Clinical trial NCT03162653: Effect of Allopurinol for Hypoxic-ischemic Brain Injury on Neurocognitive Outcome
Official title: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Encephalopathy, Hypoxic-Ischemic
Infant, Newborn, Diseases
Keywords: Allopurinol
hypothermia therapy
hypoxic-ischemic encephalopathy
neonatal oxygen deficiency
childbirth outcome
perinatal asphyxia
Lead sponsor: University Hospital Tuebingen
Sponsor class: OTHER
Collaborators: name: Technische Universität Dresden
name: UMC Utrecht
name: KU Leuven
name: University of Zurich
name: University of Vienna
name: Fundación para la Investigación del Hospital Clínico de Valencia
name: Universidade do Porto
name: Oslo University Hospital
name: Università degli Studi di Udine
name: Helsingin Ja Uudenmaan Sairaanhoitopiirin
name: University of Helsinki
name: Poznan University of Medical Sciences
name: Tartu University Hospital
name: ACE Pharmaceuticals BV
First posted: 2017-05-22
Enrollment: 760
Sex: ALL
Maximum age (years): 45
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Neonatal hypoxic-ischemic encephalopathy (HIE) 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.

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.

Detailed description: During labour and childbirth various events (such as placental abruption, uterine rupture, umbilical cord complications etc.) may result in impaired oxygenation and/or perfusion of the newborn brain which may result in brain injury termed "hypoxic-ischemic encephalopathy" (HIE). HIE is associated with development of long-term motor, cognitive, and neurosensory and memory disability and is one of the fundamental problems in perinatal medicine affecting about 5,000-20,000 infants/year in Europe (or 1-4/1000 live births in western societies) and approximately 1 million infants/year worldwide.

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.

Eligibility criteria: Inclusion criteria

Term and near-term infants with a history of disturbed labour who meet at least one criterion of perinatal acidosis (or ongoing resuscitation) and at least two early clinical signs of potentially evolving encephalopathy as defined herein:

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

* gestational age below 36 weeks
* 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

Primary outcomes:
measure: death versus severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment
timeFrame: at the age of 24 months
Secondary outcomes:
measure: Death or neurodevelopmental impairment (NDI)
timeFrame: at 24months
measure: Incidence of Death
timeFrame: at 24 months
measure: Incidence of CP
timeFrame: at 24 months
measure: GMFCS-score
timeFrame: at 24 months
measure: Motor-Composite-Score (Bayley III)
timeFrame: at 24 months
measure: Motor-Composite-Score dichotomised (Bayley III)
timeFrame: at 24 months
measure: Cognitive-Composite-Score (cognitive subscale, Bayley III)
timeFrame: at 24 months
measure: Cognitive-Composite-Score dichotomised (cognitive subscale, Bayley III)
timeFrame: at 24 months
measure: Language-Composite-Score (language subscale, Bayley III)
timeFrame: at 24 months
measure: Language-Composite-Score dichotomised (language subscale, Bayley III)
timeFrame: at 24 months
Other outcomes:
Locations:
city: Wien
country: Austria
facility: Medizinische Universitaet Wien
city: Leuven
country: Belgium
facility: Katholieke Universiteit Leuven
city: Tartu
country: Estonia
facility: Tartu Ulikool
city: Helsinki
country: Finland
facility: Helsingin Ja Uudenmaan Sairaanhoitopiirin Kuntayhtymä
city: Tübingen
country: Germany
facility: University Hospital Tübingen
city: Udine
country: Italy
facility: Universita Degli Studi Di Udine
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Oslo
country: Norway
facility: Oslo Universitetssykehus Hf
city: Poznań
country: Poland
facility: Uniwersytet Medyczny Im Karola Marcinkowskiego W Poznaniu
city: Porto
country: Portugal
facility: Universidade Do Porto
city: Valencia
country: Spain
facility: Para La Investigacion Del Hospital UniversitarioLa Fe De La Comunidad Valenciana
city: Zuerich
country: Switzerland
facility: Universitaet Zuerich
Study officials:
affiliation: University Children's Hospital Tuebingen
name: Axel Franz, Prof. Dr.
role: STUDY_DIRECTOR
affiliation: University Children's Hospital Dresden
name: Rüdiger Mario, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.