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

Periodic Reporting for period 3 - ALBINO (Effect of ALlopurinol in addition to hypothermia for hypoxic-ischemic Brain Injury on Neurocognitive Outcome)

Reporting period: 2019-01-01 to 2020-06-30

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 clinical trial has made substantial progress during the third reporting period. Overall project and consortium management have been operational; all requested administra-tive activities carried out, including Amendments amendments to the Grant agreement Agreement and periodic reports, under Work Package 1 have been completed. All consortium partners have met regularly via phone conference. Project finances have been monitored closely. Study medication manufacturing and shipping (Work Package 2) to an increasing number of sites and countries has been fully operational and running. Important achievements in Work Package 3 during period 3 include national approvals in now 11 out of 12 participat-ing countries. The number of sites actively recruiting and screening could be increased to 46, 41 of which have already included their first patient. In Work Package 4, national monitoring has been set-up in all countries, and 38 additional sites were initiated by national monitors. Database programming and data management has been extended to the follow-up phase, as the first patients have entered clinical follow-up at 2 years of age. Patient screening and ran-domization numbers (Work Package 5) rose to 500 and 154 respectively. In Work Package 6, the WP-lead and team at UMCU published their preparatory work in a peer reviewed publica-tion and rendered technical support to all other partners in providing imaging to the central database. aEEG evaluation and analysis has also successfully started under Work Package 7 during period 3 and will continue as more data is being collected. The pharmacokinetics part and analysis of the ALBINO-trial (Work Package 8) has nearly been completed by the WP-lead at KULEUVEN and cooperation partners UMCU and ACEPHARM. The first results of the PK-analysis will be presented to the scientific community and then submitted for peer reviewed publication. A state-of-the-art pharmacovigilance (Work Package 9) is in place and has taken care of safety reporting and all potentially occurring safety issues. The first Devel-opmental Safety Update Reports (DSURs) during the course of the ALBINO trial have been submitted to the national authorities. Finally, major dissemination activities carried out under Work Package 10 consisted in two peer reviewed scientific publications and a professional information video available on the study website (www.albino-study.eu).
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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