Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection: The COVID A to Z Randomized Clinical Trial | Complementary and Alternative Medicine | JAMA Network Open | JAMA Network
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Visual Abstract. Effect of Zinc and Ascorbic Acid Supplementation on Symptom Length Among Ambulatory Patients With SARS-CoV-2 Infection
Effect of Zinc and Ascorbic Acid Supplementation on Symptom Length Among Ambulatory Patients With SARS-CoV-2 Infection
Figure 1.  Patient Flow Diagram
Patient Flow Diagram

OTC indicates over the counter.

Figure 2.  Patients Experiencing Symptoms by 4-Symptom Scale
Patients Experiencing Symptoms by 4-Symptom Scale
Figure 3.  Kaplan-Meier Curves for the Primary End Point by Treatment Group
Kaplan-Meier Curves for the Primary End Point by Treatment Group
Table 1.  Baseline Characteristics of the Enrolled Population
Baseline Characteristics of the Enrolled Population
Table 2.  Primary and Secondary End Points
Primary and Secondary End Points
1.
Huang  C, Wang  Y, Li  X,  et al.  Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.   Lancet. 2020;395(10223):497-506. doi:10.1016/S0140-6736(20)30183-5PubMedGoogle ScholarCrossref
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US Centers for Disease Control and Prevention. COVID-19. Accessed January 12, 2021. https://www.cdc.gov/coronavirus/2019-ncov/index.html
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Wu  Z, McGoogan  JM.  Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.   JAMA. 2020;323(13):1239-1242. doi:10.1001/jama.2020.2648PubMedGoogle ScholarCrossref
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Gammoh  NZ, Rink  L.  Zinc in infection and inflammation.   Nutrients. 2017;9(6):E624. doi:10.3390/nu9060624PubMedGoogle Scholar
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Hemilä  H.  Vitamin C and infections.   Nutrients. 2017;9(4):E339. doi:10.3390/nu9040339PubMedGoogle Scholar
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Hemilä  H, Chalker  E.  Vitamin C for preventing and treating the common cold.   Cochrane Database Syst Rev. 2013;(1):CD000980. doi:10.1002/14651858.CD000980.pub4PubMedGoogle Scholar
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Singh  M, Das  RR.  Zinc for the common cold.   Cochrane Database Syst Rev. 2011;(2):CD001364. doi:10.1002/14651858.CD001364.pub3PubMedGoogle Scholar
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Eby  GA, Davis  DR, Halcomb  WW.  Reduction in duration of common colds by zinc gluconate lozenges in a double-blind study.   Antimicrob Agents Chemother. 1984;25(1):20-24. doi:10.1128/AAC.25.1.20PubMedGoogle ScholarCrossref
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Hemilä  H.  Zinc lozenges and the common cold: a meta-analysis comparing zinc acetate and zinc gluconate, and the role of zinc dosage.   JRSM Open. 2017;8(5):2054270417694291. doi:10.1177/2054270417694291PubMedGoogle Scholar
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Carr  AC.  Vitamin C administration in the critically ill: a summary of recent meta-analyses.   Crit Care. 2019;23(1):265. doi:10.1186/s13054-019-2538-yPubMedGoogle ScholarCrossref
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te Velthuis  AJ, van den Worm  SH, Sims  AC, Baric  RS, Snijder  EJ, van Hemert  MJ.  Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture.   PLoS Pathog. 2010;6(11):e1001176. doi:10.1371/journal.ppat.1001176PubMedGoogle Scholar
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Li  W, Moore  MJ, Vasilieva  N,  et al.  Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.   Nature. 2003;426(6965):450-454. doi:10.1038/nature02145PubMedGoogle ScholarCrossref
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Krenn  BM, Gaudernak  E, Holzer  B, Lanke  K, Van Kuppeveld  FJ, Seipelt  J.  Antiviral activity of the zinc ionophores pyrithione and hinokitiol against picornavirus infections.   J Virol. 2009;83(1):58-64. doi:10.1128/JVI.01543-08PubMedGoogle ScholarCrossref
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Hemilä  H.  Vitamin C, respiratory infections and the immune system.   Trends Immunol. 2003;24(11):579-580. doi:10.1016/j.it.2003.09.004PubMedGoogle ScholarCrossref
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Davelaar  FG, Bos  J.  Ascorbic acid and infectious bronchitis infections in broilers.   Avian Pathol. 1992;21(4):581-589. doi:10.1080/03079459208418879PubMedGoogle ScholarCrossref
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Weismann  K, Jakobsen  JP, Weismann  JE,  et al.  Zinc gluconate lozenges for common cold: a double-blind clinical trial.   Dan Med Bull. 1990;37(3):279-281.PubMedGoogle Scholar
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Meltzer  DO, Best  TJ, Zhang  H, Vokes  T, Arora  V, Solway  J.  Association of vitamin D status and other clinical characteristics with COVID-19 test results.   JAMA Netw Open. 2020;3(9):e2019722. doi:10.1001/jamanetworkopen.2020.19722PubMedGoogle Scholar
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    10 Comments for this article
    EXPAND ALL
    Faulty Intervention Design for this RCT
    Stephen Shipman, BA (Georgetown), CFA | Institutional Money Manager
    In this study, Suma et al fail to supplement the zinc with an ionophore, either hydroxychlorquine or quercetin. All successful treatments using zinc, whether as a prophylaxis or as early or late stage infection applications, have and must use the ionophore that allows easy insertion of zinc into the cell.
    CONFLICT OF INTEREST: None Reported
    Method of micronutrient administration matters
    Christopher Foley, MD ABIM | Private practice
    As someone who has actually taught nutraceutical science at the university level, I would say that this study is unfortunately flawed. First, trying to "load up" on zinc doesn't really work. It's a little like telling somebody to quit smoking and then expecting them to have an immediate reduction in cancer risk. That risk will last for more than a decade. Intracellular sink is what matters. It takes several months for intracellular levels to rise to a meaningful level, much more than a few days of loading up.

