Periodic Reporting for period 7 - ALBINO (Effect of ALlopurinol in addition to hypothermia for hypoxic-ischemic Brain Injury on Neurocognitive Outcome)
Période du rapport: 2024-07-01 au 2025-06-30
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.
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.
During RP7, the last reporting period of the ALBINO project, many tasks and activities were ongoing at high intensity, even if patient recruitment in the clinical trial had been stopped al-ready during the previous period. Work Package 1 (Project Management and Coordination) was ongoing to bring all reports and Deliverables to successful completion and to ensure communication within the Consortium and the European Commission. While manufacturing and shipping of study medication had already been completed, the focus in Work Package 2 was on data completion of drug accountability and destruction of study medication in compli-ance with GCP-requirements. Similarly, while many important tasks in Work Package 3 had been successfully completed, study coordination efforts had to continue until the end, as clin-ical sites in all countries were constantly informed and updated on remaining To-dos towards study data completion and follow-up. Work Package 4 (Data Management, Biometry and Monitoring) was the busiest work package during period 7, both at central study level and at national levels. Here, all monitoring teams worked hard to achieve the highest level of data completion possible, with a particular focus on queries and follow-up data. Besides, monitors closed as many study sites as possible. With performance of an interim analysis and, subse-quently, the end of patient recruitment during the previous reporting period, activities in Work Package 5 (Patient Recruitment and Outcome Assessment) consisted in continued perfor-mance 2-year follow-up examinations, outcome assessment, and preparatory work for the final analysis which will take place in 2026 after the last patients have undergone clinical follow-up. Work package 6 (Magnetic Resonance Imaging and Analysis) could report a major success with the establishment of a dataset of 392 MRI files collected and centrally assessed. Similar-ly, Work Package 7 could report a set of 448 (a)EEG files uploaded in the study database and near to complete central reading. Work Package 8 (Pharmacokinetics) had been successfully completed during previous periods and results published in 3 peer reviewed publications but (outside of EU-funding) additional research activities on pharmacokinetics during therapeutic hypothermia were ongoing and supported with remnant blood/plasma samples from the AL-BINO trial. Furthermore, the pharmacovigilance system (Work Packages 9) had been running successfully over the trial with all reporting obligations to regulatory authorities having been fulfilled up to now – pharmacovigilance activities will of course be ongoing until the last pa-tient completed the trial (Last Patient Last Visit). Activities in Work Package 10 included updates on the ALBINO-website and successful publication of preliminary works on auto-mated EEG analyses. Major further dissemination activities are planned after completion and final analysis of the clinical trial – as required by good scientific practice.
In total, it can be stated at the end of the EU-funding period lasting from January 2016 to June 2025, this large scale multi centre, multinational clinical trial involving 87 sites from 10 countries was successfully implemented by the ALBINO-consortium. With 506 patients in-cluded, it could not quite reach the envisaged recruitment goals, due to the extremely complex inclusion in an emergency situation and due to the very vulnerable study population. However, taking into account the successful completion of pharmacokinetics, as well as the compre-hensive MRI and EEG imaging datasets, the results of the ALBINO-trial can yield meaning-ful insights for science and also towards paediatric drug development in the future.
In total, it can be stated at the end of the EU-funding period lasting from January 2016 to June 2025, this large scale multi centre, multinational clinical trial involving 87 sites from 10 countries was successfully implemented by the ALBINO-consortium. With 506 patients in-cluded, it could not quite reach the envisaged recruitment goals, due to the extremely complex inclusion in an emergency situation and due to the very vulnerable study population. However, taking into account the successful completion of pharmacokinetics, as well as the compre-hensive MRI and EEG imaging datasets, the results of the ALBINO-trial can yield meaning-ful insights for science and also towards paediatric drug development in the future.
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
- 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