Science by press release and preprint has cooled clinician enthusiasm for the use ofin nonhospitalized patients with COVID-19, despite a pressing need for early treatments.
As, a Jan. 22 announced that the massive study missed its primary endpoint of hospitalization or death among 4,488 newly diagnosed patients at increased risk for hospitalization.
But it also touted that use of the anti-inflammatory drug significantly reduced the primary endpoint in 4,159 of those patients with polymerase chain reaction–confirmed COVID and led to reductions of 25%, 50%, and 44%, respectively, for hospitalizations, ventilations, and death.
Lead investigator Jean-Claude Tardif, MD, director of the Montreal Heart Institute Research Centre, deemed the findings a “medical breakthrough.”
When thereleased a few days later, however, newly revealed confidence intervals showed colchicine did not meaningfully reduce the need for (odds ratio, 0.50; 95% confidence interval, 0.23-1.07) or death alone (OR, 0.56; 95% CI, 0.19-1.66).
Further, the significant benefit on the primary outcome came at the cost of a fivefold increase in(11 vs. 2; P = .01), which was not mentioned in the press release.
“Whether this represents a real phenomenon or simply the play of chance is not known,” Dr. Tardif and colleagues noted later in the preprint.
“I read the preprint on colchicine and I have so many questions,” Aaron E. Glatt, MD, spokesperson for the Infectious Diseases Society of America and chief of infectious diseases, Mount Sinai South Nassau, Hewlett, N.Y., said in an interview. “I’ve been burned too many times with COVID and prefer to see better data.
“People sometimes say if you wait for perfect data, people are going to die,” he said. “Yeah, but we have no idea if people are going to die from getting this drug more than not getting it. That’s what concerns me. How many pulmonary emboli are going to be fatal versus the slight benefit that the study showed?”
The pushback to the non–peer-reviewed data on social media and via emails was so strong that Dr. Tardif posted a nearlyresponding to the many questions at play.
Chief among them was why the trial, originally planned for 6,000 patients, was stopped early by the investigators without consultation with the data safety monitoring board (DSMB).
The explanation in the letter that logistical issues like running the study call center, budget constraints, and a perceived need to quickly communicate the results left some calling foul that the study wasn’t allowed to finish and come to a more definitive conclusion.
“I can be a little bit sympathetic to their cause but at the same time the DSMB should have said no,” said David Boulware, MD, MPH, who led a recent hydroxychloroquinein COVID-19. “The problem is we’re sort of left in limbo, where some people kind of believe it and some say it’s not really a thing. So it’s not really moving the needle, as far as guidelines go.”
Indeed, a Twitter poll by cardiologist James Januzzi Jr., MD, captured the uncertainty, with 28% of respondents saying the trial was “neutral,” 58% saying “maybe but meh,” and 14% saying “colchicine for all.”
Another poll cheekily asked whether ColCORONA was the Gamestop/Reddit equivalent of COVID.
“The press release really didn’t help things because it very much oversold the effect. That, I think, poisoned the well,” said Dr. Boulware, professor of medicine in infectious diseases at the University of Minnesota, Minneapolis.
“The question I’m left with is not whether colchicine works, but who does it work in,” he said. “That’s really the fundamental question because it does seem that there are probably high-risk groups in their trial and others where they benefit, whereas other groups don’t benefit. In the subgroup analysis, there was absolutely no beneficial effect in women.”
According to the authors, the number needed to treat to prevent one death or hospitalization was 71 overall, but 29 for patients with diabetes, 31 for those aged 70 years and older, 53 for patients with respiratory disease, and 25 for those with coronary disease or.
Men are at higher risk overall for poor outcomes. But “the authors didn’t present a multivariable analysis, so it is unclear if another factor, such as a differential prevalence of smoking or, contributed to the differential benefit,” Rachel Bender Ignacio, MD, MPH, infectious disease specialist, University of Washington, Seattle, said in an interview.
Importantly, in this pragmatic study, duration and severity of symptoms were not reported, observed Dr. Bender Ignacio, who is also ainvestigator. “We don’t yet have data as to whether colchicine shortens duration or severity of symptoms or prevents long COVID, so we need more data on that.”
The overall risk for serious adverse events was lower in the colchicine group, but the difference in pulmonary embolism (PE) was striking, she said. This could be caused by a real biologic effect, or it’s possible that persons with shortness of breath and hypoxia, without evidenton chest x-ray after a positive COVID-19 test, were more likely to receive a CT-PE study.
Thealso failed to include information, later noted in the , that the MHI has submitted two patents related to colchicine: “Methods of treating a coronavirus infection using colchicine” and “Early administration of low-dose colchicine after .”
Reached for clarification, MHI communications adviser Camille Turbide said in an interview that the first patent “simply refers to the novel concept of preventing complications of COVID-19, such as admission to the hospital, with colchicine as tested in the ColCORONA study.”
The second patent, she said, refers to the “novel concept that administering colchicine early after a major adverse cardiovascular event is better than waiting several days,” as supported by the, which Dr. Tardif also led.
The patents are being reviewed by authorities and “Dr. Tardif has waived his rights in these patents and does not stand to benefit financially at all if colchicine becomes used as a treatment for COVID-19,” Ms. Turbide said.
Dr. Tardif did not respond to interview requests for this story. Dr. Glatt said conflicts of interest must be assessed and are “something that is of great concern in any scientific study.”
Cardiologist Steve Nissen, MD, of the Cleveland Clinic said in an interview that, “despite the negative results, the study does suggest that colchicine might have a benefit and should be studied in future trials. These findings are not sufficient evidence to suggest use of the drug in patients infected with COVID-19.”
He noted that adverse effects likewere expected but that the excess PE was unexpected and needs greater clarification.
“Stopping the trial for administrative reasons is puzzling and undermined the ability of the trial to give a reliable answer,” Dr. Nissen said. “This is a reasonable pilot study that should be viewed as hypothesis generating but inconclusive.”
Several sources said a new trial is unlikely, particularly given the cost and 28 trials already evaluating colchicine. Among these areand , testing whether colchicine can reduce the duration of hospitalization or death in hospitalized patients with COVID-19.
Because there are so many trials ongoing right now, including for antivirals and other immunomodulators, it’s important that, if colchicine comes to routine clinical use, it provides access to treatment for those not able or willing to access clinical trials, rather than impeding clinical trial enrollment, Dr. Bender Ignacio suggested.
“We have already learned the lesson in the pandemic that early adoption of potentially promising therapies can negatively impact our ability to study and develop other promising treatments,” she said.
The trial was coordinated by the Montreal Heart Institute and funded by the government of Quebec; the National Heart, Lung, and Blood Institute of the National Institutes of Health; Montreal philanthropist Sophie Desmarais, and the COVID-19 Therapeutics Accelerator launched by the Bill & Melinda Gates Foundation, Wellcome, and Mastercard. CGI, Dacima, and Pharmascience of Montreal were also collaborators. Dr. Glatt reported no conflicts of interest. Dr. Boulware reported receiving $18 in food and beverages from Gilead Sciences in 2018.
A version of this article first appeared on.