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

Congenital Heart Disease in Children Clinical Trial

— CRUCIAL  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04217421
• Other study ID #: METC UMCU 18-791
• Secondary ID: 2017-004596-31
• Status: Recruiting
• Phase: Phase 3
• Start date: February 14, 2020
• Est. completion date: December 31, 2028

Study information

• Verified date: May 2024
• Source: UMC Utrecht
• Contact: Manon JNL Benders, Prof. MD PhD
• Phone: 0031887554545
• Email: m.benders[@]umcutrecht.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 236
• Est. completion date: December 31, 2028
• Est. primary completion date: October 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 1 Month

Eligibility

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".

Related Conditions & MeSH terms

• Congenital Heart Disease in Children
• Heart Defects, Congenital
• Heart Diseases
• Neuroprotection

Intervention

Drug:
• Allopurinol
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
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.

Locations

Country	Name	City	State
Netherlands	University Medical Center Groningen (UMCG)	Groningen
Netherlands	Radboud University Medical Center Nijmegen (Radboudumc)	Nijmegen
Netherlands	Erasmus Medical Center Rotterdam (Erasmus MC)	Rotterdam
Netherlands	University Medical Center Utrecht (UMC Utrecht)	Utrecht

Sponsors (6)

Lead Sponsor	Collaborator
dr. M.J.N.L. Benders	ACE Pharmaceuticals BV, Erasmus Medical Center, University Medical Center Groningen, University Medical Center Nijmegen, ZonMw: The Netherlands Organisation for Health Research and Development

Country where clinical trial is conducted

Netherlands, 

References & Publications (1)

Stegeman R, Nijman M, Breur JMPJ, Groenendaal F, Haas F, Derks JB, Nijman J, van Beynum IM, Taverne YJHJ, Bogers AJJC, Helbing WA, de Boode WP, Bos AF, Berger RMF, Accord RE, Roes KCB, de Wit GA, Jansen NJG, Benders MJNL; CRUCIAL trial consortium. 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. Trials. 2022 Feb 23;23(1):174. doi: 10.1186/s13063-022-06098-y. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Relevant parenchymatous brain injury on postoperative MRI	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.	between birth and 1 month after cardiac surgery
Primary	Rate of children that are considered 'too unstable for postoperative MRI'	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.	between birth and 1 month after cardiac surgery
Primary	Incidence of mortality	Defined as death until one month postoperatively.	between birth and 1 month after cardiac surgery
Secondary	Brain injury severity score on pre- and postoperative MRI	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).	between birth and 1 month after cardiac surgery
Secondary	Volume of hypoxic-ischemic brain injury on pre- and postoperative MRI	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].	between birth and 1 month after cardiac surgery
Secondary	Global ventricular function (normal, mildly, moderately, severely, reduced) pre- and postoperatively		between birth and 1 month after cardiac surgery
Secondary	Ventricular ejection fraction (%) pre- and postoperatively		between birth and 1 month after cardiac surgery
Secondary	Brain function: Seizure activity on aEEG (presence or absence) postnatally and postoperatively		24-36 hours after birth, 6 hours before surgery, 48-72 hours after surgery
Secondary	Brain oxygenation: Regional cerebral oxygen saturation (%) postnatally and postoperatively		24-36 hours after birth, 6 hours before surgery, 48-72 hours after surgery
Secondary	General movements and motor optimality score	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).	at 3 months
Secondary	Neurodevelopment	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).	at 24 months
Secondary	Quality of Life (scores and subscores): TNO-AZL TAPQoL	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).	at 24 months