Non-Inferiority Study of Custodiol-N Versus Custodiol for Organ Preservation in Kidney, Liver, and Pancreas Transplantation Recipients

The primary objective of this study is to demonstrate the **non-inferiority** of graft preservation using Custodiol-N solution compared to Custodiol solution in terms of graft function and injury following transplantation of the kidney, liver, or kidney-pancreas. This is clinically relevant as it aims to ensure that the new preservation solution is at least as effective as the existing standard, potentially offering an alternative option for organ preservation in transplantation procedures.

Secondary objectives include evaluating various parameters related to kidney, liver, and pancreas transplantation outcomes:

• Kidney: Incidence of primary poor function (creatinine >250 μmol/l at 3 months), serum creatinine, creatinine MDRD clearance, urea, and hemoglobin levels after 3 months, requirement of dialysis until 3 months post-transplantation, and biopsy-proven rejections.
• Liver: Absolute peak LDH within 7 days post-transplantation, timing of peak GPT and LDH, serum bilirubin, GOT, GPT, LDH, total albumin, and PT at 3 months, and biliary complications including episodes of cholestasis, therapy for cholangitis, biliary leakage, and biliary strictures.
• Pancreas: Insulin requirements on days 3 and 30 and after 3 months, levels of α-amylase, lipase, and C-reactive protein (CRP) at 1 and 3 days, C-peptide and HBA1c at day 30 and 3 months, pancreatic complications such as graft pancreatitis, anastomotic leak, vascular complications (thrombosis, stenosis, bleeding), and fasting glucose at 3 months.

The clinical trial involves **patients** who are scheduled to undergo kidney, liver, or kidney-pancreatic transplantation. The study population includes both male and female participants, with an age range of 18 years and older. The participants are generally in a state of health that allows them to be considered for organ transplantation. The total number of participants is not provided by the sponsor. The trial population was selected based on specific criteria, including adult donors who meet the criteria for organ donation, both deceased and living, as well as recipients who are awaiting transplantation and have provided signed informed consent. The study does not focus on a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted. Key inclusion criteria include being a recipient of a full organ transplantation and being at least 18 years of age.

The clinical trial is a **prospective**, **randomized**, single-blind, multicenter phase III study designed to evaluate the efficacy of Custodiol-N solution compared to Custodiol solution in organ transplantation, specifically for kidney, liver, and pancreas. The primary objective is to demonstrate the non-inferiority of Custodiol-N in terms of graft preservation, focusing on graft function and injury post-transplantation. The trial is expected to run from January 8, 2019, to December 31, 2025, with participants involved for a maximum treatment period of one day. The study includes a series of visits, beginning with a screening visit to assess eligibility based on criteria such as age (≥18 years) and consent. Follow-up visits will monitor primary endpoints like delayed graft function for kidneys and liver transplantation success, measured by the area under the curve of GPT (ALT) over the first seven days post-implantation. Secondary endpoints include kidney function parameters, liver enzyme levels, and pancreatic insulin requirements. The end-of-study visit will conclude the participant's involvement, assessing long-term outcomes at three months post-transplantation. Participants may be terminated early from the study if they do not meet ongoing eligibility criteria or if adverse events occur. The trial's design ensures rigorous assessment of the investigational product's safety and efficacy, contributing valuable data to the field of organ transplantation.

The clinical trial involves the use of two experimental medications, **Custodiol-N** and **CUSTODIOL® - Perfusionslösung**, both of which are solutions intended for organ preservation and cardioplegia, respectively. **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 3 liters and a maximum treatment period of 1 day. The formulation is of chemical origin and is not a pediatric formulation.

**CUSTODIOL® - Perfusionslösung** serves as the comparator treatment in this study. It is a **solution for cardioplegia** containing 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 3 liters and a maximum treatment period of 1 day. The formulation is of chemical origin and is not a pediatric formulation.

Both solutions are manufactured by DR. FRANZ KÖHLER CHEMIE GMBH and are used in the context of organ transplantation, specifically for the preservation of kidney, liver, and pancreas grafts. The trial aims to demonstrate the non-inferiority of Custodiol-N compared to CUSTODIOL® - Perfusionslösung in terms of graft function and injury post-transplantation. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

The efficacy of the clinical trial will be assessed by evaluating the non-inferiority of graft preservation using Custodiol-N compared to Custodiol in organ transplantation, specifically for kidney, liver, and pancreas. The primary endpoints for efficacy assessment include the incidence of **delayed graft function** for kidney transplants and the area under the curve (AUC) of GPT (ALT) measurements over the first 7 days post-implantation for liver transplants. Secondary endpoints for kidney transplants include the incidence of primary poor function, serum creatinine levels, creatinine MDRD clearance, urea, hemoglobin levels after 3 months, dialysis requirements, and biopsy-proven rejections. For liver transplants, secondary endpoints include the absolute peak LDH within 7 days, the timing of peak GPT and LDH, serum bilirubin, GOT, GPT, LDH, total albumin, PT at 3 months, and biliary complications. For pancreas transplants, secondary endpoints include insulin requirements on days 3 and 30 and after 3 months, levels of α-amylase, lipase, C-reactive protein (CRP) at 1 and 3 days, C-peptide and HBA1c at day 30 and 3 months, pancreatic complications, and fasting glucose at 3 months.