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Effect of ALlopurinol in addition to hypothermia for hypoxic-ischemic Brain Injury on Neurocognitive Outcome

Periodic Reporting for period 2 - ALBINO (Effect of ALlopurinol in addition to hypothermia for hypoxic-ischemic Brain Injury on Neurocognitive Outcome)

Reporting period: 2017-07-01 to 2018-12-31

Neonatal hypoxic-ischemic encephalopathy (HIE), i.e. brain injury following insufficient oxygen supply during delivery, 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.
Temporary cooling of the baby’s body to 33.5°C (“therapeutic hypothermia”) became the only established therapy to improve outcome after perinatal brain injury caused by oxygen deficiency. Despite cooling and neonatal intensive care, 40-50% of affected children still die or suffer from long-term neurodevelopmental impairment (i.e. cerebral palsy (severe movement difficulties which are caused when the parts of the brain which control such movements do not work properly), cognitive deficits, and seizures). Additional neuroprotective interventions, i.e. interventions seeking to protect the brain from this injury, besides temporary cooling, are warranted to further improve their outcome.

The ALBINO project seeks to test such an additional neuroprotective intervention. The overall objective is to evaluate whether early postnatal administration of allopurinol in newborns with biochemical and clinical signs of insufficient oxygen supply during delivery, in addition to standard of care (including therapeutic cooling if indicated) reduces the rate of death or severe neurodevelopmental impairment.
If tested successfully, the project also seeks to develop a medication for newborn babies and to make allopurinol available for intravenous administration in children for the European market. Eventually, the project can make an important contribution to alleviate the burden of cerebral palsy and cognitive disability for children, parents and society.
The ALBINO-project made significant progress in all work packages during the second reporting period. Project management has been fully operational. The first reporting has been successfully completed. The Grant Agreement was amended twice (WP1). Manufacturing, stability testing and storage of the study medication were successfully brought forward, and distribution and shipment to various study sites have started (WP2). Study coordination at European and national levels continued to be the most comprehensive task for all beneficiaries who are national coordinators in their countries. Further ethics and regulatory approvals were obtained; cooperation with numerous additional study sites was implemented. At the end of period 2, full approvals are in place in 9 out of 12 countries, and in one additional country the national authority also approved the ALBINO study. A total of 95 study centres have confirmed their participation (WP3). The study database was activated and switched into the productive mode. Central and national monitoring has been set up in all countries. Several national monitors were trained by the central monitors (WP4). Patient recruitment started in five countries (WP5). Preparations for additional analyses and sub-studies (MRI, EEG, biomarkers) have advanced further (WPs 6-7). The first pharmacokinetics analyses were conducted, and the pharmacovigilance system was established (WPs 8-9). Various dissemination and communication activities were undertaken, and the first peer reviewed paper was published and a second one is under peer review (WP10).
If the recruitment goals of the clinical trial can be achieved and the outcomes confirm the hypothesis that Allopurinol proves a viable additional treatment option in addition to hypothermia, the project has the potential to:

- establish safety and efficacy of a novel treatment for infants with brain injury caused by oxygen deficiency complementing current standard of care and (potentially) rendering it more effective
- reduce the burden of brain injury caused by oxygen deficiency for affected children, families and society
- test and validate early indicators (so-called ‘biomarkers’) of later disability, including advanced imaging techniques in a large population of exposed infants
- provide data on the metabolism and excretion allopurinol and mannitol under normal body temperature and during cooling.
- enable a small/medium-size enterprise to grow and eventually to secure jobs or even create new jobs in Europe
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