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NCT Number: NCT04217421

Cerebrum and Cardiac Protection With Allopurinol in Neonates With Critical Congenital Heart Disease Requiring Cardiac Surgery With Cardiopulmonary Bypass

Neurodevelopmental impairment due to delayed brain development and brain injury is a fundamental problem in children with critical congenital heart disease (CCHD). Significant longterm motor-, cognitive-, and behavioral problems are the result of early postnatally and perioperatively induced brain injury. Allopurinol, a xanthine oxidase inhibitor, prevents the formation of toxic free oxygen radicals, thereby limiting hypoxia-reperfusion damage. Both animal and neonatal studies suggest that administration of allopurinol reduces hypoxic-ischemic brain injury, is cardioprotective, and safe. This study aims to evaluate the efficacy and safety of allopurinol administered early postnatally and perioperatively in children with a CCHD requiring cardiac surgery with cardiopulmonary bypass.

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Key information

Conditions

Congenital Heart Disease in Children Brain Diseases Brain Injuries Brain Ischemia Cardiovascular Abnormalities Cardiovascular Diseases Central Nervous System Diseases Cerebrovascular Disorders Congenital Abnormalities Congenital, Hereditary, and Neonatal Diseases and Abnormalities Craniocerebral Trauma Heart Defects, Congenital Heart Diseases Hypoxia Hypoxia, Brain Hypoxia-Ischemia, Brain Nervous System Diseases Neuroprotection Pathological Conditions, Signs and Symptoms Signs and Symptoms Signs and Symptoms, Respiratory Trauma, Nervous System Vascular Diseases Wounds and Injuries

Age range

Up to 1 month

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

University Medical Center Groningen (UMCG), Groningen, Netherlands

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Neonates with a prenatally or postnatally confirmed diagnosis of CCHD requiring (anticipated) cardiac surgery with CPB within the first 4 weeks of life.
  • Informed consent provided by both parents.

Exclusion criteria

  • Inability to enroll the patient before the start of delivery in case of prenatal diagnosis, or 24 hours before surgery in case of postnatal diagnosis.
  • Doubt whether the aortic arch anomaly before birth requires cardiac surgery with CPB in the neonatal period.
  • Gestational age below 36 weeks and/or birth weight less than 2000 gram.
  • Surgery not requiring cardiopulmonary bypass.
  • Decision for "comfort care only".

Treatment and study plan

Allopurinol

Drug

Allopurinol powder for solution for infusion (PFI) 20 mg/kg body weight per administration will be administered early postnatally (within 45 minutes and 12 hours after the first dose), preoperatively (12 hours before surgery), intraoperatively (during surgery) and postoperatively (24 hours after surgery) to the neonate in case of a prenatal CCHD diagnosis. Allopurinol PFI will be administered only pre-, intra- and postoperatively to the neonate in case of a postnatal CCHD diagnosis.

Mannitol

Drug

Mannitol powder for solution (PFI) placebo will be administered early postnatally (within 45 minutes and 12 hours after birth), preoperatively (12 hours before surgery), intraoperatively (during surgery), and postoperatively (24 hours after surgery) to the neonate in case of a prenatal CCHD diagnosis. Mannitol PFI-placebo will be administered only pre-, intra- and postoperatively to the neonate in case of a postnatal CCHD diagnosis.

Primary outcomes

  1. Relevant parenchymatous brain injury on postoperative MRI

    Time frame: between birth and 1 month after cardiac surgery

    The presence or absence of relevant (moderate/severe) parenchymatous (ischemic or hemorrhagic) brain injury on postoperative MRI will be assessed, using the T1/T2/DWI and SWI weighted images.

  2. Rate of children that are considered 'too unstable for postoperative MRI'

    Time frame: between birth and 1 month after cardiac surgery

    This decision is based on the circulatory and respiratory status of the child before the planned postoperative MRI, as included in local guidelines (not part of this protocol) of each participating center.

  3. Incidence of mortality

    Time frame: between birth and 1 month after cardiac surgery

    Defined as death until one month postoperatively.

Secondary outcomes

  1. Brain injury severity score on pre- and postoperative MRI

    Time frame: between birth and 1 month after cardiac surgery

    An MRI score, which includes diffusion-weighted imaging as well as assessment of the deep grey matter, white matter, and cerebellum [Weeke L, et al. J Pediatr 2018]. The score will be compared between groups (allopurinol vs placebo).

  2. Volume of hypoxic-ischemic brain injury on pre- and postoperative MRI

    Time frame: between birth and 1 month after cardiac surgery

    To assess whether there are differences between groups (allopurinol vs placebo) in volume (mm3) of hypoxic-ischemic brain lesions using a fully automatic method for detection and quantification of ischemic lesions in diffusion-weighted MR images [Murphy K, et al. Neuroimage Clin 2017].

  3. Global ventricular function (normal, mildly, moderately, severely, reduced) pre- and postoperatively

    Time frame: between birth and 1 month after cardiac surgery

  4. Ventricular ejection fraction (%) pre- and postoperatively

    Time frame: between birth and 1 month after cardiac surgery

  5. Brain function: Seizure activity on aEEG (presence or absence) postnatally and postoperatively

    Time frame: 24-36 hours after birth, 6 hours before surgery, 48-72 hours after surgery

  6. Brain oxygenation: Regional cerebral oxygen saturation (%) postnatally and postoperatively

    Time frame: 24-36 hours after birth, 6 hours before surgery, 48-72 hours after surgery

  7. General movements and motor optimality score

    Time frame: at 3 months

    Video recordings will be analyzed following the global general movement categories (normal, poor repertoire, cramped-synchronized, or chaotic) and the motor optimality score [Einspieler C, et al. Dev Med Child Neurol. 2016]. A higher score expresses a more optimal performance. Scores will be compared between groups (allopurinol vs placebo).

  8. Neurodevelopment

    Time frame: at 24 months

    To assess motor, cognitive, speech and language development using the Bayley Scales of Infant and Toddler Development - Third Edition - NL (Bayley-III-NL). An average Bayley-III-NL score is 100, one standard deviation (SD) above or below the mean concerns 15 points. Scores will be compared between groups (allopurinol vs placebo).

  9. Quality of Life (scores and subscores): TNO-AZL TAPQoL

    Time frame: at 24 months

    The TNO-AZL Questionnaire for Preschool Children's Health-Related Quality of Life (TAPQoL) will be assessed to give insight in the quality of life of both children with CCHD and their parents. A higher score indicates a better quality of life. Scores will be compared between groups (allopurinol vs placebo).

Study contacts

Contact information is provided by the study sponsor or research team.

Maaike Nijman, MD

CONTACT

[email protected]

Manon JNL Benders, Prof. MD PhD

CONTACT

[email protected]

0031887554545

Sponsors and collaborators

Lead sponsor

dr. M.J.N.L. Benders

Other

Collaborators

  • ACE Pharmaceuticals BV
  • Erasmus Medical Center
  • University Medical Center Groningen
  • University Medical Center Nijmegen
  • ZonMw: The Netherlands Organisation for Health Research and Development

Registry information

Acronym: CRUCIAL

Important dates

Study start
2020
Primary completion
2026
Study completion
2028
First posted
Jan 3, 2020
Registry last updated
May 16, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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