Efficacy of Prophylactic Rituximab in Preventing EBV Infection and PTLD in EBV-Negative Kidney Transplant Recipients

The primary objective of this study is to evaluate the efficacy of early infusion of **Rituximab** in preventing **Epstein-Barr virus (EBV)** primary infection and the occurrence of post-transplant lymphoproliferative disorder (PTLD) in EBV-negative kidney transplant recipients who receive a transplant from an EBV-positive donor. This is clinically relevant as it addresses the risk of serious complications associated with EBV in immunocompromised patients, potentially improving patient outcomes and graft survival.

Secondary objectives include:

• The occurrence of PTLD during the 5 post-transplant years.
• The occurrence of post-transplant EBV primary infection during the 5 post-transplant years.
• The kinetics of post-transplant EBV replication.
• The clinical presentation of EBV primary infection.
• The incidence of post-transplant EBV seroconversion during the 5 post-transplant years.
• The post-transplant immune reconstitution kinetics.
• The kidney allograft function and graft survival during the 5 post-transplant years.
• The recipient survival during the 5 post-transplant years.
• The tolerance of Rituximab.
• The incidence of opportunistic infections and malignancies during the 5 years after transplantation.
• The incidence of BK virus and Cytomegalovirus (CMV) infections post-transplantation.
• All the previous objectives in pediatric and adult sub-populations.

The clinical trial focuses on evaluating the efficacy of early infusion of Rituximab in preventing **Epstein Barr virus** (EBV) primary infection and post-transplant lymphoproliferative disorder (PTLD) in EBV-negative kidney transplant recipients with an EBV-positive donor. The study population includes both male and female participants, encompassing a wide age range from pediatric patients over 2 years to adults aged 18 years and older. Participants are selected based on their EBV seronegative status, confirmed by negative IgG anti-EBNA, IgG anti-VCA, and IgM anti-VCA tests conducted from six months before transplantation to the day of transplantation. The trial includes individuals undergoing kidney and kidney-pancreas simultaneous transplantation. Participants are required to have provided written informed consent, and female participants must have a negative pregnancy test and agree to use contraception throughout the study or for 12 months following the administration of Rituximab in case of early discontinuation. The trial involves a vulnerable population, but the total number of participants is not disclosed by the sponsor.

The clinical trial is designed as a **randomized**, double-blind, controlled study to evaluate the efficacy of prophylactic **Rituximab** in preventing **Epstein-Barr virus (EBV)** primary infection and post-transplant lymphoproliferative disorders in EBV-negative kidney transplant recipients. The trial will involve two arms, with participants randomly assigned to receive either Rituximab or a placebo. The study is expected to span approximately eight years, with an estimated recruitment start date of December 1, 2021, and an estimated end date of December 1, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, EBV serostatus, and informed consent. Following the initial visit, participants will receive the study drug via **intravenous infusion** and will be monitored through regular follow-up visits. These visits will occur at months 1, 2, 3, 6, 12, 24, 36, 48, and 60, during which various assessments will be conducted, including EBV viremia, seroconversion, and kidney function tests. The end-of-study visit will mark the conclusion of the participant's involvement in the trial.

The expected length of participant involvement is up to five years, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with study procedures. The primary endpoint is the one-year incidence of a composite criterion, including EBV primary infection and post-transplant lymphoproliferative disorder occurrence. Secondary endpoints include long-term incidence of PTLD, graft loss, and recipient survival, among others. The study aims to provide valuable insights into the prophylactic use of Rituximab in this patient population.

**Rituximab** is the experimental medication utilized in this clinical trial. It is a humanized anti-CD20 monoclonal antibody specifically targeting B lymphocytes, which serve as the natural reservoir for Epstein-Barr Virus (EBV). Rituximab is administered in the form of an **intravenous infusion**. The pharmaceutical form is designated as PHF00230MIG. The dosing regimen involves a maximum daily dose of 375 mg/m², with a total maximum dose of 400 mg/m². The treatment period is limited to a single administration. This medication is not formulated for pediatric use and is not classified as an orphan drug. The primary objective of administering Rituximab in this study is to evaluate its efficacy in preventing EBV primary infection and post-transplant lymphoproliferative disorder (PTLD) in EBV-negative kidney transplant recipients who have received an organ from an EBV-positive donor.

In addition to the experimental treatment, the study may involve the use of standard-of-care therapies as deemed necessary by the clinical investigators. However, no specific non-experimental treatments, such as placebo or comparator treatments, are explicitly mentioned in the trial data. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol. The trial is conducted under authorized conditions, with the status of the trial being "Authorised" as of the latest update. The study is designed to be a multicenter, randomized, two-arm trial, focusing on the prophylactic use of Rituximab in the specified patient population.

The efficacy of Rituximab in preventing **Epstein-Barr Virus (EBV)** primary infection and post-transplant lymphoproliferative disorder (PTLD) in EBV-negative kidney transplant recipients will be assessed through a series of primary and secondary endpoints. The primary endpoint is the 1-year incidence of a composite criterion, which includes EBV primary infection assessed by a positive blood EBV viral load and/or EBV seroconversion, and/or the occurrence of PTLD. Secondary endpoints include the incidence of PTLD at 1, 2, 3, 4, and 5 years post-transplantation, the incidence of primary EBV infection evaluated by EBV viremia using PCR blood tests at multiple timepoints (M1, M2, M3, M6, M12, M24, M36, M48, M60), and EBV seroconversion at similar intervals.

Additional secondary endpoints involve the delay of primary EBV infection occurrence, CD19/CD20 reconstitution at M3, M6, M12, and M24, and the number of patients requiring Rituximab for preemptive therapy due to high EBV viral load. Graft loss and allograft kidney function will be evaluated at specified intervals using the CKD-EPI formula or the Schwartz formula for pediatric patients. Recipient survival, incidence of opportunistic infections, malignancies, BKV viremia, and CMV viremia will also be monitored at designated timepoints. Treatment tolerance will be assessed by monitoring allergic reactions, neutropenia, hospitalization for febrile neutropenia, and hypogammaglobulinemia. Adverse events (AE) and serious adverse events (SAE) will be recorded, with all endpoints analyzed in specific pediatric and adult subgroups.