Effect of Allopurinol for Hypoxic-ischemic Brain Injury on Neurocognitive Outcome
NCT ID: NCT03162653
Last Updated: 2023-07-11
Study Results
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Basic Information
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RECRUITING
PHASE3
760 participants
INTERVENTIONAL
2018-03-25
2026-01-31
Brief Summary
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Hypothermic treatment became the only established therapy to improve outcome after perinatal hypoxic-ischemic insults. Despite hypothermia and neonatal intensive care, 45-50% of affected children die or suffer from long-term neurodevelopmental impairment. Additional neuroprotective interventions, beside hypothermia, are warranted to further improve their outcome.
Allopurinol is a xanthine oxidase inhibitor and reduces the production of oxygen radicals and brain damage in experimental, animal, and early human studies of ischemia and reperfusion.
This project aims to evaluate the efficacy and safety of allopurinol administered immediately after birth to near-term infants with HIE in addition to hypothermic treatment.
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Detailed Description
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In term infants with perinatal asphyxia and postnatal HIE, brain injury predominantly originates in the immediate perinatal period (in contrast to a more distant prenatally acquired brain injury) as indicated by the lack of already established brain injury on early postnatal MRI. Consequently, brain injury in this population may potentially be ameliorated by postnatal pharmacological interventions.
The most common motor disability resulting from HIE is "cerebral palsy", the other major adverse outcome is cognitive disability, which prevents affected patients to lead their lives independently (without assistance and/or financial support).
The single major cause of HIE is a perinatal hypoxic/ischemic event (perinatal asphyxia). This hypoxic insult can cause immediate (necrosis) and delayed death (apoptosis) of (especially neuronal) cells, the latter responsible for a substantial amount of HIE-associated permanent brain damage. Whereas no intervention is known to prevent necrosis, the delayed cell death by apoptosis can be reduced by therapeutic interventions: Apoptosis is in part caused by secondary energy failure which can be reduced by hypothermic treatment.
Apoptosis is also caused by xanthine oxidase-mediated production of cytotoxic oxygen radicals during reperfusion, and there is evidence that allopurinol, a xanthine-oxidase inhibitor, reduces delayed cell death in animal models of perinatal asphyxia and ischemia/reperfusion.
Allopurinol prevents adenosine degradation, oxygen radical formation, preserves NMDA receptor integrity, and consequently may reduce brain injury in HIE by several mechanisms of action which are independent from the proven beneficial effect of hypothermic treatment on cellular energy metabolism. An additional beneficial (or even synergistic?) effect of allopurinol in addition to hypothermia can therefore be expected.
As no safety concerns were known at the start of this study regarding administration of even high doses of Allopurinol to neonates a phase III study was planned instead of a pilot study or an adaptive design. Close follow-up of MR-imaging along with reporting of all safety relevant data to a Data Monitoring Committee (which includes experts for brain imaging not otherwise involved in the study) ensures patients' safety.
Primary objective of this study is to evaluate whether newborns with asphyxia and early clinical signs of hypoxic ischemic encephalopathy will benefit from early administered Allopurinol compared to placebo, both in addition to standard of care, regarding long-term follow-up such as severe neurodevelopmental impairment or death at two years.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Allopurinol
Allopurinol, powder for injection (PFI), administered in two doses. First dose (20 mg/kg in 2ml/kg sterile water for injection) given as soon as intravenous access is established and no later than 30min postnatally and second dose (10mg/kg in 1ml/kg sterile water for injection) 12 hours thereafter. The second dose will only be administered to in infants on therapeutic hypothermia. Infants who recover quickly and do not qualify for and hence do not undergo hypothermia will not receive a second dose. Administration will be by continuous infusion using a syringe pump over 10min through secure venous access.
Allopurinol
Allopurinol, powder for injection (PFI), administered in two doses. First dose (20 mg/kg in 2ml/kg sterile water for injection) given as soon as intravenous access is established and no later than 30min postnatally and second dose (10mg/kg in 1ml/kg sterile water for injection) 12 hours thereafter. The second dose will only be administered to in infants on therapeutic hypothermia. Infants who recover quickly and do not qualify for and hence do not undergo hypothermia will not receive a second dose. Administration will be by continuous infusion using a syringe pump over 10min through secure venous access.