    The vitamin C that was administered is largely not absorbed, hence
    the side effects. Most knowledgeable physicians in nutraceutical science are now using only liposomal vitamin C that is absorbed upwards of 90% instead of 20% with far fewer side effects on the G.I. tract particularly.

    Also, micronutrients don't function in a vacuum. Vitamin D is far more important, and unless this study carefully randomized individuals with vitamin D levels above or below ~ 35 ng/decaliter, the study itself would ostensibly be fairly meaningless. It's nice to see someone giving some attention to this, but one could have predicted that this particular effort would not be a very credible effort.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Broader understanding of how to use dietary supplements needed
    William Sardi, B.S. | Knowledge of Health, Inc.
    The use of dietary supplements by the public to prevent or allay symptoms of COVID-19 is large because no few medicines have been specifically licensed or approved for use against Coronavirus.

    The study did attempt to employ frequent divided doses of vitamin C to presumably achieve high blood levels given that ascorbic acid as a water-soluble nutrient is rapidly excreted; and an ample dose (50 mg as gluconate) of zinc was employed many time above typical dietary intake 10 mg). However, without measuring blood serum concentration, the study falls flat in reaching a conclusion over effectiveness/ineffectiveness of vitamin
    C in allaying symptoms. 

    Zinc elevates metallothionein, its carrier protein. Excessive zinc may bind up all of the supplemental zinc rendering it non-bioavailable. Studies showing zinc supplementation shortened the duration of cold symptoms when this trace mineral was consumed as acetate lozenges in 5 divided doses totaling ~80-90 mg elemental zinc, so zinc would be slowly absorbed in the oral cavity in a non-overwhelming dose so as not to over-produce metallothionein.

