The COVID A to Z trial was “stopped early for futility” after recruitment of only 214 patients. The intention had been to recruit 520 patients . Stopping early seems unjustified.
The COVID A to Z trial authors described the rationalization for the sample size calculation as follows: “We assumed that the standard of 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” . This indicates that the authors assumed a 1.0-day difference in time to a 50% reduction in symptom severity between the usual care arm and one of the intervention arms. This also indicates that a 1.0-day reduction was considered to be clinically important, otherwise sample size calculations would not have been based on this assumption.
The trial results were reported as follows: “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” .
Thus, time to a 50% reduction in symptom duration was 1.2 days shorter in the vitamin C arm than 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” . The authors do not explain this paradox: on the one hand, they consider that a 1.0-day reduction in symptom duration is a clinically important difference, yet on the other hand, the observed 1.2-day reduction was futile and justified early termination.
Another substantial concern with the COVID A to Z trial is that it was an “open label trial”  without a placebo administered to the control arm. Symptoms of respiratory virus infections are subjective and if there is no blinding there can be systematic bias in either direction between the treatment arms. If a patient believes that vitamin C is effective, he or she might under report symptoms. On the other hand, when patients are given an active intervention, such as vitamin C, they may observe and report symptoms at a lower threshold compared with the usual care arm. Given that the additional cost of a placebo in such a trial is marginal, it is surprising that none was used . Furthermore, it is not clear exactly what “open label trial” means and whether the patients were told what they were receiving and how that was communicated. The psychological effects can be quite different depending on how the intervention is described.
Our third concern is about the delay between the onset of symptoms and the initiation of vitamin C. For treating virus diseases, timing to initiation of treatment is important. For example, acyclovir and oseltamivir should be started as soon as possible after the first appearance of symptoms since a delay leads to less efficacy. Previously, long delays were proposed as a potential explanation for some therapeutic trials that did not find vitamin C effective [2,7]. In the Methods section, the COVID A to Z trial authors write: “Patients were randomized ... after a positive diagnosis” . However, there is no description of the time between the onset of symptoms and the start of intervention. Given that the analysis was restricted to patients with confirmed COVID-19, it seems probable that the delay between the start of symptoms and the start of treatment was over 24 hours, and may have been several days. It is unfortunate that this detail was not described .
Our fourth concern is about the distribution of vitamin C dosage: the trial report states “8000 mg of ascorbic acid [was] (to be divided over 2-3 times per day with meals)” . Intestinal absorption of vitamin C becomes saturated with high doses . Because of the decreased absorption, large single doses can cause stomach ailments. Hence, there is a big difference between administering 0.5 g/hour every hour and administering 4 grams 2 times a day. The total dose per day is the same, but the adverse effects may be much greater with the latter dosage. For example, in the large trial by Anderson et al. (1974), the dosage was "16 tablets (two every hour) on the first day of any illness" . Thomas et al. provided no justification for their choice to administer vitamin C 2-3 times per day .
Our fifth concern is the lack of commentary around the baseline vitamin C status of the patients. There is great variation in dietary vitamin C intake and consequently in baseline plasma levels. In this respect vitamin C differs substantially from other drugs, for which the control group uniformly has baseline levels of zero. If baseline levels are high, then supplemental vitamin C is less likely to have an effect than when baseline levels are low .