Phase III Randomized Study on Organ Preservation in Liver Transplantation: Custodiol-N Solution Versus Custodiol Solution

The primary objective of this study is to evaluate the **area under the curve (AUC)** of **GPT (ALT)** after liver transplantation over a period of 7 days. This measurement is clinically relevant as it provides insight into liver function and potential injury post-transplantation, which is critical for assessing the efficacy of organ preservation solutions.

Secondary objectives include:

• Evaluating the absolute peak **LDH** within 7 days after transplantation.
• Assessing initial poor function based on specific laboratory parameters, including bilirubin, **INR**, and transaminase levels, according to Olthoff criteria.
• Determining the day of peak **GPT** and peak LDH.
• Measuring serum bilirubin, **GOT**, GPT, LDH, total albumin, and **PT** at 3 and 6 months post-transplantation.
• Evaluating biliary complications, such as episodes of cholestasis, therapy for cholangitis, biliary leakage, and strictures.
• Comparing liver transplants using extended criteria donors (ECD) and DCD donors with both preservation solutions.

The clinical trial involves participants who are **recipients** awaiting their first **liver transplantation**. The study population includes both male and female subjects aged 18 years and older. Participants are required to provide signed informed consent for data use and protection prior to transplantation. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on specific inclusion criteria, such as being a recipient of a full organ transplantation. No additional lifestyle considerations, such as diet or physical activity, have been specified for this study.

The clinical trial is a **randomized**, single-blind, multicenter Phase III study designed to evaluate the efficacy of Custodiol-N solution compared to Custodiol solution in **liver transplantation**. The primary objective is to assess the area under the curve (AUC) of GPT (ALT) levels post-transplantation over a period of seven days. The trial is expected to commence on April 1, 2022, and conclude by January 31, 2025. Participants will be randomly assigned to receive either Custodiol-N or Custodiol solution, with the study maintaining a controlled environment to ensure the reliability of results.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as being a recipient awaiting their first transplant, being 18 years or older, and providing informed consent. Following the transplantation, daily assessments of GPT levels will be conducted for the first seven days. Secondary endpoints include the evaluation of peak LDH levels, application of Olthoff criteria, and MEAF score, among others. Follow-up visits will occur at three and six months post-transplantation to measure parameters like serum bilirubin and total albumin.

The expected duration of participant involvement is approximately 10 months, encompassing the initial screening, transplantation, and follow-up assessments. Conditions that may lead to early termination from the study include withdrawal of consent or any adverse events that compromise participant safety. The trial's design ensures that data collected will contribute to understanding the comparative effectiveness of the two solutions in organ preservation during liver transplantation.

The clinical trial involves the use of two experimental medications: **Custodiol** and **Custodiol-N**. **Custodiol** is a solution formulated for cardioplegia and organ preservation. It contains active substances such as **mannitol**, **histidine**, **histidine hydrochloride monohydrate**, **tryptophan**, **magnesium chloride hexahydrate**, **potassium chloride**, **sodium chloride**, **calcium chloride dihydrate**, and **oxogluric acid**. The pharmaceutical form is a solution, and it is administered via infiltration. The maximum daily dose is 4 liters, with a total maximum dose of 6 liters over a treatment period of 1 day. This product is used as a comparator in the study.

**Custodiol-N** is a solution specifically for organ preservation. It includes active substances such as **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**. Similar to Custodiol, it is administered via infiltration with a maximum daily dose of 4 liters and a total maximum dose of 6 liters over a 1-day treatment period. Custodiol-N serves as the test product in this trial.

Both solutions are classified under blood substitutes and perfusion solutions, and they are not formulated for pediatric use. The trial aims to evaluate the efficacy of these solutions in liver transplantation, specifically assessing the area under the curve (AUC) of GPT (ALT) levels post-transplantation over a 7-day period. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol.

Efficacy in this clinical trial will be assessed by evaluating the **area under the curve (AUC) GPT (ALT)** after liver transplantation over a period of 7 days. This primary endpoint involves measuring the GPT levels once per day for each liver transplant patient enrolled in the study, following the standard practice of the center laboratory. The AUC will be analyzed to compare the efficacy between the Custodiol and Custodiol-N groups.

Secondary endpoints include the absolute peak of lactate-dehydrogenase (LDH) within 7 days post-transplantation, assessed according to the site laboratory's practice. The Olthoff criteria will be applied to evaluate initial poor function, with parameters such as bilirubin levels, international normalized ratio of prothrombin (INR), and aminotransferase levels being considered. Additional assessments include the MEAF score, evaluation of the peak GPT and LDH moments, and measurement of serum bilirubin, GOT, GPT, LDH, total albumin, and PT at 3 and 6 months post-transplantation.

Further evaluations will consider the number of cholestasis episodes, therapy for cholangitis, and episodes of biliary leakage and strictures. Comparisons will also be made in liver transplants involving Extended Criteria Donors (ECD) and Donation after Circulatory Death (DCD) donors, focusing on the influence of Custodiol-N. These efficacy parameters will be collected and analyzed according to the standard practices and reference values of the site laboratories involved in the trial.