Individual Patient Data Meta-Analysis evaluating Camostat Mesilate to Treat COVID-19 in Community Settings

BackgroundIn the COVID-19 pandemic, a number of phase II and III randomized trials were launched to evaluate the effectiveness of camostat, an orally administered TMPRSS2 inhibitor previously approved for other indications, for treating SARS-CoV-2 infections. Owing to the rapidly changing landscape during the pandemic, many of these trials were unable to reach completion. Further, methods for synthesizing data for trials that were launched and not completed were critical. MethodsThis study aimed to consolidate global evidence by identifying placebo-controlled, randomized trials of camostat and analyzing their collective clinical and virologic impact on SARS-CoV-2 through an individual participant data meta-analysis. We harmonized data from the included studies and utilized Bayesian statistical models to assess virologic outcomes (measured by the rate of change in viral shedding) and clinical outcomes (based on the time to the first of two consecutive symptom-free days), adjusting for age and sex. FindingsThe meta-analysis incorporated data from six countries, totaling 431 patients across the studies; 118 patients contributed data for the primary virologic outcome and 240 for the clinical symptom outcome. Camostat did not improve the rate of change in viral load (difference in rate of change = 0.11 Ct value/day higher, 95% credible interval 2.04 lower to 2.23 higher) or time to symptom resolution (hazard ratio = 0.87, 95% credible interval 0.51, 1.55) when compared to placebo. InterpretationIn a meta-analysis prompted by a fast-changing landscape during the pandemic, we jointly synthesized evidence across multiple trials that did not meet their original recruitment goals. Despite its theoretically promising mode of action, camostat did not demonstrate a statistically significant virologic or clinical benefit in treating COVID-19, highlighting the complexity of drug repurposing in emergency health situations. FundingThis work was partially supported by The Lundbeck Foundation, LifeArc, Assistance Publique Hopitaux de Paris, anonymous donors, and awards from the National Institutes of Health. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSCamostat mesilate, a therapy widely used in Japan for over two decades to treat pancreatitis and reflux esophagitis, showed promise against SARS-CoV-2 in early laboratory and animal studies. Numerous studies evaluating camostat as a treatment for COVID-19 were launched by autumn of 2020, but later stalled due to emerging treatments that altered the equipoise for placebo-controlled trials. Among the trials that reached publication, findings were mixed. Added value of this studyOur research brings a fresh perspective by comprehensively analyzing both published and previously unseen data from randomized clinical trials on camostat. By pooling data across studies, our analysis provides a more robust assessment of the effectiveness of camostat against viral and clinical outcomes than any single study could offer. Novel analytic approaches, data sharing efforts, and international collaboration during the global health emergency are additionally described. Implications of all the available evidenceAfter thorough analysis, our study concludes that, when considering all available data, camostat does not confer a virologic or clinical advantage in the treatment of COVID-19. This conclusion underscores the importance of pooling global research efforts to build a clearer understanding of potential treatments during health emergencies.