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

Primary Purpose

Congenital Heart Disease in Children, Neuroprotection

Status

Unknown status

Phase

Phase 3

Locations

Netherlands

Study Type

Interventional

Intervention

Allopurinol

Mannitol

About this trial

This is an interventional treatment trial for Congenital Heart Disease in Children focused on measuring Congenital Heart Disease, Neuroprotection, Allopurinol, Brain injury, Cardiopulmonary bypass, Brain function, Brain oxygenation, Cardiac function, Neurodevelopmental outcome, Cardiac surgery, Hypoxic-ischemic brain injury, Neonates

Eligibility Criteria

undefined - 1 Month (Child)All SexesDoes not accept healthy volunteers

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".

Sites / Locations

VU University Medical Center (VUmc)
Academic Medical Center (AMC)
University Medical Center Groningen (UMCG)
Leiden University Medical Center (LUMC)
Radboud University Medical Center Nijmegen (Radboudumc)
Erasmus Medical Center Rotterdam (Erasmus MC)
University Medical Center Utrecht (UMC Utrecht)Recruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Allopurinol

Placebo

Arm Description

Outcomes

Primary Outcome Measures

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.

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.

Incidence of mortality

Defined as death until one month postoperatively.

Secondary Outcome Measures

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).

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].

Global ventricular function (normal, mildly, moderately, severely, reduced) pre- and postoperatively

Ventricular ejection fraction (%) pre- and postoperatively

Brain function: Seizure activity on aEEG (presence or absence) postnatally and postoperatively

Brain oxygenation: Regional cerebral oxygen saturation (%) postnatally and postoperatively

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).

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).

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).

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).

Full Information

NCT ID

NCT04217421

First Posted

November 12, 2019

Last Updated

January 13, 2020

Sponsor

dr. M.J.N.L. Benders

Collaborators

ZonMw: The Netherlands Organisation for Health Research and Development, University Medical Center Groningen, Leiden University Medical Center, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), Amsterdam UMC, location VUmc, Erasmus Medical Center, University Medical Center Nijmegen, ACE Pharmaceuticals BV

1. Study Identification

Unique Protocol Identification Number

NCT04217421

Brief Title

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

Acronym

CRUCIAL

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2020

Overall Recruitment Status

Unknown status

Study Start Date

January 1, 2020 (Actual)

Primary Completion Date

June 1, 2021 (Anticipated)

Study Completion Date

June 1, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

dr. M.J.N.L. Benders

Collaborators

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

236 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Allopurinol

Arm Type

Active Comparator

Arm Title

Placebo

Arm Type

Placebo Comparator

Intervention Type

Drug

Intervention Name(s)

Allopurinol

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Mannitol

Intervention Description

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.

Primary Outcome Measure Information:

Title

Relevant parenchymatous brain injury on postoperative MRI

Description

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.

Time Frame

between birth and 1 month after cardiac surgery

Title

Rate of children that are considered 'too unstable for postoperative MRI'

Description

Time Frame

between birth and 1 month after cardiac surgery

Title

Incidence of mortality

Description

Defined as death until one month postoperatively.

Time Frame

between birth and 1 month after cardiac surgery

Secondary Outcome Measure Information:

Title

Brain injury severity score on pre- and postoperative MRI

Description

Time Frame

between birth and 1 month after cardiac surgery

Title

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

Description

Time Frame

between birth and 1 month after cardiac surgery

Title

Global ventricular function (normal, mildly, moderately, severely, reduced) pre- and postoperatively

Time Frame

between birth and 1 month after cardiac surgery

Title

Ventricular ejection fraction (%) pre- and postoperatively

Time Frame

between birth and 1 month after cardiac surgery

Title

Brain function: Seizure activity on aEEG (presence or absence) postnatally and postoperatively

Time Frame

24-36 hours after birth, 6 hours before surgery, 48-72 hours after surgery

Title

Brain oxygenation: Regional cerebral oxygen saturation (%) postnatally and postoperatively