    The fact that both standard of care and vitamin/trace mineral treatment achieved 50% symptomatic relief at about the same time speaks for the superiority of the adaptive (specific) immune response which typically activates 5-7 days after any infection. Vitamin D is better known to activate an adaptive immune response (specific to the pathogen involved by activation of memory T-cells).
    CONFLICT OF INTEREST: Write books about and market dietary supplements
    READ MORE
    Is zinc gluconate 50mg a high dose?
    Hannah Bisht |
    The study reports to use 50mg of zinc gluconate, which contains 7mg of the elemental zinc.
    That is not a high dose.
    CONFLICT OF INTEREST: None Reported
    Bullet Proof
    H Silverstein, MD | Preventive Medicine Center
    It is generally a good idea to put on one's bullet proof vest before going into combat. Further studies should enroll patients to see if they were able to avoid developing coronavirus infection after being on vitamin D3 5,000 IU, zinc 50 mg, selenium 200 ug, and vitamin C at least 1000 (ie, 3,000) mg 5-7 days a week after 1 month of such continuing treatment vs placebo. 
    CONFLICT OF INTEREST: None Reported
    Zn levels
    James Marzolf, MD MSc MPH | non-profit foundation, Senior Director Health Sector Finance
    Do we know the participants baseline and test Zn levels? Ascorbic acid can enhance Zn uptake in many instances but this is blunted by diabetes and it appears many patients in the experimental arm had diabetes. Viruses may induce a Zn deficiency upon infection and immune response.
    CONFLICT OF INTEREST: None Reported
    50mg elemental zinc was used.
    M Sickels, MD | Private practice
    I checked with the author and verified that they did use 50mg of elemental zinc.

    If you look at figure 3, you will see that all of the treatment showed some improvement over standard of care during days 3-10, and then standard of care started catching up until it was similar to the rest (though AA alone remained somewhat better.

    Vitamin C levels in the blood are tightly controlled by the gut and in ideal (healthy, non-stressed) circumstances a modest dose of 250-500mg should max out absorption but with stress and infection, vitamin C requirements go
    up (such that ICU patients required 3000mg IV daily to maintain normal plasma levels, see DOI: 10.1016/s0022-4804(02)00083-5 ). So, the substantial dose of vitamin C used in this article should have been adequate to top off the blood levels. However, even these substantial doses of oral vitamin C would not increase levels past the 200µmol/L limit imposed by the gut (see doi:10.7326/0003-4819-140-7-200404060-00010 ) and certainly not high enough to achieve the levels that has been shown to completely inhibit viral replication (see PMID: 22931805 and doi.org/10.1073/pnas.77.5.2711 ) though that concentration is readily achievable with IV dosing.

    The hyperbolic claims of greater absorption of liposomal vitamin C are not supported by the literature, which only show relatively modest increases in plasma levels for liposomal compared to plain ascorbate at best (see doi: 10.4137/NMI.S39764 and https://isom.ca/article/the-levels-of-ascorbic-acid-in-blood-and-mononuclear-blood-cells-after-oral-liposome-encapsulated-and-oral-non-encapsulated-vitamin-c-supplementation-taken-without-and-with-iv-hydrocortisone/ ).
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Trial stopped early despite promising interim results
    Anitra Carr, PhD | University of Otago, Christchurch, New Zealand
    The most striking aspect of this study is that the observed decrease in time to 50% reduction of symptoms in the vitamin C group, and combination vitamin C and zinc group, of 1.2 days (i.e. 5.5 days vs 6.7 days in the standard care group) was greater than the 1.0 day decrease anticipated by the authors in their sample size calculations (i.e. 5.0 days vs 6.0 days for standard care). 

    Another issue with the study design is that the duration of infection prior to presentation to outpatients and initiation of intervention was not reported and was likely variable.
    CONFLICT OF INTEREST: None Reported
    Study population selection likely excluded high-risk patients most likely to benefit.
    Miklos Salgo, PhD, MD | Retired
    In this study, the authors selected ambulatory patients recruited from outpatient facilities and thus may have underrepresented high-risk patients such as the elderly and minorities. Older patients, males and racial or ethnic minorities are demographic groups at high risk of infection, progression of diseases and death from COVID-19. These groups have also been shown to be likely to have zinc (Ref. 1) or Angiotensin-Converting Enzyme 2 (ACE2, Ref. 2) deficiency. Thus, the study may have inadvertently underrepresented exactly those patients (e.g. zinc deficient) most likely to benefit from zinc supplementation.

