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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

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

Conditions
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BK Viremia, Kidney Transplant Infection, Kidney Transplant Failure and Rejection

Intervention / Treatment
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* Drug: Immunosuppression reduction/modification + intravenous immunoglobulin
* Other: Immunosuppression reduction/modification


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Immunosuppression reduction/modification + Intravenous Immunoglobulin<br>Receives Immunosuppression reduction/modification + Intravenous Immunoglobulin | Drug: Immunosuppression reduction/modification + intravenous immunoglobulin<br>* Participants will receive intravenous immunoglobulin along with immunosuppression reduction/modification.<br>* Other names: Human immunoglobulin;|
| Other: Immunosuppression reduction/modification<br>Receives Immunosuppression reduction/modification as part of standard of care. | Other: Immunosuppression reduction/modification<br>* Participants will receive immunosuppression reduction/modification.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 11 - 13 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BKPyV final viral load | Compare the number of participants in the intervention and control groups with a BK Polyomavirus viral load to <1000 copies/mL | 12 weeks | 
| eGFR decline | 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 | 12, 24 & 48 weeks | 
| All cause death | Compare the mortality rate in the intervention and control groups. | 12, 24 & 48 weeks | 
| Graft loss | Compare the number of graft survival and death-censored graft survival participants in the intervention and control groups. | 12, 24 & 48 weeks | 
| Acute rejection of kidney and/or pancreas allografts | Compare the number of acute rejections (cellular and antibody mediated) episodes between the intervention and control groups. | 12 & 48 weeks | 
| Donor Specific Anti-HLA Antibody | Compare the number of participants that develop de novo donor-specific antibodies between the intervention and control groups | 12 & 48 weeks | 
| Infusion reactions and/ or venous thromboembolism events | Compare the incidence rate (number) of infusion reactions and venous thromboembolism between the intervention and control groups | 12 weeks | 
| Hospitalisations due to infection events | Compare the number of hospitalisation due to infection between the intervention and control groups. | Baseline,1,2,3,4,5,6,7,8,10,12,24,48 weeks | 
| 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 | Baseline,1,2,3,4,5,6,7,8,10,12,24,48 weeks | 
| EuroQol-5 Dimension-5 Level for adults/ Health Utilities Index-3 for children | Compare the outcomes of health-related quality of life between the intervention and control groups. | Baseline, 12, 24 & 48 weeks | 
| BK polyomavirus associated nephropathy events | Compare the number of participants that develop BK polyomavirus associated nephropathy between the intervention and control groups | 12 & 48 weeks | 
| Any cancer diagnosis or cancer related death | Compare the incidence rate (number) of cancer outcomes between the intervention and control groups. | 24 & 48 weeks | 
| Composite ranked outcome | Compare the long-term composite ranked outcome between the intervention and control groups | 24 & 48 weeks | 
| Adverse events of special interest and serious adverse events | Compare the incidence rate (number) of safety related events between intervention and control group. | Baseline,1,2,3,4,5,6,7,8,10,12,24,48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kidney transplantation, Intravenous immunoglobulin, Virus, Nephropathy, Clinical trial, Nephrology