Phase II Randomized Study Comparing Custodiol-N and Custodiol Cardioplegia in Pediatric Congenital Heart Malformation Surgery

The primary objective of this clinical trial is the **safety assessment** of two methods of cardioplegia in cardiac surgery for congenital heart malformation in children. This is achieved through continuous adverse events (AEs) reporting up to 30 days postoperatively and evaluating myocardial protection in surviving patients by quantifying perioperative CK-MB levels until postoperative day 2 and postoperative day 7 or discharge. This is clinically relevant as it aims to ensure the safety and efficacy of cardioplegia solutions, which are critical in protecting the heart during surgery.

Secondary objectives include:

• Description of **hemodynamics**, including vital signs, blood gas parameters, catecholamine support, and milrinone support.
• Description of echocardiography findings.
• Description of cardiac injury, including creatinine kinase and troponin levels.
• Assessment of hospital/ICU stay, including readmissions and duration, as well as mortality.
• Description of surgical procedures, including the number of intraoperative administrations/re-administrations of cardioplegia.
• Description of 12-Lead-ECG findings.
• Description of cardiac arrhythmias, including the need for a pacemaker.

The clinical trial involves a study population comprising **children** with **congenital heart malformation**. Participants range in age from birth to less than 18 years, encompassing both male and female subjects. The trial includes a vulnerable population, as it involves minors undergoing congenital heart surgery with cardiopulmonary bypass and cardioplegia. The sponsor has not provided the total number of participants. Selection criteria necessitate written informed consent from patients and/or their legal guardians, who must also demonstrate an understanding of the trial's nature and implications. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial's primary focus is on assessing safety through continuous adverse events reporting and myocardial protection in surviving patients.

The clinical trial is a **prospective randomized, single-blind, multicenter phase II study** designed to compare two methods of cardioplegia in cardiac surgery for children with **congenital heart malformation**. The trial involves the use of two products: Custodiol-N and Custodiol, both of which are solutions used for organ preservation and cardioplegia, respectively. The primary objective is to assess the safety of these methods, focusing on continuous adverse events reporting up to 30 days postoperatively and myocardial protection, as measured by perioperative CK-MB levels until postoperative day 7 or discharge. Secondary endpoints include the description of hemodynamics, cardiac injury, hospital/ICU stay, and cardiac arrhythmias.

The trial is expected to commence recruitment on March 31, 2025, and conclude by September 30, 2027. Participants will be involved in the study from birth to less than 18 years of age, provided they are undergoing congenital heart surgery with cardiopulmonary bypass and cardioplegia. Written informed consent from the patients and/or their legal guardians is required before enrollment. The study design includes an initial screening visit to confirm eligibility based on the inclusion criteria, followed by the surgical procedure and subsequent follow-up visits to monitor safety and efficacy outcomes. The end-of-study visit will occur on postoperative day 7 or at discharge, whichever comes first.

Participants are expected to be involved in the study for a maximum of 30 days postoperatively. Conditions that may lead to early termination from the study include withdrawal of consent by the legal guardians, significant protocol deviations, or any adverse events that compromise the safety of the participant. The trial is not categorized as low intervention and is classified as a therapeutic exploratory and confirmatory trial, focusing on a novel formulation of an existing product. The study aims to provide valuable insights into the safety and efficacy of these cardioplegia methods in pediatric cardiac surgery.

The clinical trial involves the use of two experimental medications: **Custodiol® - Perfusionslösung** and **Custodiol-N**. **Custodiol® - Perfusionslösung** is a **solution for cardioplegia** used in cardiac surgery. It is administered via **infiltration** and is composed of several active substances, including **mannitol**, **tryptophan**, **magnesium chloride hexahydrate**, **potassium chloride**, **sodium chloride**, **calcium chloride dihydrate**, **L-histidine**, **L-histidine hydrochloride**, and **oxogluric acid**. The maximum daily and total dose is 50 milliliters per kilogram, with a treatment period limited to one day. This solution is intended for heart perfusion and is not a pediatric formulation.

**Custodiol-N** is a **solution for organ preservation** also administered via **infiltration**. It contains a complex mixture of active substances, including **alanine**, **arginine**, **deferoxamine**, **histidine**, **aspartic acid**, **glycine**, **tryptophan**, **sucrose**, **calcium**, **magnesium**, **potassium**, **sodium**, **N-hydroxy-3,4-dimethoxy-N-methyl-benzamide**, **N-acetylhistidine**, **chloride ion**, and **oxogluric acid**. The maximum daily and total dose for Custodiol-N is 60 milliliters per kilogram, with a treatment period also limited to one day. This solution is used for organ preservation and is not formulated for pediatric use.

Both solutions are manufactured by **DR. FRANZ KÖHLER CHEMIE GMBH** and are composed entirely of chemical substances. The trial aims to compare the efficacy and safety of these two methods of cardioplegia in pediatric cardiac surgery due to congenital heart malformation. Participant compliance and dosing schedules are monitored to ensure adherence to the protocol. No non-experimental treatments, such as standard-of-care therapy or placebo, are used in this study.

Efficacy in this clinical trial will be assessed through the primary endpoint of **myocardial protection** in surviving patients. This will be evaluated by quantifying perioperative CK-MB levels (U/l) until postoperative day 7, with the area under the curve being a key measure. Secondary endpoints include a comprehensive description of hemodynamics, such as vital signs, blood gas parameters, and the need for catecholamine and milrinone support. Additional assessments will cover cardiac injury markers like creatinine kinase and troponin, as well as hospital and ICU stay metrics, including readmissions and duration, and mortality rates. The trial will also document the number of intraoperative administrations of cardioplegia, 12-lead ECG results, and the occurrence of cardiac arrhythmias, including the need for a pacemaker.