Abstract: medRxiv preprint doi: https://doi.org/10.1101/2020.11.08.20222638; this version posted December 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Mathematical analysis of Córdoba calcifediol trial suggests strong role for Vitamin D in reducing ICU admissions of hospitalized COVID-19 patients Irwin Jungreis​1,2*​ and Manolis Kellis​1,2 1​ MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA 2​ Broad Institute of MIT and Harvard, Cambridge, MA *​ Corresponding author: ​iljungr@csail.mit.edu Abstract A randomized controlled trial of calcifediol (25-hydroxyvitamin D​3​) as a treatment for hospitalized COVID-19 patients in Córdoba, Spain, found that the treatment was associated with reduced ICU admissions with very large effect size and high statistical significance, but the study has had limited impact because it had only 76 patients and imperfect blinding, and did not measure vitamin D levels pre- and post-treatment or adjust for several comorbidities. Here we reanalyze the reported results of the study using rigorous and well established statistical techniques, and find that the randomization, large effect size, and high statistical significance address many of these concerns. We show that random assignment of patients to treatment and control groups is highly unlikely to distribute comorbidities or other prognostic indicators sufficiently unevenly to account for the large effect size. We also show that imperfect blinding would need to have had an implausibly large effect to account for the reported results. Finally, comparison with two additional randomized clinical trials of vitamin D supplementation for COVID-19 in India and Brazil indicates that early intervention and rapid absorption may be crucial for the observed benefits of vitamin D. We conclude that the Córdoba study provides sufficient evidence to warrant immediate, well-designed pivotal clinical trials of early calcifediol administration in a broader cohort of inpatients and outpatients with COVID-19.