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

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ClinicalTrials.gov Identifier: NCT03162653
Recruitment Status : Recruiting
First Posted : May 22, 2017
Last Update Posted : May 10, 2018
Sponsor:
Collaborators:
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
Helsinki University
University Hospital Ostrava
Poznan University of Medical Sciences
Tartu University Hospital
ACE Pharmaceuticals BV
Information provided by (Responsible Party):
University Hospital Tuebingen

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 Type : Interventional  (Clinical Trial)
Estimated 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 : March 25, 2018
Estimated Primary Completion Date : November 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: 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
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)).




Primary Outcome Measures :
  1. death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment [ Time Frame: 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 :
  1. Death or neurodevelopmental impairment (NDI) [ Time Frame: 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

  2. Incidence of Death [ Time Frame: at 24 months ]
  3. Incidence of CP [ Time Frame: at 24 months ]
    Incidence of CP according to SCPE criteria [SCPE Dev Med Child Neurol 2000]

  4. GMFCS-score [ Time Frame: 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.

  5. Motor-Composite-Score (Bayley III) [ Time Frame: at 24 months ]
    The numerical data of the motor-composite-score.

  6. Motor-Composite-Score dichotomised (Bayley III) [ Time Frame: at 24 months ]
    The motor-composite-score will be dichotomised at the cut-off <85 versus ≥85

  7. Cognitive-Composite-Score (cognitive subscale, Bayley III) [ Time Frame: at 24 months ]
    The numerical data of the cognitive-composite-score.

  8. Cognitive-Composite-Score dichotomised (cognitive subscale, Bayley III) [ Time Frame: at 24 months ]
    The cognitive-composite-score will be dichotomised at the cut-off <85 versus ≥85

  9. Language-Composite-Score (language subscale, Bayley III) [ Time Frame: at 24 months ]
    The raw numerical data of the language-composite-score.

  10. Language-Composite-Score dichotomised (language subscale, Bayley III) [ Time Frame: at 24 months ]
    The language-composite-score will be dichotomised at the cut-off <85 versus ≥85



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 45 Minutes   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03162653


Contacts
Contact: Oldershausen Gabriele +49 7071 29-86176 Albino@med.uni-tuebingen.de

Locations
Austria
Medizinische Universitaet Wien Active, not recruiting
Wien, Austria, 1090
Belgium
Katholieke Universiteit Leuven Active, not recruiting
Leuven, Belgium, 3000
Estonia
Tartu Ulikool Not yet recruiting
Tartu, Estonia, 50090
Contact: Renata Poláčková, Prof. Dr.         
Finland
Helsingin Ja Uudenmaan Sairaanhoitopiirin Kuntayhtymä Active, not recruiting
Helsinki, Finland, 00029
Germany
University Hospital Tübingen Recruiting
Tübingen, Germany, 72076
Contact: Axel R Franz, MD    +49707129 ext 0    albino@med.uni-tuebingen.de   
Contact: Gabriele von Oldershausen    +49707129 ext 0    albino@med.uni-tuebingen.de   
Principal Investigator: Axel R Franz, MD         
Sub-Investigator: Christian Maiwald, MD         
Sub-Investigator: Jörg Arand, MD         
Italy
Universita Degli Studi Di Udine Active, not recruiting
Udine, Italy, 33100
Netherlands
Universitair Medisch Centrum Utrecht Recruiting
Utrecht, Netherlands, 3584 CX
Contact: Manon Benders, Prof. MD PhD         
Norway
Oslo Universitetssykehus Hf Active, not recruiting
Oslo, Norway, 0450
Poland
Uniwersytet Medyczny Im Karola Marcinkowskiego W Poznaniu Active, not recruiting
Poznań, Poland, 61701
Portugal
Universidade Do Porto Not yet recruiting
Porto, Portugal, 4099 002
Contact: Hercilia Guimarães, Prof. MD PhD         
Spain
Para La Investigacion Del Hospital UniversitarioLa Fe De La Comunidad Valenciana Not yet recruiting
Valencia, Spain, 46026
Contact: Maximo Vento, Prof. MD PhD         
Switzerland
Universitaet Zuerich Not yet recruiting
Zuerich, Switzerland, 8006
Contact: Dirk Bassler, Prof. Dr.         
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
Helsinki University
University Hospital Ostrava
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

Additional Information:
Responsible Party: University Hospital Tuebingen
ClinicalTrials.gov Identifier: NCT03162653     History of Changes
Other Study ID Numbers: ALBINO
First Posted: May 22, 2017    Key Record Dates
Last Update Posted: May 10, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by University Hospital Tuebingen:
Allopurinol
hypothermia therapy
hypoxic-ischemic encephalopathy
neonatal oxygen deficiency
childbirth outcome
perinatal asphyxia

Additional relevant MeSH terms:
Craniocerebral Trauma
Ischemia
Brain Injuries
Brain Diseases
Hypoxia
Infant, Newborn, Diseases
Hypoxia-Ischemia, Brain
Hypoxia, Brain
Pathologic Processes
Central Nervous System Diseases
Nervous System Diseases
Trauma, Nervous System
Wounds and Injuries
Signs and Symptoms, Respiratory
Signs and Symptoms
Brain Ischemia
Cerebrovascular Disorders
Vascular Diseases
Cardiovascular Diseases
Mannitol
Allopurinol
Diuretics, Osmotic
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Gout Suppressants
Antirheumatic Agents