ABSTRACT
Background: There is currently no approved treatment for patients with COVID-19 who have not been hospitalized, a setting in which early intervention may curb progression to more severe disease requiring hospitalization. We report longitudinal biomarker sampling from a Phase III (PINETREE) clinical trial to evaluate prognostic biomarkers of COVID-19 and to better understand the early remdesivir (RDV) treatment response. Methods: A Phase III, randomized, double-blind, placebo controlled, multicenter study was conducted to evaluate the efficacy and safety of RDV for outpatients with early stage COVID-19 who are at higher risk of disease progression (NCT04501952). Inclusion criteria were ≥60 years of age or ≥12 years of age with at least one risk factor for severe COVID-19 disease. All individuals had ≤7 days of symptoms prior to randomization. A total of 562 participants were randomized 1:1 to RDV or placebo. Serum and plasma were collected for biomarker analyses in 312 patients at days 1, 3, and 14 post-treatment. All biomarker values were adjusted for baseline age and stratified by sex. Results: RDV demonstrated an 87% reduction in risk for the primary composite endpoint of COVID-19-related hospitalization or all-cause death by day 28 (0.7% [2/279]) compared with placebo (5.3% [15/283]) (p=0.008). RDV treatment was associated with improved clinical outcomes in participants with higher risk of hospitalization or death from COVID-19, including individuals ≥60 years of age, males, and/or those with diabetes, obesity, and hypertension. Furthermore, we found that biomarkers associated with inflammation and coagulation, including lactate dehydrogenase (p<0.001) and procalcitonin (p<0.001), were prognostic for COVID-19 related hospitalization or all-cause death by day 28. Finally, we found that RDV improved some biomarkers associated with COVID-19 severity by day 3 of treatment, including peripheral lymphopenia, monocyte count, and decreased neutrophil-to-lymphocyte ratio compared to placebo (pWilcox<0.05). Conclusion: Our findings suggest that RDV treatment improves COVID-19 outcomes in high-risk SARS-CoV-2 infected individuals, particularly in those ≥60 years of age, male, and/or with diabetes, obesity, and hypertension. Biomarkers of COVID-19 severity that were prognostic for poor outcomes were identified in early infection. Furthermore, our results suggest that RDV treatment leads to more rapid recovery in the lymphopenia that is commonly associated with more severe COVID-19.