A European trial to evaluate the effect of Allopurinol administered very early after birth on brain injury in children with oxygen deficiency during birth

• Register: EUCTR
• Last refreshed on: 26 April 2021
• Main ID: EUCTR2016-000222-19-BE
• Date of registration: 30/07/2018
• Prospective Registration: Yes
• Primary sponsor: University Hospital Tuebingen
• Public title: A European trial to evaluate the effect of Allopurinol administered very early after birth on brain injury in children with oxygen deficiency during birth
• Scientific 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) - ALBINO
• Target sample size: 846
• Recruitment status: NA
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-000222-19
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: multicenter trial If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belgium, Estonia, Finland, Germany, Netherlands, Norway, Portugal, Spain, Switzerland

Contacts

• Name: Clinical Trial Center
• Affiliation: Center for Pediatric Clinical Studies

• Name: Clinical Trial Center
• Affiliation: Center for Pediatric Clinical Studies

Key inclusion & exclusion criteria

Inclusion criteria:
Term and near-term infants with a history of disturbed labour who meet at least one sign of perinatal asphyxia and early clinical signs of potentially evolving encephalopathy as defined herein:
Perinatal asphyxia:
At least 1 out of the following 4criteria 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 (i.e. a base excess = -16mmol/l)
- Need for ongoing cardiac massage at/beyond 5 min postnatally
- Need for adrenalin administration during resuscitation or 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)
Are the trial subjects under 18? yes
Number of subjects for this age range: 846
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
- gestational age below 36 weeks
- birth weight below 2500 g
- postnatal age >30min at the end of the screening phase
- severe congenital malformation or syndrome requiring neonatal
surgery or affecting long-term outcome
- patient considered “moribund” or decision for “comfort care only”
before study drug administration
- parents declined study participation as response to community
engagment
- both parents are insufficiently fluent in the study site’s national language or English or do not have the intellectual capacity to understand the study procedures and to give consent as judged by the personel who had been in contact with the mother/father before delivery.
- both parents/guardians underaged, in case of single parent/guardian this one underaged



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Perinatal Asphyxia, hypoxic-ischemic brain injury
MedDRA version: 20.0 Level: PT Classification code 10028923 Term: Neonatal asphyxia System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders
MedDRA version: 20.0 Level: PT Classification code 10014633 Term: Encephalopathy neonatal System Organ Class: 10029205 - Nervous system disorders

Intervention(s)

Trade Name: ACEPURIN
Product Name: Allokid
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: Allopurinol sodium
CAS Number: 17795-21-0
Other descriptive name: ALLOPURINOL SODIUM
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Powder for solution for injection
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: at the age of two years

Main Objective: To evaluate whether in newborns with asphyxia and early clinical signs of hypoxic-ischemic encephalopathy, early postnatal allopurinol compared to placebo (mannitol) administered in addition to standard of care (including therapeutic hypothermia if indicated) reduces the incidence of death or severe neurodevelopmental impairment (as defined herein) at 24 months of age.

Primary end point(s): Death or severe neurodevelopmental impairment at the age of two years (where severe neurodevelopmental impairment is defined as any of the following: cognitive or language delay defined as mental developmental index (MDI) cognitive or language score on the Bayley Scales of Infant Development (3rd edition) < 85 and/or cerebral palsy according to SCPE criteria [SCPE Dev Med Child Neurol 2000].

Secondary Objective: To evaluate the effect of allopurinol in addition to hypothermia (if indicated) on:
- components of the primary outcome variable
- brain injury assessed by magnetic resonance imaging,
- amplitude integrated electroencephalogram,
- full scale electroencephalogram,
- laboratory biomarkers and markers of peroxidation
- heart function assessed by echocardiography
To evaluate the safety of allopurinol in neonates treated with hypothermia.
To study pharmacokinetics of allopurinol (verum) and mannitol (placebo) in neonates treated with hypothermia and not treated with hypothermia

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Secondary endpoints will be analysed at 24 months corrected age between the two treatment groups.

Secondary end point(s): 1) 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). This will be analyzed by Cochrane-Mantel-Haenzel- X²-Test.
2) Incidence of death
Incidence of death will be analyzed by Cochrane-Mantel-Haenzel- X²-Test.
3) Incidence of CP
Incidence of CP will be analyzed by Cochrane-Mantel-Haenzel- X²-Test.
4) 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 (separate document not part of this protocol) will be analysed. GMFCS-score consists of six categories. Analysis will be done by using Wilcoxon-Mann-Whitney test.
5) Motor-Composite-Score (Bayley III)
The nummerical 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 sensitivity below 50 points.
6) 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-Haenzel- X²-Test.
7) Cognitive-Composite-Score (cognitive subscale, Bayley III)
The nummerical 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 sensitivity below 50 points.
8) 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-Haenzel- X²-Test.
9) Language-Composite-Score (language subscale, Bayley III)
The raw nummerical 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 sensitivity below 50 points.
10) 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-Haenzel- X²-Test.
11) Single Components of primary endpoint - Graph
Single components and observed combinations of the primary endpoint (healthy, death, CP, language-composite-score <85, cognitive-composite-score <85) will be displayed graphically stratified for the two treatment groups.

Secondary ID(s)

2016-000222-19-DE

H2020-PHC-18-2015-667224

Source(s) of Monetary Support

European Union

Ethics review

Status: Approved
Approval date: 18/12/2018
Contact: