Planning an antibiotic duration trial for acute graft pyelonephritis after kidney transplantation

Univ Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

Abstract

Project Summary Approximately 14% of the US population have chronic kidney disease, and over 700,000 people have kidney failure. Kidney transplantation is an important treatment modality for kidney failure, and over 200,000 Americans live with a kidney transplant. Unfortunately, infectious complications remain an important threat to vulnerable kidney transplant recipients. Acute graft pyelonephritis is a common bacterial infection after kidney transplantation, which is associated with increased risk for mortality and graft loss. The evidence base supporting duration of antibiotics for acute graft pyelonephritis is limited. We propose here to plan for a pragmatic, open-label, non-inferiority, multi-center, randomized, controlled, strategy trial to determine the optimal antibiotic treatment duration for acute graft pyelonephritis in kidney transplantation recipients. Currently, recommendations based on limited evidence suggest 14- to 21-day duration. Shorter antibiotic durations allow for significantly decreased antibiotic exposure with lower rates of side effects, resistance development, and healthcare costs. We propose the highly innovative DURATIONS approach to randomize patients to six separate duration arms (i.e. 7, 9, 12, 14, 18, and 21 days). A duration-response curve is then modeled allowing the identification of an optimal treatment duration. We will also use innovation in our endpoints by using the desirability of outcome ranking (DOOR) approach for our secondary endpoint, and by exploring carriage of multidrug resistance and dynamics of C-reactive protein in our exploratory endpoints. The primary endpoint will be a composite of all-cause mortality, decreased renal allograft function, and relapsed infection. All-cause mortality and allograft function are longer term outcomes that are proposed to be assessed at 180 days post-randomization, whereas relapsed infection is assessed at 60 days. Key inclusion criteria will focus enrollment on hospitalized kidney transplant recipients with microbiology confirmed bacterial acute allograft pyelonephritis with sufficient renal function. Key exclusion criteria will include polymicrobial infection, pyelonephritis occurring within 30 days of transplantation, and undrained renal abscess. Planning activities supported by this award will include finalizing the protocol based on input from NIAID/DMID, FDA, external advisors, and key collaborators. Systematic review of the evidence and feasibility assessments will further inform the protocol decisions. Sample size will be finalized as part of the planning activities and will depend on estimated proportion of participants with the outcome, loss-to-follow-up, and the non-inferiority margin. Recruitment of key collaborators and site selection from large US transplant centers will be performed. Regulatory planning activities will include IRB submission and determination of the need for Investigational New Drug (IND) application in consultation with FDA. If required, this application will be submitted and revised during the funding period.