This study has been transitioned to CTIS with ID 2024-513041-37-00 check the CTIS register for the current data. Primary objective of this study is to significantly reduce relevant (moderate/severe) parenchymatous brain injury on postoperative MRI…
ID
Source
Brief title
Condition
- Congenital cardiac disorders
- Cardiac and vascular disorders congenital
- Congenital and peripartum neurological conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary outcome is a composite endpoint of relevant (moderate/severe)
parenchymatous brain injury on postoperative MRI or too instable for
postoperative MRI or mortality.
A sample size of 236 patients (both with prenatal and postnatal diagnosis), of
which 188 patients with a prenatal diagnosis is needed, when allopurinol is
hypothesized to reduce the primary outcome with 20% compared to placebo
(two-sided alpha 5%, power 80%). The effect size of 20% is a relevant and
viable expectation, and is based on the results of previous neuroprotective
studies on neonatal head cooling and allopurinol in neonates with brain injury
due to perinatal asphyxia and around cardiac surgery. Primary analysis will be
performed with 1 interim analysis at n=118 for the total group and at n=94 for
the prenatal diagnosis group, with the option to stop for (1) efficacy, based
on O'Brien Flemming type alpha-spending, or (2) futility, based on conditional
power analysis. Forty-eight patients with postnatal diagnosis will be enrolled
and secondary analyses for primary outcome assessment.
Secondary outcome
Secondary outcome measures are PK of allopurinol (subgroup); redox and
antioxidant state of allopurinol (subgroup); brain injury score and volume of
hypoxic-ischemic brain injury (MRI); cardiac function (echocardiography,
subgroup MRI); brain function (amplitude integrated electroencephalogram aEEG);
brain oxygenation (near-infrared spectroscopy NIRS); motor outcome at 3 months
(general movements GMs); cognitive, motor, speech/language outcome at 24 months
(Bayley scales of infant development Bayley-III-NL); quality of life at 24
months (TNO-AZL TAPQoL questionnaire); cost-effectiveness of allopurinol at 3
and 24 months.
Background 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 behavioural 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 early postnatally
and perioperatively reduces hypoxic-ischemic brain injury, is cardioprotective
and safe.
Study objective
This study has been transitioned to CTIS with ID 2024-513041-37-00 check the CTIS register for the current data.
Primary objective of this study is to significantly reduce relevant
(moderate/severe) parenchymatous brain injury on postoperative MRI for the
total group (both prenatal and postnatal diagnosis) and the prenatal diagnosis
group, which is needed to apply for market registration of allopurinol for this
indication in the prenatal diagnosis group. Additionally, to show a beneficial
trend in the postnatal diagnosis group. Secondary objectives are to improve
cardiac function, brain function and oxygenation and neurodevelopmental outcome
and to investigate pharmacokinetics (PK), redox and antioxidant state and
cost-effectiveness of allopurinol, and quality of life.
Study design
The proposed study is a phase III, randomized, double-blinded,
placebo-controlled, Dutch multicenter trial. All 4 Dutch Pediatric
Cardiothoracic Surgery Centers will participate, including (1) University
Medical Center (UMC) Utrecht (sponsor), (2) UMC Groningen, and (3) Erasmus
Medical Center (EMC) Rotterdam and RadboudUMC Nijmegen.
Intervention
Prenatal diagnosis:
Allopurinol powder for solution for infusion (PFI) 20 mg/kg or mannitol
PFI-placebo will be administered early postnatally (within 45 minutes and 12
hours after the first dose), preoperatively (12 hours before surgery),
intraoperatively (during start of cardiopulmonary bypass) and postoperatively
(24 hours after surgery) to the neonate in case of a prenatal CCHD diagnosis.
Postnatal diagnosis:
Allopurinol PFI 20 mg/kg or mannitol PFI-placebo will be administered
preoperatively (12 hours before surgery), intraoperatively (during start of
cardiopulmonary bypass) and postoperatively (24 hours after surgery) to the
neonate in case of a postnatal CCHD diagnosis.
Study burden and risks
In this study population most of the study procedures are considered as
standard clinical care, including echocardiography, aEEG/NIRS (and MRI of the
brain, GMs, and BSITD-III-NL within the UMC Utrecht). Study related procedures
are MRI of the brain, GMs, BSITD-III-NL (in the participating centers other
than UMC Utrecht), and TAPQoL and HTA questionnaires (in all centers).
Additionally, only in the UMC Utrecht in a subpopulation blood samples will be
taken for determination of pharmacokinetics of allopurinol, and cardiac MRI*s
will be performed (immediately after clinically indicated brain MRIs). After
completion of the pharmacokinetics sub-study, a redox sub-study with blood- and
urine sampling will be carried out in both the UMC Utrecht and the EMC
Rotterdam to determine the effect of allopurinol on the redox/antioxidant
status.
All prior preclinical and clinical studies in neonates show potential neuro-
and cardioprotective effects of allopurinol without relevant side effects. The
potential advantages of allopurinol administration in neonates with critical
congenital heart disease outweigh the burden and risks, which are minimal.
There is a considerable change that allopurinol reduces (hypoxic-ischemic)
brain injury, improves cardiac function and long term neurodevelopmental
outcome (quality of life) in the group neonates receiving allopurinol. In
addition, the risk on side effects through the study medication is much smaller
than the risk on brain injury, lifelong handicaps and death due to the
underlying critical congenital heart disease.
Lundlaan 6
Utrecht 3584 EA
NL
Lundlaan 6
Utrecht 3584 EA
NL
Listed location countries
Age
Inclusion criteria
Neonates with a prenatally or postnatally confirmed diagnosis of CCHD requiring
(anticipated) cardiac surgery with CBP within the first 4 weeks of life are
eligible for inclusion. This includes neonates with the following cardiac
defects 1) Transposition of the great arteries with or without a ventricular
septal defect undergoing arterial switch operation with ventricular septal
defect closure if needed; 2) Univentricular hearts: hypoplastic left and right
heart syndrome, or variant undergoing Norwood Stage I or Sano palliation; 3)
Aortic arch anomalies: interrupted, hypoplastic aortic arch and/or coarctation
of the aorta with or without intracardiac defects (ventricular/atrial septal
defect, or (sub)aortic stenosis) who undergo complete biventricular repair
and/or aortic arch repair; 4) Other variants: truncus arteriosus, total
anomalous pulmonary venous connection, or tetralogy of Fallot. Written informed
consent of both parents is required prior to inclusion.
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*.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-513041-37-00 |
| EudraCT | EUCTR2017-004596-31-NL |
| ClinicalTrials.gov | NCT04217421 |
| CCMO | NL62772.041.18 |