key: cord-0974669-ixjye9vg authors: Patel, Oneel; Chinni, Vidyasagar; El‐Khoury, John; Perera, Marlon; Neto, Ary S.; McDonald, Christine; See, Emily; Jones, Daryl; Bolton, Damien; Bellomo, Rinaldo; Trubiano, Jason; Ischia, Joseph title: A pilot double‐blind safety and feasibility randomized controlled trial of high‐dose intravenous zinc in hospitalized COVID‐19 patients date: 2021-03-09 journal: J Med Virol DOI: 10.1002/jmv.26895 sha: a3aaacacf38727ffeb12a992f09cc98c241d0ab7 doc_id: 974669 cord_uid: ixjye9vg Zinc inhibits replication of the SARS‐CoV virus. We aimed to evaluate the safety, feasibility, and biological effect of administering high‐dose intravenous zinc (HDIVZn) to patients with COVID‐19. We performed a Phase IIa double‐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 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. Cheap, safe, and easily administered interventions to improve outcomes associated with COVID-19 infection remain an important goal. Zinc and Zn-salts inhibit viral infections in clinical and experimental settings, 1-10 including replication of SARS-coronavirus (SARS-CoV). 8 Thus, zinc supplementation might be beneficial in patients with COVID-19. [11] [12] [13] [14] [15] [16] [17] Clinical trials have been registered to test the efficacy of zinc against COVID, mostly with oral zinc supplementation. 18 However, the bioavailability of enterally administered zinc is low. 15 Thus, logically, intravenous zinc at a high dose should be the preferred mode of administration. 15 Unfortunately, no studies have assessed the feasibility, safety, and impact on zinc levels of high-dose intravenous zinc (HDIVZn). We designed a Phase IIa pilot double-blind randomized controlled trial (RCT) to determine the feasibility, safety, and biological efficacy of HDIVZn in subjects with COVID-19. The Austin Health Human Research Ethics Committee approved this study (HREC/62996/Austin-2020-208572(v3) and the trial was prospectively registered (Australia New Zealand Clinical Trial Register Registration no. ACTRN12620000454976). A detailed clinical trial protocol has been published previously. 19 Briefly, we randomized consenting COVID-19 confirmed hospitalized adults with oxygen saturation (SpO 2 ) of 94% or less while on ambient air to either daily HDIVZn or saline placebo. Colorless pharmaceutical grade Zinc Chloride (ZnCl 2 ) stock solution obtained from Phebra Pty Ltd was diluted in 250 ml of normal saline and infused via F I G U R E 1 Flow chart showing patient recruitment and randomisation peripheral intravenous access over 3 h at a dose of 0.5 mg/kg/day (elemental zinc concentration, 0.24 mg/kg/day) for a maximum of 7 days, or until hospital discharge or death. The investigators, study coordinators, treating physicians, bedside nurses, and patients/family remained blinded to the allocated study solution. The serum trace metal analysis was carried out by Austin Pathology using inductively coupled plasma mass spectrometry (ICP-MS). Continuous variables are presented as means ± standard deviation and compared between groups with the Wilcoxon rank-sum test. We randomized 33 adults to either HDIVZn (n = 15) or placebo (n = 18; Figure 1 and Table 1 ). Hypertension, diabetes mellitus, and chronic cardiovascular disease were frequently present. We observed no drugrelated severe adverse events during 94 administrations of HDIVZn However, three HDIVZn patients reported infusion site irritation, two on Day 4, and one on Day 6. 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 increased serum zinc levels above the deficiency cutoff of 10.7 µmol/l (p < .001) on Day 6. In contrast, serum zinc levels with placebo remained below this value ( Figure 2A ). In contrast, serum copper, calcium, and magnesium were within the normal range at baseline and were not affected by HDIVZn. As most of the patients enrolled in our study were donating blood across multiple trials, we had limited ability to collect enough blood samples to perform all the planned 20 In a Japanese study among a cohort of 29 COVID-19 patients, 9 (31%) were found to be zinc deficient. 21 There is no globally accepted cutoff level for zinc deficiency. However, Hotz et al. 22 based on the data from the second National Health and Nutrition Examination Survey (NHANES II) suggested that for males greater than 10 years of age serum zinc levels below 61-74 μg/dl (9.3-11.3 µmol/l) depending on the fasting status can be considered as a cutoff value for zinc deficiency. Furthermore, the International Zinc Nutrition Consultative Group (IZiNCG) 23 has defined 10.7 µmol/l as a cutoff value for zinc deficiency, and this value was previously used in an Australian study. 