Colchicine Promising in COVID-19 Treatment?

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Colchicine, an anti-inflammatory drug used to treat gout and rheumatic disease, may be a promising treatment for COVID-19, a randomized, open-label trial suggests.

In the Greek Study in the Effects of Colchicine in COVID-19 Complications Prevention (GRECCO-19), investigators randomly assigned 105 patients who had COVID-19 to receive either the standard of care or the standard of care plus colchicine for 3 weeks. They found that for patients in the colchicine group, the time to clinical deterioration improved, although there were no significant differences between the groups in cardiac and inflammatory biomarkers.

"Colchicine is an old drug utilized for its anti-inflammatory and antimitotic effects," lead author Spyridon Deftereos, MD, PhD, professor of cardiology, Second Department of Cardiology, "Attikon" University Hospital National and Kapodistrian University of Athens, told theheart.org | Medscape Cardiology.

"While our study did not directly evaluate the mechanisms of action, we believe the key lies on its anti-inflammatory properties combined with an antithrombogenic effect that was indeed observed in our cohort and has also been reported in the literature," he said.

The study was published online June 24 in JAMA Network Open.

Inflammatory Response

Deftereos and colleagues have studied the effects of colchicine in a variety of clinical settings for the past decade. Being familiar with its safety profile, potential pathophysiologic mechanisms, and clinical actions, Deftereos said, "It was inevitable for us not to wonder whether it could be of benefit in a disease in which inflammatory response plays a crucial role."

To address the question, the researchers conducted an open-label, prospective study that spanned roughly 3 weeks (April 3 to April 27, 2020).

They randomly assigned 105 patients who had COVID-19 (58.1% men; median age, 64 years; interquartile range [IQR], 54 – 76 years) to receive either low-dose colchicine (1.5-mg loading dose, followed by 0.5 mg after 60 min and then maintenance doses of 0.5 mg/day twice daily) plus standard medical treatment (n = 50 patients) or standard treatment only (n = 55 patients).

The treatment groups were "largely similar" in demographic characteristics, clinical status at presentation, baseline laboratory evaluation, and baseline clinical score (4 in both groups). Most patients were being treated with chloroquine or hydroxychloroquine and azithromycin (98.1% and 92.4%, respectively).

The researchers established three primary endpoints and three secondary endpoints. Primary endpoints included maximum high-sensitivity cardiac troponin level; time for C-reactive protein (CRP) to reach >3 times the upper reference limit; and time to deterioration by 2 points on a 7-point clinical status scale. Secondary endpoints included percentage of participants who required mechanical ventilation; all-cause mortality; and the number, type, severity, and seriousness of adverse events.

Results showed that hospital duration was 1 day longer in the control group compared to the colchicine group (median duration, 12 days [IQR, 9 – 22] vs 13 days [IQR, 9 – 18]; P = .91).

No significant differences were found between the groups in the first two primary outcomes. The median peak high-sensitivity cardiac troponin values were 0.0112 (0.0043 – 0.0093) ng/mL in the control group and 0.008 (0.004 – 0.0135) ng/mL in the colchicine group (P = .34). The median maximum CRP levels were 4.5 (1.4 – 8.9) mg/dL in the control group and 3.1 (0.8 – 9.8) mg/dL in the colchicine group (P = .73).

However, the clinical primary endpoint rate was 14.0% in the control group vs 1.8% in the colchicine group (odds ratio, 0.11; 95% confidence interval, .01 – .96; P = .02).

The mean event-free survival time was 18.6 (.83) days in the control group vs 20.7 (.31) days in the colchicine group (log rank P = .03). Most adverse events were similar in the two groups; however, diarrhea was more frequent in the colchicine group than in the control group.

There was an attenuation of the maximum D-dimer levels in the colchicine group vs the control group, "suggesting an anti-inflammatory and antithrombogenic effect," the authors note.

Improved time to clinical deterioration "was our prespecified clinical endpoint, as per protocol design, [and] indeed, the clinical endpoint occurred only in 1 of 55 patients in the colchicine group and in 7 of 50 patients in the control group," Deftereos said.

Of the eight patients who met the clinical endpoint, one required noninvasive mechanical ventilation, six required invasive mechanical ventilation, and one suffered sudden cardiorespiratory arrest.

"Therefore, we may consider that colchicine treatment is of benefit for treatment of such patients," Deftereos said. Still, they call the results hypothesis-generating and conclude they should be "interpreted with caution."

Encouraging Data

Commenting on the study for theheart.org | Medscape Cardiology, Amir B. Rabbani, MD, assistant clinical professor, UCLA David Geffen School of Medicine, Los Angeles, called colchicine "an attractive therapeutic target for the treatment of COVID-19 patients because it works on multiple different pathways, rather than inhibiting one factor."

If future studies, such as the COLCORONA study and his own group's COLHEART-19 study, now ongoing, show similar results, "colchicine may become a standard tool in the COVID-19 therapeutic toolbox," suggested Rabbani, who is the author of an accompanying editorial and was not involved with the study.

Although more data are needed "to understand where colchicine will fall in the treatment spectrum, initial data are encouraging that there will be benefit as possibly an important adjunct to antiviral therapy," Rabbani suggested, adding, "It remains to be seen if long-term treatment with colchicine may prevent some of the debilitating post-COVID symptoms."

Urgent Situation

Deftereos called COVID-19 an "urgent situation" that "literally changed the way clinicians and researchers take decisions."

During the first COVID-19 wave, therapeutic algorithms included treatments for which no randomized trial data were available, and "inclusion of a drug in the suggested therapeutic algorithm remains in the responsibility of local authorities, after evaluation of the data that slowly but steadily accumulated," he pointed out.

He noted that multiple trials of colchicine are recruiting patients, and some plan to recruit larger populations and patients with mild COVID-19 who do not require hospitalization.

"Evidence-based medicine process is rather like a marathon rather than a sprint. We tried to contribute in this procedure with our study," Deftereos concluded.

The study was funded by ELPEN Pharmaceuticals, Acarpia Pharmaceuticals, and Karian Pharmaceuticals. Deftereos reports no relevant financial relationships. The other authors' disclosures are listed on the original article. Rabbani reports no relevant financial relationships.

JAMA Netw Open. Published online June 24, 2020. Full text, Editorial

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