Abstract: Received: 6 December 2020 | Revised: 18 January 2021 | Accepted: 20 January 2021 DOI: 10.1002/jmv.26895 SHORT COMMUNICATION A pilot double‐blind safety and feasibility randomized controlled trial of high‐dose intravenous zinc in hospitalized COVID‐19 patients Oneel Patel1 | Vidyasagar Chinni1,2 | John El‐Khoury1,2 | Marlon Perera1,2 | Ary S. Neto3,4 | Christine McDonald5 | 1,6 | Damien Bolton Daryl Jones 1,2 Joseph Ischia 1 Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia 1,2 | 4,6 Rinaldo Bellomo Emily See6 | Jason Trubiano | 7 | Abstract Zinc inhibits replication of the SARS‐CoV virus. We aimed to evaluate the 2 Department of Urology, Austin Health, Heidelberg, Victoria, Australia safety, feasibility, and biological effect of administering high‐dose intravenous 3 zinc (HDIVZn) to patients with COVID‐19. We performed a Phase IIa double‐ Australian and New Zealand Intensive Care‐Research Centre, Monash University, Melbourne, Victoria, Australia 4 Centre for Integrated Critical Care, The University of Melbourne, Parkville, Victoria, Australia 5 Department of Respiratory and Sleep Medicine, Austin Health, Heidelberg, Victoria, Australia 6 Department of Intensive Care, Austin Hospital, Heidelberg, Victoria, Australia blind, randomized controlled trial to compare HDIVZn to placebo in hospitalized patients with COVID‐19. We administered trial treatment per day for a maximum of 7 days until either death or hospital discharge. We measured zinc concentration at baseline and during treatment and observed patients for any significant side effects. For eligible patients, we randomized and administered treatment to 33 adult participants to either HDIVZn (n = 15) or placebo (n = 18). We observed no serious adverse events throughout the study for a total of 94 HDIVZn administrations. However, three participants in the HDIVZn group 7 Department of Infectious Disease, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia Correspondence Joseph Ischia, Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, VIC, Level 8, Lance Townsend Building, Australia. Email: jjischia@unimelb.edu.au reported infusion site irritation. Mean serum zinc on Day 1 in the placebo, and the HDIVZn group was 6.9 ± 1.1 and 7.7 ± 1.6 µmol/l, respectively, consistent with zinc deficiency. HDIVZn, but not placebo, increased serum zinc levels above the deficiency cutoff of 10.7 µmol/l (p < .001) on Day 6. Our study did not reach its target enrollment because stringent public health measures markedly reduced patient hospitalizations. Hospitalized COVID‐19 patients demonstrated zinc deficiency. This can be corrected with HDIVZn. Such treatment appears safe, feasible, and only associated with minimal peripheral infusion site irritation. This pilot study justifies further investigation of this treatment in COVID‐19 patients. KEYWORDS COVID‐19, randomized controlled trial, trial protocol, zinc Abbreviations: HDIVZn, high dose intravenous zinc; HFNC, high‐flow nasal cannula; NIV, noninvasive ventilation. J Med Virol. 2021;93:3261–3267. wileyonlinelibrary.com/journal/jmv © 2021 Wiley Periodicals LLC | 3261 3262 1 | PATEL | INTRODUCTION 2 | Cheap, safe, and easily administered interventions to improve ET AL. ME THO D S 2.1 | Human ethics outcomes associated with COVID‐19 infection remain an important goal. Zinc and Zn‐salts inhibit viral infections..