乌鸦传媒

Anti-inflammatory oral drug colchicine improved COVID-19 outcomes for patients with relatively mild cases, according to certain topline results from the announced in a .

Overall, the drug used for gout and rheumatic diseases reduced risk of death or hospitalizations by 21% versus placebo, which "approached statistical significance."

However, there was a significant effect among the 4,159 of 4,488 patients who had their diagnosis of COVID-19 confirmed by a positive PCR test:

• 25% fewer hospitalizations
• 50% less need for mechanical ventilation
• 44% fewer deaths

If upheld after peer review -- a to the medRxiv preprint server -- colchicine could become the first oral drug proven to benefit non-hospitalized patients with COVID-19.

"Our research shows the efficacy of colchicine treatment in preventing the 'cytokine storm' phenomenon and reducing the complications associated with COVID-19," principal investigator Jean-Claude Tardif, MD, of the Montreal Heart Institute, said in the press release. He predicted its use "could have a significant impact on public health and potentially prevent COVID-19 complications for millions of patients."

Currently, the "tiny list of outpatient therapies that work" for COVID-19 includes convalescent plasma and monoclonal antibodies, which "are logistically challenging (require infusions, must be started very early after symptom onset)," Ilan Schwartz, MD, PhD, an infectious diseases researcher at the University of Alberta in Edmonton.

The COLCORONA findings were "very encouraging," Martin Landray, MB ChB, PhD, of the Big Data Institute at the University of Oxford in England. His group's trial has already randomized more than 6,500 hospitalized patients to colchicine versus usual care as one of the arms of the platform trial, though he did not offer any findings from that study.

"Different stage of disease so remains an important question," he tweeted. "Maybe old drugs can learn new tricks!" Landray added, pointing to dexamethasone.

A small open-label, randomized trial from Greece had also shown less clinical status deterioration in hospitalized patients on colchicine.

"I think this is an exciting time. Many groups have been pursuing lots of different questions related to COVID and its complications," commented Richard Kovacs, MD, immediate past-president of the American College of Cardiology. "We're now beginning to see the fruit of those studies."

The COLCORONA announcement came late Friday, following closely on the heels of the topline results from the ACTIVE-4a, REMAP-CAP, and ATTACC trials showing a significant morbidity and mortality advantage to therapeutic-dose anticoagulation in non-ICU patients in the hospital for COVID-19.

COLCORONA was conducted remotely, without in-person contact, with participants across Canada, the U.S., Europe, South America, and South Africa. It randomized participants double-blind to colchicine 0.5 mg or a matching placebo twice daily for the first 3 days and then once daily for the last 27 days.

Participants were ages 40 and older, not hospitalized at the time of enrollment, and had at least one risk factor for COVID-19 complications: age 70-plus, obesity, diabetes, uncontrolled hypertension, known asthma or chronic obstructive pulmonary disease, known heart failure, known coronary disease, fever of ≥38.4°C (101.12°F) within the last 48 hours, dyspnea at presentation, or certain blood cell abnormalities.

The trial was planned to enroll 6,000 patients, but it was stopped after about 75% were recruited because of the burden it was creating for site investigators and for central administration.

Although the press release provided only scant details on the results, the manuscript posted later filled in some of the gaps. For one thing, they made clear that, despite nearly 4,500 patients enrolled, they experienced too few events to demonstrate a statistically significant benefit for colchicine for most outcomes.

The manuscript also covered adverse events, which the press release had omitted. Diarrhea, the most common, was reported about twice as often with colchicine than with placebo (13.7% vs 7.3%). Pneumonia was somewhat less frequent with the active drug. Perhaps most worrisome, 11 patients assigned to colchicine experienced pulmonary embolism versus two in the placebo group.

"We don't know enough to bring this into practice yet," argued Kovacs.

The centuries-old drug has long been used for gout and arthritis and more recently for pericarditis along with showing promise in cardiovascular secondary prevention.

However, the drug isn't as inexpensive in the U.S. as in Canada, Kovacs noted.

Some physicians also warned about the potential for misuse of the findings and attendant risks.

Dhruv Nayyar, MD, of the University of Toronto, that he has already had "patients inquiring why we are not starting colchicine for them. Science by press release puts us in a difficult position while providing care. I just want to see the data."

Angela Rasmussen, MD, a virologist with the Georgetown Center for Global Health Science and Security's Viral Emergence Research Initiative in Washington, agreed, "When HCQ [hydroxychloroquine] was promoted without solid data, there was at least one death from an overdose. We don't need people self-medicating with colchicine."

As was the case with hydroxychloroquine before the papers proved little efficacy in COVID-19, Kovacs told 乌鸦传媒: "We always get concerned when these drugs are repurposed that we might see an unintended run on the drug and lessen the supply."

Citing the well-known diarrheal side effect of colchicine, infectious diseases specialist Edsel Salvana, MD, of the University of Pittsburgh and University of the Philippines in Manila, a plea for use only in the trial-proven patient population with confirmed COVID-19 -- not prophylaxis.

The dose used was on par with that used in cardiovascular prevention and other indications, so the diarrhea incidence would probably follow the roughly 10% rate seen in the , Kovacs suggested.

In the clinic, too, there are some cautions. As Elin Roddy, MD, a respiratory physician at Shrewsbury and Telford Hospital NHS Trust in England, : "Lots of drug interactions with colchicine potentially -- statins, macrolides, diltiazem -- we have literally been running up to the ward to cross off clarithromycin if RECOVERY randomises to colchicine."

This story was updated Jan. 27 to reflect the manuscript's publication without peer review.

Comment