    References:

    1.
    Jothimani D, Kailasam E, Danielraj S et al, COVID-19: Poor outcomes in patients with zinc deficiency,
    International Journal of Infectious Diseases, Vol 100, 2020, pp 343-349, ISSN 1201-9712, https://doi.org/10.1016/j.ijid.2020.09.014

    2. Verdecchia P, Cavallini C, Spanevello A, Angeli F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med. 2020;76:14-20. doi:10.1016/j.ejim.2020.04.037
    CONFLICT OF INTEREST: None Reported
    READ MORE
    End of a Myth
    Paul Allen, MD, PhD | University Hospital
    It is nice to see that individuals have the courage to take on myths and attempt to prove them either correct and therefore not a myth or to demonstrate with no bias that the myth is just that and not a real effect. Well done!
    CONFLICT OF INTEREST: None Reported
    Original Investigation
    Public Health
    February 12, 2021

    Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection: The COVID A to Z Randomized Clinical Trial

    Author Affiliations
    • 1Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio
    • 2Neurologic Institute, Respiratory Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
    • 3Department of Infectious Diseases, Cleveland Clinic Florida, Weston
    JAMA Netw Open. 2021;4(2):e210369. doi:10.1001/jamanetworkopen.2021.0369
    Visual Abstract. Effect of Zinc and Ascorbic Acid Supplementation on Symptom Length Among Ambulatory Patients With SARS-CoV-2 Infection
    Effect of Zinc and Ascorbic Acid Supplementation on Symptom Length Among Ambulatory Patients With SARS-CoV-2 Infection
    Key Points

    Question  Do high-dose zinc, high-dose ascorbic acid, and/or a combination of the 2 reduce the duration of symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)?

    Findings  In this randomized clinical trial of 214 patients with confirmed SARS-CoV-2 infection receiving outpatient care, there was no significant difference in the duration of symptoms among the 4 groups.

    Meaning  These findings suggest that treatment with zinc, ascorbic acid, or both does not affect SARS-CoV-2 symptoms.

    Abstract

    Importance  There is limited evidence regarding early treatment of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to mitigate symptom progression.

    Objective  To examine whether high-dose zinc and/or high-dose ascorbic acid reduce the severity or duration of symptoms compared with usual care among ambulatory patients with SARS-CoV-2 infection.

    Design, Setting, and Participants  This multicenter, single health system randomized clinical factorial open-label trial enrolled 214 adult patients with a diagnosis of SARS-CoV-2 infection confirmed with a polymerase chain reaction assay who received outpatient care in sites in Ohio and Florida. The trial was conducted from April 27, 2020, to October 14, 2020.

    Intervention  Patients were randomized in a 1:1:1:1 allocation ratio to receive either 10 days of zinc gluconate (50 mg), ascorbic acid (8000 mg), both agents, or standard of care.

    Outcomes  The primary end point was the number of days required to reach a 50% reduction in symptoms, including severity of fever, cough, shortness of breath, and fatigue (rated on a 4-point scale for each symptom). Secondary end points included days required to reach a total symptom severity score of 0, cumulative severity score at day 5, hospitalizations, deaths, adjunctive prescribed medications, and adverse effects of the study supplements.

    Results  A total of 214 patients were randomized, with a mean (SD) age of 45.2 (14.6) years and 132 (61.7%) women. The study was stopped for a low conditional power for benefit with no significant difference among the 4 groups for the primary end point. Patients who received usual care without supplementation achieved a 50% reduction in symptoms at a mean (SD) of 6.7 (4.4) days compared with 5.5 (3.7) days for the ascorbic acid group, 5.9 (4.9) days for the zinc gluconate group, and 5.5 (3.4) days for the group receiving both (overall P = .45). There was no significant difference in secondary outcomes among the treatment groups.

    Conclusions and Relevance  In this randomized clinical trial of ambulatory patients diagnosed with SARS-CoV-2 infection, treatment with high-dose zinc gluconate, ascorbic acid, or a combination of the 2 supplements did not significantly decrease the duration of symptoms compared with standard of care.

