Effect of Allopurinol for Hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO)
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| ClinicalTrials.gov Identifier: NCT03162653 |
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Recruitment Status : Unknown
Verified May 2018 by University Hospital Tuebingen.
Recruitment status was: Recruiting
First Posted : May 22, 2017
Last Update Posted : May 11, 2018
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Sponsor:
University Hospital Tuebingen
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
University of Helsinki
University Hospital Ostrava
Poznan University of Medical Sciences
Tartu University Hospital
ACE Pharmaceuticals BV
Information provided by (Responsible Party):
University Hospital Tuebingen
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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 |
| Arm | Intervention/treatment |
|---|---|
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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.
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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. |
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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.
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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 :
- 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 :
- 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
- Incidence of Death [ Time Frame: at 24 months ]
- Incidence of CP [ Time Frame: at 24 months ]Incidence of CP according to SCPE criteria [SCPE Dev Med Child Neurol 2000]
- 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.
- Motor-Composite-Score (Bayley III) [ Time Frame: at 24 months ]The numerical data of the motor-composite-score.
- 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
- Cognitive-Composite-Score (cognitive subscale, Bayley III) [ Time Frame: at 24 months ]The numerical data of the cognitive-composite-score.
- 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
- Language-Composite-Score (language subscale, Bayley III) [ Time Frame: at 24 months ]The raw numerical data of the language-composite-score.
- 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
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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
University of Helsinki
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:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | University Hospital Tuebingen |
| ClinicalTrials.gov Identifier: | NCT03162653 |
| Other Study ID Numbers: |
ALBINO |
| First Posted: | May 22, 2017 Key Record Dates |
| Last Update Posted: | May 11, 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:
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Allopurinol hypothermia therapy hypoxic-ischemic encephalopathy |
neonatal oxygen deficiency childbirth outcome perinatal asphyxia |
Additional relevant MeSH terms:
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Brain Injuries Brain Diseases Hypoxia-Ischemia, Brain Hypoxia, Brain Infant, Newborn, Diseases Ischemia Hypoxia Pathologic Processes Central Nervous System Diseases Nervous System Diseases Craniocerebral Trauma Trauma, Nervous System Wounds and Injuries Signs and Symptoms, Respiratory Brain Ischemia |
Cerebrovascular Disorders Vascular Diseases Cardiovascular Diseases Allopurinol Mannitol Antimetabolites Molecular Mechanisms of Pharmacological Action Enzyme Inhibitors Gout Suppressants Antirheumatic Agents Free Radical Scavengers Antioxidants Protective Agents Physiological Effects of Drugs Diuretics, Osmotic |