Efficacy of Tocilizumab in Chronic Active Antibody-Mediated Rejection in Kidney Transplant Recipients: A Randomized Controlled Multicenter Study

The primary objective of this study is to evaluate the efficacy of adding **tocilizumab** (TCZ) to the standard of care (SOC) in comparison to SOC alone in slowing the decline of graft function in kidney transplant recipients with late/chronic active antibody-mediated rejection (AMR). This is assessed by the estimated glomerular filtration rate (eGFR) at 24 months after the start of treatment. The clinical relevance of this objective lies in its potential to improve long-term graft survival and function, which is critical for the quality of life and health outcomes of kidney transplant recipients.

Secondary objectives include:

• Comparing the efficacy between treatment regimens by assessing differences from baseline in the composite iBox risk prediction score at 12 and 24 months.
• Assessing the safety of TCZ for the treatment of late/chronic active AMR over a 24-month period.
• Comparing efficacy by evaluating differences in the evolution of donor-specific antibodies (DSA) and their strength, graft histology, proteinuria, renal function (measured GFR and eGFR), patient survival, and graft survival (overall and death-censored) at various time points.
• Evaluating the incidence and Banff-grade of acute rejection and new chronic active T-cell mediated rejection.
• Assessing transplant-specific well-being, adherence to immunosuppressive medications, and perceived threat of graft rejection, as well as identifying differences in responsiveness and adherence to treatment in relation to demographic factors and treatment arms.

The clinical trial focuses on individuals diagnosed with **chronic active antibody-mediated rejection** in kidney transplant recipients. The study population includes both male and female participants aged 18 years and older, who are at least six months post-transplantation. Participants must have a biopsy-proven diagnosis of late active or chronic active antibody-mediated rejection according to the Banff 2022 criteria. The trial does not involve a vulnerable population. Participants are required to have an estimated glomerular filtration rate (eGFR) of at least 20 ml/min/1.73 m², and female participants of childbearing potential must use adequate contraception and have a negative pregnancy test. Additionally, individuals previously infected with COVID-19 must be asymptomatic for at least one month before the screening visit and re-established on background immunosuppressants for at least one month prior to randomization. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed as a **randomized controlled open-label multicenter study** to evaluate the efficacy of adding **tocilizumab** to the standard of care (SOC) in slowing the decline of graft function in kidney transplant recipients with late or chronic active antibody-mediated rejection (AMR). The trial will assess the primary endpoint of the mean rate of change in estimated glomerular filtration rate (eGFR) from baseline to 24 months after the start of treatment. Secondary endpoints include changes in composite iBox risk score, safety profiles, evolution of donor-specific antibodies (DSA), histologic changes, proteinuria, renal function, and incidence of patient and graft survival over a period of 36 months.

Participants will be involved in the study for a maximum duration of 36 months, with the treatment period lasting 24 months. The trial will commence with a screening visit to confirm eligibility based on criteria such as age, post-transplantation period, biopsy-proven diagnosis of AMR, and eGFR levels. Following randomization, participants will undergo regular follow-up visits at 1 month, then every 3 months, to monitor eGFR and other secondary endpoints. The end-of-study visit will occur at 36 months to evaluate long-term outcomes.

Inclusion criteria require participants to be at least 18 years old, recipients of a kidney transplant from either a living or deceased donor, and at least 6 months post-transplantation. Participants must have a biopsy-proven diagnosis of late or chronic active AMR and meet specific health conditions, including being EBV IgG-positive and asymptomatic for COVID-19 for at least one month prior to the screening visit. Female participants of childbearing potential must use adequate contraception and have a negative pregnancy test. Conditions for early termination from the study include withdrawal of consent, significant adverse events, or non-compliance with study procedures.

The clinical trial involves the administration of **tocilizumab**, marketed under the name RoActemra, as the experimental medication. RoActemra is provided as a 162 mg **solution for injection** in a pre-filled syringe. The pharmaceutical form is a solution intended for subcutaneous injection. The maximum daily dose is 162 mg, with a total maximum dose of 16,848 mg over the treatment period. The administration schedule involves subcutaneous injections, with the frequency determined by the study protocol. The treatment period extends up to 24 months. Tocilizumab is a protein-based therapeutic agent, specifically classified under the ATC code L04AC07, and is not designated as an orphan drug. Participant compliance with the dosing regimen will be monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental treatment, the study includes a standard-of-care (SOC) therapy as a comparator. The primary objective is to evaluate the efficacy of adding tocilizumab to the SOC in slowing the decline of graft function in kidney transplant recipients with late/chronic active antibody-mediated rejection (AMR). The SOC therapy will be administered according to established clinical guidelines and practices, serving as a control to assess the added benefit of tocilizumab. The study is designed as a randomized controlled open-label multicenter trial, ensuring rigorous evaluation of the treatment outcomes.

The efficacy of the clinical trial will be assessed primarily by evaluating the mean rate of change in the estimated glomerular filtration rate (**eGFR**) from baseline to 24 months after the start of treatment. This will be measured at 1 month, then every 3 months for 36 months, using the Modification of Diet for Renal Disease (MDRD) 4-variable equation, which is particularly effective in predicting kidney function in transplant recipients. The testing will be conducted by accredited chemistry laboratories.

Secondary efficacy endpoints include changes from baseline in the mean composite iBox risk score at 12 and 24 months, evolution of donor-specific antibodies (DSA) at 12, 24, and 36 months, and histologic changes in protocol biopsy at 12 and 24 months. Additional assessments will include changes in proteinuria, renal function as measured by iohexol clearance and eGFR, and incidence of patient and graft survival, acute rejection, and chronic active T-cell mediated rejection at specified intervals. Patient-reported outcomes related to transplant-specific well-being, symptom burden, and adherence to immunosuppressive medications will also be evaluated at baseline, 12, 24, and 36 months.