    Trial Registration  ClinicalTrials.gov Identifier: NCT04342728

    Introduction

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel strain of enveloped RNA virus that has emerged as a deadly virus resulting in an international pandemic. Common symptoms at the onset of disease mimic influenza and include fever, nonproductive cough, myalgia, and fatigue.1 The US Centers for Disease Control and Prevention (CDC) list of SARS-CoV-2 symptoms includes fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, and diarrhea.2 In China, most patients (81%) with a confirmed diagnosis experienced only mild symptoms and did not require hospitalization or further care beyond supportive treatment.3 However, given the latency of the disease and prolonged incubation period, even patients who present with mild symptoms may progress to requiring hospitalization, prescription medication therapy, and mechanical ventilation and/or death.

    Zinc gluconate and ascorbic acid are commonly available over-the-counter supplements that patients take for the treatment of viral illnesses. Zinc has been purported to increase polymorphonuclear cells’ ability to fight infection, and ascorbic acid is an antioxidant that may play a role in immune response.4,5 Limited evidence suggests that high doses of ascorbic acid and zinc gluconate may reduce duration of common cold symptoms and decrease the severity of symptoms.6-9 However, the role of zinc gluconate and ascorbic acid in decreasing symptoms and improving recovery in patients diagnosed with SARS-CoV-2 infection is uncertain. The current study sought to determine whether zinc and/or ascorbic acid reduces the severity or duration of symptoms associated with SARS-CoV-2 compared with usual care.

    Methods

    The COVID A to Z study was a prospective randomized clinical open-label trial at multiple hospitals within a single health system, involving sites in Ohio and Florida. This study was approved by the Cleveland Clinic institutional review board and followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. All patients participating in the study provided written informed consent. Enrolled participants remained in their own home settings, and all study visits and/or procedures were conducted virtually, via telephone, email, computer, or laptop. The trial was designed to enroll approximately 520 adult patients diagnosed with SARS-CoV-2 infection with a polymerase chain reaction–based assay as outpatients who would likely remain in the outpatient setting for treatment. The full protocol of the study is available in Supplement 1.

    Patients were included in the study if they had a new diagnosis in an outpatient setting and were aged 18 years or older. Women of childbearing potential had to confirm a menstrual period within the past 30 days or previous sterilization, and those who were perimenopausal required a negative pregnancy test. Women of childbearing potential were required to have a confirmed negative pregnancy test to be enrolled. Patients were excluded if they were hospitalized, resided outside of Ohio or Florida, were pregnant, were actively lactating, or had advanced chronic kidney disease, liver disease awaiting transplantation, or a history of calcium oxalate kidney stones. Race/ethnicity were self-reported. The patient flow diagram is shown in Figure 1.

    Treatment Design

    Patients were randomized in a 1:1:1:1 allocation strategy to 1 of 4 treatment strategies with a treatment duration of 10 days after a positive diagnosis. The 4 treatment strategies were as follows: (1) 8000 mg of ascorbic acid (to be divided over 2-3 times per day with meals), (2) 50 mg of zinc gluconate at bedtime, (3) both therapies, or (4) usual care without any study medications. The randomization grid was designed via the REDCap database and based on 25% of anticipated enrolled patients in each of the 4 groups. An automatically created link in REDCap randomized the patient to the supplement group based on the randomization grid.

    Patients were asked to track their systemic illness daily based on symptoms. Patients were also asked to complete a questionnaire at the beginning of the study and every week after until day 28 to assess whether they were hospitalized or experienced adverse effects from the supplements. For each symptom, the patients assigned a score of 0 to 3 (with 0 indicating no symptoms; 1, mild symptoms; 2, moderate symptoms; and 3, severe symptoms). In the original analysis plan, patients recorded a questionnaire with only 4 symptoms (ie, fever/chills, shortness of breath, cough, and fatigue) for scores ranging from 0 to 12. However, based on CDC guidelines, the study protocol was amended on July 16, 2020, and the symptom questionnaire was expanded to include a total of 12 symptoms (ie, fevers/chills, shortness of breath, cough, fatigue, muscle or body aches, headache, new loss of taste, new loss of smell, congestion or runny nose, nausea, vomiting, and diarrhea), creating a score ranging from 0 to 36.2 The original 4-symptom scale was collected from all patients. The 12-symptom scale was only collected from patients enrolled after the July 16, 2020, amendment.

