Abstract: Original Investigation | Public Health Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection The COVID A to Z Randomized Clinical Trial Suma Thomas, MD, MBA; Divyang Patel, MD, MS; Barbara Bittel, BSN, RN; Kathy Wolski, MPH; Qiuqing Wang, MS; Anirudh Kumar, MD, MS; Zachary J. Il’Giovine, MD; Reena Mehra, MD, MS; Carla McWilliams, MD; Steve E. Nissen, MD; Milind Y. Desai, MD, MBA Abstract IMPORTANCE There is limited evidence regarding early treatment of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to mitigate symptom progression. OBJECTIVE To examine whether high-dose zinc and/or high-dose ascorbic acid reduce the severity or duration of symptoms compared with usual care among ambulatory patients with SARS-CoV-2 infection. Key Points Question Do high-dose zinc, high-dose ascorbic acid, and/or a combination of the 2 reduce the duration of symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)? Findings In this randomized clinical trial of 214 patients with confirmed SARS- DESIGN, SETTING, AND PARTICIPANTS This multicenter, single health system randomized clinical CoV-2 infection receiving outpatient factorial open-label trial enrolled 214 adult patients with a diagnosis of SARS-CoV-2 infection care, there was no significant difference confirmed with a polymerase chain reaction assay who received outpatient care in sites in Ohio and in the duration of symptoms among the Florida. The trial was conducted from April 27, 2020, to October 14, 2020. 4 groups. Meaning These findings suggest that INTERVENTION Patients were randomized in a 1:1:1:1 allocation ratio to receive either 10 days of zinc gluconate (50 mg), ascorbic acid (8000 mg), both agents, or standard of care. treatment with zinc, ascorbic acid, or both does not affect SARS-CoV-2 symptoms. OUTCOMES The primary end point was the number of days required to reach a 50% reduction in symptoms, including severity of fever, cough, shortness of breath, and fatigue (rated on a 4-point scale for each symptom). Secondary end points included days required to reach a total symptom severity score of 0, cumulative severity score at day 5, hospitalizations, deaths, adjunctive prescribed medications, and adverse effects of the study supplements. RESULTS A total of 214 patients were randomized, with a mean (SD) age of 45.2 (14.6) years and 132 (61.7%) women. The study was stopped for a low conditional power for benefit with no significant + Visual Abstract + Invited Commentary + Supplemental content Author affiliations and article information are listed at the end of this article. difference among the 4 groups for the primary end point. Patients who received usual care without supplementation achieved a 50% reduction in symptoms at a mean (SD) of 6.7 (4.4) days compared with 5.5 (3.7) days for the ascorbic acid group, 5.9 (4.9) days for the zinc gluconate group, and 5.5 (3.4) days for the group receiving both (overall P = .45). There was no significant difference in secondary outcomes among the treatment groups. CONCLUSIONS AND RELEVANCE In this randomized clinical trial of ambulatory patients diagnosed with SARS-CoV-2 infection, treatment with high-dose zinc gluconate, ascorbic acid, or a combination of the 2 supplements did not significantly decrease the duration of symptoms compared with standard of care. TRIAL REGISTRATION..