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This transcript has been edited for clarity.
Welcome to Impact factor, your weekly dose of comments on a new medical study. I’m Dr. F. Perry Wilson, from the Yale School of Medicine.
Wouldn’t it be nice if there was a treatment for COVID-19 that was safe, effective, cheap and out of the control of faceless pharmaceutical executives, more indebted to shareholders than to patients? The dream of such a magic bullet has led to a series of similar claims that a particular drug – or supplement, in some cases – has dramatic effects against COVID-19. We first saw this with hydroxychloroquine, but a similar advertising campaign involved vitamin D, ivermectin, melatonin, vitamin C and, of course, zinc.
What made the claims so compelling were two things. One was a dose of biological plausibility. Biologists can argue that there was some underlying reason why a particular vitamin would help, usually citing beneficial effects on immune function or a reduction in inflammatory cytokines. But more than that, these drugs had a history of underdog. These unpretentious agents who have been with us for decades or more can become our most powerful ally against this scourge of a virus. Preliminary data used to be widely publicized, but, as I indicated in relation to vitamin D, we had been burned before. Many of us wanted to see randomized clinical trials before committing to any of these potential cures.
This week, we had one of those trials, appearing in JAMA Network Open, looking at the ability of zinc and vitamin C – alone or in combination – to reduce symptoms of COVID-19 in outpatients.
This was a 2 x 2 factorial design, as you can see here. Patients were randomized to usual care or to one of three treatment arms in an approximately equal manner.
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These were outpatients, so we wouldn’t see many difficult results. Instead, the researchers used a classification-based symptom scoring method. Each day, participants were asked about four symptoms, which they rated on a scale of 0 to 3, giving a range of symptom scores from 0-12. The primary outcome was the time to halve symptom scores; in other words, if you start with 4, the time it takes to get to 2; or if you start at 10, the time it takes to get to 5. This is a bit of an odd result, as it assumes some mathematical equivalence where I don’t think it exists, but I suppose it’s the best we can get.
Here are the symptoms over time for the entire study cohort. You can see an overall decrease in moderate symptoms (in yellow) in favor of mild symptoms (in green).
Thomas S, et al. JAMA Netw Open. 2021; 4: e210369. doi: 10.1001 / jamanetworkopen.2021.0369
But when you stratify by treatment, the time to 50% reduction of symptoms was basically the same: about 5.5 to 6.5 days, depending.
Thomas S, et al. JAMA Netw Open. 2021; 4: e210369. doi: 10.1001 / jamanetworkopen.2021.0369
No individual symptom was resolved more quickly with zinc, vitamin C or the combination. Basically, the population looked like what we expected: a few days of fever, with persistent cough and fatigue.
The hospitalization rate did not differ significantly, although it was slightly higher in the supplement groups. And luckily there were only three deaths – one in the vitamin C group and two in the combined group.
In terms of side effects, there was nothing crazy. But obviously, the authors saw more in the treatment groups than in the usual treatment group, especially GI things.
Now, zinc apologists will no doubt notice the lack of a zinc ionophore (like chloroquine or pyrithione) as one of the reasons why it didn’t work. And again, I remind everyone that biological plausibility is not the end of medical research, but the beginning; it is the minimum barrier to be passed to conduct a final judgment ethically, not an end in itself. I will be delighted to read any impending randomized tests of the hydroxychloroquine-zinc combination that arise.
More broadly, I think we just need to accept the fact that a cure for COVID is very unlikely to be in our closets. Many chemicals have activity against pathogens in test tubes, just as many products work in vitro against cancer. But this essay reminds us that, most of the time, biologically promising agents do not survive the rigors of real-world testing. Keep hope, but bring data.
F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of the Yale Clinical and Translational Research Accelerator. His scientific communication work can be found at the Huffington Post, NPR and here at Medscape. He tweets @fperrywilson and hosts a repository of your communication work at www.methodsman.com.
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