A Phase 3 interventional study of Allopurinol and Mannitol in Encephalopathy, Hypoxic-Ischemic and Infant, Newborn, Diseases, sponsored by University Hospital Tuebingen. Recruiting at 12 sites in 12 countries. Open to participants aged Up to 45 Minutes. Per ClinicalTrials.gov, last updated 2023-07-11.
Sponsored by University Hospital Tuebingen · Phase 3, Interventional, and Treatment
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.
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.
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
Early clinical signs of potentially evolving encephalopathy:
At least 2 out of the following 4 criteria must be met:
Exclusion criteria
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.
Drug: Allopurinol
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.
Drug: Mannitol
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, 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)).
death versus severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment
Where severe neurodevelopmental impairment is defined as any of the following: cognitive or language delay defined as a cognitive-composite-score or a language-composite-score on the Bayley Scales of Infant and Toddler Development (3rd edition) \< 85 and/or cerebral palsy (CP) according to SCPE criteria \[SCPE Dev Med Child Neurol 2000\]. In case of missing Bayley III test results, Bayley II or other developmental test results or PARCA-R parent questionnaire results may substitute for the Bayley III test result in a predefined hierarchical order. Primary endpoint with three mutually exclusive responses (healthy, death, composite outcome for impairment) will be analyzed in the two treatment groups by a generalized logits model according to Bishop, Fienberg, Holland 1975 with SAS 9.4 procedure proc catmod.
Time frame: at the age of 24 months
Death or neurodevelopmental impairment (NDI)
The primary endpoint will be reconstituted as dichotomised composite secondary endpoint (survival without NDI versus Death or language-composite-score \< 85 or cognitive-composite score \<85 or cerebral palsy present). In case of missing Bayley III test results, Bayley II or other developmental test results or PARCA-R parent questionnaire results may substitute for the Bayley III test result in a predefined hierarchical order. This will be analyzed by Cochrane-Mantel-Haenszel- X²-Test.
Time frame: at 24months
Incidence of Death
Incidence of death will be analyzed by Cochrane-Mantel-Haenszel- X²-Test.
Time frame: at 24 months
Incidence of CP
Incidence of CP according to SCPE criteria \[SCPE Dev Med Child Neurol 2000\] will be analyzed by Cochrane-Mantel-Haenszel- X²-Test.
Time frame: at 24 months
GMFCS-score
GMFCS-Score for quantification of the effects of cerebral palsy and other motor impairments (adapted from Palisano et al. \[Palisano Med Child Neurol 1997\]) using the ALBINO-GMFCS-score sheet will be analysed. GMFCS-score consists of six categories. Analysis will be done by using Wilcoxon-Mann-Whitney test.
Time frame: at 24 months
Motor-Composite-Score (Bayley III)
The numerical data of the motor-composite-score will be analysed using Wilcoxon-Mann-Whitney test. The use of this test accounts for the fact that data will be cut due to lack of sensitivity below 50 points.
Time frame: at 24 months
Motor-Composite-Score dichotomised (Bayley III)
The motor-composite-score will be dichotomised at the cut-off \<85 versus ≥85 and analysed by Cochrane-Mantel-Haenszel- X²-Test.
Time frame: at 24 months
Cognitive-Composite-Score (cognitive subscale, Bayley III)
The numerical data of the cognitive-composite-score will be analysed using Wilcoxon-Mann-Whitney test. The use of this test accounts for the fact that data will be cut due to lack of sensitivity below 50 points.
Time frame: at 24 months
Cognitive-Composite-Score dichotomised (cognitive subscale, Bayley III)
The cognitive-composite-score will be dichotomised at the cut-off \<85 versus ≥85 and analysed by Cochrane-Mantel-Haenszel- X²-Test.
Time frame: at 24 months
Language-Composite-Score (language subscale, Bayley III)
The raw numerical data of the language-composite-score will be analysed using Wilcoxon Mann-Whitney test. The use of this test accounts for the fact that data will be cut due to lack of sensitivity below 50 points.
Time frame: at 24 months
Language-Composite-Score dichotomised (language subscale, Bayley III)
The language-composite-score will be dichotomised at the cut-off \<85 versus ≥85 and analysed by Cochrane-Mantel-Haenszel- X²-Test
Time frame: at 24 months
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University Hospital Tuebingen