24 Serum zinc levels less than 60 μg/dl (9.1 µmol/l) are defined as clinical zinc deficiency in Japan. However, in a recently published Japanese study, the zinc deficiency cutoff value was set at <70 μg/dl (10.7 µmol/l) to enable direct comparison with domestic and international information. 21 A previous study has determined that the mean serum zinc in the Australian population is 13 ± 2.4 and 13 ± 2.5 µmol/l for men and women, respectively. 24 One of the leading causes of zinc deficiency is aging; however, in a well-characterized cohort of healthy Australians with an average age of 70.6 ± 7 years, the serum zinc levels were 12.7 ± 2.5 µmol/l. 25 In our study, 100% of patients (33/33) were zinc deficient as the mean serum zinc values in the placebo, and the HDIVZn group were 6.9 ± 1.1 and 7.7 ± 1.6 µmol/l, respectively, well below the zinc deficiency cutoff value of 10.7 µmol/l. Therefore, our results suggest that such zinc deficiency seen in COVID-19 patients may be an acute phase reaction, specifically due to COVID-19 infection. 26 Zinc deficiency has been associated with a twofold increase in complication rates, 20 The authors declare that there are no conflict of interests. 3. Hospitalized, no supplemental oxygen 1 (7.1) 1 (5.6) Efficacy of zinc against common cold viruses: an overview Effect of zinc salts on respiratory syncytial virus replication Observation on clinical efficacy of combined therapy of zinc supplement and jinye baidu granule in treating human cytomegalovirus infection Recurrent herpes labialis: a pilot study of the efficacy of zinc therapy Zinc ions inhibit replication of rhinoviruses PDTC inhibits picornavirus polyprotein processing and RNA replication by transporting zinc ions into cells Pyrrolidine dithiocarbamate reduces coxsackievirus B3 replication through inhibition of the ubiquitin-proteasome pathway Zn 2+ inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture Poliovirus RNA-dependent RNA polymerase (3D(pol)). Divalent cation modulation of primer, template, and nucleotide selection Characterization of the large picornaviral polypeptides produced in the presence of zinc ion The potential impact of zinc supplementation on COVID-19 pathogenesis Zinc and respiratory tract infections: perspectives for COVID-19 (Review) Can Zn be a critical element in COVID-19 treatment? Enhancing immunity in viral infections, with special emphasis on COVID-19: a review Why is it worth testing the ability of zinc to protect against ischaemia reperfusion injury for human application Zinc preconditioning protects against renal ischaemia reperfusion injury in a preclinical sheep large animal model Protective effect of zinc preconditioning against renal ischemia reperfusion injury is dose dependent Zinc and COVID-19: basis of current clinical trials Randomised controlled trial for high-dose intravenous zinc as adjunctive therapy in SARS-CoV-2 (COVID-19) positive critically ill patients: trial protocol COVID-19: poor outcomes in patients with zinc deficiency Analysis of the predictive factors for a critical illness of COVID-19 during treatment relationship between serum zinc level and critical illness of COVID-19 Suggested lower cutoffs of serum zinc concentrations for assessing zinc status: reanalysis of the second National Health and Nutrition Examination Survey data (1976-1980) International Zinc Nutrition Consultative Group (IZiNCG) technical document #1. Assessment of the risk of zinc deficiency in populations and options for its control Zinc status of northern Tasmanian adults Decreased serum zinc is an effect of ageing and not Alzheimer's disease Plasma zinc concentrations are depressed during the acute phase response in children with falciparum malaria Prediction of survival odds in COVID-19 by zinc, age and selenoprotein P as composite biomarker Treatment of SARS-CoV-2 with high dose oral zinc salts: a report on four patients A randomized trial of hydroxychloroquine as postexposure prophylaxis for COVID-19 COVID-19 outpatients: early riskstratified treatment with zinc plus low-dose hydroxychloroquine and azithromycin: a retrospective case series study Zinc sulfate in combination with a zinc ionophore may improve outcomes in hospitalized COVID-19 patients Zinc bioavailability and homeostasis A pilot double-blind safety and feasibility randomized controlled trial of high-dose intravenous zinc in hospitalized COVID-19 patients