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

NCT04217421 | Recruiting Phase 3 DMC

• 2 other identifiers: METC UMCU 18-7912017-004596-31
• Study Type: interventional
• Target: 236
• Locations: 1 country
• Sites: 4

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.

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

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (9)

• Brain injury severity score on pre- and postoperative MRI

  between birth and 1 month after cardiac surgery

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

  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

Study Arms (2)

Allopurinol

ACTIVE COMPARATOR

Drug: Allopurinol

Placebo

PLACEBO COMPARATOR

Drug: Mannitol

Interventions

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.

Allopurinol

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.

Placebo

Eligibility Criteria

• Age: Up to 1 Month
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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".

Sponsors & Collaborators

• dr. M.J.N.L. Benders: lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator
• University Medical Center Groningen: collaborator
• Erasmus Medical Center: collaborator
• University Medical Center Nijmegen: collaborator
• ACE Pharmaceuticals BV: collaborator

Study Sites (4)

University Medical Center Groningen (UMCG)

Groningen, 9700 RB, Netherlands

RECRUITING

Radboud University Medical Center Nijmegen (Radboudumc)

Nijmegen, 6525 GA, Netherlands

ACTIVE NOT RECRUITING

Erasmus Medical Center Rotterdam (Erasmus MC)

Rotterdam, 3015 GD, Netherlands

RECRUITING

University Medical Center Utrecht (UMC Utrecht)

Utrecht, 3584 EA, Netherlands

RECRUITING

Related 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.

  PMID: 35197082 BACKGROUND

MeSH Terms

Conditions

Heart Defects, Congenital; Brain Injuries; Hypoxia-Ischemia, Brain

Interventions

Allopurinol; Mannitol

Condition Hierarchy (Ancestors)

Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries; Brain Ischemia; Cerebrovascular Disorders; Hypoxia, Brain; Vascular Diseases; Hypoxia; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Sugar Alcohols; Alcohols; Organic Chemicals; Carbohydrates

Study Officials

• 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)

  PRINCIPAL INVESTIGATOR

• Nicolaas (Koos) JG Jansen, MD PhD

  University Medical Center Utrecht (UMC Utrecht)

  STUDY DIRECTOR

• Raymond Stegeman, MD

  University Medical Center Utrecht (UMC Utrecht)

  STUDY DIRECTOR

Central Study Contacts

Manon JNL Benders, Prof. MD PhD

CONTACT

0031887554545; m.benders@umcutrecht.nl

Maaike Nijman, MD

CONTACT

m.nijman@umcutrecht.nl

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor, Head of Neonatology, MD

Study Record Dates

• First Submitted: November 12, 2019
• First Posted: January 3, 2020
• Study Start: February 14, 2020
• Primary Completion (Estimated): October 31, 2026
• Study Completion (Estimated): December 31, 2028
• Last Updated: May 16, 2024

Record last verified: 2024-05

Locations

NL (4)