A non-inferiority, randomised and controlled trial to compare the safety, tolerability and preliminary efficacy between standard and Torque Teno virus-guided immunosuppression in stable adult kidney transplant recipients with low immunological risk in the first year after transplantation

The primary objective of this study is to demonstrate the **non-inferiority** of Torque Teno virus (TTV)-guided immunosuppression compared to standard tacrolimus (TAC) dosing in terms of safety, tolerability, and preliminary efficacy in stable adult kidney transplant recipients with low immunological risk during the first year post-transplantation. This is clinically relevant as it may offer a personalized approach to immunosuppression, potentially reducing adverse effects and improving patient outcomes.

Secondary objectives include the assessment of TTV-guided immunosuppression in stable adult kidney transplant patients with low immunological risk in the first year after transplantation according to secondary endpoints. This evaluation aims to further understand the potential benefits and limitations of TTV-guided therapy in this patient population.

The clinical trial involves participants who are **post kidney transplantation** recipients. The study population includes both male and female adults aged 18 years and older. Participants are stable kidney transplant patients with low immunological risk in the first year after transplantation. The trial population was selected based on specific criteria, including being at least 93 days post-transplantation and receiving TAC-based immunosuppression. The study does not provide information on the total number of participants. Participants are required to have provided written informed consent. The trial includes a vulnerable population, and lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided data on the total number of participants.

The clinical trial is designed as a **randomized**, controlled study to evaluate the safety, tolerability, and preliminary efficacy of Torque Teno virus-guided immunosuppression compared to standard tacrolimus dosing in stable adult kidney transplant recipients. The trial is conducted in a **double-blind** manner to ensure unbiased results. The study targets individuals who have undergone kidney transplantation and are at low immunological risk within the first year post-transplantation. The trial is expected to last until May 2025, with participant recruitment having commenced in August 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as being an adult recipient of a kidney allograft, post day 93 following transplantation, and currently on tacrolimus-based immunosuppression. Written informed consent is required. Follow-up visits will be scheduled to monitor the primary and secondary endpoints, which include the occurrence of infectious disease events, allograft rejection, death, and graft loss. Secondary endpoints will assess individual components of the primary endpoint, estimated glomerular filtration rate, and other health-related measures.

The expected length of participant involvement is up to 36 months, corresponding to the maximum treatment period with tacrolimus. Conditions that may lead to early termination from the study include the development of severe adverse events or non-compliance with study protocols. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the overall outcomes of the trial. The study aims to provide valuable insights into the optimization of immunosuppressive therapy in kidney transplant recipients.

The clinical trial involves the administration of **Tacrolimus**, a chemical compound used as an immunosuppressant. The study utilizes three different pharmaceutical forms of Tacrolimus. The first form is a **prolonged-release capsule, hard**, designed for oral administration. The dosage is calculated based on the participant's body weight, with a maximum daily dose of 0.3 mg/kg and a total maximum dose of 75.6 mg/kg over the treatment period. The treatment duration is set for a maximum of 36 months. Participants are required to take the medication orally, and compliance is monitored through regular assessments.

The second form of Tacrolimus used in the trial is a **concentrate for solution for infusion**. This form is administered via infusion, allowing for direct delivery into the bloodstream. The dosing regimen mirrors that of the oral form, with a maximum daily dose of 0.3 mg/kg and a total maximum dose of 75.6 mg/kg over the course of the study. The infusion is conducted under controlled conditions to ensure accurate dosing and participant safety.

The third form is a **capsule, hard**, also intended for oral administration. Similar to the prolonged-release capsule, the dosage is determined by the participant's weight, with the same maximum daily and total dose limits. The treatment period is consistent across all forms, with a maximum duration of 36 months. Participants are instructed to adhere to the dosing schedule, and compliance is monitored through periodic evaluations.

In addition to the experimental treatments, the study may include standard-of-care therapy as a comparator to evaluate the efficacy and safety of Tacrolimus in different formulations. No placebo is used in this trial. The study aims to assess the non-inferiority of Torque Teno virus-guided immunosuppression compared to standard Tacrolimus dosing in stable adult kidney transplant recipients with low immunological risk within the first year post-transplantation.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is a composite measure that includes the occurrence of infectious disease events requiring inpatient treatment, application of anti-infective drugs, or reduction of immunosuppression, excluding SARS-CoV-2 infections. It also includes allograft rejection detected upon indication biopsy, death, and graft loss. These events will be monitored and recorded throughout the trial duration.

Secondary endpoints will provide additional insights into the efficacy of the treatment. These include the evaluation of single components of the composite primary endpoint, the composite of all primary endpoint components with specific scoring by medical personnel, and the assessment of severe infections and rejections. Other secondary measures include the estimated glomerular filtration rate (eGFR) using current CKD EPI and MDRD methods, rejection detected by protocol biopsy at month 12 post-transplantation, and the presence of **de novo** donor-specific antibodies (DSA). Plasma Torque Teno Virus (TTV) load, **TAC** trough level and dose, and changes in TAC trough target levels will also be assessed.

Additional secondary endpoints involve health-related quality of life measured by SF-36 and MTSOSD-59R questionnaires, drug adherence assessed through various methods including MEMS® Buttons and the BAASIS questionnaire, and the occurrence of adverse events and serious adverse events (AEs/SAEs). The development of malignancies and episodes of infection due to SARS-CoV-2 will also be monitored. These efficacy parameters will be collected and analyzed at specified time points throughout the trial to determine the non-inferiority of TTV-guided immunosuppression compared to standard TAC dosing in stable adult kidney transplant recipients.