ALBINO: Effect of Allopurinol for Hypoxic-ischemic Brain Injury on Neurocognitive Outcome

Sponsor

University Hospital Tuebingen (Other)

Overall Status

Recruiting

CT.gov ID

NCT03162653

Collaborator

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 (Other), Helsingin Ja Uudenmaan Sairaanhoitopiirin (Other), University of Helsinki (Other), Poznan University of Medical Sciences (Other), Tartu University Hospital (Other), ACE Pharmaceuticals BV (Other)

846

Enrollment

Locations

Arms

86.2

Anticipated Duration (Months)

70.5

Patients Per Site

0.8

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Encephalopathy, Hypoxic-Ischemic Infant, Newborn, Diseases	Drug: Allopurinol Drug: Mannitol	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

846 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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)

Actual Study Start Date :

Mar 25, 2018

Anticipated Primary Completion Date :

Jun 1, 2025

Anticipated Study Completion Date :

Jun 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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.	Drug: 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 Comparator: 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.	Drug: 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)).

Arm

Intervention/Treatment

Active Comparator: 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.

Drug: Allopurinol

Placebo Comparator: 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.

Drug: 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)).

Outcome Measures

Primary Outcome Measures

death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment [at the age of 24 months]
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]. Primary endpoint will be analyzed in the two treatment groups by chi-square omnibus test with three possible exclusive outcomes (healthy, death, composite outcome for impairment) and post-hoc testing in case of revealing a p-value < 0.05 within the omnibus test [Engel and Franz IJSMR 2016].

Secondary Outcome Measures

Death or neurodevelopmental impairment (NDI) [at 24months]
survival without NDI versus Death or language-composite-score < 85 or cognitive-composite-score <85 or cerebral palsy - analysed by Cochrane-Mantel-Haenzel- X²-Test
Incidence of Death [at 24 months]
Incidence of CP [at 24 months]
Incidence of CP according to SCPE criteria [SCPE Dev Med Child Neurol 2000]
GMFCS-score [at 24 months]
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.
Motor-Composite-Score (Bayley III) [at 24 months]
The numerical data of the motor-composite-score.
Motor-Composite-Score dichotomised (Bayley III) [at 24 months]
The motor-composite-score will be dichotomised at the cut-off <85 versus ≥85
Cognitive-Composite-Score (cognitive subscale, Bayley III) [at 24 months]
The numerical data of the cognitive-composite-score.
Cognitive-Composite-Score dichotomised (cognitive subscale, Bayley III) [at 24 months]
The cognitive-composite-score will be dichotomised at the cut-off <85 versus ≥85
Language-Composite-Score (language subscale, Bayley III) [at 24 months]
The raw numerical data of the language-composite-score.
Language-Composite-Score dichotomised (language subscale, Bayley III) [at 24 months]
The language-composite-score will be dichotomised at the cut-off <85 versus ≥85

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 45 Minutes

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Medizinische Universitaet Wien	Wien	Austria	1090
2	Katholieke Universiteit Leuven	Leuven	Belgium	3000
3	Tartu Ulikool	Tartu	Estonia	50090
4	Helsingin Ja Uudenmaan Sairaanhoitopiirin Kuntayhtymä	Helsinki	Finland	00029
5	University Hospital Tübingen	Tübingen	Germany	72076
6	Universita Degli Studi Di Udine	Udine	Italy	33100
7	Universitair Medisch Centrum Utrecht	Utrecht	Netherlands	3584 CX
8	Oslo Universitetssykehus Hf	Oslo	Norway	0450
9	Uniwersytet Medyczny Im Karola Marcinkowskiego W Poznaniu	Poznań	Poland	61701
10	Universidade Do Porto	Porto	Portugal	4099 002
11	Para La Investigacion Del Hospital UniversitarioLa Fe De La Comunidad Valenciana	Valencia	Spain	46026
12	Universitaet Zuerich	Zuerich	Switzerland	8006

Sponsors and Collaborators

University Hospital Tuebingen
Technische Universität Dresden
UMC Utrecht
KU Leuven
University of Zurich
University of Vienna
Fundación para la Investigación del Hospital Clínico de Valencia
Universidade do Porto
Oslo University Hospital
Università degli Studi di Udine
Helsingin Ja Uudenmaan Sairaanhoitopiirin
University of Helsinki
Poznan University of Medical Sciences
Tartu University Hospital
ACE Pharmaceuticals BV

Investigators

Study Director: Axel Franz, Prof. Dr., University Children's Hospital Tuebingen
Principal Investigator: Rüdiger Mario, Prof. Dr., University Children's Hospital Dresden