Neither vitamin C nor zinc worked in a randomized trial
by Molly Walker
High doses of zinc and vitamin C (ascorbic acid) had no impact on the course of symptoms in patients with mild COVID-19, a randomized trial found.
With a 50% reduction in symptoms as the primary endpoint, there was no difference in the number of days to achieve this whether patients received zinc gluconate, ascorbic acid, both supplements, or neither, reported Milind Desai, MD, of the Cleveland Clinic, and colleagues. All patients also received standard outpatient care.
Furthermore, there were no differences in secondary endpoints, including days to symptom resolution, symptom severity, hospitalizations, or deaths, the authors wrote in JAMA Network Open .
The study was stopped early for futility after an interim analysis was conducted when 214 patients were enrolled; the researchers planned to include 520 patients.
"According to the current study, these supplements cannot be recommended to reduce symptom morbidity" in patients with mild COVID-19, Desai and colleagues concluded.
Oral supplements have been proposed "to reduce the duration and severity of viral infection by stimulating the immune response," noted Erin Michos, MD, of Johns Hopkins University School of Medicine in Baltimore, and Miguel Cainzos-Achirica, MD, of Houston Methodist in Texas, in an accompanying editorial ; zinc and vitamin D were reported to be among the treatments President Trump received for COVID-19.
“We applaud the researchers of the COVID A to Z study for adding rigorous science to their efforts to prove its effectiveness and challenge popular beliefs,” the editorialists wrote. “Unfortunately, these two supplements fell short of expectations.”
They widened the disconnect between "mechanistic and/or observational research and the final results of well-conducted randomized controlled trials." Observational associations between vitamin D and numerous health outcomes, for example, were never replicated in placebo-controlled trials.
Desai and colleagues designed the COVID A to Z study as an open-label, randomized trial conducted at several hospitals in Ohio and Florida from April to October 2020. Patients aged 18 years or older were eligible if they had a new diagnosis of COVID-19, confirmed by RT-PCR testing. The primary endpoint was the number of days required to achieve a 50% reduction in symptoms, including the severity of fever, cough, shortness of breath, and fatigue.
Patients were randomly assigned to usual care plus 8,000 mg of ascorbic acid (2–3 times daily with meals), 50 mg of zinc gluconate at bedtime, both, or neither supplements. Of the 214 patients, 50 were randomly assigned to usual care alone, 48 to ascorbic acid, 58 to zinc, and 58 to both therapies plus usual care.
The average age of the participants was 45 years, and 62% were women. Approximately one-third reported currently or previously smoking, and approximately one-quarter said they previously used vitamins and minerals.
Patients receiving only standard care achieved the primary outcome in a mean of 6.7 days, compared to 5.5 days for patients in the ascorbic acid group, 5.9 days in the zinc gluconate group, and 5.5 days in the group receiving both treatments. The number of hospitalizations and deaths did not differ significantly between the treatment groups.
However, adverse effects from the supplements were not uncommon .
Limitations to the included data: there was no placebo group and the trial was open-label, and stratification of symptoms by age, sex, race, or duration of symptoms before the trial was not taken into account during the analysis. Some potential confounding factors, such as vitamin D levels, were also not examined.