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

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.

Study Overview

• Status: Recruiting
• Conditions: Congenital Heart Disease in Children; Neuroprotection
• Intervention / Treatment: Drug: Allopurinol; Drug: Mannitol

• Study Type: Interventional
• Enrollment (Anticipated): 236
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Manon JNL Benders, Prof. MD PhD; Phone Number: 0031887554545; Email: m.benders@umcutrecht.nl
• Study Contact Backup: Name: Maaike Nijman, MD; Email: m.nijman@umcutrecht.nl

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Not yet recruiting
    • VU University Medical Center (VUMC)
    • Contact: Anton HLC van Kaam, Prof. MD PhD
    • Principal Investigator: Anton HLC van Kaam, Prof. MD PhD
  • Amsterdam, Netherlands, 1105 AZ
    • Not yet recruiting
    • Academic Medical Center (AMC)
    • Contact: Anton HLC van Kaam, Prof. MD PhD
    • Principal Investigator: Anton HLC van Kaam, Prof. MD PhD
  • Groningen, Netherlands, 9700 RB
    • Not yet recruiting
    • University Medical Center Groningen (UMCG)
    • Contact: Arend F Bos, Prof. MD PhD
    • Contact: Nicolaas (Koos) JG Jansen, MD PhD
    • Principal Investigator: Arend F Bos, Prof. MD PhD
    • Sub-Investigator: Nicolaas (Koos) JG Jansen, MD PhD
  • Leiden, Netherlands, 2333 ZA
    • Not yet recruiting
    • Leiden University Medical Center (LUMC)
    • Contact: Sylke J Steggerda, MD PhD
    • Principal Investigator: Sylke J Steggerda, MD PhD
  • Nijmegen, Netherlands, 6525 GA
    • Not yet recruiting
    • Radboud University Medical Center Nijmegen (Radboudumc)
    • Contact: W A Helbing, Prof. MD PhD
    • Principal Investigator: W A Helbing, Prof. MD PhD
  • Rotterdam, Netherlands, 3015 GD
    • Not yet recruiting
    • Erasmus Medical Center Rotterdam (Erasmus MC)
    • Contact: Ingrid M van Beynum, MD PhD
    • Principal Investigator: Ingrid M van Beynum, MD PhD
  • Utrecht, Netherlands, 3584 EA
    • Recruiting
    • University Medical Center Utrecht (UMC Utrecht)
    • Sub-Investigator: Nicolaas (Koos) JG Jansen, MD PhD
    • Contact: Manon JNL Benders, Prof. MD PhD
    • Contact: Maaike Nijman, MD
    • Principal Investigator: Manon JNL Benders, Prof. MD PhD
    • Principal Investigator: Johannes (Hans) MPJ Breur, MD PhD
    • Sub-Investigator: Raymond Stegeman, MD
    • Sub-Investigator: Maaike Nijman, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.
• Patient considered "moribund".
• Decision for "comfort care only".

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: 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.
Active Comparator: Allopurinol	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
Incidence of mortality	Defined as death until one month postoperatively.	between birth and 1 month after cardiac surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
Global ventricular function (normal, mildly, moderately, severely, reduced) pre- and postoperatively		between birth and 1 month after cardiac surgery
Ventricular ejection fraction (%) pre- and postoperatively		between birth and 1 month after cardiac surgery
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
Brain oxygenation: Regional cerebral oxygen saturation (%) postnatally and postoperatively		24-36 hours after birth, 6 hours before surgery, 48-72 hours after surgery
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
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
Executive functioning in comparison to healthy controls	Both 'hot' executive functions (snack and gift delay tasks) and 'cool' executive functions (six boxes, memory for location, and visual search task) will be tested and scored. A higher score indicates a better performance. The results of the executive function tasks will be compared with healthy children from the PreCool study [Veen A, Veen I van der, Heurter AMH, et al. Pre-Cool cohortonderzoek, technisch rapport tweejarigen cohort. Amsterdam: Kohnstamm Instituut Rapport 877, Projectnummer 20379]. A higher score reflects a more optimal perfomance. Scores will be compared between groups (allopurinol vs placebo).	at 24 months
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

Collaborators and Investigators

• Sponsor: dr. M.J.N.L. Benders
• Collaborators: University Medical Center Groningen; Erasmus Medical Center; Amsterdam UMC, location VUmc; Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Leiden University Medical Center; ZonMw: The Netherlands Organisation for Health Research and Development; University Medical Center Nijmegen; ACE Pharmaceuticals BV
• Investigators: Principal Investigator: Manon JNL Benders, Prof. MD PhD, University Medical Center Utrecht (UMC Utrecht); Principal Investigator: Johannes (Hans) MPJ Breur, MD PhD, University Medical Center Utrecht (UMC Utrecht); Study Director: Nicolaas (Koos) JG Jansen, MD PhD, University Medical Center Utrecht (UMC Utrecht); Study Director: Raymond Stegeman, MD, University Medical Center Utrecht (UMC Utrecht)

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2020
• Primary Completion (Anticipated): June 1, 2021
• Study Completion (Anticipated): June 1, 2023

Study Registration Dates

• First Submitted: November 12, 2019
• First Submitted That Met QC Criteria: December 31, 2019
• First Posted (Actual): January 3, 2020

Study Record Updates

• Last Update Posted (Actual): January 18, 2020
• Last Update Submitted That Met QC Criteria: January 13, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: Congenital Heart Disease; Neuroprotection; Allopurinol; Cardiac function; Cardiac surgery; Neonates; Cardiopulmonary bypass; Brain injury; Neurodevelopmental outcome; Brain function; Brain oxygenation; Hypoxic-ischemic brain injury
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Diseases; Heart Defects, Congenital; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites; Protective Agents; Natriuretic Agents; Diuretics, Osmotic; Diuretics; Antioxidants; Free Radical Scavengers; Gout Suppressants; Mannitol; Allopurinol
• Other Study ID Numbers: METC UMCU 18-791; 2017-004596-31 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No