Evaluation of Intravenous Human Normal Immunoglobulin for Prevention of BK Virus Viremia in Kidney Transplant Recipients with Low Neutralizing Antibody Titers

The primary objective of this study is to evaluate the impact of preventive administration of **intravenous immunoglobulins (IVIG)** on the incidence of BK virus (BKV) viremia, specifically when levels exceed 3 log10 copies/mL, in kidney transplant recipients who exhibit low titers of neutralizing antibodies against the donor's BKV strain at the time of transplantation. This is clinically relevant as BKV viremia can lead to significant complications, including graft dysfunction and loss, in kidney transplant patients.

Secondary objectives include assessing the following in a prospective cohort: the kinetics of BKV neutralizing antibodies (NAbs), the incidence of BKV-related diseases, episodes of graft rejection, graft survival, the incidence of Torque Teno Virus (TTV) viremia, the evolution of B and T-cell repertoire against BKV, the tolerance of IVIG, and the concentration of BKV NAbs in administered IVIG. These assessments are crucial for understanding the broader immunological and clinical impacts of IVIG administration in this patient population.

The clinical trial involves **adult patients** aged 18 years and older who have undergone **kidney transplantation** and may include those who have received multiple organ transplants. Both male and female participants are included in the study, and the population is not considered vulnerable. Participants are required to have a general understanding of the study's purpose and risks, and must provide written informed consent. They should also be affiliated with a medical insurance scheme. The study focuses on individuals with low titers of neutralizing antibodies against the donor's BKV strain at the time of transplantation. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the impact of **intravenous immunoglobulin** (IVIG) administration on the incidence of BK virus (BKV) viremia in kidney transplant recipients. This study is a multicenter, randomized, double-blind, controlled trial. The trial will span approximately four years, with an estimated recruitment start date of August 21, 2022, and an estimated end date of August 21, 2026. Participants will be involved in the study for a maximum treatment period of 52 weeks.

The trial will include several study visits, beginning with a screening visit to assess eligibility based on criteria such as age (≥ 18 years), kidney transplant status, and informed consent. Following the screening, participants will undergo a baseline visit on the day of transplantation (D0), where initial measurements, including BKV neutralizing antibody titers, will be recorded. Subsequent follow-up visits are scheduled at D10, D31, D52, and months 3, 6, and 12 (M3, M6, M12) post-transplantation. These visits will monitor primary and secondary endpoints, including the incidence of BKV viremia and viruria, BKV nephropathy, and the evolution of T and B-cell repertoires against BKV.

The primary endpoint is the incidence of BKV viremia (> 3 log10 copies/mL) six months after transplantation. Secondary endpoints include BKV NAb titers, incidence of BKV viruria, TTV viremia, and graft function assessed by GFR using the CKD-EPI formula. The end-of-study visit at M12 will evaluate patient and graft survival, as well as the tolerance of IVIG and any adverse effects. Participants may be withdrawn from the study early if they experience severe adverse effects or if they withdraw consent. The trial aims to provide valuable insights into the preventive potential of IVIG in managing BKV viremia in kidney transplant recipients.

The clinical trial involves the administration of **Privigen 100 mg/ml solution for infusion**, which is an experimental medication used to prevent BKV viremia in kidney transplant recipients. The active substance in this medication is **human normal immunoglobulin**, a structurally diverse substance derived from blood. The pharmaceutical form of Privigen is a solution for infusion, and it is administered via **intravenous injection**. The dosage is calculated based on the patient's body weight, with a maximum daily dose of 1000 mg/kg and a total maximum dose of 3000 mg/kg over the treatment period. The treatment duration is set for a maximum of 52 weeks. The administration schedule and dosage are determined by the study protocol, and participant compliance is monitored throughout the trial.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the administration of Privigen to assess its efficacy in reducing the incidence of BKV viremia in patients with low titers of neutralizing antibodies against the donor's BKV strain at the time of transplantation. The trial is conducted under strict compliance monitoring to ensure adherence to the dosing schedule and to evaluate the safety and effectiveness of the treatment.

Efficacy in this clinical trial will be assessed primarily by measuring the incidence of **BKV viremia** exceeding 3 log10 copies/mL six months post-transplantation. This primary endpoint will provide a direct evaluation of the intervention's impact on viral load in kidney transplant recipients. Secondary endpoints will include a comprehensive set of parameters to further evaluate efficacy. These include the measurement of BKV neutralizing antibody (NAb) titers at various timepoints: the day of transplantation (D0), D10, D31, D52, and months 3, 6, and 12 (M3, M6, M12). Additionally, the incidence of BKV viruria and viremia, as well as TTV viremia, will be assessed at these same intervals. The evolution of T and B-cell repertoire against BKV will be monitored at D0, M3, M6, and M12.

Other secondary endpoints include the incidence of BKV nephropathy, the time of occurrence and duration of viruria, viremia, and BKV-associated nephropathy (BKVAN), and the genotype of replicative BKV. The predictive value of pre-transplantation BKV NAb titers for post-transplantation BKV replication will also be evaluated. Renal function will be assessed using the GFR calculated by the CKD-EPI formula at M3, M6, and M12. The percentage of patients with donor-specific antibodies (DSA) and the incidence of biopsy-proven antibody-mediated and acute cellular rejection, according to the Banff classification, will be recorded at M3 and M12. Patient and graft survival will be evaluated at M12, alongside the tolerance of IVIG and any adverse or severe adverse effects. These efficacy parameters will be collected and analyzed according to the trial's predefined schedule to ensure a comprehensive assessment of the intervention's impact.