Evaluation of Immunosuppression Management Using BK Polyomavirus-Specific T Cells in BKPyV DNAemia Post-Kidney Transplantation with Prednisolone and Drug Combination

The primary objective of this study is to demonstrate that not reducing **immunosuppressive therapy** in the experimental group is non-inferior to reducing immunosuppressive therapy according to standard care guidelines in the control group. This is evaluated with regard to the time to end of **BK Polyomavirus DNAemia** in kidney transplant patients diagnosed with BKPyV-DNAemia (≥ 10,000 IU/ml) and BKPyV-specific CD4 T cells ≥0.5 cells/µl. This objective is clinically relevant as it aims to optimize immunosuppressive management in patients with BKPyV-DNAemia, potentially improving patient outcomes and reducing the risk of graft loss.

Secondary objectives include: - Demonstrating that not reducing immunosuppressive therapy is superior to reducing it concerning renal function. - Evaluating the correlation between BKPyV-specific CD4 T cells, doses, and trough levels of immunosuppressants. - Showing that treatment decisions based on BKPyV-specific CD4 T cells are feasible. These objectives aim to further understand the relationship between immunosuppressive therapy and BKPyV-specific immune responses, which could lead to more personalized and effective treatment strategies.

The clinical trial involves participants diagnosed with **BK Polyomavirus DNAemia** following kidney transplantation. The study population includes both male and female subjects, encompassing a vulnerable population. Participants are selected based on specific inclusion criteria, such as having undergone kidney transplantation, presenting with BKPyV-DNAemia levels of at least 10,000 IU/ml, and possessing BKPyV-specific CD4 T cells equal to or greater than 0.5 cells/µl. The age range of participants spans from children to adults, specifically those aged 7 to 18 years, as well as adults. The trial does not provide information on the total number of participants, as this data was not disclosed by the sponsor. Participants are required to maintain their current immunosuppression regime without changes for at least four weeks prior to trial entry. Lifestyle considerations include adherence to contraceptive measures for both men and women of childbearing potential. The trial aims to assess the non-inferiority of not reducing immunosuppressive therapy compared to the standard care guidelines in terms of the time to resolution of BKPyV-DNAemia.

The clinical trial is designed to evaluate the **safety** and efficacy of immunosuppressive therapy management in patients with **BK Polyomavirus DNAemia** following kidney transplantation. This trial employs a randomized, double-blind, controlled design to compare the outcomes of maintaining versus reducing immunosuppressive therapy. The primary objective is to determine if maintaining immunosuppression is non-inferior to the standard care of reducing it, with the primary endpoint being the time to resolution of BK Polyomavirus DNAemia. The trial is expected to span a duration of approximately seven years, with recruitment starting in April 2025 and concluding in October 2032.

Participants will undergo a series of study visits, beginning with an inclusion visit to assess eligibility based on criteria such as kidney transplantation status and specific **BK Polyomavirus** markers. Follow-up visits will occur regularly to monitor the primary and secondary endpoints, including changes in estimated glomerular filtration rate, occurrence of acute rejection episodes, and levels of BK Polyomavirus-specific CD4 T cells. The end-of-study visit will finalize data collection and assess the long-term outcomes of the treatment strategies.

Participant involvement is anticipated to last up to nine months, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include significant protocol deviations, adverse events, or withdrawal of consent. The trial will utilize a range of immunosuppressive agents, including **prednisolone**, **mycophenolate mofetil**, **sirolimus**, **belatacept**, **tacrolimus**, **everolimus**, **azathioprine**, **ciclosporin**, and **mycophenolic acid**, administered either orally or via intravenous infusion, depending on the specific agent. The trial is classified as a low-intervention study, reflecting its focus on optimizing existing therapeutic strategies rather than introducing new treatments.

The clinical trial involves the administration of several **experimental medications** to evaluate their safety and efficacy in the context of BK Polyomavirus DNAemia after kidney transplantation. **Prednisolone** is administered in the form of a gastro-resistant tablet. The maximum daily dose is 250 mg, with a total maximum dose of 68,437.5 mg over a treatment period of up to 9 months. The route of administration is oral.

**Mycophenolate mofetil** is provided as a film-coated tablet, with a maximum daily dose of 2 g and a total maximum dose of 547.5 g over the same treatment period. This medication is also administered orally.

**Sirolimus** is administered as a coated tablet, with a maximum daily dose of 40 mg and a total maximum dose of 10,950 mg. The administration route is oral, and the treatment period is up to 9 months.

**Belatacept** is delivered as a solution for infusion, with a maximum daily dose of 6 mg/kg and a total maximum dose of 1,642 mg/kg. The route of administration is intravenous infusion, and the treatment period is up to 9 months.

**Tacrolimus** is provided in the form of a prolonged-release capsule, with a maximum daily dose of 0.30 mg/kg and a total maximum dose of 82.12 mg/kg. The administration route is oral, with a treatment period of up to 9 months.

**Everolimus** is administered as tablets, with a maximum daily dose of 10 mg and a total maximum dose of 2,737.5 mg. The route of administration is oral, and the treatment period is up to 9 months.

**Azathioprine** is provided as a film-coated tablet, with a maximum daily dose of 4 mg/kg and a total maximum dose of 1,095 mg/kg. The administration route is oral, with a treatment period of up to 9 months.

**Ciclosporin** is administered as a soft capsule, with a maximum daily dose of 6 mg/kg and a total maximum dose of 1,642.5 mg/kg. The route of administration is oral, and the treatment period is up to 9 months.

**Mycophenolic acid** is provided as a gastro-resistant tablet, with a maximum daily dose of 1,440 mg and a total maximum dose of 394,200 mg. The administration route is oral, with a treatment period of up to 9 months.

All medications are administered according to the specified dosing schedules, and participant compliance is monitored throughout the trial. The trial aims to assess the non-inferiority of not reducing immunosuppressive therapy compared to standard care guidelines in patients with BK Polyomavirus DNAemia.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the time from randomization to the end of **BK Polyomavirus (BKPyV)-DNAemia**, defined as the first time point after randomization with BKPyV DNA levels below 1,000 IU/ml or a decline in BKPyV DNA of more than 1 log10 IU/ml, which is recognized as a surrogate marker for the clearance of BKPyV infection. Secondary endpoints include changes from baseline to month 9 in estimated glomerular filtration rate (eGFR), occurrence of acute rejection episodes, occurrence of donor-specific antibodies, occurrence of graft loss, number and dose of immunosuppressants, trough levels of immunosuppressants, overall and CNI immunosuppressive scale (IS) units, level of BKPyV-specific CD4 T cells, and occurrence of BKPyV re-infections.