Effect of ALlopurinol in addition to hypothermia for hypoxicischemic Brain Injury on Neurocognitive Outcome

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Tuebingen AöR

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

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

Trial duration

26 Mar 2018 → 22 Apr 2026

Decision date (initial)

2024-09-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

European Union

External identifiers

EU CT number

2024-511322-31-00

EudraCT number

2016-000222-19

ClinicalTrials.gov

NCT03162653

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Pharmacodynamic, Therapy, Safety

To evaluate whether in newborns with asphyxia and early clinical signs of hypoxic ischemic
encephalopathy, early postnatal allopurinol compared to placebo administered in addition to
standard of care (including therapeutic hypothermia if indicated) reduces the incidence of death or
severe neurodevelopmental impairment (defined as cerebral palsy, or cognitive or language
impairment, the latter defined as cognitive- and the language-composite scores of the Bayley Scales
of Infant and Toddler Development (3rd edition) <85) at 24 months of age.

Secondary objectives 3

1. To evaluate the effect of allopurinol in addition to hypothermia (if indicated) on the 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
2. To evaluate the safety of allopurinol in neonates treated with hypothermia.
3. To study pharmacokinetics of allopurinol (verum) and mannitol (placebo) in neonates treated with hypothermia and not treated with hypothermia

Conditions and MedDRA coding

Brain injury termed “hypoxic-ischemic encephalopathy” (HIE) as a result of various events during labour and childbirth such as placental abruption, uterine rupture, umbilical cord complications, etc.)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. Severe perinatal metabolic acidosis or ongoing cardiopulmonary resuscitation at 5 min after birth
2. Early clinical signs of potentially evolving encephalopathy

Exclusion criteria 5

1. gestational age below 36 weeks
2. birth weight below 2500 g
3. postnatal age >30min at the end of screening phase
4. severe congenital malformation or syndrome requiring neonatal surgery or affecting long-term outcome
5. patient considered “moribund” / “non-viable” (e.g., lack of spontaneous cardiac activity and ongoing chest compression at 30min)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Death versus severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years

Secondary endpoints 10

1. Death or neurodevelopmental impairment (NDI) The primary endpoint will be reconstituted as dichotomised composite secondary endpoint (survival without NDI versus Death or languagecomposite- score < 85 or cognitive-composite-score <85 or cerebral palsy present).
2. Incidence of CP Incidence of CP will be analyzed by Cochrane-Mantel-Haenzel- X²-Test.
3. 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.
4. Motor-Composite-Score (Bayley III)
5. Motor-Composite-Score dichotomised (Bayley III) The motor-composite-score will be dichotomised at the cut-off <85 versus ≥85
6. Cognitive-Composite-Score (cognitive subscale, Bayley III)
7. Cognitive-Composite-Score dichotomised (cognitive subscale, Bayley III) The cognitive-composite-score will be dichotomised at the cut-off <85 versus ≥85
8. Language-Composite-Score (language subscale, Bayley III)
9. Language-Composite-Score dichotomised (language subscale, Bayley III) The language-composite-score will be dichotomised at the cut-off <85 versus ≥85
10. Single Components of primary endpoint - Graph Single components and observed combinations of the primary endpoint (healthy, death, CP, language-composite-score <85, cognitivecomposite- score <85) will be displayed graphically stratified for the two treatment groups.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Tuebingen AöR

Sponsor organisation

Universitaetsklinikum Tuebingen AöR

Address

Geissweg 3, Innenstadt Innenstadt

City

Tübingen

Postcode

72076

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Tuebingen AöR

Contact name

Axel Franz

Public contact point

Organisation

Universitaetsklinikum Tuebingen AöR

Contact name

Axel Franz

Locations

9 EU/EEA countries · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 31 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications