Pharmacologic Ascorbic Acid as Early Therapy for Hospitalized Patients with COVID-19: A Randomized Clinical Trial
Dagan Coppock, Pierre-Christian Violet, Gustavo Vasquez, Katherine Belden, Michael Foster, Bret Mullin, Devon Magee, Isabelle Mikell, Lokesh Shah, Victoria Powers, Brian Curcio, Daniel Monti, Mark Levine
Life, doi:10.3390/life12030453
Despite the widespread availability of effective vaccines, new cases of infection with severe acute respiratory syndrome coronavirus-2, the cause of coronavirus disease 2019 (COVID-19), remain a concern in the settings of vaccine hesitancy and vaccine breakthrough. In this randomized, controlled, phase 2 trial, we hypothesized that high-dose ascorbic acid delivered intravenously to achieve pharmacologic concentrations may target the high viral phase of COVID-19 and thus improve early clinical outcomes. Sixty-six patients admitted with COVID-19 and requiring supplemental oxygen were randomized to receive either escalating doses of intravenous ascorbic acid plus standard of care or standard of care alone. The demographic and clinical characteristics were well-balanced between the two study arms. The primary outcome evaluated in this study was clinical improvement at 72 h after randomization. While the primary outcome was not achieved, point estimates for the composite outcome and its individual components of decreased use of supplemental oxygen, decreased use of bronchodilators, and the time to discharge were all favorable for the treatment arm. Possible favorable effects of ascorbic acid were most apparent during the first 72 h of hospitalization, although these effects disappeared over the course of the entire hospitalization. Future larger trials of intravenous ascorbic acid should be based on our current understanding of COVID-19 with a focus on the potential early benefits of ascorbic in hospitalized patients.
outcomes during the 72-h window after randomization, consistent with our hypotheses. Further consistent with our hypotheses, these trends were nullified as the curves crossed later in the hospitalization. As secondary endpoints, both the times to discharge and a 50% reduction in oxygenation were statistically non-significant when measured over the entire hospitalization. This pattern was not wholly unexpected. As noted above, an early benefit was consistent with our proposed mechanism of action. Regarding safety, the proportion of patients who experienced a clinical decline in the treatment arm did not meet stopping rules and the trial was continued to its full accrual. Though the point estimates were higher for serious adverse events and clinical decline in the first 36 h, the study was not powered to detect these differences, which were not statistically significant. Our trial had limitations. In retrospect, the study was small with optimistic outcome assumptions. Outcomes in this trial were defined in the early part of the pandemic, and do not reflect our current understanding of COVID-19 as a disease process. Furthermore, our patient risk stratification, while focused on age and comorbidities, may be improved in future studies. An emphasis on more severe underlying metabolic disease (i.e., diabetes), as opposed to any pulmonary or cardiovascular disease, may better improve patient selection and risk analyses. Viral load and specific analyses of lymphocyte populations were..
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