Overview
Sponsor-declared trial summary
Phase
Therapeutic confirmatory (Phase III)
Status
Authorised, recruiting
Participants planned
236
Countries
1
Sites
3
Brain injury in neonates with critical congenital heart disease requiring cardiac surgery with cardiopulmonary bypass.
To evaluate whether in newborns with critical congenital heart disease, early postnatal (after birth) and perioperative (around cardiac surgery with cardiopulmonary bypass) allopurinol compared to placebo (mannitol) administration reduces relevant (moderate / severe) parenchymatous brain injury on postoperative MRI.
Key facts
- Sponsor
- Universitair Medisch Centrum Utrecht
- Participant type
- Pediatric, Patients
- Age range
- 0-17 years
- Gender
- Male and Female
- Therapeutic area
- Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
- Trial duration
- 14 Feb 2020 → ongoing
- Decision date (initial)
- 2024-07-31
- Transition trial
- Yes
- Low-intervention
- No
- Rare-disease indication
- No
- Vulnerable population
- Yes
- Funding sources
- Stichting Hartekind · ZonMw · Friends of WKZ
External identifiers
- EU CT number
- 2024-513041-37-00
- EudraCT number
- 2017-004596-31
- ClinicalTrials.gov
- NCT04217421
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Therapy, Pharmacokinetic, Safety, Efficacy
To evaluate whether in newborns with critical congenital heart disease, early postnatal (after birth) and perioperative (around cardiac surgery with cardiopulmonary bypass) allopurinol compared to placebo (mannitol) administration reduces relevant (moderate / severe) parenchymatous brain injury on postoperative MRI.
Secondary objectives 6
- To evaluate the effect of allopurinol on: Brain injury severity score and volume of hypoxic-ischemic injury (MRI)
- To evaluate the effect of allopurinol on Brain function (amplitude integrated electroenchepalogram) and oxygenation (near-infrared spectroscopy).
- To evaluatie the effect of allopurinol on Cardiac function (echocardiography).
- To evaluate the effect of Allopurinol on Neurodevelopmental outcome (general movements, Bayley scales of infant development and executive functioning).
- To evaluate the effect of Allopurinol on quality of life
- To evaluate the cost-effectiveness of allopurinol
Conditions and MedDRA coding
Brain injury in neonates with critical congenital heart disease requiring cardiac surgery with cardiopulmonary bypass.
| Version | Level | Code | Term | System organ class |
|---|---|---|---|---|
| 20.0 | LLT | 10010495 | Congenital heart disease NOS | 10010331 |
| 21.1 | PT | 10067967 | Brain injury | 100000004852 |
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 1
- Neonates with a prenatally (before birth) or postnatally (after birth) confirmed diagnosis of critical congenital heart disease requiring neonatal cardiac surgery with cardiopulmonary bypass within the first 4 weeks of life
Exclusion criteria 6
- Inability to enroll the patient before the start of delivery, in case of prenatal diagnosis or 24h before surgery in case op 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.
- Patient considered "moribund".
- Decision for "comfort care only"
- Surgery not requiring cardiopulmonary bypass.
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 1
- Primary outcome is a composite endpoint of relevant (moderate / severe) parenchymatous brain injury on postoperative MRI or too instable for postoperative MRI or mortality.
Secondary endpoints 8
- Brain injury severity score and volume of hypoxic-ischemic brain injury (pre- and postoperative MRI)
- Brain function: background pattern and seizure activity (postnatal and perioperative amplitude integrated electroencephalogram).
- Cerebral oxygenation (postnatal and perioperative near-infrared spectroscopy).
- Cardiac function (pre- and postoperative echocardiography).
- Neurodevelopmental outcome (general movements at 3 months and Bayley scales of infant development and executive functioning testing at 24 months).
- Quality of life (TNO-TAPQOL at 24 months)
- Cost effectiveness of allopurinol (questionnaires during hospital stay at 3 and 24 months)
- Pharmacokinetics of allopurinol (substudy: postnatally, perioperatively)
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 1
ACEPURIN, poeder voor infusievloeistof 1g/100 ml
PRD844449 · Product
- Active substance
- Allopurinol Sodium
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 40 mg/kg milligram(s)/kilogram
- Max total dose
- 120 mg/kg milligram(s)/kilogram
- Max treatment duration
- 1 Month(s)
- Authorisation status
- Authorised
- ATC code
- M04AA01 — ALLOPURINOL
- Marketing authorisation
- RVG 09974
- MA holder
- ACE PHARMACEUTICALS BV
- MA country
- Netherlands
- Paediatric formulation
- No
- Orphan designation
- Yes
- Orphan designation number
- EU/3/15/1493
- Modified vs. Marketing Authorisation
- Yes
- Modification description
- A suitable allopurinol formulation for critically ill neonates was developed for safe administration of allopurinol already within the first 45 minutes of life. Dosing of allopurinol in the neonate will be 20 mg/kg BW per gift. The weight of a eutrophic term neonate is between 2500g and 4500g. Therefore, a quantity of 100 mg allopurinol per vial is most appropriate. Allopurinol 100 mg pfi (Allokid®) is based on the formulation, composition, and production process of the authorized product ACEPURIN® (1 g allopurinol pfi). The amount of excipients and active ingredient are adapted to obtain the desired 100 mg allopurinol per vial.
