AzTrials
AzTrials

Congenital Heart Disease in ChildrenPhase 3CRUCIALNCT04217421

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

A Phase 3 study testing Allopurinol and Mannitol in people with Congenital Heart Disease in Children and Neuroprotection, run by dr. M.J.N.L. Benders at 4 sites in Netherlands.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages Up to 1 month
What is being tested?
Allopurinol and Mannitol
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
236 participants
Where
4 sitesNetherlands
Study dates
14 Feb 2020to 31 Dec 2028
Phase
Phase 3
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 1 month
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • 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.

Who cannot join

  • 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".

Trial locations and contacts

4 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Manon JNL Benders, Prof. MD PhD contact

0031887554545

m.benders@umcutrecht.nl

Maaike Nijman, MD contact

m.nijman@umcutrecht.nl

Netherlands4 sites, 3 recruiting

  • University Medical Center Groningen (UMCG)

    Groningen, 9700 RB

    Arend F Bos, Prof. MD PhD

    Nicolaas (Koos) JG Jansen, MD PhD

    Recruiting

  • Radboud University Medical Center Nijmegen (Radboudumc)

    Nijmegen, 6525 GA

    Active, not recruiting

  • Erasmus Medical Center Rotterdam (Erasmus MC)

    Rotterdam, 3015 GD

    Ingrid M van Beynum, MD PhD

    Ingrid M van Beynum, MD PhD

    Recruiting

  • University Medical Center Utrecht (UMC Utrecht)

    Utrecht, 3584 EA

    Manon JNL Benders, Prof. MD PhD

    Maaike Nijman, MD

    Recruiting

Other trials in Netherlands

About this study

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.

Being tested
Allopurinol, Mannitol
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
Medical subject headings
Heart Defects, Congenital, Brain Injuries, Hypoxia-Ischemia, Brain

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AllopurinolDrug

    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.

  • MannitolDrug

    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.

Study groups in NCT04217421
Study groupRoleWhat they receive
AllopurinolActive comparatorNot described
Receives: Drug: Allopurinol
PlaceboPlacebo comparatorNot described
Receives: Drug: Mannitol

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: between birth and 1 month after cardiac surgery

  2. 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.

    Measured: between birth and 1 month after cardiac surgery

  3. Incidence of mortality

    Defined as death until one month postoperatively.

    Measured: between birth and 1 month after cardiac surgery

Secondary outcomes (9)

  1. 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).

    Measured: between birth and 1 month after cardiac surgery

  2. 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].

    Measured: between birth and 1 month after cardiac surgery

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

    Measured: between birth and 1 month after cardiac surgery

  4. Ventricular ejection fraction (%) pre- and postoperatively

    Measured: between birth and 1 month after cardiac surgery

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

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

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

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

  7. 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).

    Measured: at 3 months

  8. 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).

    Measured: at 24 months

  9. 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).

    Measured: at 24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted3 Jan 2020
  2. Study start14 Feb 2020
  3. Primary completion31 Oct 2026 (estimated)
  4. Study completion31 Dec 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
236 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04217421
Sponsor's protocol ID
METC UMCU 18-791
Other IDs
2017-004596-31, 2017
Acronym
CRUCIAL
Status last verified
May 2024
First submitted
12 Nov 2019
Last updated
16 May 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

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.

    PubMed 35197082

  • 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.

    PubMed 39147988

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Allopurinol and Mannitol in people with Congenital Heart Disease in Children and Neuroprotection, run by dr. M.J.N.L. Benders at 4 sites in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 16 May 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Manon JNL Benders, Prof. MD PhD (0031887554545, m.benders@umcutrecht.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Relevant parenchymatous brain injury on postoperative MRI (time frame: between birth and 1 month after cardiac surgery). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04217421, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 May 2024.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in