Abstract: Vitamin C may increase the recovery rate of outpatient cases of SARS-CoV-2 infection by 70%: reanalysis of the COVID A to Z Randomized Clinical Trial Harri Hemilä (  harri.hemila@helsinki.fi ) University of Helsinki, Helsinki, Finland https://orcid.org/0000-0002-4710-307X Anitra Carr University of Otago, Christchurch, New Zealand https://orcid.org/0000-0002-5890-2977 Elizabeth Chalker University of Sydney, Sydney, Australia https://orcid.org/0000-0003-1593-3770 Research Article Keywords: Ascorbic acid, COVID-19, Common cold, Randomized controlled trials, SARS-CoV-2, Statistics, Time factors, Treatment outcome, Zinc Posted Date: March 1st, 2021 DOI: https://doi.org/10.21203/rs.3.rs-289381/v1 License:   This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Version of Record: A version of this preprint was published at Frontiers in Immunology on May 10th, 2021. See the published version at https://doi.org/10.3389/fimmu.2021.674681. Page 1/10 Abstract The COVID A to Z trial (JAMA Netw Open. 2021;4:e210369) is important as it focused specifically on SARS-CoV-2 coronavirus patients and examined a high dose of vitamin C which was previously predicted to reduce the duration of respiratory virus infections by about 20%. Unfortunately, there are several limitations in the trial methods. The COVID A to Z trial was “stopped early for futility”. In the sample size calculation, the authors assumed a 1.0 day shorter symptoms by intervention. Duration of symptoms was reduced by 1.2 days in the vitamin C arm compared with the usual care arm. Given that the observed vitamin C effect was 20% greater than the expected effect (1.2 vs. 1.0), it is illogical to have stopped the trial early because of “futility”. In this reanalysis we calculated the rate ratio of recovery between the vitamin C and usual care arms and found that vitamin C increased the rate of recovery by 70% (95% CI 6.8% to 170%, P = 0.025). Furthermore, we calculated quantile treatment effect of vitamin C. At the 60th percentile level of symptom distribution, duration was 9 days in the usual care arm, and 6 days in the vitamin C arm, which corresponds to reduction in symptom duration by 3 days (95% CI 3 to 4.6 days; P < 0.001). The analysis of the quantile treatment effect indicates that there may be around 30% reduction in symptom duration in patients with the longest symptoms. Our reanalysis indicates a need for methodologically sound trials with larger numbers of patients to investigate the treatment effects of vitamin C against SARS-CoV-2.