Clinical trial NCT04217421: Cerebrum and Cardiac Protection With Allopurinol in Neonates With Critical Congenital Heart Disease Requiring Cardiac Surgery With Cardiopulmonary Bypass
Official title: Cerebrum and Cardiac Protection With Allopurinol in Neonates With Critical Congenital Heart Disease Requiring Cardiac Surgery With Cardiopulmonary Bypass
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Congenital Heart Disease in Children
Neuroprotection
Keywords: Congenital Heart Disease
Neuroprotection
Allopurinol
Brain injury
Cardiopulmonary bypass
Brain function
Brain oxygenation
Cardiac function
Neurodevelopmental outcome
Cardiac surgery
Hypoxic-ischemic brain injury
Neonates
Lead sponsor: UMC Utrecht
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
name: University Medical Center Groningen
name: Erasmus Medical Center
name: University Medical Center Nijmegen
name: ACE Pharmaceuticals BV
First posted: 2020-01-03
Enrollment: 236
Sex: ALL
Maximum age (years): 1
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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".

Primary outcomes:
measure: Relevant parenchymatous brain injury on postoperative MRI
timeFrame: between birth and 1 month after cardiac surgery
measure: Rate of children that are considered 'too unstable for postoperative MRI'
timeFrame: between birth and 1 month after cardiac surgery
measure: Incidence of mortality
timeFrame: between birth and 1 month after cardiac surgery
Secondary outcomes:
measure: Brain injury severity score on pre- and postoperative MRI
timeFrame: between birth and 1 month after cardiac surgery
measure: Volume of hypoxic-ischemic brain injury on pre- and postoperative MRI
timeFrame: between birth and 1 month after cardiac surgery
measure: Global ventricular function (normal, mildly, moderately, severely, reduced) pre- and postoperatively
timeFrame: between birth and 1 month after cardiac surgery
measure: Ventricular ejection fraction (%) pre- and postoperatively
timeFrame: between birth and 1 month after cardiac surgery
measure: Brain function: Seizure activity on aEEG (presence or absence) postnatally and postoperatively
timeFrame: 24-36 hours after birth, 6 hours before surgery, 48-72 hours after surgery
measure: Brain oxygenation: Regional cerebral oxygen saturation (%) postnatally and postoperatively
timeFrame: 24-36 hours after birth, 6 hours before surgery, 48-72 hours after surgery
measure: General movements and motor optimality score
timeFrame: at 3 months
measure: Neurodevelopment
timeFrame: at 24 months
measure: Quality of Life (scores and subscores): TNO-AZL TAPQoL
timeFrame: at 24 months
Other outcomes:
Locations:
city: Groningen
country: Netherlands
facility: University Medical Center Groningen (UMCG)
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center Nijmegen (Radboudumc)
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center Rotterdam (Erasmus MC)
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht (UMC Utrecht)
Study officials:
affiliation: University Medical Center Utrecht (UMC Utrecht)
name: Manon JNL Benders, Prof. MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Medical Center Utrecht (UMC Utrecht)
name: Johannes (Hans) MPJ Breur, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Medical Center Utrecht (UMC Utrecht)
name: Nicolaas (Koos) JG Jansen, MD PhD
role: STUDY_DIRECTOR
affiliation: University Medical Center Utrecht (UMC Utrecht)
name: Raymond Stegeman, MD
role: STUDY_DIRECTOR
References:
citation: 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.