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)

Perinatal asphyxia 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
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 effect is
expected with adjuvant earlier neuroprotective interventions, beside
hypothermia, this is 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 preliminary human
studies of ischemia and reperfusion, if administered early after the insult.

This study has been transitioned to CTIS with ID 2024-511322-31-00 check the CTIS register for the current data.

To evaluate whether in newborns with asphyxia and early clinical signs of
hypoxic ischemic encephalopathy, early postnatal allopurinol compared to
placebo administered in addition to standard of care (including therapeutic
hypothermia if indicated) improves the neurologic prognosis.

A placebo-controlled, (double-)blinded, randomized multicenter trial (Phase
III)

Intervention medication: Allopurinol, powder for injection (PFI), administered
in two doses. First dose (20 mg/kg in 2ml/kg sterile water for injection)
within 30min postnatal and second dose (10mg/kg in 1ml/kg sterile water for
injection) 12 hours thereafter, only if the infant undergoes therapeutic
hypothermia.
Placebo medication: Mannitol, PFI, 20mg/kg in the same volume and at the same
time intervals as the intervention group - (2nd dose 10mg/kg only if the infant
undergoes therapeutic hypothermia).

The most important burden to patients are the blood samples. These will be
coordinated with clinically required blood samples, preferably collected
through an existing arterial or central venous access and the blood loss will
be minimal (<2ml/kg in total). The neurodevelopmental follow up at 24 months
may not be standard in the smaller centrums, but this will be only one
examination and is most of the times fun for children. In case MRI or EEG is
not clinically indicated because of good recovery, we will ask separate
informed consent for these examinations. As far as reported in the previous
trials of antenatal [Torrance, Pediatrics 2009, Kaandorp, Arch Dis. Childhood
F&N 2014] and postnatal [vanBel, Pediatrics 1998, Gunes, Pediatr Neurol
2007, Benders, Arch Dis Child 2006] allopurinol in perinatal asphyxia and high
dose allopurinol in other clinical settings in neonates and infants [Clancy,
Pediatrics 2001], there is no evidence for significant adverse effects of
allopurinol in newborn infants even at high doses. Irritation of the vascular
and peri-vascular tissue (transitional redness, swelling and tenderness) may
occasionally occur and have uniformly been transient in previous studies
However, the pH of allopurinol is high, so a secure intravenous access is
essential to prevent extravasation and the consequential possible harm to the
patient. The burden and risks are in our opinion acceptable, considering the
importance for additional neuroprotection to reduce the mortality and morbidity
and the possible benefits for the intervention group.