One of the largest clinical studies conducted 100% remotely and involving individuals with COVID-19 isolated at home has just been completed. While the authors say colchicine reduces the risk of hospitalization and death, other scientists remain skeptical.
ColCorona started at the start of the pandemic, in March 2020. This phase III trial initiated by the Montreal Heart Institute (ICM) assesses whether taking colchicine for 30 days in individuals over 40 years of age with COVID-19 prevents lung complications and death. Participants had to have at least one risk factor from a list that ranged from fever to uncontrolled hypertension.
The study was to recruit 6,000, in Canada, but also in South Africa, Brazil, Spain, Greece and the United States. It eventually came to a halt after recruiting 75% of participants, due to the logistical difficulties associated with 24-hour telephone support for patients, as well as the dire need for solutions as health systems are under pressure, say Researchers.
what are the results? For now, alone a pre-publication is available, which is the initial version of a scientific article, before the peer review process begins. The authors write there that “in outpatients with COVID-19, colchicine reduces the composite rate of death or hospitalization.” We are talking about a 21% decrease in the relative risk of death or hospitalization. The real risk becomes clearer when you look at it this way: 5.8% of participants who received the placebo either stayed in hospital or died, compared to 4.7% of participants who took the drug.
Critics
On Twitter, where the scientific community is very active, congratulations are piling up, but criticism is also rising. Because the effect of the drug on the main objective of the study (to reduce hospitalizations and deaths) is not statistically significant, which was not specified in the January 23 press release which made a lot of noise. Thus, the decrease in risks of 21% mentioned earlier could be the result of chance and not the fact of the drug.
The effect only becomes significant when the approximately 330 participants who were not diagnosed with COVID-19 by PCR are removed from the dataset. The reduction in the relative risk of death and hospitalization drops to 25% and becomes statistically sound, according to the usual benchmarks. To speak again in terms of absolute risk: the rate of hospitalization or death is 6% in the placebo group, against 4.6% for participants who took colchicine and were diagnosed by PCR.
Despite the criticism, “we haven’t changed our view of the situation one iota,” says Dr Jean-Claude Tardif, principal investigator of the study and director of the ICM Research Center, speaking of the thirty researchers in six countries who carried out the clinical trial. It is still believed to be quite a clinically convincing result. We must not forget that this is an unreal situation, COVID-19. We would have liked it if everyone had a PCR test to confirm the diagnosis, but in March, April and May there was a shortage of reagents, a shortage of tests, so we ended up with 7% of patients who had no PCR. In a pandemic context, the team believes it is worth using the drug, which is inexpensive.
In a sense, it makes sense to remove this data from the scan, as there is no certainty that they actually caught the SARS-CoV-2 virus. Maybe they had another virus, so colchicine didn’t do anything for them. On the other hand, modifying a dataset along the way is risky: we can move away from the neutrality sought in science, as our columnist explains. Controversy, Jean-Francois Cliche, on the website of Soleil. “We had prespecified, in our statistical analysis plan, that we had a major interest in looking more specifically at patients who had a PCR diagnosis,” answers Dr.r Late. It was last November, long before we looked at the data. ”
For the Dre Caroline Samer, pharmacologist and professor of medicine at the Geneva University Hospitals, the verdict is clear: “the study is insignificant on its main objective and the recruitment ended early for logistical reasons. We cannot therefore conclude anything on the basis of this study ”.
For the time being, the College of Physicians of Quebec and the Order of Pharmacists of Quebec ask their members to exercise caution, according to Profession Santé.
The results other clinical studies will clarify the effect of colchicine … but in hospitalized patients (for the moment, only the small trial of 105 patients GREEK-19 has been published in JAMA Network Open).
At the end of November, the drug was notably added to the large British clinical study RECOVERY, which is testing different drugs. The latter had shown the effectiveness of dexamethasone in COVID-19 patients hospitalized in July 2020. Regarding colchicine, “the data is reviewed by an independent data monitoring committee that decides when the data is sufficiently conclusive to stop each branch of the trial said Caroline Wood, communications manager for the Nuffield Department of Population Health at Oxford University. Until then, those responsible for the trial do not have access to the data. We expect that the result will be known in the coming months. ”
A molecule with multiple uses
Colchicine is an inexpensive medicine used to control gout and viral pericarditis. It also appears to reduce the risk of complications after a heart attack, according to another international trial led by Dr.r Late and published at the end of 2019. “Colchicine has only one known target: a protein called tubulin,” explains the professor. It therefore interferes with the assembly of microtubules [sortes de structures de soutien] inflammatory cells ”.
In doing so, it indirectly prevents the production of inflammatory substances. “These substances are produced under different circumstances, including when crystals form in the cell,” continues the cardiologist. Uric acid crystals, as is the case for gout, or cholesterol crystals, hence the interest of colchicine in preventing complications after heart attacks. SARS-CoV-2 causes the inflammatory storm presumably by activating the same mechanisms, so to us, it’s obvious that colchicine should work. “Work that the team carried out on rats in which one had been induced a severe acute respiratory syndrome had also given encouraging results in December 2020: the researchers had noted a significant reduction lung damage with colchicine.
Colchicine has been used for 2,000 years both as a remedy and as a poison, says a review of the literature on the properties of the drug. This one must certainly be well dosed (like many other drugs, by the way!) Therapeutic errors have led to poisoning in the past, according to a communication of the National Institute of Public Health of Quebec. “At low concentration, colchicine stops the formation of microtubules, while at high concentration, it causes depolymerization,” we can read. Thus, this substance interferes with several cellular functions such as mitosis, intracellular transport, maintenance of cell structure and inflammatory processes. Its toxic potential is significant, since microtubules are present throughout the body, particularly in tissues and organs with a high rate of cell renewal. “
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