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This transcript has been edited for clarity.
Welcome to Impact factor, your weekly dose comments on a new medical study. I’m Dr. F. Perry Wilson from Yale School of Medicine.
Wouldn’t it be nice if there was a treatment for COVID-19 that was safe, effective, cheap, and beyond the control of anonymous pharma administrators who owe more to shareholders than patients? The dream of such a magic bullet has led to a number of similar claims that a particular drug – or in some cases, supplement – has dramatic effects against COVID-19. We first saw it with hydroxychloroquine, but similar hype surrounded 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 might say there was an underlying reason why a particular vitamin would help, usually stating beneficial effects on immune function or a reduction in inflammatory cytokines. But more than that, these drugs had something of an underdog story. These humble agents who have been with us for decades or more could become our most powerful ally against this scourge of a virus. Preliminary data was often breathlessly hyped, but, as I pointed out with regard to vitamin D, we were previously burned. Many of us wanted to see the randomized trials before committing to any of these potential treatments.
This week we received such a test 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 similarly randomized to usual care or to one of three treatment arms.
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These were outpatients, so we wouldn’t see many difficult results. The researchers previously used a rank-based symptom scoring method. Each day, participants were asked about four symptoms, which they rated on a scale of 0 to 3, with a symptom score of 0-12. The primary outcome measure was time to halve the symptom score; in other words, if you start at a 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 a weird outcome because it assumes a mathematical equivalence that I don’t think exists, but I think it’s the best it can be.
Here are the symptoms over time for the entire study cohort. You can see a general 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 stratified by treatment, the time to 50% symptom reduction was basically the same across the board: 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 resolved faster with zinc, vitamin C, or the combination. In short, the population looked like we were used to: a fever for a few days, with persistent cough and fatigue.
The number of hospital admissions 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 combo group.
In terms of side effects, there was nothing crazy. But obviously the authors saw more in the treatment groups than the usual care group, mostly GI stuff.
Now zinc apologists will no doubt notice the lack of a zinc ionophore (such as chloroquine or pyrithione) as one reason why this 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 limit that must be met in order to conduct a final process ethically, not an end in itself. I’d like to do a readout of any upcoming randomized hydroxychloroquine zinc combo studies that come out.
More generally, I think we have to accept the fact that it is quite unlikely that there is a cure for COVID in our closets. Many chemicals have activity against pathogens in test tubes, just as many things work against cancer in vitro. But this trial reminds us that, more often than not, biologically promising agents don’t 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 Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR and here on Medscape. He tweets @fperrywilson and hosts a repository of his communications work at www.methodsman.com.
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