Evaluation of Tacrolimus and Ciclosporin in Preventing HLA Sensitization in Patients with Late Renal Graft Failure: A Randomized Controlled Trial

The primary objective of this study is to compare the degree of **HLA sensitization** at 2 years in patients with late renal graft failure, defined as occurring more than 3 months post-transplantation. This comparison is between patients receiving reduced immunosuppressant treatment and those who stop immunosuppression at 6 months. Understanding the impact of immunosuppression on HLA sensitization is clinically relevant as it may influence the management of immunosuppressive therapy in patients with late renal graft failure, potentially affecting their eligibility for future transplants.

Secondary objectives include comparing the following outcomes at 2 years between the two treatment groups: - Mortality for any reason - Days of hospitalization for any reason - Percentage of patients effectively relisted during follow-up - Percentage of patients transplanted - Percentage of patients delisted for any reason - Incidence of infection - Incidence of cardiovascular events - Incidence of cancer - Incidence of graft-intolerance syndrome requiring graft nephrectomy or percutaneous embolization of the non-functioning graft - Erythropoietin resistance index - Residual renal function - Number of circulating memory B-cells. Additionally, the study aims to compare the incidence of adverse events in both treatment arms. These secondary objectives are crucial for evaluating the broader clinical implications of modifying immunosuppressive therapy in this patient population.

The clinical trial involves participants who have experienced **renal transplantation** and are facing late renal graft failure, defined as occurring more than three months post-transplant. The study population includes both male and female subjects, aged 18 years and older, who have previously received at least one renal transplant. Participants are required to have a retained kidney graft that has failed for any reason but survived at least three months. They must be on dialysis, either hemodialysis or peritoneal dialysis, for a maximum of six months at the time of randomization, while maintaining an uninterrupted immunosuppressive regimen of calcineurin inhibitors, such as tacrolimus or cyclosporine, and steroids. The trial does not involve a vulnerable population. Participants are either already relisted or candidates to relist for deceased donor kidney transplantation, as per the treating physician's criteria. The sponsor has not provided the total number of participants involved in the study.

The clinical trial is designed as a **randomized**, open, prospective, parallel-group study with a duration of 24 months. The primary objective is to compare the degree of human leukocyte antigen (HLA) sensitization at two years in patients with late renal graft failure who receive reduced immunosuppressant treatment versus those who stop immunosuppression at six months. The trial involves the use of **tacrolimus** and **ciclosporin**, administered orally in various formulations, including hard capsules, soft capsules, and prolonged-release tablets. The maximum treatment period for participants is 720 days, with a maximum daily dose of 20 mg for tacrolimus and 500 mg for ciclosporin.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, previous renal transplant history, and current dialysis status. Following randomization, participants will be monitored through regular follow-up visits to evaluate the degree of HLA sensitization and other health parameters. The end-of-study visit will occur at the 24-month mark, where the primary endpoint, the difference in HLA sensitization between the two treatment arms, will be assessed. The expected length of participant involvement is up to 24 months, with conditions for early termination including non-compliance with the study protocol or adverse health events that necessitate withdrawal.

The clinical trial involves the administration of several **experimental medications**. One of the primary medications is Prograf, which contains the active substance **tacrolimus**. Prograf is available in hard capsule form with dosages of 0.5 mg, 1 mg, and 5 mg. The medication is administered orally, with a maximum daily dose of 20 mg and a total maximum dose of 14400 mg over a treatment period of up to 720 days. The pharmaceutical form is a hard capsule, and the medication is produced by Astellas Pharma S.A.

Another experimental medication used in the trial is Sandimmun Neoral, which contains the active substance **ciclosporin**. This medication is available in soft capsule form with dosages of 25 mg, 50 mg, and 100 mg. It is also administered orally, with a maximum daily dose of 500 mg and a total maximum dose of 360000 mg over the same treatment period of 720 days. Sandimmun Neoral is manufactured by Novartis Farmacéutica S.A.

Advagraf, another formulation containing **tacrolimus**, is used in the trial in the form of prolonged-release hard capsules. Available dosages include 0.5 mg, 1 mg, 3 mg, and 5 mg. The administration route is oral, with the same dosing limits as Prograf, and it is produced by Astellas Pharma Europe B.V.

Conferoport, also containing **tacrolimus**, is provided in prolonged-release hard capsules with dosages of 0.5 mg, 1 mg, 2 mg, 3 mg, and 5 mg. The administration is oral, with a maximum daily dose of 20 mg and a total maximum dose of 14400 mg over 720 days. This medication is manufactured by Sandoz Farmacéutica, S.A.

Envarsus, another **tacrolimus** formulation, is available in prolonged-release tablet form with dosages of 0.75 mg, 1 mg, and 4 mg. It is administered orally, with the same dosing limits as other tacrolimus formulations, and is produced by Chiesi Farmaceutici S.p.A.

Adoport, containing **tacrolimus**, is available in hard capsule form with dosages of 0.5 mg, 1 mg, 2 mg, and 5 mg. The administration is oral, with a maximum daily dose of 20 mg and a total maximum dose of 14400 mg over 720 days. This medication is manufactured by Sandoz Farmacéutica, S.A.

All medications are administered orally, and participant compliance is monitored throughout the trial. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The focus is on evaluating the effects of these immunosuppressive agents in patients with late renal graft failure.

Efficacy in this clinical trial will be assessed by evaluating the primary endpoint, which is the difference in the degree of human leukocyte antigen (HLA) sensitization between the two treatment arms at two years. This will be measured using the calculated panel reactive antibody (cPRA) percentage. The trial involves patients with late renal graft failure who are either continuing immunosuppression or stopping it at six months. The cPRA percentage will be collected and analyzed to determine the level of HLA sensitization, providing a quantitative measure of the immune response in patients. The assessment will be conducted at the two-year mark to compare the outcomes of the two different treatment strategies. The trial is designed to ensure that the data collected is robust and reliable, allowing for a clear comparison of the efficacy of continued versus discontinued immunosuppression in preventing HLA sensitization.