Early phase dose‐finding trials in virology

Abstract

Little has been published in terms of dose-finding methodology in virology. Aside from a few papers focusing on HIV, the considerable progress in dose-finding methodology of the last 25 years has focused almost entirely on oncology. While adverse reactions to cytotoxic drugs may be life threatening, for anti-viral agents we anticipate something different: side effects that provoke the cessation of treatment. This would correspond to treatment failure. On the other hand, success would not be yes/no but would correspond to a range of responses, from small, no more than say 20% reduction in viral load to the complete elimination of the virus. Less than total success matters since this may allow the patient to achieve immune-mediated clearance. The motivation for this article is an upcoming dose-finding trial in chronic norovirus infection. We propose a novel methodology whose goal is twofold: first, to identify the dose that provides the most favorable distribution of treatment outcomes, and, second, to do this in a way that maximizes the treatment benefit for the patients included in the study. K E Y W O R D S continual reassessment method, coronavirus, dose-finding, early phase trials, norovirus, virology 1 INTRODUCTION This introduction has three subsections: the first provides a broad description of our goals, the second a summary of the study motivating this current work, and, finally, a subsection making these goals more specific and anticipating the section that follows on statistical methodology. 1.1 Background and motivation Antiviral agents can fail to be of benefit to a patient in two different ways. The first is where the toxic side effects are such that the patient is unable to take the full course of treatment, thereby not being in a position to experience treatment benefit. The second type of failure is where the treatment is well tolerated but fails to achieve a meaningful clinical or virological effect, for example, a lessening of symptoms, reduction in viral load, or complete elimination of the virus (or, for some viruses, induction of viral latency). When viral load is the main focus, efficacy may be categorized into three or possibly more outcomes, ranging from a small, insignificant reduction in viral load to a large reduction or total elimination (or suppression) of the virus. Given a new candidate treatment, and some range of possible treatment levels, This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.