CRN dismisses new study investigating effects of zinc and vitamin C on COVID-19 as poorly designed and haphazard

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The Council for Responsible Nutrition (CRN; Washington, D.C.) is leveling criticism at a recent study published in JAMA Open Network called “Effect of high-dose zinc and ascorbic acid supplementation vs usual care on symptom length and reduction among ambulatory patients with SARS-CoV-2 infection,” as well as an accompanying commentary called “Supplements for the Treatment of Mild COVID-19—Challenging Health Beliefs With Science From A to Z.” ^1,2 The multicenter, single health system randomized clinical factorial open-label trial enrolled 214 adult patients diagnosed with SARS-CoV-2 infection, and randomized them to receive either zinc gluconate (50 mg), ascorbic acid (8000 mg), both agents, or standard of care for ten days.

The primary endpoint researchers were looking for was a 50% reduction in symptoms, including severity of fever, cough, shortness of breath, and fatigue (rated on a 4-point scale for each symptom). Secondary end points included days required to reach a total symptom severity score of 0, cumulative severity score at day five, hospitalizations, deaths, adjunctive prescribed medications, and adverse effects of the study supplements. The study was eventually stopped for a low conditional power for benefit, finding no significant differences between the four groups for the primary endpoint.

“Publication of this study and the accompanying commentary does nothing to advance our understanding of the role of nutrients in reducing the risk of COVID-19 and provides little insight for treating the disease. The study is plagued by a poor, open-label design, insufficient number of participants, substantial differences in the health status of participants by group, and the expectation that essential nutrients should behave like high-powered pharmaceuticals,” says Steve Mister, president and CEO of CRN, in a press release. “It’s not surprising this weak study design and haphazard approach would lead to unclear results. What’s more disappointing is that JAMA published it at all and accompanied it with a commentary that recklessly makes broad generalizations about the role of dietary supplements in the prevention and treatment of COVID-19. The sleight of hand potentially deters future research that may demonstrate the valuable role nutrients play in supporting immune function over time and preventing COVID-19 in particular.

Among the limitations of the study was the difference in health status between participants in each group. For example, 29% of subjects in the vitamin C and zinc group had a history of diabetes compared to only 9% in the standard of care group. While differences between groups did not meet the standard for statistical significance, the vitamin C and the vitamin C with zinc groups did achieve 50% reduction in their symptoms 1.2 days sooner than the standard of care group. “This finding did not achieve statistical significance by the time the study was prematurely terminated for ‘futility’—having enrolled less than half the intended number,” explains Mister. “If the study had fully enrolled, the differences in outcomes between groups may have reached statistical significance.”

While some adverse events such as nausea, diarrhea, and stomach cramps were reported in the zinc and vitamin C groups, the events were predictable for the high therapeutic doses administered, which exceeded the recommended Upper Levels. “Rather than examining moderate doses of zinc and vitamin C for prevention and generally supporting immune health, this was a treatment study with a short duration of intervention (10 days), using high doses of zinc and vitamin C, and only examining patients already positive for COVID-19. It’s a positive outcome when long-recognized nutrients also perform as powerful pharmaceuticals; but when they don’t, it’s hardly a reason to dismiss their long-term benefits,” says Mister.

“Even more disturbing is the commentary by Michos and Cainzos-Achiria that cites the study as evidence that ‘rigorous science’ challenges ‘popular beliefs’ and demonstrates how these supplements fail to ‘live up to their hype.’ Their editorial reads like a conclusion in search of a premise: that dietary supplements should be viewed as a waste of time just waiting for science to disprove their presumed benefits,” he continues. “This kind of misapplication of a poorly conducted study has the potential effect of dissuading other serious researchers from investigating the potential of a wide range of supplements, such as vitamin C, vitamin D, zinc, melatonin and others, for their ability to support immune function and resistance to respiratory infections, including COVID-19.”

Reference

1. Thomas S et al. ““Effect of high-dose zinc and ascorbic acid supplementation vs usual care on symptom length and reduction among ambulatory patients with SARS-CoV-2 infection.” JAMA Network Open, vol. 4, no. 2 (2021)
2. Michos ED et al. “Supplements for the Treatment of Mild COVID-19—Challenging Health Beliefs With Science From A to Z.” JAMA Network Open, vol. 4, no. 2 (2021)