Comparison of Custodiol-N and Custodiol Solutions for Organ Perfusion in Pediatric Heart Transplantation: A Phase II Randomized Single-Blind Multicenter Study

The primary objective of this study is to evaluate the **safety** of two organ preservation solutions, Custodiol and Custodiol-N, in pediatric patients undergoing heart transplantation. This is clinically relevant as ensuring the safety of preservation solutions is critical to improving transplant outcomes and minimizing adverse events in this vulnerable population. Continuous adverse event reporting will be conducted up to 3 months to assess safety.

Secondary objectives include:

• Monitoring vital parameters up to day 7.
• Conducting laboratory tests, including cardiac troponin and creatinine kinase (CKMB), up to day 7.
• Assessing haemodynamics from the termination of cardiopulmonary bypass until transfer to the intensive care unit (ICU).
• Recording death occurrences up to 3 months.
• Evaluating graft survival up to 3 months.
• Tracking readmission to ICU up to 3 months.
• Measuring the length of ICU stay up to 3 months.
• Determining catecholamine requirements up to day 7.
• Assessing the need for milrinone support up to day 7.
• Evaluating the need for pacemaker therapy up to day 7.
• Determining the need for mechanical circulatory support post-transplantation.
• Analyzing echocardiographic markers of function and rejection up to day 7.
• Monitoring cardiac arrhythmias up to day 7.

The clinical trial focuses on **paediatric patients** undergoing heart transplantation, specifically comparing the safety of two organ preservation solutions, Custodiol and Custodiol-N. The study population includes both male and female participants from birth to less than 18 years of age. Participants are recipients awaiting their first transplant and must be listed on the waiting list for heart transplantation. The trial involves a vulnerable population, as it includes children. The sponsor has not provided information regarding the total number of participants. Participants and/or their legal guardians must have the ability to understand the nature and consequences of the clinical trial, and written informed consent is required prior to enrolment. The trial does not specify any particular lifestyle considerations such as diet or physical activity. Deceased donors must meet the standard criteria for organ donation. The sponsor has not disclosed further details about the selection process or additional demographic characteristics of the trial population.

The clinical trial is a **prospective randomized single-blind multicenter phase II study** designed to evaluate the safety of two organ preservation solutions, Custodiol and Custodiol-N, in pediatric patients undergoing heart transplantation. The trial will involve participants from birth to less than 18 years of age who are awaiting their first heart transplant. The study will be conducted over an estimated period from April 1, 2023, to March 31, 2027. The trial will include a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as the ability to understand the trial and provide informed consent, and listing on the heart transplantation waiting list.

Participants will be randomly assigned to receive either Custodiol or Custodiol-N during the transplantation procedure. The primary endpoint is the safety assessment, which involves continuous adverse event reporting up to three months post-transplantation. Secondary endpoints include monitoring vital parameters, laboratory tests, and echocardiographic markers up to seven days, as well as graft survival, ICU readmission, and other clinical outcomes up to three months. Follow-up visits will occur at specified intervals to collect data on these endpoints, with the end-of-study visit marking the conclusion of participant involvement.

The expected length of participant involvement is up to three months, with conditions for early termination including withdrawal of consent or any adverse events that compromise participant safety. The trial's methodology ensures rigorous data collection and analysis to compare the safety profiles of the two solutions, contributing valuable insights into pediatric heart transplantation practices.

The clinical trial involves the use of two organ preservation solutions, **Custodiol-N** and **CUSTODIOL® - Perfusionslösung**, to assess their safety in pediatric patients undergoing heart transplantation. **Custodiol-N** is a **solution for organ preservation** that contains a combination 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 solution is administered via **infiltration** with a maximum daily dose of 60 milliliters per kilogram, and the treatment period is limited to one day. The solution is manufactured by DR. FRANZ KÖHLER CHEMIE GMBH and is not a pediatric formulation.

**CUSTODIOL® - Perfusionslösung** serves as the comparator treatment in this study. It is a **solution for cardioplegia** and includes active substances such as mannitol, tryptophan, magnesium chloride hexahydrate, potassium chloride, sodium chloride, calcium chloride dihydrate, L-histidine, L-histidine hydrochloride, and oxogluric acid. Similar to Custodiol-N, this solution is also administered via **infiltration** with a maximum daily dose of 60 milliliters per kilogram, and the treatment period is restricted to one day. This product is also produced by DR. FRANZ KÖHLER CHEMIE GMBH and is not specifically formulated for pediatric use.

Both solutions are used as part of the standard organ preservation protocol in the clinical trial, with the primary objective being the safety assessment through continuous adverse event reporting up to three months post-transplantation. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol.

The efficacy of the clinical trial will be assessed through a series of secondary endpoints designed to evaluate various physiological and clinical parameters in pediatric patients undergoing heart transplantation. These endpoints include the monitoring of vital parameters such as heart rate, blood pressure, and body temperature up to day 7 post-transplantation. Laboratory tests will be conducted to measure cardiac biomarkers, specifically cardiac **troponin** and creatinine kinase (CK-MB), with CK-MB peak values being recorded from 4 to 168 hours after the release of the aortic cross clamp. Measurements will be taken at specified intervals: 4, 8, 12, 16, 20, 24 hours ± 30 minutes, and 32, 40, 48, 56, 64, 72 hours ± 2 hours. The area under the curve (AUC) values for CK-MB and troponin will also be calculated from visits 1 to 7.

Additional assessments include hematology and clinical chemistry evaluations pre-operatively and during post-transplant visits 1, 3, and 7. Hemodynamic parameters will be recorded at the termination of cardiopulmonary bypass and at 4, 8, and 12 hours after aortic cross clamp release, but only until the patient is transferred to the intensive care unit. The trial will also track outcomes such as death, graft survival, and readmission to the ICU up to 3 months post-transplantation. Other parameters include the length of ICU stays, catecholamine requirement, antihypertensive intake, milrinone support, pacemaker therapy, and device therapy needs up to 3 months. Echocardiographic markers of cardiac function and rejection, such as ejection fraction and ventricular volumes, will be evaluated up to day 7, along with the occurrence, severity, and type of cardiac arrhythmias.