From A to Z, Supplements Fail for COVID-19
— Neither vitamin C (a.k.a. ascorbic acid) nor zinc pan out in randomized trial
by Molly Walker, Associate Editor, MedPage Today February 12, 2021

High-dose 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 50% reduction in symptoms as the primary endpoint, there was no difference in the number of days to reach it 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 usual outpatient care.

In addition, there was no difference in secondary endpoints, including days to symptom resolution, severity of symptoms, hospitalizations, or deaths, the authors wrote in JAMA Network Open.

The study was stopped early for futility after an interim analysis conducted when 214 patients were enrolled; the researchers planned to include 520 patients.

“Based on 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 duration and severity of viral infection by boosting 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 reportedly among the treatments President Trump received during his bout with COVID-19.

“We applaud the COVID A to Z Study investigators for adding rigorous science by testing their efficacy and challenging popular beliefs,” the editorialists wrote. “Unfortunately, these two supplements failed to live up to their hype.”

They expanded on the disconnect between “mechanistic and/or observational research and the eventual findings from well-conducted” randomized controlled trials. Observational associations between vitamin D and numerous health outcomes, for example, were never replicated in placebo-controlled trials.

Michos and Cainzos-Achirica also cited hydroxychloroquine’s failures in prospective COVID-19 trials.

Desai and colleagues designed the COVID A to Z Study as an open-label randomized trial at multiple hospitals in Ohio and Florida from April to October 2020. Patients 18 and older were eligible if they had a new diagnosis of COVID-19, confirmed via RT-PCR testing. Primary endpoint was the number of days required to reach 50% reduction in symptoms, including severity of fever, cough, shortness of breath, and fatigue.

Patients were randomized to usual care plus 8,000 mg ascorbic acid (2-3 times a day with meals), 50 mg zinc gluconate at bedtime, both, or neither supplement. Of the 214 patients, 50 were randomized to usual care alone, 48 to ascorbic acid, 58 to zinc, and 58 to both therapies plus usual care.

Mean participant age was 45, and 62% were women. About a third reported currently or formerly smoking, and about a quarter said they used vitamins and minerals previously.

Patients who received only usual care achieved the primary outcome at a mean of 6.7 days versus 5.5 days for patients in the ascorbic acid group, 5.9 days in the zinc gluconate group and 5.5 days in the both treatment group. Number of hospitalizations and deaths did not vary significantly among treatment groups.

Adverse effects from the supplements, however, were not uncommon.

Limitations to the data included there was no placebo group and the trial was open-label, and stratification of symptoms by age, sex, race, or duration of symptoms prior to testing was not taken into account during the analysis. Some potential confounders, such as vitamin D levels, were also not examined.