Time Frame

24-36 hours after birth, 6 hours before surgery, 48-72 hours after surgery

Title

General movements and motor optimality score

Description

Time Frame

at 3 months

Title

Neurodevelopment

Description

Time Frame

at 24 months

Title

Executive functioning in comparison to healthy controls

Description

Time Frame

at 24 months

Title

Quality of Life (scores and subscores): TNO-AZL TAPQoL

Description

Time Frame

at 24 months

10. Eligibility

Sex

All

Maximum Age & Unit of Time

1 Month

Accepts Healthy Volunteers

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Manon JNL Benders, Prof. MD PhD

Phone

0031887554545

m.benders@umcutrecht.nl

First Name & Middle Initial & Last Name or Official Title & Degree

Maaike Nijman, MD

m.nijman@umcutrecht.nl

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Manon JNL Benders, Prof. MD PhD

Organizational Affiliation

University Medical Center Utrecht (UMC Utrecht)

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Johannes (Hans) MPJ Breur, MD PhD

Organizational Affiliation

University Medical Center Utrecht (UMC Utrecht)

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Nicolaas (Koos) JG Jansen, MD PhD

Organizational Affiliation

University Medical Center Utrecht (UMC Utrecht)

Official's Role

Study Director

First Name & Middle Initial & Last Name & Degree

Raymond Stegeman, MD

Organizational Affiliation

University Medical Center Utrecht (UMC Utrecht)

Official's Role

Study Director

Facility Information:

Facility Name

VU University Medical Center (VUmc)

City

Amsterdam

ZIP/Postal Code

1081 HV

Country

Netherlands

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Anton HLC van Kaam, Prof. MD PhD

First Name & Middle Initial & Last Name & Degree

Anton HLC van Kaam, Prof. MD PhD

Facility Name

Academic Medical Center (AMC)

City

Amsterdam

ZIP/Postal Code

1105 AZ

Country

Netherlands

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Anton HLC van Kaam, Prof. MD PhD

First Name & Middle Initial & Last Name & Degree

Anton HLC van Kaam, Prof. MD PhD

Facility Name

University Medical Center Groningen (UMCG)

City

Groningen

ZIP/Postal Code

9700 RB

Country

Netherlands

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Arend F Bos, Prof. MD PhD

First Name & Middle Initial & Last Name & Degree

Nicolaas (Koos) JG Jansen, MD PhD

First Name & Middle Initial & Last Name & Degree

Arend F Bos, Prof. MD PhD

First Name & Middle Initial & Last Name & Degree

Nicolaas (Koos) JG Jansen, MD PhD

Facility Name

Leiden University Medical Center (LUMC)

City

Leiden

ZIP/Postal Code

2333 ZA

Country

Netherlands

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Sylke J Steggerda, MD PhD

First Name & Middle Initial & Last Name & Degree

Sylke J Steggerda, MD PhD

Facility Name

Radboud University Medical Center Nijmegen (Radboudumc)

City

Nijmegen

ZIP/Postal Code

6525 GA

Country

Netherlands

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

W A Helbing, Prof. MD PhD

First Name & Middle Initial & Last Name & Degree

W A Helbing, Prof. MD PhD

Facility Name

Erasmus Medical Center Rotterdam (Erasmus MC)

City

Rotterdam

ZIP/Postal Code

3015 GD

Country

Netherlands

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Ingrid M van Beynum, MD PhD

First Name & Middle Initial & Last Name & Degree

Ingrid M van Beynum, MD PhD

Facility Name

University Medical Center Utrecht (UMC Utrecht)

City

Utrecht

ZIP/Postal Code

3584 EA

Country

Netherlands

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Manon JNL Benders, Prof. MD PhD

First Name & Middle Initial & Last Name & Degree

Maaike Nijman, MD

First Name & Middle Initial & Last Name & Degree

Manon JNL Benders, Prof. MD PhD

First Name & Middle Initial & Last Name & Degree

Johannes (Hans) MPJ Breur, MD PhD

First Name & Middle Initial & Last Name & Degree

Nicolaas (Koos) JG Jansen, MD PhD

First Name & Middle Initial & Last Name & Degree

Raymond Stegeman, MD

First Name & Middle Initial & Last Name & Degree

Maaike Nijman, MD

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

35197082

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.

Results Reference

derived

Learn more about this trial

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

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