Placebo
mannitol, powder for injection (PFI), administered in two doses. First dose (20 mg/kg in 2ml/kg sterile water for injection) given as soon as intravenous access is established and no later than 30min postnatally and second dose (10mg/kg in 1ml/kg sterile water for injection) 12 hours thereafter. The second dose will only be administered to in infants on therapeutic hypothermia. Infants who recover quickly and do not qualify for and hence do not undergo hypothermia will not receive a second dose. Administration will be by continuous infusion using a syringe pump over 10min through secure venous access.
Mannitol
Placebo (Mannitol, PFI, 20mg/kg in the same volume and at the same time intervals as the intervention group - (2nd dose 10mg/kg only if infant undergoes therapeutic hypothermia)).
Interventions
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Allopurinol
Allopurinol, powder for injection (PFI), administered in two doses. First dose (20 mg/kg in 2ml/kg sterile water for injection) given as soon as intravenous access is established and no later than 30min postnatally and second dose (10mg/kg in 1ml/kg sterile water for injection) 12 hours thereafter. The second dose will only be administered to in infants on therapeutic hypothermia. Infants who recover quickly and do not qualify for and hence do not undergo hypothermia will not receive a second dose. Administration will be by continuous infusion using a syringe pump over 10min through secure venous access.
Mannitol
Placebo (Mannitol, PFI, 20mg/kg in the same volume and at the same time intervals as the intervention group - (2nd dose 10mg/kg only if infant undergoes therapeutic hypothermia)).
Eligibility Criteria
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Inclusion Criteria
Severe perinatal metabolic acidosis or ongoing cardiopulmonary resuscitation at 5 min after birth:
At least 1 out of the following 5 criteria must be met
* Umbilical (or arterial or reliable venous) blood gas within 30 min after birth with pH\<7.0
* Umbilical (or arterial or reliable venous) blood gas within 30 min after birth with base deficit ≥16 mmol/l
* Need for ongoing cardiac massage at/beyond 5 min postnatally
* Need for adrenalin administration during resuscitation
* APGAR score ≤5 at 10min AND
Early clinical signs of potentially evolving encephalopathy:
At least 2 out of the following 4 criteria must be met:
* Altered state of consciousness (reduced or absent response to stimulation or hyperexcitability)
* Severe muscular hypotonia or hypertonia,
* Absent or insufficient spontaneous respiration (e.g., gasping only) with need for respiratory support at 10 min postnatally
* Abnormal primitive reflexes (absent suck or gag or corneal or Moro reflex) or abnormal movements (e.g., potential clinical correlates of seizure activity)
Exclusion Criteria
* birth weight below 2500 g
* postnatal age \>30min at the end of screening phase
* severe congenital malformation or syndrome requiring neonatal surgery or affecting long-term outcome
* patient considered "moribund" / "non-viable" (e.g., lack of spontaneous cardiac activity and ongoing chest compression at 30min)
* decision for "comfort care only" before study drug administration
* parents declined study participation as response to measures of community engagement
* both parents are insufficiently fluent in the study site's national language(s) or English or do not seem to have the intellectual capacity to understand the study procedures and to give consent as judged by the personnel who had been in contact with the mother/father before delivery.
* both parents/guardians less than 18 years of age, in case of single parent/guardian this one less than 18 years of age
45 Minutes
ALL
No
Sponsors
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Technische Universität Dresden
OTHER
UMC Utrecht
OTHER
KU Leuven
OTHER
University of Zurich
OTHER
University of Vienna
OTHER
Fundación para la Investigación del Hospital Clínico de Valencia
OTHER
Universidade do Porto
OTHER
Oslo University Hospital
OTHER
Università degli Studi di Udine
UNKNOWN
Helsingin Ja Uudenmaan Sairaanhoitopiirin
UNKNOWN
University of Helsinki
OTHER
Poznan University of Medical Sciences
OTHER
Tartu University Hospital
OTHER
ACE Pharmaceuticals BV
OTHER
University Hospital Tuebingen
OTHER
Responsible Party
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Principal Investigators
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Axel Franz, Prof. Dr.
