Abstract: medicina Article Evidence for the Efficacy of a High Dose of Vitamin D on the Hyperinflammation State in Moderate-to-Severe COVID-19 Patients: A Randomized Clinical Trial Neven Sarhan 1 , Ahmed E. Abou Warda 2 , Rania M. Sarhan 3 , Marian S. Boshra 3 , Gomaa Mostafa-Hedeab 4, * , Bashayer F. ALruwaili 5 , Haytham Soliman Ghareeb Ibrahim 6 , Mona F. Schaalan 1 and Shaimaa Fathy 1 1 2 3 4 5 6 * Citation: Sarhan, N.; Abou Warda, A.E.; Sarhan, R.M.; Boshra, M.S.; Mostafa-Hedeab, G.; ALruwaili, B.F.; Ibrahim, H.S.G.; Schaalan, M.F.; Fathy, S. Evidence for the Efficacy of a High Dose of Vitamin D on the Hyperinflammation State in Moderate-to-Severe COVID-19 Patients: A Randomized Clinical Trial. Medicina 2022, 58, 1358. https://doi.org/10.3390/ medicina58101358 Academic Editor: Silvia Angeletti Received: 14 September 2022 Accepted: 20 September 2022 Published: 27 September 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in Clinical Pharmacy Department, Faculty of Pharmacy, Misr International University, Cairo 11828, Egypt Clinical Pharmacy Department, Faculty of Pharmacy, October 6 University, P.O. Box 12585, Giza 12585, Egypt Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, P.O. Box 62514, Beni-Suef 62511, Egypt Pharmacology Department, Medical College, Jouf University, Sakaka 72388, Saudi Arabia Community and Family Medicine Department, Division of Family Medicine, Medical College, Jouf University, Sakaka 72388, Saudi Arabia Cardiology Department, Faculty of Medicine, El-Fayoum University, P.O. Box 63514, El Fayoum 63511, Egypt Correspondence: gomaa@ju.edu.sa; Tel.: +966-5346-2739 Abstract: Background and Objectives: Vitamin D supplementation plays a key effect in lowering cytokine storms among COVID-19 patients by influencing the activity of the renin-angiotensin system and the production of the angiotensin-2 converting enzyme. The study was conducted to explore the effect of high-dose intramuscular vitamin D in hospitalized adults infected with moderate-tosevere SARS-CoV-2 in comparison with the standard of care in the COVID-19 protocol. Materials and Methods: Two groups of patients were compared in this prospective randomized controlled trial as the vitamin D was administered orally to group 1 (alfacalcidol 1 mcg/day) and intramuscularly to group 2 (cholecalciferol 200,000 IU). One hundred and sixteen participants were recruited in total, with fifty-eight patients in each group. Following the Egyptian Ministry of Health’s policy for COVID-19 management, all patients received the same treatment for a minimum of five days. Results: A significant difference was recorded in the length of hospital stay (8.6 versus 6.8 days), need for high oxygen or non-invasive mechanical ventilator (67% versus 33%), need for a mechanical ventilator (25% versus 75%), clinical improvement (45% versus 55%), the occurrence of sepsis (35% versus 65%), and in the monitored laboratory parameters in favor of high-dose vitamin D. Moreover, clinical improvement was significantly associated with the need for low/high oxygen, an invasive/noninvasive mechanical ventilator (MV/NIMV), and diabetes, while mortality was associated with the need for MV, ICU admission, atrial fibrillation, chronic obstructive pulmonary disease, asthma, and the occurrence of secondary infection. Conclusions: Our study showed that high-dose vitamin D was considered a promising treatment in the suppression of cytokine storms among..