Abstract
.As the global COVID-19 pandemic continues, unabated and clinical trials demonstrate limited effective pharmaceutical interventions, there is a pressing need to accelerate treatment evaluations. Among options for accelerated development is the evaluation of drug combinations in the absence of prior monotherapy data. This approach is appealing for a number of reasons. First, combining two or more drugs with related or complementary therapeutic effects permits a multipronged approach addressing the variable pathways of the disease. Second, if an individual component of a combination offers a therapeutic effect, then in the absence of antagonism, a trial of combination therapy should still detect individual efficacy. Third, this strategy is time saving. Rather than taking a stepwise approach to evaluating monotherapies, this strategy begins with testing all relevant therapeutic options. Finally, given the severity of the current pandemic and the absence of treatment options, the likelihood of detecting a treatment effect with combination therapy maintains scientific enthusiasm for evaluating repurposed treatments. Antiviral combination selection can be facilitated by insights regarding SARS-CoV-2 pathophysiology and cell cycle dynamics, supported by infectious disease and clinical pharmacology expert advice. We describe a clinical evaluation strategy using adaptive combination platform trials to rapidly test combination therapies to treat COVID-19.
Highlights
To illustrate, a recent large-scale compound repurposing effort identified more than 20 antivirals that should be further investigated for application for COVID-19.3 Antiviral agents for COVID-19 can be categorized by two broad mechanisms of action: 1) those targeting viral proteins or nucleic acids related to infection of host cells, viral production via hijacking cellular machinery, or release from host cells and circulation of virions; and 2) those targeting essential host functions for viral replication including agents such as interferon that boost the cellular immune response to infection
We describe a clinical evaluation strategy using adaptive combination platform trials to rapidly test combination therapies to treat COVID-19
A recent large-scale compound repurposing effort identified more than 20 antivirals that should be further investigated for application for COVID-19.3 Antiviral agents for COVID-19 can be categorized by two broad mechanisms of action: 1) those targeting viral proteins or nucleic acids related to infection of host cells, viral production via hijacking cellular machinery, or release from host cells and circulation of virions; and 2) those targeting essential host functions for viral replication including agents such as interferon that boost the cellular immune response to infection
Summary
Development of combination treatment strategies entails a stepwise evaluation process whereby first the individual components of a potential combination regimen are tested for clinical efficacy in isolation or as individual arms within a trial evaluating both single and combination regimens. This strategy allows sequential compilation of evidence for each drug before studying combinations, as outlined by the U.S Food and Drug Administration in describing the so-called combination rule.[9]. This process is both scientifically rigorous and safe, it is slow, and may delay identification of unexpected synergistic effects, resulting in failure to evaluate potentially potent treatment cocktails
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