CeRebrUm and CardIac Protection with ALlopurinol in Neonates with Critical Congenital Heart Disease Requiring Cardiac Surgery with Cardiopulmonary Bypass (CRUCIAL): study protocol of a phase III, randomized, quadruple-blinded, placebo-controlled, Dutch multicenter trial
Raymond Stegeman,
Maaike Nijman,
Johannes M. P. J. Breur,
Floris Groenendaal,
Felix Haas,
Jan B. Derks,
Joppe Nijman,
Ingrid M. van Beynum,
Yannick J. H. J. Taverne,
Ad J. J. C. Bogers,
Willem A. Helbing,
Willem P. de Boode,
Arend F. Bos,
Rolf M. F. Berger,
Ryan E. Accord,
Kit C. B. Roes,
G. Ardine de Wit,
Nicolaas J. G. Jansen,
Manon J. N. L. Benders,
on behalf of the CRUCIAL trial consortium
Affiliations
Raymond Stegeman
Department of Neonatology, Wilhelmina Children’s Hospital, University Medical Center (UMC) Utrecht, Utrecht University
Maaike Nijman
Department of Neonatology, Wilhelmina Children’s Hospital, University Medical Center (UMC) Utrecht, Utrecht University
Johannes M. P. J. Breur
Department of Pediatric Cardiology, Wilhelmina Children’s Hospital, UMC Utrecht, Utrecht University
Floris Groenendaal
Department of Neonatology, Wilhelmina Children’s Hospital, University Medical Center (UMC) Utrecht, Utrecht University
Felix Haas
Congenital Cardiothoracic Surgery, Wilhelmina Children’s Hospital, UMC Utrecht, Utrecht University
Jan B. Derks
Department of Obstetrics, Wilhelmina Children’s Hospital, UMC Utrecht, Utrecht University
Joppe Nijman
Department of Pediatric Intensive Care, Wilhelmina Children’s Hospital, UMC Utrecht, Utrecht University
Ingrid M. van Beynum
Department of Pediatrics, Division of Pediatric Cardiology, Academic Center for Congenital Heart Disease, Erasmus Medical Center (MC) - Sophia Children’s Hospital
Yannick J. H. J. Taverne
Department of Cardiothoracic Surgery, Erasmus MC, Erasmus University Rotterdam
Ad J. J. C. Bogers
Department of Cardiothoracic Surgery, Erasmus MC, Erasmus University Rotterdam
Willem A. Helbing
Department of Pediatrics, Division of Pediatric Cardiology, Academic Center for Congenital Heart Disease, Erasmus Medical Center (MC) - Sophia Children’s Hospital
Willem P. de Boode
Department of Neonatology, Radboudumc, Radboud Institute for Health Sciences, Amalia Children’s Hospital
Arend F. Bos
Division of Neonatology, Beatrix Children’s Hospital, UMC Groningen, University of Groningen
Rolf M. F. Berger
Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children’s Hospital, UMC Groningen, University of Groningen
Ryan E. Accord
Center for Congenital Heart Diseases, Department of Cardiothoracic Surgery, UMC Groningen, University of Groningen
Kit C. B. Roes
Department of Health Evidence, Section Biostatistics, Radboudumc, Radboud University Nijmegen
G. Ardine de Wit
Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht University
Nicolaas J. G. Jansen
Department of Pediatric Intensive Care, Wilhelmina Children’s Hospital, UMC Utrecht, Utrecht University
Manon J. N. L. Benders
Department of Neonatology, Wilhelmina Children’s Hospital, University Medical Center (UMC) Utrecht, Utrecht University
Abstract Background Neonates with critical congenital heart disease (CCHD) undergoing cardiac surgery with cardiopulmonary bypass (CPB) are at risk of brain injury that may result in adverse neurodevelopment. To date, no therapy is available to improve long-term neurodevelopmental outcomes of CCHD neonates. Allopurinol, a xanthine oxidase inhibitor, prevents the formation of reactive oxygen and nitrogen species, thereby limiting cell damage during reperfusion and reoxygenation to the brain and heart. Animal and neonatal studies suggest that allopurinol reduces hypoxic-ischemic brain injury and is cardioprotective and safe. This trial aims to test the hypothesis that allopurinol administration in CCHD neonates will result in a 20% reduction in moderate to severe ischemic and hemorrhagic brain injury. Methods This is a phase III, randomized, quadruple-blinded, placebo-controlled, multicenter trial. Neonates with a prenatal or postnatal CCHD diagnosis requiring cardiac surgery with CPB in the first 4 weeks after birth are eligible to participate. Allopurinol or mannitol-placebo will be administered intravenously in 2 doses early postnatally in neonates diagnosed antenatally and 3 doses perioperatively of 20 mg/kg each in all neonates. The primary outcome is a composite endpoint of moderate/severe ischemic or hemorrhagic brain injury on early postoperative MRI, being too unstable for postoperative MRI, or mortality within 1 month following CPB. A total of 236 patients (n = 188 with prenatal diagnosis) is required to demonstrate a reduction of the primary outcome incidence by 20% in the prenatal group and by 9% in the postnatal group (power 80%; overall type 1 error controlled at 5%, two-sided), including 1 interim analysis at n = 118 (n = 94 with prenatal diagnosis) with the option to stop early for efficacy. Secondary outcomes include preoperative and postoperative brain injury severity, white matter injury volume (MRI), and cardiac function (echocardiography); postnatal and postoperative seizure activity (aEEG) and regional cerebral oxygen saturation (NIRS); neurodevelopment at 3 months (general movements); motor, cognitive, and language development and quality of life at 24 months; and safety and cost-effectiveness of allopurinol. Discussion This trial will investigate whether allopurinol administered directly after birth and around cardiac surgery reduces moderate/severe ischemic and hemorrhagic brain injury and improves cardiac function and neurodevelopmental outcome in CCHD neonates. Trial registration EudraCT 2017-004596-31. Registered on November 14, 2017. ClinicalTrials.gov NCT04217421. Registered on January 3, 2020