    Patients were contacted by study coordinators weekly via email or daily via telephone to assess scores and hospitalizations, adverse effects, and additional medications. Patients seen in the emergency department (without an inpatient hospitalization) during the course of the study were asked to take study supplement(s) if the emergency department visit occurred within the initial 10 days of the study and to continue daily symptom assessments. Patients admitted to the hospital during the course of study were considered treatment failures and were no longer be required to continue study supplementation or track their daily symptoms.

    Trial End Points

    The primary end point was the number of days required to reach a 50% reduction in symptom severity score from peak symptom score. This end point is reported for both the 4-symptom score available for all patients and the subset of patients for whom the 12-symptom score was available. Additional end points were the number of days required to reach a total symptom severity score of 0, cumulative severity score at day 5, hospitalizations, deaths, adjunctive prescribed medications, and adverse effects of the study supplements.

    Interim Analysis

    An operational and safety monitoring board (OSMB) within the Cleveland Clinic was established in April 2020 to provide safety monitoring and evaluate operational performance of all SARS-COV-2–related studies at the Cleveland Clinic. None of the OSMB members were involved in the conduct of the study. Due to slower than expected enrollment, an interim analysis was conducted at approximately 40% of expected enrollment (214 of 520 patients). Stopping for superiority would only be considered if any treatment group achieved P < .001 compared with placebo. Stopping for futility would be considered if the conditional power was less than 30% for any (or all) treatment groups compared with placebo.

    Statistical Analysis

    We assumed that the usual care group would achieve a 50% reduction in symptom severity in a mean (SD) of 6 (3) days and that at least 1 of the other 3 study groups would achieve a 50% reduction in a mean (SD) of 5 (3) days. Assuming a sample size in each of the 4 groups of 130 patients, a 1-way analysis of variance would have 80% power (2-sided α of .05) to detect a difference in means of 1 day with a common SD of 3 days.

    Patients were categorized as either meeting the primary end point or failing to meet the primary end point. Patients who died or were hospitalized during the study were counted as treatment failures. The primary end point was defined as the number of days from the time of peak symptom score to a 50% resolution in those achieving a 50% reduction within the study time frame. Patients who were asymptomatic at baseline were classified as missing when calculating the days to a 50% reduction in symptom score. In a sensitivity analysis, the number of days to reach a 50% reduction was set to 28 days for patients considered treatment failures. The original analysis plan was to evaluate all pairwise treatment comparisons with adjustment for multiple comparisons using the Tukey method. Because the study was stopped early for futility, the overall F-test P value from an analysis of variance is reported for all end points, summarizing number of days to 50% reduction. Nominal P values from the χ2 statistic are reported for categorical variables. Kaplan-Meier curves were created comparing the primary end point among the 4 treatments. The Kaplan Meier plot and P value from the log-rank test of the null hypothesis of no difference between the 4 survival curves were made using the survminer package in R version 3.6.1 (R Project for Statistical Computing). Statistical significance was set at P < .05, and all tests were 2-tailed.

    Results
    Early Stopping

    The OSMB met on October 23, 2020, and recommended stopping the study for futility. The futility criteria was met for the 3 active treatment groups compared with the usual care group. Data on the 214 patients enrolled at the time of study termination are the final data for this study.

    Baseline Characteristics

    A total of 214 patients were enrolled and randomized from April 27, 2020, to October 14, 2020. Of the 214 patients, 50 (23.4%) were randomized to usual care, 48 (22.4%) were randomized to ascorbic acid only, 58 (27.1%) were randomized to zinc gluconate only, and 58 (27.1%) to both supplements. Baseline characteristics of study participants are reported in Table 1. The mean (SD) age of study participants was 45.2 (14.6) years. There were 132 (61.7%) women in the study and 68 people (31.8%) reported currently or formerly smoking. At least one-quarter of participants used vitamins and minerals previously (56 [26.2%]). The mean (SD) symptom composite score (of 12 possible points) at baseline was 4.3 (1.9) points and was similar across treatment groups (Figure 2). In the subset of patients with a 12-symptom score (36 possible points) the mean (SD) was 11.6 (5.6) points.