Role: STUDY_DIRECTOR
University Children's Hospital Tuebingen
Rüdiger Mario, Prof. Dr.
Role: PRINCIPAL_INVESTIGATOR
University Children's Hospital Dresden
Locations
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Medizinische Universitaet Wien
Vienna, , Austria
Katholieke Universiteit Leuven
Leuven, , Belgium
Tartu Ulikool
Tartu, , Estonia
Helsingin Ja Uudenmaan Sairaanhoitopiirin Kuntayhtymä
Helsinki, , Finland
University Hospital Tübingen
Tübingen, , Germany
Universita Degli Studi Di Udine
Udine, , Italy
Universitair Medisch Centrum Utrecht
Utrecht, , Netherlands
Oslo Universitetssykehus Hf
Oslo, , Norway
Uniwersytet Medyczny Im Karola Marcinkowskiego W Poznaniu
Poznan, , Poland
Universidade Do Porto
Porto, , Portugal
Para La Investigacion Del Hospital UniversitarioLa Fe De La Comunidad Valenciana
Valencia, , Spain
Universitaet Zuerich
Zurich, , Switzerland
Countries
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Central Contacts
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Facility Contacts
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Katrin Klebermaß-Schrehof, Assoz. Prof.
Role: primary
Karel Allegaert, Prof. Dr.
Role: primary
Gunnar Naulaers, Prof. Dr.
Role: backup
Renata Poláčková, Prof. Dr.
Role: primary
Marjo Metsäranta, Dr.
Role: primary
Isabella Mauro, MD
Role: primary
Manon Benders, Prof. MD PhD
Role: primary
Tom Stiris, Prof. MD PhD
Role: primary
Maximo Vento, Prof. MD PhD
Role: primary
Dirk Bassler, Prof. Dr.
Role: primary
References
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Maiwald CA, Annink KV, Rudiger M, Benders MJNL, van Bel F, Allegaert K, Naulaers G, Bassler D, Klebermass-Schrehof K, Vento M, Guimaraes H, Stiris T, Cattarossi L, Metsaranta M, Vanhatalo S, Mazela J, Metsvaht T, Jacobs Y, Franz AR; ALBINO Study Group. Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic-ischemic brain injury on neurocognitive outcome (ALBINO): study protocol of a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III). BMC Pediatr. 2019 Jun 27;19(1):210. doi: 10.1186/s12887-019-1566-8.
Annink KV, Franz AR, Derks JB, Rudiger M, Bel FV, Benders MJNL. Allopurinol: Old Drug, New Indication in Neonates? Curr Pharm Des. 2017;23(38):5935-5942. doi: 10.2174/1381612823666170918123307.
Deferm N, Annink KV, Faelens R, Schroth M, Maiwald CA, Bakkali LE, van Bel F, Benders MJNL, van Weissenbruch MM, Hagen A, Smits A, Annaert P, Franz AR, Allegaert K; ALBINO Study Group. Glomerular Filtration Rate in Asphyxiated Neonates Under Therapeutic Whole-Body Hypothermia, Quantified by Mannitol Clearance. Clin Pharmacokinet. 2021 Jul;60(7):897-906. doi: 10.1007/s40262-021-00991-6. Epub 2021 Feb 21.
Engel C, Rudiger M, Benders MJNL, van Bel F, Allegaert K, Naulaers G, Bassler D, Klebermass-Schrehof K, Vento M, Vilan A, Falck M, Mauro I, Metsaranta M, Vanhatalo S, Mazela J, Metsvaht T, van der Vlught R, Franz AR; ALBINO Study Group. Detailed statistical analysis plan for ALBINO: effect of Allopurinol in addition to hypothermia for hypoxic-ischemic Brain Injury on Neurocognitive Outcome - a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III). Trials. 2024 Jan 24;25(1):81. doi: 10.1186/s13063-023-07828-6.
Related Links
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official study homepage
Other Identifiers
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2016-000222-19
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
ALBINO
Identifier Type: -
Identifier Source: org_study_id
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