Morgenstern, J. Is zinc the cure for COVID?, First10EM, February 20, 2023. Available at:
The quixotic search for a cure to the common cold has spilled into an ongoing search for the cure to COVID. Honestly, I am sort of over it, but I do have to admit both would be pretty great. So, as I was recently informed on the internet, is zinc the cure for COVID?
Ben Abdallah S, Mhalla Y, Trabelsi I, et al. Twice-Daily Oral Zinc in the Treatment of Patients With Coronavirus Disease 2019: A Randomized Double-Blind Controlled Trial. Clin Infect Dis. 2023 Jan 13;76(2):185-191. doi: 10.1093/cid/ciac807. PMID: 36367144 NCT05212480
VIZIR was a multicenter, prospective, randomized, double-blind trial from 3 hospitals in Tunisia.
Adult patients with a PCR confirmed diagnosis of COVID-19.
Exclusions: severe comorbidities, malignancies, need for immediate ICU admission, unsuitability for oral medications, cognitive impairment.
Zinc – 25 mg PO twice daily for 15 days.
The manuscript lists multiple primary outcomes, including mortality, ICU admission, and the composite. Clinicaltrials.gov only lists a single primary outcome: mortality.
Their final study population is 470, out of 1200 patients screened. The mean age was 54 and about half were male. 23% had high blood pressure and 20% had diabetes. 23% had received at least 1 COVID vaccine and 20% were fully vaccinated.
There was no statistical difference in the original primary outcome of 30 day mortality. Mortality was 6.5% in the zinc group and 9.2% in the placebo group (OR 0.68, 95% CI 0.34-1.35).
The manuscript reports a positive outcome in a new primary outcome: composite of ICU admission and mortality. Combined it was 10.4% with zinc and 16.7% with placebo (OR 0.58, 95% CI 0.33-0.99) The ICU admission rate was statistically different (OR 0.43, 95% CI 0.21-0.87)
The methodology of this trial was great, being a double-blind trial with allocation concealment. Unfortunately, despite that, I don’t think the results are believable.
The big problem with this trial is that they clearly cheated. Their primary outcome, as listed in their protocol, was mortality. It wasn’t statistically significant. After the data was collected, they changed their primary outcome to a composite that was statistically significant, but you just aren’t allowed to do that. This was a negative trial. Although that doesn’t exclude the possibility of benefit, this trial clearly should not be interpreted as positive. (Also, why do journals never check the registered protocol? What is the value of editors and peer review?)
It is also suspicious that this new primary outcome just barely squeaked under the bar for statistical significance, with a p value of 0.04 or a 95% confidence interval on the odds ratio that reaches 0.99. There is no way to know for sure, but that certainty smells like p-hacking.
On top of that, there is something incredibly bizarre about this study population. Despite excluding the sickest patients, such as those with significant co-morbidities and those requiring ICU treatment, the placebo group had a 30 day mortality of 9.2%! Although vaccination rates were low, we haven’t seen a 10% mortality rate in any population at any time in the pandemic. I can’t explain it, but something is very odd about this population, and it is clear that these results would not apply in Canada, or almost anywhere else in the world.
Zinc has a long history of borderline evidence for the management of viral illnesses. It is strongly embraced by the alternative medicine crowd, but mostly has not yet been promoted to real medicine, as it would be if the evidence were strong enough. There are systematic reviews that have somewhat promising results, but the individual studies are never very convincing. Despite decades of study, it still isn’t clear if zinc helps, which tells you that it definitely isn’t a miracle cure. (For some more history, see this post on Science Based Medicine.)
Although the risks of harm are very low, the chance of benefit is also very low, and there are still costs. I don’t think, based on this trial, there is any reason to be prescribing zinc.
Despite the headlines, this multicenter RCT of zinc for COVID-19 was actually negative for its primary outcome. Although there remains a lot of uncertainty, when considering the very low pretest probability that zinc would save lives, there is no reason to be prescribing it at this time.
Ben Abdallah S, Mhalla Y, Trabelsi I, et al. Twice-Daily Oral Zinc in the Treatment of Patients With Coronavirus Disease 2019: A Randomized Double-Blind Controlled Trial. Clin Infect Dis. 2023 Jan 13;76(2):185-191. doi: 10.1093/cid/ciac807. PMID: 36367144