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
Authors: Qiuqing Wang
Kathy Wolski
Steve E Nissen
Suma Thomas
Divyang Patel
Reena Mehra
Carla McWilliams
Anirudh Kumar
Barbara Bittel
Zachary J Il&#x27;Giovine
Milind Y Desai
Journal: JAMA Network Open (2021)
Discipline: CLINICAL MEDICINE
Keywords: novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; high-dose zinc; high-dose ascorbic acid; symptom progression; ambulatory patients
Affiliations: Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio., Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio, Neurologic Institute, Respiratory Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio., Department of Infectious Diseases, Cleveland Clinic Florida, Weston.

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. 

Retracted: No

PubPeer comments:
 # Therapeutic 8 g day of vitamin C increases recovery rate from SARS-CoV-2 infection by 71% (P = 0.036) based on the randomized trial by Thomas et al. (2021) Thomas et al. [1] reported a trial on the effect of vitamin C and zinc on SARS-CoV-2 infection. There is significant interest in this topic, however the benefits of vitamin C were overlooked and the zinc dose was very low and likely to be inadequate to have an effect. **Vitamin C.** Thomas et al. [1] randomly allocated SARS-CoV-2 outpatients to the u201cstandard of careu201d (50 patients) and 8 g day vitamin C (48 patients). They reported that the average time to a 50% reduction in symptoms was 6.7 days in the standard of care group and 5.5 days in the vitamin C group. This 1.2-day difference corresponds to an 18% reduction in the duration of symptoms of SARS-CoV-2 in the vitamin C group. In the Statistical Analysis section, Thomas et al. state: *u201cWe 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) daysu201d.* This indicates that the authors assumed that a 1.0-day reduction in symptom duration between the two groups was a clinically important difference, otherwise they would not have based their sample size calculation on this assumption. Given that the observed effect is 20% greater than the expected effect (1.2 vs. 1.0), it is illogical to have stopped the study early because of *u201cfutilityu201d* [1]. The authors do not explain this paradox: on the one hand they state that a 1.0-day reduction in symptom duration is clinically important, but on the other hand that a 1.2-day reduction is futile. Furthermore, the statistical difference between the primary outcomes in the vitamin C and standard of care participants was not analyzed properly in the Thomas et al. report [1]. Thomas et al. published the number of patients who recovered (with the primary endpoint u201c50% reduction in symptomsu201d) on a given day in their Figure 3. I calculated the rate of recovery in the vitamin C group compared to the standard of care group, see the statistical analysis below, and found that vitamin C increased the rate of recovery by 71% (95% CI 3.4% to 182%, P = 0.036). This direct comparison of recovery rate between the vitamin C and the standard of care groups was not published by Thomas et al. [1]. In the Introduction, Thomas et al. write that *u201cLimited evidence suggests that high doses of ascorbic acid ... may reduce duration of common cold symptoms and decrease the severity of symptomsu201d*, referring to the Cochrane review on vitamin C and the common cold [2]. This is misleading given that the Cochrane review reported that 31 comparisons examined the effect of regular vitamin C on 9745 episodes of common cold duration. In adults the duration of colds was reduced by 7.7% (95% CI 3.7% to 11.8%, P = 0.00018) and in children by 14.2% (95% CI 7.3% to 21.1%, P = 0.000053)u201d [2: Analysis 2.1]. This is very strong evidence by most standards. A dose-response effect for vitamin C on common cold duration has also been indicated, with a prediction that 6-8 g day doses might shorten viral upper respiratory infections by some 20% [2-4]. This prediction is consistent with the 18% effect observed by Thomas et al. with the dosage of 8 g day [1]. Furthermore, there are indications that vitamin C might also have effects on more serious infections caused by SARS-CoV-2 [5]. **Zinc.