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Welcome to Impact factor, your weekly dose of comments on a new medical study. I’m Dr. F. Perry Wilson of the Yale School of Medicine.
Wouldn’t it be nice if there was a treatment for COVID-19 that was safe, effective, inexpensive, and beyond the control of faceless pharmaceutical executives considered more for shareholders than patients? The dream of such a magic bullet has led to a number of similar claims that a given drug – or supplement, in some cases – has dramatic consequences 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 credibility. Biologists may argue that there was some underlying reason why a given vitamin may help, with reference to 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 can become our most powerful ally against this plague of a virus. Preliminary data were often hyped out of breath, but, as I noted with respect to vitamin D, we had been burned before. Many of us wanted to see the randomized trials before committing to any of these potential drugs.
This week we got one such trial, which appears in JAMA Network open, look at the ability of zinc and vitamin C – alone or in combination – to reduce COVID-19 symptoms in outpatients.
It was a 2 x 2 factory design, as you can see here. Patients were randomized to approximately equal care to regular care or to one of the three treatment arms.
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These were outpatients, so we are not going to see very difficult outcomes. Rather, the researchers used a rank-based symptom measurement method. Participants were asked each day about four symptoms, which they rated on a scale of 0 to 3, giving a symptom score of 0-12. The primary outcome was the time to halve the symptom score; in other words, if you start at a 4, the time it takes to get to a 2; or if you start at 10, the time it takes to get to 5.. This is a strange outcome because it assumes a mathematical equivalence where I do not think it exists, but I think it is as good as we can get.
Here are the symptoms that are presented to the entire study group over time. 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 if you stratify according to treatment, the reduction of the symptom to 50% 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 resolved faster with zinc, vitamin C or the combination. Basically, the population looked like 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 fortunately there were only three deaths – one in the vitamin C group and two in the combination group.
As for side effects, there was nothing crazy. But obviously the authors saw more in the treatment groups than in the regular care group, mostly GI things.
Zinc apologists will no doubt notice the lack of zinc ionophore (such as chloroquine or pirithion) as the reason why it does not work. And once again, I remind everyone that biological credibility is not the end of medical research, but the beginning; it is the minimum crossbar to ethically a definitive trial, not an end in itself. I would love to do a reading of the upcoming randomized trials that contain hydroxychloroquine zinc.
More generally, I think we should just accept the fact that it is quite unlikely that a drug for COVID is sitting in our closets. Many chemicals work against pathogens in test tubes, just as many things work against cancer in vitro. But this trial reminds us that biologically promising agents often do not survive the rigor of actual testing. Keep hope, but bring data with you.
F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale’s Clinical and Translational Research Accelerator. His scientific communication work can be found in the Huffington Post, on NPR and here on Medscape. He tweets @fperrywilson and presents a repository for his communication work at www.methodsman.com.
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