A Trial to Treat Polyomavirus Infections (BKPyV) in Kidney and Simultaneous Kidney Pancreas Transplant Recipients (BEAT-BK)

A Trial to Treat Polyomavirus Infections (BKPyV) in Kidney and Simultaneous Kidney Pancreas Transplant Recipients

An Adaptive Randomised Controlled Trial to Treat Polyomavirus Infections (BKPyV) in Kidney and Kidney Pancreas Transplant Recipients

BEAT-BK will see the effect of immunosuppression reduction/modification with and without IVIG on BKPyV infection, allograft function, allograft loss, acute transplant rejection, immunosuppression load and death in kidney and simultaneous kidney pancreas transplant recipients with polyomavirus infections (BKPyV).

BKPyV infection is a rare but also devastating disease in kidney and SPK transplant recipients. Immunosuppression used in transplantation minimises the risk of acute rejection and eventual graft loss, but suppression of the immune system increases the risk of opportunistic infections and reactivation of latent viruses causing disease, such as BKPyV infection. Therefore, balancing the complications of excessive versus inadequate immunosuppression is a key priority for patients and health professionals. The BEAT-BK trial is designed through a structured, consensus process, and informed by the pilot observational data generated by the investigators. The conventional immunosuppression reduction approach may include judicious reduction in the doses of calcineurin inhibitors and anti-proliferative agents, or conversion to less potent immunosuppression therapy such as a switch from tacrolimus to cyclosporine, or mycophenolate to azathioprine. While adjuvant therapy is not commonly used, 63% of participants would consider IVIG as a 'rescue', when conventional therapy has failed, or the graft function is deteriorating rapidly. IVIG is a nondepleting agent containing natural antibodies with potential antiviral and immunomodulatory properties. It is used against some chronic infections (Epstein-Barr virus) and the treatment of antibody-mediated rejection in kidney transplantation. In BKPyV infection, the certainty of the evidence for IVIG is very low due to imprecision, and high risk of bias (small, case series, retrospective cohorts), but it holds promise based on findings from our observational data (n = 50). Recipients with BKPyV-DNAemia who received IVIG as adjuvant therapy were more likely to achieve complete viral clearance at 12 months (77.3% vs. 33.3%, p < 0.01) and less likely to relapse (11% vs. 27.3%, p=0.01) compared to recipients who received conventional therapy alone.

Participants will receive intravenous immunoglobulin along with immunosuppression reduction/modification.

Composite ordinal outcome based on all cause death, allograft loss, eGFR decline, acute allograft rejection or BKV load > 1000 copies/mL, and immunosuppression load.

All participants will be allocated a rank at 12 weeks between rank 5 (worst) and rank 1 (best). The primary comparison of interest is between participants randomised to intravenous immunoglobulin (IVIG) and participants randomised to the control arm. Outcome measures include: Rank 5 - all cause death, allograft loss, eGFR decline ≥10mls/min 1.73². Rank 4 - acute allograft rejection or BK viral load to >1000 copies/mL. Ranks 3, 2, and 1 - the degree of immunosuppression reduction relative to baseline immunosuppression.

Compare the number of participants in the intervention and control groups with a BK Polyomavirus viral load to <1000 copies/mL

Compare the number of participants in the intervention and control groups with an estimated glomerular filtration rate (eGFR) decline ≥ 10 ml/min/1.73 m2

Compare the number of graft survival and death-censored graft survival participants in the intervention and control groups.

Compare the number of acute rejections (cellular and antibody mediated) episodes between the intervention and control groups.

Compare the number of participants that develop de novo donor-specific antibodies between the intervention and control groups

Compare the incidence rate (number) of infusion reactions and venous thromboembolism between the intervention and control groups

Number of infectious events requiring antimicrobial (antibacterial, antiviral, antifungal, antiprotozoal) therapy.

Compare the number of infectious events requiring antimicrobial therapy between the intervention and control groups

Compare the number of participants that develop BK polyomavirus associated nephropathy between the intervention and control groups

Inclusion Criteria: Aged 2 years or above Have received a kidney or simultaneous pancreas-kidney transplant Have a sustained BKPyV-Viremia (detected by RT-PCR with viral counts ≥ 5 x 10³ copies/mL on two separate occasions within 3 weeks prior to randomisation) Be able to provide informed consent or consent given by a parent or guardian (if age <18 years) or other authorised person Exclusion Criteria: Contraindications to receiving IVIG as a treatment Current active acute rejection (≤ 3 months prior) Treating clinicians would regard as unsafe to be enrolled Limited life expectancy (< 12 months) Pregnancy Receiving Belatacept as part of their immunosuppression protocol Currently undergoing or who have previously received, viral-specific T-cell therapy for BK viremia Prior infection and treatment for BKPyV-Viremia Received IVIG treatment in the past with last IVIG treatment < 4 weeks prior to randomisation