    Primary Outcome

    There was no significant difference in the primary outcome of days required to reach a 50% reduction in symptoms among the 4 study groups. Patients who received usual care without supplementation achieved a 50% reduction in symptoms in a mean (SD) of 6.7 (4.4) days compared with a mean (SD) of 5.5 (3.7) days for patients receiving ascorbic acid, a mean (SD) of 5.9 (4.9) days for patients receiving zinc gluconate, and a mean (SD) of 5.5 (3.4) days for patients receiving both ascorbic acid and zinc gluconate supplementation (overall P value = 0.45; log-rank P = .25) (Figure 3).

    Secondary Outcomes

    There was no significant difference in any of the secondary outcomes, including number of days to reach no presence of fever, cough, shortness of breath, or fatigue. The mean (SD) composite 4-symptom score at day 5 was 3.2 (2.2) points and did not differ among the 4 study groups. A total of 17 patients (7.9%) were hospitalized before the 28-day study period ended, and 3 patients (1.4%) died after enrollment in the study (Table 2). However, both the number of hospitalizations and deaths did not significantly vary among the 4 treatment groups. Less than 3% of the population had medications added to treat coronavirus disease 2019 (COVID-19)–related symptoms, and less than 10% of the population experienced an adverse effect related to the supplement, with slightly more adverse effects, including nausea, diarrhea, and stomach cramps, in the group receiving ascorbic acid only (eTable in Supplement 2).

    Serious Adverse Events

    The data safety monitoring board noted 4 serious adverse events, including 3 patients who died from COVID-19 and another patient who was admitted to the hospital for a chronic obstructive pulmonary disease exacerbation during the study period. The board did not believe that any of the adverse events were caused by individual treatments that patients received as a part of the study.

    Discussion

    The COVID A to Z study was designed to examine whether patients treated with zinc gluconate, ascorbic acid, or a combination of both treatments would experience a shortened duration of symptoms associated with SARS-CoV-2 compared with usual care. A significantly faster reduction in symptoms was not observed in any of the active treatment groups vs usual care. Based on an interim analysis, the study was stopped for futility.

    The data about oral ascorbic acid and zinc are inconsistent, with some trials suggesting that high doses of ascorbic acid and zinc gluconate may reduce the duration of common cold symptoms and decrease the severity of symptoms, while other studies have shown no benefit.6-9 The data for intravenous ascorbic acid is also variable, with a meta-analysis review that investigated the role of ascorbic acid in critically ill patients10 showing no significant association with mortality but variable associations with secondary end points, including duration of ventilator support and hospital length of stay. Ongoing clinical trials in China and the United States are investigating the potential role of intravenous ascorbic acid in reducing respiratory failure requiring mechanical ventilation in patients with SARS-CoV-2. In addition, ascorbic acid, zinc, and vitamin D are being studied for the prevention of SARS-CoV-2 infection. What is unknown is whether ascorbic acid and zinc gluconate can shorten the duration or prevent progression of the disease.

    In terms of biologic plausibility, zinc is known to play a role in immune function via antibody and white blood cell production.4 Zinc supplementation has been suggested to increase polymorphonuclear cells’ ability to fight infection, while there is evidence that zinc deficiency increases pro-inflammatory cytokines and decreases the production of antibodies. Zinc has also been implicated in coronavirus biology.11 Angiotensin-converting enzyme 2 is a zinc metalloprotease that is important for cellular entry of coronavirus.12 In addition, studies on SARS, a coronavirus, have shown that zinc can inhibit its ribonucleic acid polymerase.11 However, the biologic activity of zinc against viruses may require ionophores, such as pyrithione, to block viral replication.13 Ascorbic acid is known to be an antioxidant, and a variety of studies have suggested that it can affect the immune system.14 Moreover, in vitro and in vivo studies in avians have shown that ascorbic acid could be protective against coronavirus, and human trials have found that it may decrease susceptibility to viral respiratory infections and pneumonia.15

    However, based on the current study, these supplements cannot be recommended to reduce symptom morbidity in such patients. High-dose zinc gluconate, ascorbic acid, or both supplements did not reduce SARS-CoV-2 symptoms. Most consumers of ascorbic acid and zinc are taking significantly lower doses of these supplements, so demonstrating that even high-dose ascorbic acid and zinc had no benefit suggests clear lack of efficacy. In addition, administering supplements with unproven benefit can be detrimental due to adverse effects. Zinc has been shown to cause a metallic taste, dry mouth, and gastrointestinal intolerance in high doses.16 Ascorbic acid can cause gastrointestinal intolerance, and in the current study, a significantly higher proportion of patients in the ascorbic acid subgroups reported adverse effects, including nausea, diarrhea, and stomach cramps.

