Evaluation of Reduced Immunosuppression Regimen with Tacrolimus, Prednisolone, and Mycophenolate Sodium in Older Adult Kidney Transplant Recipients with End-Stage Renal Disease

The primary objective of this study is to evaluate the efficacy of a **lower immunosuppression regimen** compared to the standard regimen in terms of patient and graft survival during the first year after kidney transplantation in individuals with **end-stage renal disease**. This is clinically relevant as optimizing immunosuppression can potentially improve outcomes and reduce adverse effects in older adult kidney transplant recipients.

Secondary objectives include:

• Assessing the safety of a lower immunosuppression regimen compared to the standard regimen, with potential benefits in first-year patient mortality, surgical complications, hospitalization, viral infections due to CMV and BK, and patient's quality of life and frailty.
• Evaluating the effectiveness of a lower immunosuppression regimen in terms of graft primary non-function, allograft rejection, first-year allograft survival and function, and development of donor-specific antibodies (DSA).
• Exploring potential benefits of a lower immunosuppression regimen on markers of the net state of immunosuppression and infection during the first year after transplantation.
• Determining the proportion of patients who can maintain the prescribed immunosuppression without adverse events.
• Estimating the 5-year death-censored graft survival with a lower immunosuppression regimen.

The clinical trial involves participants diagnosed with **end-stage renal disease** who are undergoing renal transplantation. The study population includes both male and female subjects aged 70 years and older. Participants are required to be in generally stable health to undergo transplantation, with specific criteria such as a pre-transplant calculated panel reactive antibody (cPRA) of 50% or less and a kidney with a cold ischemia time of less than 30 hours. The trial does not include vulnerable populations. Lifestyle considerations such as diet and physical activity are not specified. The total number of participants is not provided by the sponsor. Selection criteria include the ability to understand and provide written informed consent, and male participants are required to use a dual barrier method of contraception. The trial aims to evaluate the effectiveness of a lower immunosuppression regimen compared to the standard regimen in terms of patient and graft survival during the first year post-transplantation.

The clinical trial is designed as a **randomized**, open, prospective, parallel-group study with a duration of 12 months. The primary objective is to evaluate the efficacy of a reduced immunosuppression regimen compared to the standard regimen in patients with **end-stage renal disease** who have undergone kidney transplantation. The trial will assess patient and graft survival over the first year post-transplantation. Participants will be randomly assigned to one of the treatment arms, receiving either the reduced or standard immunosuppression regimen. The study will involve the administration of **tacrolimus**, **prednisolone**, **mycophenolate sodium**, **basiliximab**, and **methylprednisolone**, with specific dosing regimens and routes of administration, including oral and intravenous methods.

The trial will commence with an inclusion (screening) visit to determine eligibility based on criteria such as age, transplant history, and pre-transplant conditions. Participants must be 70 years or older, receiving their first ABO-compatible renal transplant, and meet other specified criteria. Following the screening, eligible participants will be enrolled and randomized into the study. The trial will include several follow-up visits to monitor the participants' health status, medication adherence, and any adverse events. These visits will occur at regular intervals throughout the study duration, with specific assessments conducted at 1, 3, 6, and 12 months. The end-of-study visit will occur at the 12-month mark, where final evaluations of patient and graft outcomes will be conducted.

Participant involvement is expected to last for the entire 12-month period unless early termination is warranted. Conditions that may lead to early termination include significant adverse events, non-compliance with the study protocol, or withdrawal of consent. The primary endpoint is the composite outcome of patient survival with a functioning graft at 12 months. Secondary endpoints include mortality rates, incidence of graft rejection, and other clinical outcomes. The trial will also explore additional parameters such as viral infections, immune response markers, and quality of life assessments. The estimated recruitment start date is July 2025, with the trial expected to conclude by June 2029.

The clinical trial involves the administration of several medications, each with specific roles and administration protocols. **Tacrolimus** is utilized as an experimental medication in this study. It is administered orally in a pharmaceutical form identified as PHF00170MIG. The dosage is calculated based on body weight, with a maximum daily dose of 0.1 mg/kg and a total maximum dose of 36.5 mg/kg over a treatment period of up to 12 months. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

**Prednisolone** is another medication used in the trial, administered orally in the form PHF00245MIG. The maximum daily dose is set at 20 mg, with a total maximum dose of 2210 mg over a treatment period of up to 363 days. This medication serves as a standard-of-care therapy, and its administration is closely monitored to ensure participant compliance and safety.

**Mycophenolate Sodium** is included in the study as an auxiliary treatment. It is provided in a gastro-resistant tablet form, with a maximum daily dose of 1.44 g and a total maximum dose of 30.24 g over a 42-day period. The administration route is oral, and participant adherence to the dosing regimen is evaluated regularly.

**Basiliximab** is administered intravenously as part of the trial's auxiliary treatments. The pharmaceutical form is identified as PHF675, with a maximum daily dose of 20 mg and a total maximum dose of 40 mg over a 2-day period. This medication is used to support the primary treatment regimen, and its administration is carefully controlled and documented.

Additionally, **Methylprednisolone Acetate** combined with **Lidocaine Hydrochloride Monohydrate** is administered intravenously. The pharmaceutical form is PHF00243MIG, with a maximum daily dose of 250 mg and a total maximum dose of 375 mg over a 2-day period. This combination serves as a comparator treatment, and its administration is monitored to ensure consistency and participant safety.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the composite outcome of patient survival with a functioning graft at 12 months in both treatment arms. This will provide a direct measure of the effectiveness of the reduced immunosuppression regimen compared to the standard regimen in maintaining graft function and patient survival.

Secondary endpoints include a variety of clinical outcomes and measures. These encompass mortality for any reason, rate of primary non-function graft, incidence of surgical complications, days of hospitalization, number of readmissions and their causes, and incidence of **Cytomegalovirus (CMV)** and **BK viremia**. Additionally, the incidence of CMV invasive disease, BK nephropathy, clinical graft acute rejection, and subclinical graft rejection will be evaluated. Graft function will be assessed through estimated glomerular filtration rate (eGFR) and proteinuria at 12 months, along with donor-specific antibodies (DSA) and estimated 5-year death-censored graft survival using the iBox prognostication system.

Patient-reported outcomes and measures (PREM and PROMS) will be collected at randomization and at 12 months. Frailty will be assessed using the Fried and FRAIL scale before transplant and at 12 months. Exploratory endpoints include Torquetenovirus RT-PCR at 1, 3, 6, and 12 months, and the count of CD4/CD8 lymphocyte subpopulations, C3 levels, and IgG levels at 1, 3, and 12 months. These assessments will be conducted in both treatment arms to provide a comprehensive evaluation of the trial's efficacy.