Evaluation of Allopurinol Sodium for Cerebral and Cardiac Protection in Neonates with Critical Congenital Heart Disease Undergoing Cardiopulmonary Bypass

The primary objective of this study is to assess whether early postnatal and perioperative administration of **allopurinol** compared to placebo (mannitol) reduces moderate to severe parenchymatous brain injury in neonates with critical congenital heart disease undergoing cardiac surgery with cardiopulmonary bypass. This is clinically relevant as it aims to mitigate brain injury, a significant complication in this vulnerable population, potentially improving neurological outcomes.

Secondary objectives include evaluating the effect of allopurinol on various parameters: - Brain injury severity score and volume of hypoxic-ischemic injury as observed on MRI. - Brain function using amplitude-integrated electroencephalogram and oxygenation assessed by near-infrared spectroscopy. - Cardiac function through echocardiography. - Neurodevelopmental outcomes, including general movements, Bayley scales of infant development, and executive functioning. - Quality of life. - Cost-effectiveness of allopurinol treatment.

The clinical trial involves **neonates** diagnosed with critical congenital heart disease, necessitating neonatal cardiac surgery with cardiopulmonary bypass within the first four weeks of life. The study population includes both male and female subjects, and it is noted that the participants are considered a vulnerable population due to their age and medical condition. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on a confirmed diagnosis of critical congenital heart disease, either prenatally or postnatally. No specific lifestyle considerations such as diet or physical activity are mentioned, given the age and health status of the participants. The study aims to assess the impact of early postnatal and perioperative administration of allopurinol compared to placebo on reducing moderate to severe parenchymatous brain injury in this specific patient group.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy of **allopurinol sodium** in reducing brain injury in neonates with critical congenital heart disease requiring cardiac surgery with cardiopulmonary bypass. The trial will involve the administration of allopurinol sodium or a placebo (mannitol) intravenously. The primary objective is to assess whether allopurinol reduces moderate to severe parenchymatous brain injury as observed on postoperative MRI. The trial is expected to commence recruitment on July 31, 2024, and conclude by October 31, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the diagnosis of critical congenital heart disease. The inclusion criteria specify neonates requiring cardiac surgery within the first four weeks of life. Following the screening, participants will be randomly assigned to receive either the active treatment or placebo. The study will include follow-up visits to monitor brain injury severity, brain function, cerebral oxygenation, and cardiac function through various assessments such as MRI, electroencephalogram, and echocardiography. The end-of-study visit will evaluate neurodevelopmental outcomes and quality of life at 24 months, using standardized scales and questionnaires.

The expected duration of participant involvement is up to 24 months, with the possibility of early termination if the participant experiences significant adverse events, becomes too unstable for postoperative MRI, or in the event of mortality. The trial will also explore secondary endpoints, including the cost-effectiveness of allopurinol and its pharmacokinetics in a substudy. The study is categorized as a Phase III trial and is not considered low intervention. The trial's design ensures rigorous assessment of the primary and secondary outcomes, contributing valuable data to the understanding of allopurinol's potential benefits in this vulnerable population.

The clinical trial involves the administration of **ACEPURIN**, a pharmaceutical formulation containing **allopurinol sodium** as the active substance. This medication is provided in the form of a **solution for infusion** and is intended for intravenous administration. The dosage is calculated based on the participant's body weight, with a maximum daily dose of 40 mg/kg and a total maximum dose of 120 mg/kg. The treatment period is limited to one day. The medication is manufactured by ACE Pharmaceuticals BV and is classified under the ATC code M04AA01, which corresponds to allopurinol. The primary objective of the trial is to assess the efficacy of allopurinol in reducing moderate to severe parenchymatous brain injury in newborns with critical congenital heart disease undergoing cardiac surgery with cardiopulmonary bypass.

The study also includes a **placebo** group, where participants receive a placebo formulation known as **Placebo Mannitol 100mg pfi**. This placebo is administered intravenously, mirroring the administration route of the experimental medication. The placebo is designed to match the experimental treatment in terms of appearance and administration schedule, ensuring blinding of the study. The maximum daily and total doses for the placebo are identical to those of the experimental treatment, set at 40 mg/kg and 120 mg/kg, respectively, over a one-day treatment period. The use of a placebo allows for a controlled comparison to evaluate the true efficacy of allopurinol sodium in the target population.

Efficacy in this clinical trial will be assessed through a combination of primary and secondary endpoints. The primary endpoint is a composite measure that includes the occurrence of relevant (moderate/severe) parenchymatous brain injury as observed on postoperative MRI, instability preventing postoperative MRI, or mortality. Secondary endpoints encompass a range of parameters to provide a comprehensive evaluation of the intervention's impact. These include the **brain injury severity score** and the volume of hypoxic-ischemic brain injury assessed via pre- and postoperative MRI, brain function evaluated through postnatal and perioperative amplitude-integrated electroencephalogram for background pattern and seizure activity, and cerebral oxygenation measured using postnatal and perioperative near-infrared spectroscopy.

Additional secondary endpoints involve cardiac function assessed by pre- and postoperative echocardiography, neurodevelopmental outcomes evaluated through general movements at 3 months and the Bayley scales of infant development and executive functioning testing at 24 months, and quality of life measured by the TNO-TAPQOL at 24 months. The cost-effectiveness of allopurinol will be analyzed using questionnaires administered during the hospital stay at 3 and 24 months. Furthermore, a substudy will investigate the pharmacokinetics of allopurinol postnatally and perioperatively. These assessments will be conducted at specified timepoints to ensure a thorough analysis of the treatment's efficacy in neonates with critical congenital heart disease undergoing cardiac surgery with cardiopulmonary bypass.