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

NCT03162653 | Unknown Phase 3 DMC

• 2 other identifiers: ALBINO2016-000222-19
• Study Type: interventional
• Target: 760
• Locations: 11 countries
• Sites: 11

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.

Conditions

Encephalopathy, Hypoxic-Ischemic; Infant, Newborn, Diseases

Keywords

Allopurinol; hypothermia therapy; hypoxic-ischemic encephalopathy; neonatal oxygen deficiency; childbirth outcome; perinatal asphyxia

Outcome Measures

Primary Outcomes (1)

• 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.

  at the age of 24 months

Secondary Outcomes (10)

• Death or neurodevelopmental impairment (NDI)

  at 24months

• Incidence of Death

  at 24 months

• Incidence of CP

  at 24 months

• GMFCS-score

  at 24 months

• Motor-Composite-Score (Bayley III)

  at 24 months

Study Arms (2)

Allopurinol

ACTIVE COMPARATOR

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

PLACEBO COMPARATOR

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

Interventions

Allopurinol DRUG

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

Mannitol DRUG

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)).

Placebo

Eligibility Criteria

• Age: Up to 45 Minutes
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

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

Study Sites (12)

Medizinische Universitaet Wien

Vienna, 1090, Austria

RECRUITING

Katholieke Universiteit Leuven

Leuven, 3000, Belgium

RECRUITING

Tartu Ulikool

Tartu, 50090, Estonia

RECRUITING

Helsingin Ja Uudenmaan Sairaanhoitopiirin Kuntayhtymä

Helsinki, 00029, Finland

RECRUITING

University Hospital Tübingen

Tübingen, 72076, Germany

RECRUITING

Universita Degli Studi Di Udine

Udine, 33100, Italy

RECRUITING

Universitair Medisch Centrum Utrecht

Utrecht, 3584 CX, Netherlands

RECRUITING

Oslo Universitetssykehus Hf

Oslo, 0450, Norway

RECRUITING

Uniwersytet Medyczny Im Karola Marcinkowskiego W Poznaniu

Poznan, 61701, Poland

WITHDRAWN

Universidade Do Porto

Porto, 4099 002, Portugal

WITHDRAWN

Para La Investigacion Del Hospital UniversitarioLa Fe De La Comunidad Valenciana

Valencia, 46026, Spain

RECRUITING

Universitaet Zuerich

Zurich, 8006, Switzerland

RECRUITING

Related Publications (4)

• 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.

  PMID: 31248390 BACKGROUND

• 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.

  PMID: 28925896 BACKGROUND

• 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.

  PMID: 33611729 BACKGROUND

• 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.

  PMID: 38267942 DERIVED

Related Links

• official study homepage

MeSH Terms

Conditions

Hypoxia-Ischemia, Brain; Infant, Newborn, Diseases

Interventions

Allopurinol; Mannitol

Condition Hierarchy (Ancestors)

Brain Ischemia; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hypoxia, Brain; Vascular Diseases; Cardiovascular Diseases; Hypoxia; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Sugar Alcohols; Alcohols; Organic Chemicals; Carbohydrates

Study Officials

• Axel Franz, Prof. Dr.

  University Children's Hospital Tuebingen

  STUDY DIRECTOR

• Rüdiger Mario, Prof. Dr.

  University Children's Hospital Dresden

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Oldershausen Gabriele

CONTACT

+49 7071 29-86176; Albino@med.uni-tuebingen.de

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 18, 2017
• First Posted: May 22, 2017
• Study Start: March 25, 2018
• Primary Completion: January 31, 2026
• Study Completion: January 31, 2026
• Last Updated: July 11, 2023

Record last verified: 2023-07

Locations

NO (1); CH (1); ES (1); PL (1); FI (1); NL (1); IT (1); BE (1); PT (1); AU (1); DE (1)