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Coronavirus disease 2019 (COVID-19) is a major cause of death and disability worldwide, totaling 89.4 million cases and 1.9 million deaths globally as of January 9, 2021.2 As a result of high-quality science, several vaccines efficacious against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed in record time and deployment started, offering hope for an end to the pandemic. However, given the limited availability and uptake of vaccines, the emergence of new, more infectious variant strains of the virus, and the potential for future seasonal outbreaks, the identification of therapies that can effectively improve prognosis in patients infected with SARSCoV-2 remains a critical area of research. Commonly available oral supplements, such as zinc and ascorbic acid (ie, vitamin C), have been proposed to reduce the duration and severity of viral infections by boosting immune response.3 Even former US President Donald Trump was reportedly treated with zinc and vitamin D throughout his COVID-19 treatment in October 2020.4 Although the evidence supporting supplements as a treatment for viral infections is rather limited,3 in a context of rapidly increasing COVID-19 deaths and urgent need for effective therapeutic options, whether these molecules could benefit patients with COVID-19 is a research question worth evaluating. Thomas et al5 report the results of the COVID A to Z Study, an open-label, 4-group, randomized clinical trial (RCT) that tested the efficacy of high-dose zinc gluconate, ascorbic acid, and their combination for their ability to shorten the duration of COVID-19–related symptoms compared with usual care alone. The authors planned to include 520 adult outpatients with confirmed SARS-CoV-2 infection, and the primary end point was the number of days required to reach a 50% reduction in symptom severity. However, after an interim analysis, the safety monitoring board recommended the study be stopped early for futility after enrollment of only 214 participants because of the low probability of detecting significant differences between the study groups in terms of the primary end point. Some limitations of the study by Thomas et al5 are worth discussing. First, enrollment was restricted to outpatients, thus limiting generalizability to hospitalized patients with COVID-19. Second, interventions were not blinded, a placebo was not used in the control group, and outcomes were reported by study participants. This could have exaggerated the potential benefit of the interventions; yet, the study yielded null findings, providing further reassurance that the early trial termination did not conceal detection of a true benefit. Finally, the small size prevented conducting subgroup analyses by relevant clinical characteristics, although those would have to be interpreted cautiously in the context of overall null findings. The supplement industry is estimated to be worth approximately $300 billion globally.6 More than one-half of US adults report taking at least 1 vitamin or supplement for various health reasons, with little evidence of efficacy to support their widespread use.7 The best evidence to guide clinical recommendations comes from well-designed RCTs. Given the widespread public use of supplements, such as zinc and ascorbic acid, for the prevention and treatment of viral infections, we + Related article