Periodic Reporting for period 5 - ALBINO (Effect of ALlopurinol in addition to hypothermia for hypoxic-ischemic Brain Injury on Neurocognitive Outcome)
Berichtszeitraum: 2021-07-01 bis 2022-12-31
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.
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 the fifth period, the ALBINO-project as a whole and the clinical trial were up and running. Project management (WP1) focused on reporting obligations and regular exchange among the consortium members in monthly video meetings. One amendment to the Consortium Agreement was prepared. Ordering and distribution of study medication (WP2) to a large number of study sites in 11 countries continued smoothly. Efforts to recruit and open further study centres in WP3 resulted in 11 new study centres from four countries joining the clinical trial. With an increasing number of study patients entering the stage of clinical follow-up, data management and monitoring in WP4 have been focussing on training and development of information related to the clinical follow-up phase, while routine remote monitoring and on-site visits have been ongoing at the same time. Patient screening and recruitment efforts by all sites in WP5 during the 5th period reached 565 (screened) and 135 (included in the trial), bringing total recruitment sibnce the beginning of the trial to 1527 screened and 396 randomized patients. Central reading and scoring of MRI (WP6) and EEG (WP7) imaging had been established during previous reporting periods and were proceeding well during the fifth reporting period alt-hough uploading of imaging files has been slightly lagging behind overall patient recruitment. The Coordinator in close collaboration with WP 6 and 7 leads has launched an assessment and measures to shorten the time gab between data entry and uploading of imaging data. The pharmacokinetic analyses of both Allopurinol and Mannitol (placebo) have been completed, and the results were published in two additional peer-reviewed articles in Clinical Pharmacokinetics. Work in WP 9 (Pharmacovigilance of the clinical trial) consisted in routine safety reporting as requested by the regulatory authorities. Dissemination activities in WP 10 were focussed on presentation and publication of the results in WP 8 to the scientific community.
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