Placebo 1
N/A · Product
- Other product name
- N/A
- Pharmaceutical form
- N/A
- Route of administration
- INTRAVENOUS
- Max daily dose
- 40 mg/kg milligram(s)/kilogram
- Max total dose
- 120 mg/kg milligram(s)/kilogram
- Max treatment duration
- 1 Month(s)
- ATC code
- N/A — N/A
- Marketing authorisation
- N/A
- MA holder
- N/A
- MA country
- Iceland
- Paediatric formulation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
Universitair Medisch Centrum Utrecht
- Sponsor organisation
- Universitair Medisch Centrum Utrecht
- Address
- Heidelberglaan 100
- City
- Utrecht
- Postcode
- 3584 CX
- Country
- Netherlands
Scientific contact point
- Organisation
- Universitair Medisch Centrum Utrecht
- Contact name
- MJNL Benders
Public contact point
- Organisation
- Universitair Medisch Centrum Utrecht
- Contact name
- MJNL Benders
Locations
1 EU/EEA country · 3 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| Netherlands | Authorised, recruiting | 236 | 3 |
| Rest of world | — | 0 | — |
Investigational sites
Country notifications
Trial-start, recruitment-start, end and early-termination notifications submitted per Member State
| Country | Trial start | Trial end | Recruitment start | Recruitment end | Early termination |
|---|---|---|---|---|---|
| Netherlands | 2020-02-14 |
Oversight and notifications
Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77
Serious breaches 1 · Art. 52 CTR
Serious breach SB-114466
- Sponsor became aware
- 2026-01-12
- Date of breach
- 2026-01-11
- Submission date
- 2026-01-13
- Member states concerned
- Netherlands
- Categories
- Protocol
- Areas impacted
- Data reliability or robustness
- Benefit-risk balance changed
- No
- Description
- On 12 January 2026, participant CRUC-UMCU-096 was scheduled for surgery and was admitted to the Leeuw ward prior to the procedure. On Sunday evening, the ward was contacted regarding the administration of dose 3 at 9:00 PM, and again early Monday morning regarding the preparation of dose 4.
On Monday morning, 12 January, the nurse on duty discovered that the study medication box of CRUC-UMCU-096 contained 6 vials, instead of 5 vials, and informed the study team. At that time, another CRUCIAL study participant (CRUC-UMCU-097) was also admitted to the Leeuw ward, and one vial was missing from that participant’s study medication box.
It is therefore likely that during the evening shift, a vial was mistakenly taken from the study medication box of CRUC-UMCU-097 and placed in the medication box of CRUC-UMCU-096, constituting a mix-up of study medication and a deviation from protocol requirements regarding correct handling and allocation of investigational medicinal product.
Following this finding, the study team contacted the hospital pharmacy to verify whether the vials concerned contained the same study medication. This was confirmed. Subsequently, the Principal Investigator and Sub-Principal Investigator were informed about the incident. A protocol violation form was completed, and the event was reported as a serious breach in CTIS. - Sponsor actions
- 12-1-2025 Hospital pharmacy was informed.
12-01-2025 PI and sub PI were informed.
13-01-2026 Important deviation form was written and a serious breach was reported in CTIS.
In the future, when multiple CRUCIAL study participants are admitted to the ward simultaneously, nurses will be specifically reminded to ensure that they select the correct study medication box for each participant.
| Organisation | City | Country | Type |
|---|---|---|---|
| Universitair Medisch Centrum Utrecht | Utrecht | Netherlands | Sponsor (non commercial) |
Results and documents
Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial
Documents 10 files
Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.
| Type | Title | Version |
|---|---|---|
| Protocol (for publication) | D1_Protocol 2024-513041-37-00_CLEAN | 4 |
| Recruitment arrangements (for publication) | K1_Recruitment arrangements | 2 |
| Subject information and informed consent form (for publication) | L1_SIS ICF postnatale diagnose nl EMC_CLEAN | 6 |
| Subject information and informed consent form (for publication) | L1_SIS ICF postnatale diagnose nl UMCG_CLEAN | 6 |
| Subject information and informed consent form (for publication) | L1_SIS ICF postnatale diagnose nl UMCU_CLEAN | 6 |
| Subject information and informed consent form (for publication) | L1_SIS ICF prenatale diagnose nl EMC_CLEAN | 6 |
| Subject information and informed consent form (for publication) | L1_SIS ICF prenatale diagnose nl UMCG_CLEAN | 6 |
| Subject information and informed consent form (for publication) | L1_SIS ICF prenatale diagnose nl UMCU_CLEAN | 6 |
| Summary of Product Characteristics (SmPC) (for publication) | E2_SMPC Allopurinol | 2025-01 |
| Synopsis of the protocol (for publication) | D1_Protocol synopsis NL 2024-513041-37-00 | v2.4 |
Application history
3 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2024-07-08 | Netherlands | Acceptable with conditions 2024-07-31
|
2024-07-31 |
| 2 | SUBSTANTIAL MODIFICATION | SM-7 | 2025-06-06 | Netherlands | Acceptable 2025-08-20
|
2025-08-21 |
| 3 | SUBSTANTIAL MODIFICATION | SM-8 | 2026-03-02 | Netherlands | Acceptable 2026-04-09
|
2026-04-09 |