Personalised randomised controlled trial designs-a new paradigm to define optimal treatments for carbapenem-resistant infections

Abstract

Antimicrobial resistance is impacting treatment decisions for, and patient outcomes from, bacterial infections worldwide, with particular threats from infections with carbapenem-resistant Enterobacteriaceae, Acinetobacter baumanii, or Pseudomonas aeruginosa. Numerous areas of clinical uncertainty surround the treatment of these highly resistant infections, yet substantial obstacles exist to the design and conduct of treatment trials for carbapenem-resistant bacterial infections. These include the lack of a widely acceptable optimised standard of care and control regimens, varying antimicrobial susceptibilities and clinical contraindications making specific intervention regimens infeasible, and diagnostic and recruitment challenges. The current single comparator trials are not designed to answer the urgent public health question, identified as a high priority by WHO, of what are the best regimens out of the available options that will significantly reduce morbidity, costs, and mortality. This scenario has an analogy in network meta-analysis, which compares multiple treatments in an evidence synthesis to rank the best of a set of available treatments. To address these obstacles, we propose extending the network meta-analysis approach to individual randomisation of patients. We refer to this approach as a Personalised RAndomised Controlled Trial (PRACTical) design that compares multiple treatments in an evidence synthesis, to identify, overall, which is the best treatment out of a set of available treatments to recommend, or how these different treatments rank against each other. In this Personal View, we summarise the design principles of personalised randomised controlled trial designs. Specifically, of a network of different potential regimens for life-threatening carbapenem-resistant infections, each patient would be randomly assigned only to regimens considered clinically reasonable for that patient at that time, incorporating antimicrobial susceptibility, toxicity profile, pharmacometric properties, availability, and physician assessment. Analysis can use both direct and indirect comparisons across the network, analogous to network meta-analysis. This new trial design will maximise the relevance of the findings to each individual patient, and enable the top-ranked regimens from any personalised randomisation list to be identified, in terms of both efficacy and safety.