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)

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