Title

Effect of Allopurinol for Hypoxic-ischemic Brain Injury on Neurocognitive Outcome
Effect of ALlopurinol in Addition to Hypothermia for Hypoxic-ischemic Brain Injury on Neurocognitive Outcome - a Blinded Randomized Placebo-controlled Parallel Group Multicenter Trial for Superiority (Phase III)
  • Phase

    Phase 3
  • Study Type

    Interventional
  • Status

    Recruiting
  • Study Participants

    846
Neonatal hypoxic-ischemic encephalopathy (HIE) is a major cause of death or long-term disability in infants born at term in the western world, affecting about 1-4 per 1.000 life births and consequently about 5-20.000 infants per year in Europe.

Hypothermic treatment became the only established therapy to improve outcome after perinatal hypoxic-ischemic insults. Despite hypothermia and neonatal intensive care, 45-50% of affected children die or suffer from long-term neurodevelopmental impairment. Additional neuroprotective interventions, beside hypothermia, are warranted to further improve their outcome.

Allopurinol is a xanthine oxidase inhibitor and reduces the production of oxygen radicals and brain damage in experimental, animal, and early human studies of ischemia and reperfusion.

This project aims to evaluate the efficacy and safety of allopurinol administered immediately after birth to near-term infants with HIE in addition to hypothermic treatment.
Study Started
Mar 25
2018
Primary Completion
Jun 30
2025
Anticipated
Study Completion
Jun 30
2025
Anticipated
Last Update
Sep 17
2021

Drug Allopurinol

Allopurinol, powder for injection (PFI), administered in two doses. First dose (20 mg/kg in 2ml/kg sterile water for injection) given as soon as intravenous access is established and no later than 30min postnatally and second dose (10mg/kg in 1ml/kg sterile water for injection) 12 hours thereafter. The second dose will only be administered to in infants on therapeutic hypothermia. Infants who recover quickly and do not qualify for and hence do not undergo hypothermia will not receive a second dose. Administration will be by continuous infusion using a syringe pump over 10min through secure venous access.

Drug Mannitol

Placebo (Mannitol, PFI, 20mg/kg in the same volume and at the same time intervals as the intervention group - (2nd dose 10mg/kg only if infant undergoes therapeutic hypothermia)).

Allopurinol Active Comparator

Allopurinol, powder for injection (PFI), administered in two doses. First dose (20 mg/kg in 2ml/kg sterile water for injection) given as soon as intravenous access is established and no later than 30min postnatally and second dose (10mg/kg in 1ml/kg sterile water for injection) 12 hours thereafter. The second dose will only be administered to in infants on therapeutic hypothermia. Infants who recover quickly and do not qualify for and hence do not undergo hypothermia will not receive a second dose. Administration will be by continuous infusion using a syringe pump over 10min through secure venous access.

Placebo Placebo Comparator

mannitol, powder for injection (PFI), administered in two doses. First dose (20 mg/kg in 2ml/kg sterile water for injection) given as soon as intravenous access is established and no later than 30min postnatally and second dose (10mg/kg in 1ml/kg sterile water for injection) 12 hours thereafter. The second dose will only be administered to in infants on therapeutic hypothermia. Infants who recover quickly and do not qualify for and hence do not undergo hypothermia will not receive a second dose. Administration will be by continuous infusion using a syringe pump over 10min through secure venous access.

Criteria

Inclusion criteria

Term and near-term infants with a history of disturbed labour who meet at least one criterion of perinatal acidosis (or ongoing resuscitation) and at least two early clinical signs of potentially evolving encephalopathy as defined herein:

Severe perinatal metabolic acidosis or ongoing cardiopulmonary resuscitation at 5 min after birth:

At least 1 out of the following 5 criteria must be met

Umbilical (or arterial or reliable venous) blood gas within 30 min after birth with pH<7.0
Umbilical (or arterial or reliable venous) blood gas within 30 min after birth with base deficit ≥16 mmol/l
Need for ongoing cardiac massage at/beyond 5 min postnatally
Need for adrenalin administration during resuscitation
APGAR score ≤5 at 10min AND

Early clinical signs of potentially evolving encephalopathy:

At least 2 out of the following 4 criteria must be met:

Altered state of consciousness (reduced or absent response to stimulation or hyperexcitability)
Severe muscular hypotonia or hypertonia,
Absent or insufficient spontaneous respiration (e.g., gasping only) with need for respiratory support at 10 min postnatally
Abnormal primitive reflexes (absent suck or gag or corneal or Moro reflex) or abnormal movements (e.g., potential clinical correlates of seizure activity)

Exclusion criteria

gestational age below 36 weeks
birth weight below 2500 g
postnatal age >30min at the end of screening phase
severe congenital malformation or syndrome requiring neonatal surgery or affecting long-term outcome
patient considered "moribund" / "non-viable" (e.g., lack of spontaneous cardiac activity and ongoing chest compression at 30min)
decision for "comfort care only" before study drug administration
parents declined study participation as response to measures of community engagement
both parents are insufficiently fluent in the study site's national language(s) or English or do not seem to have the intellectual capacity to understand the study procedures and to give consent as judged by the personnel who had been in contact with the mother/father before delivery.
both parents/guardians less than 18 years of age, in case of single parent/guardian this one less than 18 years of age
No Results Posted