** In addition to the standard of care group and the vitamin C group, Thomas et al. included two further groups in their trial: zinc gluconate group and zinc gluconate together with vitamin C group [1]. Examination of zinc was motivated by three previous publications [6-8]. However, their reference 6 is the outdated version of the Cochrane review from year 2011. The same Cochrane authors published a revised updated Cochrane review in 2013. However, the updated Cochrane review was retracted because of data plagiarism [9,10]. Therefore reference 6 should not be cited. The two other papers were focused on zinc lozenges which are intended to be dissolved slowly in the mouth [7,8]. Thomas et al. do not clearly describe the type of tablet they used, but *u201c50 mg of zinc gluconate at bedtimeu201d* [1] suggests that they administered a regular zinc tablet and not zinc lozenges. Furthermore, the RCTs that have found zinc lozenges to be beneficial, have administered the lozenges 6 times or more per day [8], so that a single dose at the bedtime does not test the intervention that has been reported to be effective. The first randomized trial on zinc lozenges used about 200 mg day of elemental zinc [7], but doses between 80 and 92 mg day of elemental zinc were later found to be effective [8]. The dosage used by Thomas et al. of 50 mg day of zinc gluconate [1] corresponds to just 7.2 mg day of elemental zinc which is less than 1 10th of the dose of elemental zinc used in the lozenge trials which have reported benefit to common cold patients [7,8]. Thus, the cited zinc lozenge references [7,8] do not provide any justification for a single dose of 50 mg day of zinc gluconate at bedtime. An individual patient data meta-analysis [11] of three RCTs in which 80u201392 mg day of elemental zinc were administered as zinc acetate lozenges to 199 common cold patients calculated that zinc lozenges increased the rate of recovery by 215% (95% CI 110% to 370%, P = 10exp[-7]). Further trials on zinc lozenges should test lozenges and protocols comparable with those used in these three trials, and not ordinary zinc tablets with doses less than 1 10th of those found effective in earlier trials. **Conclusions of the Thomas trial.** Despite the limitations, the trial by Thomas et al. [1] found a statistically significant benefit of 8 g day vitamin C on the rate of recovery from SARS-CoV-2. It is a shame that the trial was stopped early when the observed effect was 20% greater than expected, and that the significant benefits on the recovery rate were not published. Further well-designed trials on vitamin C and zinc lozenges for the SARS-CoV-2 virus and other respiratory virus infections are warranted. [Moderator: edited for relevance to the present article] **References** 1. Thomas S, Patel D, Bittel B, Wolski K, Wang Q, Kumar A, Il Giovine ZJ, Mehra R, McWilliams C, Nissen SE, Desai MY. 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. JAMA Netw Open. 2021 Feb 1;4(2):e210369. https: doi.org 10.1001 jamanetworkopen.2021.0369 2. https: doi.org 10.1002 14651858.CD000980.pub4 https: helda.helsinki.fi handle 10138 225864 3. https: doi.org 10.3390 nu9040339 4. https: doi.org 10.1016 0895-4356(96)00189-8 https: doi.org 10.1016 0895-4356(96)00191-6 https: helda.helsinki.fi handle 10250 8082 https: helda.helsinki.fi handle 10138 225873 https: www.mv.helsinki.fi home hemila H HH_1996_JCE.pdf https: www.mv.helsinki.fi home hemila H 1996_L_JCE.pdf 5. https: doi.org 10.3389 fmed.2020.559811 6. https: doi.org 10.1002 14651858.CD001364.pub3 7. https: doi.org 10.1128 AAC.25.1.20 8. https: doi.org 10.1177 2054270417694291 9. https: helda.helsinki.fi handle 10138 153180 10. https: doi.org 10.1002 14651858.CD001364.pub5 11. https: doi.org 10.1093 ofid ofx059 ##################################################################### **Statistical printouts for the analysis of recovery rate in the Thomas et al. trial [1]** ![file] , 
 # Reanalysis A reanalysis of The COVID A to Z Randomized Clinical Trial is available at a preprint server: https: www.researchsquare.com article rs-289381 v1 , 
 ## Reanalysis A reanalysis of The COVID A to Z Randomized Clinical Trial is published: https: doi.org 10.3389 fimmu.2021.674681 , 
 **A further quantile treatment effect analysis of the COVID A to Z trial was published in:** https: doi.org 10.3390 life12010062 ,