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

Background In 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. Methods This 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. Findings The 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. Interpretation In 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. Funding This work was partially supported by The Lundbeck Foundation, LifeArc, Assistance Publique Hôpitaux de Paris, anonymous donors, and awards from the National Institutes of Health. Evidence before this study Camostat 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 study Our 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 evidence After 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. ### Competing Interest Statement This manuscript is partially supported by the National Institutes of Health, the funding source of Stanford's Center for Clinical and Translational Education and Research award, under the Biostatistics, Epidemiology and Research Design Shared Resource: UL1TR003142 and Stanford Cancer Institute's Biostatistics Shared Resource (BSR): P30CA124435. The trial and work at Stanford was supported in part by anonymous donors to Stanford University and also under a Materials Transfer Agreement with Ono Pharmaceutical Co., Ltd. The trial at CRUK was funded by LifeArc. The trial in Aarhus was funded by The Lundbeck Foundation. The trial at APHP was funded by the Assistance Publique Hopitaux de Paris. Ono Pharmaceutical Co., Ltd., provided study drug. US is an advisor to Regeneron and Gilead and her institution received research support from the National Institutes of Health, the Agency for Healthcare Research and Quality, and Pfizer, Inc. All other authors declare no competing interests. ### Funding Statement This work was partially supported by The Lundbeck Foundation, LifeArc, anonymous donors, and awards from the National Institutes of Health. The funders had no role in data collection, analysis, or the decision to publish. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ethics committees/IRBs of all individual studies gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The statistical analysis plan and code are available upon request to the corresponding author (HH). The individual patient data from any specific study included in this analysis are not available through this request.