Abstract: life Article Pharmacologic Ascorbic Acid as Early Therapy for Hospitalized Patients with COVID-19: A Randomized Clinical Trial Dagan Coppock 1, * , Pierre-Christian Violet 2 , Gustavo Vasquez 1 , Katherine Belden 1 , Michael Foster 3 , Bret Mullin 3 , Devon Magee 3 , Isabelle Mikell 4 , Lokesh Shah 4 , Victoria Powers 4 , Brian Curcio 5 , Constantine Daskalakis 5 , Daniel Monti 6 and Mark Levine 2, * 1 2 3 4 5 6



 Citation: Coppock, D.; Violet, P.-C.; Vasquez, G.; Belden, K.; Foster, M.; Mullin, B.; Magee, D.; Mikell, I.; Shah, L.; Powers, V.; et al. Pharmacologic Ascorbic Acid as Early Therapy for Hospitalized Patients with COVID-19: A Randomized Clinical Trial. Life 2022, 12, 453. https:// doi.org/10.3390/life12030453 Academic Editor: Ramón Cacabelos Received: 29 January 2022 Accepted: 15 March 2022 Published: 19 March 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in * Division of Infectious Diseases, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, 1015 Chestnut Street, Philadelphia, PA 19107, USA; gvasquezmd@gmail.com (G.V.); katherine.belden@jefferson.edu (K.B.) Molecular and Clinical Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA; pierre-christian.violet@nih.gov Jefferson Clinical Research Institute, Thomas Jefferson University, 833 Chestnut Street, Philadelphia, PA 19107, USA; mfoster610@gmail.com (M.F.); bret.mullin@jefferson.edu (B.M.); devon.magee@jefferson.edu (D.M.) Sidney Kimmel Medical College, Thomas Jefferson University, 1015 Walnut Street, Philadelphia, PA 19107, USA; isabelle.mikell@students.jefferson.edu (I.M.); lokesh.shah@students.jefferson.edu (L.S.); tori.powers@students.jefferson.edu (V.P.) Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Sidney Kimmel Medical College, Thomas Jefferson University, 1015 Chestnut Street, Philadelphia, PA 19107, USA; curciob@arcadia.edu (B.C.); constantine.daskalakis@jefferson.edu (C.D.) Department of Integrative Medicine and Nutritional Sciences, Sidney Kimmel Medical College, Thomas Jefferson University, 925 Chestnut Street, Philadelphia, PA 19107, USA; daniel.monti@jefferson.edu Correspondence: dagan.coppock@jefferson.edu (D.C.); markl@bdg8.niddk.nih.gov (M.L.) Abstract: 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,..