    Strengths and Limitations

    There are several strengths and limitations that should be acknowledged. A major strength is the pragmatic design of the study and its novel primary end point, which was based on a symptom assessment questionnaire (time to reduction in symptom score by 50%). A major limitation was that there was no placebo control group; the current study was open label, and patients were not masked to which therapy they received. Patients were recruited in a single health system, and therefore, the outcomes in our health system may not represent the outcomes of patients in other health care settings. However, it should be acknowledged that patients were recruited from multiple outpatient facilities in Ohio and Florida. It is possible that certain groups with higher susceptibility (eg, older patients and patients from minority racial/ethnic groups) were underrepresented in the current study and the results may not be broadly generalizable. Also, stratification of symptoms by age, sex, race, or duration of symptoms prior to testing were not taken into consideration in the current analysis. Furthermore, the doses of zinc and ascorbic acid, while well tolerated, could be lower than amounts needed to shorten the duration of symptoms, and patients could have previously taken supplements such as zinc and ascorbic acid before enrolling in the study. Recent studies have also demonstrated that vitamin D deficiency is associated with increased risk of SARS-CoV-2 infection and an increased risk of hospitalization,17 so the potential role of other supplements in decreasing SARS-CoV-2 symptoms cannot be concluded from our study. Randomized trials are currently being performed to answer whether vitamin D supplementation can benefit patients diagnosed with SARS-CoV-2.

    Conclusions

    In this randomized clinical trial, ambulatory patients diagnosed with SARS-CoV-2, treatment were treated with high doses of zinc gluconate, ascorbic acid, or a combination of zinc gluconate and ascorbic acid. These interventions did not significantly shorten the duration of symptoms associated with the virus compared with usual care.

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    Article Information

    Accepted for Publication: January 9, 2021.

    Published: February 12, 2021. doi:10.1001/jamanetworkopen.2021.0369

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Thomas S et al. JAMA Network Open.

    Corresponding Author: Milind Y. Desai, MD, MBA, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Ave, Desk J1-5, Cleveland, OH 44195 (desaim2@ccf.org).

    Author Contributions: Dr Desai had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Thomas, Patel, Bittel, Kumar, Mehra, McWilliams, Nissen, Desai.

    Acquisition, analysis, or interpretation of data: Thomas, Patel, Bittel, Wolski, Wang, Kumar, Il’Giovine, Mehra, Nissen, Desai.

    Drafting of the manuscript: Thomas, Patel, Bittel, Kumar, Il’Giovine, Mehra, Desai.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Wolski, Wang, Kumar, Desai.

    Obtained funding: Thomas, Kumar, Desai.

    Administrative, technical, or material support: Thomas, Bittel, Kumar, Nissen, Desai.

    Supervision: Thomas, Bittel, Kumar, Il’Giovine, Nissen, Desai.

    Conflict of Interest Disclosures: Dr McWilliams reported receiving consulting fees from Gilead Sciences outside the submitted work. Dr Desai reported receiving grants from Myokardia outside the submitted work and being supported by the Haslam Family Endowed Chair in Cardiovascular Medicine. No other disclosures were reported.

    Data Sharing Statement: See Supplement 3.

    Additional Contributions: Serpil Erzurum, MD, James Young, MD, Daniel Culver, MD, Joan Booth, RN, Nancy Obuchowski, MPH, and John Petrich, RPh (Cleveland Clinic), were members of the operational and safety monitoring board. They were not compensated for their time. We would like to thank Samantha Xu, BS (Cleveland Clinic), for help with logistics of study set-up and coordination. She was compensated for her time.

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