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| ID | Type | Description | Link |
|---|---|---|---|
| 2017-004596-31 | EudraCT Number |
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| Name | Class |
|---|---|
| ZonMw: The Netherlands Organisation for Health Research and Development | OTHER |
| University Medical Center Groningen | OTHER |
| Erasmus Medical Center | OTHER |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Allopurinol | Active Comparator |
| |
| Placebo | Placebo Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Manon JNL Benders, Prof. MD PhD | Contact | 0031887554545 | m.benders@umcutrecht.nl | |
| Maaike Nijman, MD | Contact | m.nijman@umcutrecht.nl |
| Name | Affiliation | Role |
|---|---|---|
| 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 |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Medical Center Groningen (UMCG) | Recruiting | Groningen | 9700 RB | Netherlands |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35197082 | Background | 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. | |
| 39147988 |
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| University Medical Center Nijmegen |
| OTHER |
| ACE Pharmaceuticals BV | OTHER |
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| 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. |
|
| 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 |
| 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 |
| 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 |
| Radboud University Medical Center Nijmegen (Radboudumc) | Active, not recruiting | Nijmegen | 6525 GA | Netherlands |
| Erasmus Medical Center Rotterdam (Erasmus MC) | Recruiting | Rotterdam | 3015 GD | Netherlands |
|
| University Medical Center Utrecht (UMC Utrecht) | Recruiting | Utrecht | 3584 EA | Netherlands |
|
| Derived |
| Chu WY, Nijman M, Stegeman R, Breur JMPJ, Jansen NJG, Nijman J, van Loon K, Koomen E, Allegaert K, Benders MJNL, Dorlo TPC, Huitema ADR; CRUCIAL trial consortium. Population Pharmacokinetics and Target Attainment of Allopurinol and Oxypurinol Before, During, and After Cardiac Surgery with Cardiopulmonary Bypass in Neonates with Critical Congenital Heart Disease. Clin Pharmacokinet. 2024 Aug;63(8):1205-1220. doi: 10.1007/s40262-024-01401-3. Epub 2024 Aug 15. |
| ID | Term |
|---|---|
| D006330 | Heart Defects, Congenital |
| D001930 | Brain Injuries |
| D020925 | Hypoxia-Ischemia, Brain |
| ID | Term |
|---|---|
| D018376 | Cardiovascular Abnormalities |
| D002318 | Cardiovascular Diseases |
| D006331 | Heart Diseases |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D006259 | Craniocerebral Trauma |
| D020196 | Trauma, Nervous System |
| D014947 | Wounds and Injuries |
| D002545 | Brain Ischemia |
| D002561 | Cerebrovascular Disorders |
| D002534 | Hypoxia, Brain |
| D014652 | Vascular Diseases |
| D000860 | Hypoxia |
| D012818 | Signs and Symptoms, Respiratory |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000493 | Allopurinol |
| D008353 | Mannitol |
| ID | Term |
|---|---|
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D013402 | Sugar Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
| D002241 | Carbohydrates |
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