Encephalopathy, Hypoxic-IschemicPhase 3ALBINONCT03162653
Effect of Allopurinol for Hypoxic-ischemic Brain Injury on Neurocognitive Outcome
A Phase 3 study testing Allopurinol and Mannitol in people with Encephalopathy, Hypoxic-Ischemic and Infant, Newborn, Diseases, run by University Hospital Tuebingen at 12 sites in 12 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages Up to 45 minutes
- Conditions the study is for
- Encephalopathy, Hypoxic-Ischemic, Infant, Newborn, Diseases
- What is being tested?
- Allopurinol and Mannitol
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 760 participants
- Where
- 12 sitesin 12 countries
- Study dates
- 25 Mar 2018to 31 Jan 2026
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 45 minutes
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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
Show all 14Show fewer
- 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)
Who cannot join
- 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
Show all 9Show fewer
- 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
Trial locations and contacts
12 sites in 12 countries.
12 sites in 12 countries
Austria1 site, 1 recruiting
- Recruiting
Medizinische Universitaet Wien
Vienna, 1090
Katrin Klebermaß-Schrehof, Assoz. Prof.
Belgium1 site, 1 recruiting
- Recruiting
Katholieke Universiteit Leuven
Leuven, 3000
Karel Allegaert, Prof. Dr.
Gunnar Naulaers, Prof. Dr.
Estonia1 site, 1 recruiting
- Recruiting
Tartu Ulikool
Tartu, 50090
Renata Poláčková, Prof. Dr.
Finland1 site, 1 recruiting
- Recruiting
Helsingin Ja Uudenmaan Sairaanhoitopiirin Kuntayhtymä
Helsinki, 00029
Marjo Metsäranta, Dr.
Germany1 site, 1 recruiting
- Recruiting
University Hospital Tübingen
Tübingen, 72076
Axel R Franz, MD, +49707129 ext. 0, albino@med.uni-tuebingen.de
Gabriele von Oldershausen, +49707129 ext. 0, albino@med.uni-tuebingen.de
Italy1 site, 1 recruiting
- Recruiting
Universita Degli Studi Di Udine
Udine, 33100
Isabella Mauro, MD
Netherlands1 site, 1 recruiting
- Recruiting
Universitair Medisch Centrum Utrecht
Utrecht, 3584 CX
Manon Benders, Prof. MD PhD
Norway1 site, 1 recruiting
- Recruiting
Oslo Universitetssykehus Hf
Oslo, 0450
Tom Stiris, Prof. MD PhD
Poland1 site
- Withdrawn
Uniwersytet Medyczny Im Karola Marcinkowskiego W Poznaniu
Poznan, 61701
Spain1 site, 1 recruiting
- Recruiting
Para La Investigacion Del Hospital UniversitarioLa Fe De La Comunidad Valenciana
Valencia, 46026
Maximo Vento, Prof. MD PhD
Switzerland1 site, 1 recruiting
- Recruiting
Universitaet Zuerich
Zurich, 8006
Dirk Bassler, Prof. Dr.
About this study
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)
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.
Read more
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.
Read the detailed description
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.
- Being tested
- Allopurinol, Mannitol
- Keywords
- Allopurinol, hypothermia therapy, hypoxic-ischemic encephalopathy, neonatal oxygen deficiency, childbirth outcome, perinatal asphyxia
- Medical subject headings
- Hypoxia-Ischemia, Brain, Infant, Newborn, Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AllopurinolDrug
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.
MannitolDrug
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)).
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Mannitol |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: at the age of 24 months
Secondary outcomes (10)
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.
Measured: at 24months
Incidence of Death
Incidence of death will be analyzed by Cochrane-Mantel-Haenszel- X²-Test.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: at 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 May 2017
- Study start25 Mar 2018
- Primary completion31 Jan 2026 (estimated)
- Study completion31 Jan 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Encephalopathy, Hypoxic-IschemicStudies of the same condition, open and under way.
- More trials run by University Hospital TuebingenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 760 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Hospital Tuebingen
- Sponsor type
- University, hospital or other
- 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, Poznan University of Medical Sciences, Tartu University Hospital, ACE Pharmaceuticals BV
- Responsible party
- Sponsor
- Investigators
- Axel Franz, Prof. Dr., Study director, University Children's Hospital TuebingenRüdiger Mario, Prof. Dr., Principal investigator, University Children's Hospital Dresden
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03162653
- Sponsor's protocol ID
- ALBINO
- Other IDs
- 2016-000222-19, 2016
- Acronym
- ALBINO
- Status last verified
- Jul 2023
- First submitted
- 18 May 2017
- Last updated
- 11 Jul 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
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.
PubMed 31248390Annink 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.
PubMed 28925896Deferm 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.
PubMed 33611729Engel 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.
PubMed 38267942
Study at a glance
From the registry record, last updated by the sponsor on 11 Jul 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT03162653
- Acronym / sponsor ID
- ALBINO / ALBINO
- Keywords
- Allopurinol, hypothermia therapy, hypoxic-ischemic encephalopathy, neonatal oxygen deficiency, childbirth outcome, perinatal asphyxia
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 760 participants (estimated)
- Lead sponsor
- University Hospital TuebingenUniversity, hospital or other
- 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, Poznan University of Medical Sciences, Tartu University Hospital, ACE Pharmaceuticals BV
- Study start
- 25 Mar 2018 (actual)
- Primary completion
- 31 Jan 2026 (estimated)
- Study completion
- 31 Jan 2026 (estimated)
- First posted
- 22 May 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Allopurinol | Active comparator | Drug: AllopurinolAllopurinol, 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 | Placebo comparator | Drug: Mannitolmannitol, 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. |
Who may qualify
- Ages
- Up to 45 minutes
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (14 listed)
- 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
Key exclusion criteria (9 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AllopurinolAllopurinol, 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 |
| MannitolPlacebo (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)). | Drug | Placebo |
Primary outcome
death versus 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]. 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.
10 secondary outcomes
Death or neurodevelopmental impairment (NDI)
Time frame: at 24months
Incidence of Death
Time frame: at 24 months
Incidence of CP
Time frame: at 24 months
GMFCS-score
Time frame: at 24 months
Motor-Composite-Score (Bayley III)
Time frame: at 24 months
Motor-Composite-Score dichotomised (Bayley III)
Time frame: at 24 months
Cognitive-Composite-Score (cognitive subscale, Bayley III)
Time frame: at 24 months
Cognitive-Composite-Score dichotomised (cognitive subscale, Bayley III)
Time frame: at 24 months
Language-Composite-Score (language subscale, Bayley III)
Time frame: at 24 months
Language-Composite-Score dichotomised (language subscale, Bayley III)
Time frame: at 24 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Jul 2023.
- Background: PubMed 31248390Maiwald 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.
- Background: PubMed 28925896Annink 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.
- Background: PubMed 33611729Deferm 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.
- Derived from this study: PubMed 38267942Engel 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.
- official study homepageLink provided by the sponsor.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Axel Franz, Prof. Dr. study director
University Children's Hospital Tuebingen
Rüdiger Mario, Prof. Dr. principal investigator
University Children's Hospital Dresden
12 sites in 12 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Allopurinol and Mannitol in people with Encephalopathy, Hypoxic-Ischemic and Infant, Newborn, Diseases, run by University Hospital Tuebingen at 12 sites in 12 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 11 Jul 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 12 sites in Austria, Belgium, Estonia, Finland, Germany and 7 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Oldershausen Gabriele (+49 7071 29-86176, Albino@med.uni-tuebingen.de), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
death versus severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment (time frame: at the age of 24 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03162653, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jul 2023.