High-dose zinc, ascorbic acid does not shorten COVID-19 symptom duration

High doses of zinc gluconate, ascorbic acid, or both do not shorten the duration of COVID-19 symptoms more than standard of care (SoC) in outpatients diagnosed with SARS-CoV-2, according to results of the prospective COVID A to Z trial.

“A significantly faster reduction in symptoms was not observed in any of the active treatment groups vs usual care,” said the investigators.

This multicentre, open-label trial was conducted in a single health system between April 27 and October 14, 2020 and involved 214 adult outpatients (mean age 45.2 years, 61.7 percent female, 71.7 percent White) from Ohio and Florida, US, with PCR-confirmed SARS-CoV-2 infection. They were randomized 1:1:1:1 to receive zinc gluconate (50 mg at bedtime), ascorbic acid (8,000 mg divided over 2–3 doses with meals), both, or SoC for 10 days. Follow-up “visits” were conducted virtually.

Patients who were hospitalized, pregnant, actively lactating, or with advanced chronic kidney disease, liver disease awaiting transplantation, or a history of calcium oxalate kidney stones, were excluded.

At baseline, composite symptom score was a mean 4.3 points among patients with data on four symptoms* and similar between the four groups. Among the subgroup of patients with data on 12 symptoms, the mean composite score was 11.6 points.

Among patients with four-symptom data, 50 percent reduction in symptom score from peak symptom score took a mean 5.9 days, with no significant difference between groups (mean 5.9, 5.5, 5.5, and 6.7 days for the zinc gluconate, ascorbic acid, both, and SoC groups, respectively; p_overall=0.45). [JAMA Network Open 2021;4:e210369]

A similar finding was noted among patients with 12-symptom data (mean 6.4 days overall; mean 6.6, 6.6, 6.2, and 6.2 days for the zinc gluconate, ascorbic acid, both, and SoC groups, respectively; p=0.97).

The 4-symptom composite score was 0 after a mean 10.6 days, with no significant difference between groups (mean 10.8, 12.1, 9.7 and 9.9 days for the zinc gluconate, ascorbic acid, both, and SoC groups, respectively; p=0.29).

The mean composite symptom score at day 5 among patients with four-symptom data was 3.2 points and comparable between groups (p=0.94). Seventeen patients were hospitalized over the 28-day study period and there were three deaths after enrolment, with no significant difference between groups for either outcome.

Adjunctive prescribed medications for COVID-19 symptoms were required in <3 percent of patients. Less than 10 percent of patients experienced adverse effects (AEs) from the supplements. AEs such as nausea, diarrhoea, and stomach cramps were common in the ascorbic acid group. Four serious AEs were documented including three COVID-19 deaths and one hospitalization for exacerbation of chronic obstructive pulmonary disease, though none were deemed related to treatment.

The study was stopped early for futility following interim analysis.

According to the investigators, previous studies on high-dose oral zinc and ascorbic acid have yielded contrasting results with regard to symptom improvement in common colds.

However, in this study, high doses of zinc gluconate, ascorbic acid, or both did not reduce symptoms of SARS-CoV-2 faster than SoC. Noting that individuals who regularly consume these supplements are doing so in much lower doses, the lack of benefit with high doses “suggests clear lack of efficacy,” they said. There are also potential risks of consuming supplements with no evidence of benefit.

The investigators pointed out that studies are ongoing to assess the role of intravenous ascorbic acid in reducing SARS-CoV-2 progression, and ascorbic acid, zinc, and vitamin D for SARS-CoV-2 prevention.