Periodic Reporting for period 4 - ALBINO (Effect of ALlopurinol in addition to hypothermia for hypoxic-ischemic Brain Injury on Neurocognitive Outcome) Reporting period: 2020-07-01 to 2021-06-30 Summary of the context and overall objectives of the project 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. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far Despite the impact of the COVID-19 pandemic on trial performance and project implementation in general, good progress and some crucial achievements can be reported for the ALBINO project during the 4th reporting period. While project management (Work Package 1) and study medication manufacturing and distribution (Work Package 2) have been well estab-lished and ongoing, recruitment and activation of clinical sites (Work Package3) could be fur-ther expanded. At the end of this reporting period 73 clinical sites in 10 countries have received Sponsor’s “green light” for recruitment. 60 of these centers have already started screening patients, and 50 have already included at least one patient. Thus, national and central monitoring to assure supervision of and support centers in data entry (Work Package 4) was also performed at high intensity. In Work Package 5, the number of patients screened for inclusion almost doubled from 500 at the end of the 3rd reporting period to 962 at the end of the 4th period. The number of patients fully randomized and included in the ALBINO-trial rose from 154 to 261. Progress in patient recruitment hat positive effects on data collection activities in Work packages 6 and 7. Meanwhile, 133 MRI-recordings and 289 aEEG or mchEEG-recordings have been uploaded for central reading and analysis by the WP6 and WP 7 teams. Work Package 8 was nearly completed during the 3rd reporting period. During period 4, efforts in Work Package 8 were dedicated to publish/disseminate the results. One paper (on the placebo) was successfully published in “Clinical Pharmacokinetics”, while a second article on Allopurinol was submitted for publication ( second revision of the manuscript being currently considered by the journal). The teams and partners involved in Pharmacovigilance duties (Work Package 9) carried out the requested safety supervision and reporting duties (the 3rd Developmental Safety Update Report DSUR 2020 was submitted to national authorities and Ethics Committees in September 2020). Besides scientific publications, dissemination and communication activities (Work Package 10) were limited due to the pandemic, and, where possible, took place in online formats. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) 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 Official project logo
