Back on January 23, 2021, TrialSite reported that the Montreal Heart Institute’s COLCOONA trial’s results showed promise. The study involving 4,488 COVID-19 patients was associated with statistically significant reductions in the risk of death or hospitalization as compared to placebo. The gout drug colchicine actually reduced hospitalizations, the need for mechanical ventilation, and deaths due to COVID-19. These findings, suggested its authors, possibly introduced the first oral drug that could be used to treat non-hospitalized patients with COVID-19. However, those findings only applied to those actually diagnosed with PCR-confirmed COVID-19 and had not yet been peer-reviewed nor published. That status has most certainly changed as the prestigious journal The Lancet recently showcased COLCORONA and thus, reminds all of the importance of the potential of repurposed, generic, drugs as a potential tool in the war against COVID-19.
Early on, the researchers involved with this study undertook extensive searches to find anti-inflammatory agents that could be used against SRS-CoV-2, the virus behind COVID-19, which turned up the anti-inflammatory agent colchicine.
What is Colchicine?
Many may have not heard of this drug unless they or a loved one have struggled with gout or Bechet’s disease, or for that matter, pericarditis and familial Mediterranean fever. An orally administered medication, the drug was approved for medical use in the United States in 1961 and, according to some accounts, is the 201st-most commonly prescribed medication in America with over two million prescriptions.
With a narrow therapeutic index, overdosing represents a material risk hence use is controlled by prescription. Side effects include gastrointestinal disturbance but other more serious ones are possible as, with many drugs, it can actually be dangerous if used in the wrong way. The Food and Drug Administration (FDA) label is included here.
Colchicine is now available in generic forms but was actually quite expensive when it became part of the “Unapproved Drugs Initiative,” leading to extensive testing for efficacy and safety of it and other unapproved drugs in use. The price went up apparently 2000%, bringing its pharmaceutical owner URL Pharma a small fortune. By 2012, Takeda had acquired URL Pharma for $800 million and the rights to “Colcrys,” which, at the time, generated revenues of $1.2 billion, making it a blockbuster level drug.
Because of that FDA initiative, essentially a monopoly was granted to the drug in the U.S. as the patent was issued in 2009 and expires in 2029. Hence while there are numerous generic drug makers producing versions of colchicine around the world, such as in the UK in the U.S., that patent expires in 2029.
The COLCORONA Phase 3 randomized controlled, investigator-initiated clinical trial sought to assess the safety and efficacy of orally administered colchicine (0.5 mg twice per day for the first 3 days and thereafter a dose once per day for 27 days) against placebo. Led by the Montreal Heart Institute, the study involved six countries including Brazil, Canada, Greece, South Africa, Spain, and the United States.
Launched during the height of the pandemic’s first wave, actual enrollment ended in December of 2020. With 4,488 patients (53.9% women; median age 54.0 years, IQR 47.0-61.0) enrolled, 2235 of them were randomly assigned to the study drug (colchicine), and thus 2,253 patients received a placebo. As reported in The Lancet, the study endpoint was met in 104 (4.7%) in the study drug group and 131 (5.8%) of 2,253 patients in the placebo group (odds ratio [OR] 0.79, 95.1 CI 0.61-1.03; p=0.081).
The primary endpoint for those 4,159 PCR confirmed COVID-19 cases manifest in 96 (4.6%) of 2,075 patients in the study group and 126 (6.0%) of the 2,084 patients receiving a placebo (OR 0·75, 0·57–0·99; p=0·042).
Serious Adverse Events
This was looked on with interest as again the drug has a narrow therapeutic index and hence if used the wrong way can cause numerous problems, like most drugs. Interestingly, serious adverse events occurred more in the placebo group (6.3%) than in the study drug group (4.9%) with a p value of 0.051.
Interpretation of Study Authors
The study results were not as impressive when observing the “community-treated patients,” that is, individuals that were not required to undergo a mandatory diagnostic test. In fact, as reported in the journal, they “were not statistically significant.” On the other hand, for those patients that were PCR-confirmed with COVID-19, the study drug actually lowered “the composite of death or hospital admission than placebo.” The authors suggested that due to a complete lack of any authorized oral treatment for COVID-19, the safe and inexpensive anti-inflammatory agent should be considered at least in cases involving individuals at risk for COVID-19 complications once identified as positive for the novel coronavirus. The authors do recommend additional studies in “community-treated patients.”
NHLBI Point of View
Yves Rosenberg, MD, MPH, chief of the Atherothrombosis and Coronary Artery Disease Branch at the National Heart, Lung, and Blood Institute, part of the National Institutes of Health (NIH), declared, “The COLCORONA study expands on our knowledge of the role of oral, cheap and widely available repurposed drugs such as colchicine to treat people early on to prevent serious complications of COVID-19 and can help practitioners and their patients make informed treatment decisions.”
The study was funded by the following:
- Government of Quebec (Canada)
- The Bill & Melinda Gates Foundation
- The National Heart, Lung and Blood Institute (NIH)
- The Montreal Heart Institute Foundation
- The NYU Grossman School of Medicine
- The Rudin Family Foundation
- Sophie Desmarais (philanthropist)
Jean-Claude Tardif, MD, FRCPC, FACC, FCAHS, Director Research Center, Montreal Heart Institute
For other authors, follow the link.