Abstract: [ Original Article High‑dose Intravenous Vitamin C in Early Stages of Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A Double‑blind, Randomized, Controlled Clinical Trial Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, Iran 1 Department of Pulmonary and Critical Care, Shariati Hospital, Tehran University of Medical Science, Tehran, Iran 2 Advanced Thoracic Research Center, Tehran University of Medical Science, Tehran, Iran 3 Liver and Pancreatobiliary Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran 4 Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran 5 Endocrinology and Metabolism Research Center, Tehran University of Medical Sciences, Tehran, Iran 6 Department of Internal Medicine, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran 7 Abstract Zohre Labbani‑Motlagh1, Shahideh Amini1,2, Rasoul Aliannejad2,3, Anahita Sadeghi4, Gita Shafiee5, Ramin Heshmat5,6, Mohamadreza Jafary7, Mona Talaschian8, Maryam Akhtari9,10, Ahmadreza Jamshidi9, Mahdi Mahmoudi9,10, Kourosh Sadeghi1 Objective: Based on previous studies in the sepsis population, Vitamin C could prevent injuries when administered in high doses and before the damage is established. This study aimed to evaluate the protective potentials of high‑dose Vitamin C in the progression of coronavirus disease 2019 (COVID‑19). Methods: A double‑blind, placebo‑controlled clinical trial was conducted. Patients with moderate‑to‑severe disease severity based on the World Health Organization definition were enrolled and received 12 g/d Vitamin C (high‑dose intravenous Vitamin C [HDIVC]) or placebo for 4 days. Sequential Organ Failure Assessment (SOFA) score as a primary outcome, National Early Warning Score, Ordinal Scale of Clinical Improvement, and cytokine storm biomarkers were recorded on days 0, 3, and 5. Survival was also assessed on day 28 after enrollment. Findings: Seventy-four patients (37 patients in each group) were enrolled from April 5, 2020, to November 19, 2020, and all patients completed follow‑up. A lower increase in SOFA score during the first 3 days of treatment (+0.026 vs. +0.204) and a higher decrease in this parameter in the last 2 days (−0.462 vs. −0.036) were observed in the treatment group. However, these differences did not reach a significance level (P = 0.57 and 0.12, respectively). Other indices of clinical and biological improvement, length of hospitalization, and intensive care unit admission days were the same between the two groups. Treatment did not affect the 28‑day mortality. Conclusion: Among patients with moderate‑to‑severe disease of COVID‑19, the use of HDIVC plus standard care resulted in no significant difference in SOFA score or 28‑day mortality compared to the standard care alone. Keywords: Coronavirus disease 2019, high‑dose Vitamin C, inflammation, severe acute respiratory syndrome coronavirus 2 Department of Internal Medicine, Tehran University of Medical Sciences, Tehran, Iran