An adaptive, randomized controlled trial to treat BK polyomavirus infections (BKPyV) in pediatric kidney transplant recipients

Extending the limited kidney transplant (KT) life is a priority in an era of severe organ shortage. Among the major causes for premature KT loss are opportunistic viral infections. BK polyoma virus (BKPyV) DNAemia occurs in 15-20% in the first year after KT and has no proven preventive or therapeutic strategy or agent beyond reduction in immunosuppression (IS), which carries the risk of acute rejection (AR). The BEAT-BK adaptive pragmatic trial in adult KT recipients is a randomized, controlled, and multicenter trial will evaluate the herapeutic efficacy of intravenous immunoglobulin (IVIG) for sustained BKPyV DNAemia. IVIG contains natural antibodies to BKPyV that have shown benefit in small retrospective case series (including our own) of KT recipients with BKPyV DNAemia. The adult BEAT-BK trial will enroll 280 eligible KT recipients (mostly adults, a few children) to randomize 1:1 to either structured IS reduction/modification alone (standard of care), or IS reduction/modification + IVIG (study arm). The trial will use a ranked global scores primary outcome (death, allograft loss, reduction in estimated glomerular filtration rate (eGFR) > 10 ml/min/1.73m2 from baseline, AR, lack of viral clearance, reduction in IS load). Children get excluded from most transplant trials and are at high risk of a primary BKPyV infection at KT, for multiple reasons. Due to lack of prior exposure and immunity in many of these children, this primary BKPyV infection can be severe during a period of maximal IS. We therefore propose a planning grant that will develop the infrastructure and documents to conduct the BEAT-BK USA kids trial, to mimic the ongoing adult trial. In a prospective cohort of 120 multi-ethnic pediatric KT recipients across 7 major USA sites, we will perform the following Specific Aims, based on the hypotheses that: A) addition of IVIG (total dose 2 gm/kg over 8 weeks) to standardized IS reduction/modification, will increase the viral clearance rate; and B) will reduce the BKPyV DNAemia relapse rate; and C) will reduce the proportion with a drop in eGFR > 10 ml/min/1.73m2. Eligible subjects will be KT recipients 2 years and older with sustained BKPyV > 1000 viral DNA copies/ml on 2 separate occasions within 3 weeks prior to randomization. All primary endpoints will be evaluated at 12 weeks post-randomization, with further follow up for another 36 weeks, to also measure a series of secondary outcomes. To enhance efficiency, our trial design will replicate the adult trial adaptation of sample size based on accumulating data and pre-specified decision criteria. We will also adopt a pragmatic design where the IS alteration strategy can be tailored specifically to the characteristics of the participants, based on pre-specified guidelines. Our pediatric trial will also uniquely assess the capacity of exploratory novel mechanistic biomarkers to predict the various study outcomes. By study end, we will know if IVIG has true efficacy to clear sustained BKPyV DNAemia without relapse and with maintained allograft function.