Vitamin C May Increase the Recovery Rate of Outpatient Cases of SARS-CoV-2 Infection by 70%: Reanalysis of the COVID A to Z Randomized Clinical Trial


 The COVID A to Z trial (JAMA Netw Open. 2021;4:e210369) is important as it focused specifically on SARS-CoV-2 coronavirus patients and examined a high dose of vitamin C which was previously predicted to reduce the duration of respiratory virus infections by about 20%. Unfortunately, there are several limitations in the trial methods. The COVID A to Z trial was “stopped early for futility”. In the sample size calculation, the authors assumed a 1.0 day shorter symptoms by intervention. Duration of symptoms was reduced by 1.2 days in the vitamin C arm compared with the usual care arm. Given that the observed vitamin C effect was 20% greater than the expected effect (1.2 vs. 1.0), it is illogical to have stopped the trial early because of “futility”. In this reanalysis we calculated the rate ratio of recovery between the vitamin C and usual care arms and found that vitamin C increased the rate of recovery by 70% (95% CI 6.8% to 170%, P = 0.025). Furthermore, we calculated quantile treatment effect of vitamin C. At the 60th percentile level of symptom distribution, duration was 9 days in the usual care arm, and 6 days in the vitamin C arm, which corresponds to reduction in symptom duration by 3 days (95% CI 3 to 4.6 days; P < 0.001). The analysis of the quantile treatment effect indicates that there may be around 30% reduction in symptom duration in patients with the longest symptoms. Our reanalysis indicates a need for methodologically sound trials with larger numbers of patients to investigate the treatment effects of vitamin C against SARS-CoV-2.


of [9]) 3
Recovery data in the R data set is consistent with the extracted spreadsheet data 4 Cox regression for vitamin C effect on recovery rate from SARS-CoV-2 5 Calculation of the 95% CI to the 60 th percentage level 6 Figure S1: Redrawn survival curve for the effect of vitamin C on recovery from SARS-CoV-2 7 Table S2. Effect of vitamin C on symptom duration by percentile ranges 8 Problems in the zinc intervention in the COVID A to Z Randomized Clinical Trial 9 Extraction of data on recovery from SARS-CoV-2 The recovery data in the COVID A to Z Randomized Clinical Trial [9] was published as survival curve in Figure 3, which is copied below. When the number of patients is quite low, as in this case, it is possible to back-calculate from the survival curve the number of patients who recovered on each downward step. The size of the steps was measured from the digital figure as pixels and the scale of the figure as pixels was used to determine the number of recovered patients on each step. A spreadsheet was used to transform the pixel-values to the number of persons who recovered.
Furthermore, the figure reported the number of patients still sick on each even day.   The left-hand side of this table shows the measurement of the steps in Figure 3, seen previous page.
The right-hand side shows the number of patients who recovered by the end of the given day.

Coefficients:
Value Lower Bd Upper Bd Std Error T Value Pr(>|t|) (Intercept) 9.00e+00 9.00e+00 9.00e+00 0.00e+00 9.28e+11 0.00e+00 Thomas$vitC -3.00e+00 -3.00e+00 2.70e+00 1.45e+00 -2.06e+00 3.92e-02  On the 60 th percentile, the duration of symptoms was 9 days in the usual care group, and 6 days in the vitamin C group, corresponding to QTE of 3 days. On the 87 th percentile, duration of symptoms was 15 days in the usual care group, and 8 days in the vitamin C group, corresponding to QTE of 7 days. There were 6 censored observations in the usual care group and therefore the analysis is cut at the 88 th percentile level.

Problems in the zinc intervention in the COVID A to Z Randomized Clinical Trial
In addition to the usual care group and the vitamin C group, the COVID A to Z Randomized that zinc lozenges increased the rate of recovery by 215% (95% CI 110% to 370%, P = 10 -7 ). The most recent zinc acetate lozenge trial did not find benefit, which might be caused by low dose, rapidly dissolving lozenges, and short treatment [S14]. Nevertheless, for 2 days after the end of zinc/placebo use, the zinc participants recovered significantly slower compared with the placebo participants (p=0.003), which could be caused by the rebound effect so that the discontinuation of the zinc lozenge treatment had a physiological effect in the harmful direction. Although that finding does not justify the usage of the particular lozenge, the finding is consistent with zinc lozenges having genuine effects on the common cold.
Further trials on zinc lozenges should test lozenges and protocols comparable with those used in the trials that reported benefit, and not ordinary zinc tablets administered once per day.