Abstract: Calcifediol treatment and COVID-19-related outcomes X. Nogues1,2, D. Ovejero1, J.M. Quesada-Gomez3, R. Bouillon4, D. Arenas5, J. Pascual5, J. Villar-Garcia6, A. Rial2, C. Gimenez-Argente2, ML. Cos2, J. Rodriguez-Morera2, I. Campodarve2, R. Guerri-Fernandez1,6, M. Pineda-Moncusí1 and N. Garcia-Giralt1 Affiliations 1. IMIM (Hospital del Mar Research Institute), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Barcelona, Spain 2. Internal Medicine Department, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain 3. Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC). Fundación Progreso y Salud. CIBER de Fragilidad y Envejecimiento Saludable (CIBERFES). Hospital Universitario Reina Sofía. Universidad de Córdoba. Menéndez Pidal s/n, 14004, Córdoba, Spain. jmquesada@uco.es 4. Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, Herestraat, 3000 Leuven, Belgium. Roger.bouillon@kuleuven.be – orchid number 0000 -00026446-6763 5. Department of Nephrology, Hospital del Mar-IMIM, Barcelona, Spain 6. Department of Infectious Diseases, Hospital del Mar-IMIM, Barcelona, Spain. Corresponding author: Natalia Garcia-Giralt, PhD Postdoc Researcher in CIBER in frailty and healthy ageing Associate Lecturer of University of Barcelona e-mail: ngarcia@imim.es This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3771318 Summary Background COVID-19 is a major health problem because of acute respiratory distress syndrome, saturation of intensive care units (ICU) and mortality. Methods Our study aims to elucidate the effect of calcifediol [25(OH)D3] treatment on ICU admission and mortality, in patients admitted to COVID-19 wards of Hospital del Mar, Barcelona, Spain. A total of 930 participants were included. Participants (n=551) were randomly assigned to calcifediol treatment (532 ug on day one and 266 ug on day 3, 7, 15, and 30) at the time of hospital admission or as controls (n=379). Findings ICU assistance was required by 110 (11.8%) participants. Out of 551 patients treated with calcifediol at admission, 30 (5.4%) required ICU, compared to 80 out of 379 controls (21.1%; p<0.0001). Logistic regression of calcifediol treatment on ICU admission, adjusted by age, gender, linearized 25(OH)D levels at baseline, and comorbidities showed that treated patients had a reduced risk to require ICU (RR 0.18 [95% CI 0.11;0.29]). Baseline 25(OH)D levels inversely correlated with the risk of ICU admission (RR 0.53 [95% CI 0.35;0.80]). Overall mortality was 10%. In the Intention-to-treat analysis, 36 (6.5%) out of 551 patients treated with calcifediol at admission died compared to 57 patients (15%) out of 379 controls (p=0.001). Adjusted results showed a reduced mortality for more of 60%. Higher baseline 25(OH)D levels were significantly associated with decreased mortality (RR 0.40 [95% CI 0.24;0.67]). Age and obesity were also predictors of mortality. Interpretation In patients hospitalized with COVID-19, calcifediol treatment at the time of hospitalization significantly reduced ICU admission and mortality. Funding CIBERFES and FIS (ISCIII), and FEDER funds This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3771318 Research in context Evidence before this study Adequate vitamin D status has emerged as a potentially preventing..