incidence of subcutaneous fat necrosis, incidence of acute kidney injury, mortality
Time Frame
72 hours
Secondary Outcome Measure Information:
Title
Number of patients with cutaneous injury
Description
New-onset of skin breakdown, bruising, ecchymosis or petechiae, within 24 hours after the end of the maneuver (comparing to the previous baseline assessment)
Time Frame
24 hours
Title
Number of patients with transient and persistent pain defined as a premature infant pain profile (PIPP) score >7
Description
Pain measured by PIPP score > 7 will be considered as an episode of pain. A patient will be considered to have persistent pain if PIPP score is higher than the baseline score 6 hours after the maneuver.
Time Frame
24 hours
Other Pre-specified Outcome Measures:
Title
aEEG
Description
Background pattern/s (and relative duration) before (2 hours) and after (2 hours) RIC. Background pattern/s include classifying the tracings by lower margin of tracing in microvolts and upper margin of tracing in microvolts. Normal aEEG pattern vs continuous normal voltage, discontinuous normal voltage, burst suppression, low voltage, or flat +/- seizures. Normal aEEG pattern: lower margin >5 microvolts and upper margin >10 microvolts. Presence of sleep-wake cycles and seizures.
Time Frame
4 hours
Title
Biomarkers
Description
Blood collected at 72 hours will be used to measure biomarkers for brain injury: S100B, blood brain-derived neurotrophic factor, total Tau, and neuron-specific enolase as measured in nanograms per milliliter. Blood will also be bio banked for additional immune-related analysis, but will not be used for genetic analysis.
Time Frame
72 hours
Title
MRI including diffusion-weighted imaging and spectroscopy
Description
MRI will be done between day 4 and 7 of age, as per standard of care, and scored for injury severity. MRI will be scored according to Weeke et al. criteria (Journal of Pediatrics 2018).
Time Frame
7 days
Title
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)
Description
Neurodevelopment: cognitive, motor, and language impairment defined as a Bayley Scales of Infant and Toddler Development (3rd edition) scores < 85 (impairment) and <70 (severe impairment). Deafness or hearing impairment. Blindness or visual impairment.
Time Frame
18-24 months
Title
Number of patients with deafness or hearing impairment on decibel scale at 18-24 months corrected age
Description
Deafness or hearing impairment on decibel scale
Time Frame
18-24 months
Title
Number of patients with blindness or visual impairment on visual acuity scale at 18-24 months corrected age
Description
Blindness or visual impairment on visual acuity scale
Time Frame
18-24 months

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Brian Kalish, MD
Phone
416-813-7654
Ext
301433
Email
brian.kalish@sickkids.ca
First Name & Middle Initial & Last Name or Official Title & Degree
Rosanna Yankanah, MSc
Phone
416-813-7654
Ext
202919
Email
rosanna.yankanah@sickkids.ca
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Brian Kalish, MD
Organizational Affiliation
The Hospital for Sick Children
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Hospital for Sick Children
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Brian Kalish, MD
Email
brian.kalish@sickkids.ca
First Name & Middle Initial & Last Name & Degree
Emily Lo, MD
Email
emily.lo@sickkids.ca
First Name & Middle Initial & Last Name & Degree
Brian Kalish, MD
First Name & Middle Initial & Last Name & Degree
Emily Lo, MD

12. IPD Sharing Statement

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RIC in HIE: A Safety and Feasibility Trial

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