ANSWERS TO FREQUENTLY ASKED QUESTIONS
Here are the answers to some of the questions posed on social media and/or in emails :
1- The decision to stop the study early, once we had reached 75% of the target number of patients, was made by the investigators, without any consultation with the DSMB or any knowledge of any unblinded data, due to several considerations. COLCORONA required the creation and maintenance of a central study call center active 24 hours per day in 4 languages throughout the study duration of 10 months, which was managed by our research nurses and staff. This novel approach to a clinical trial in the context of a pandemic created several logistical and human problems. A few nurses suffered burn-outs after having worked 6-7 days per week for >6 months, one nurse fell asleep while driving and had a serious accident after a long research work day, and another staff member had a seizure most likely in part because of sleep deprivation. We also faced a significant budgetary problem after having been unable to obtain additional funding, which became necessary in relation to having paid a large number of staff in overtime hours for 10 months. The Research Center of the Montreal Heart Institute, a public institution, is not allowed to face budget deficits. We also considered that COLCORONA had already recruited a much larger number of patients testing an orally administered medication in the ambulatory setting than any other study in COVID. Finally, a most important factor that we considered was the timing of providing study results to society. Stopping the study after approximately 4500 patients had completed their 30-day follow-up would allow to communicate results in January 2021. We could not predict the date at which we could reach 6000 enrolled patients, if at all possible, because of the highly variable recruitment rate which was largely dependent on the appearance and disappearance of waves of new COVID-19 cases in the different regions. For example, recruitment in Quebec (Canada), on which the study largely depended, fluctuated from as high as 25 patients per day down to less than 5 patients per day in between waves. Patient recruitment in Spain also suddenly, dramatically and persistently decreased earlier in 2020, in part due to an increasing percentage of younger patients being infected in that country and who could not meet the eligibility criteria. Patient recruitment was persistently highly challenging in the U.S. despite the large number of cases. Ultimately, considering all of the above-mentioned issues, our decision was that it would be much more preferable to communicate results in January 2021 in the hope of preventing complications of COVID-19 in ambulatory patients, instead of delivering results anywhere between April and October 2021 at a time when vaccination efforts might be successful.
2- COLCORONA was a randomized, placebo-controlled, double-blinded study. The steering committee members, including myself as chairman, were never unblinded throughout the study duration. The Data Safety Monitoring Board (DSMB) met every 2 weeks during the entire duration of the study, performed two pre-specified interim analyses in 2020 and only informed the steering committee that there were no safety issues and that the study could continue as planned. The DSMB was chaired by Dr. Jean Rouleau, ex-dean of medicine at the University of Montreal; Drs Marc Pfeffer and Lisa Rosenbaum from Harvard Medical School; Dr. George Wells statistician from Ottawa, Dr. Cécile Tremblay microbiologist from the Centre Hospitalier Universitaire de Montréal; and Dr. Georges Wyse clinical trialist from Alberta, Canada; DSMB members were highly experienced. The open sessions of the DSMB meetings were also attended by a representative of the US NIH and by a statistician of the Gates Foundation. The last study visit occurred on January 19, 2021, the database was then cleaned and locked and statistical analyses were performed by experienced biostatisticians at our coordinating center. We were presented the results on January 22, 2021 by the biostatisticians. The DSMB attests to the accuracy of this answer.
3- We issued a press release on January 22, 2021, because of the importance in our opinion of the COLCORONA results. The scientific journal to which we submitted the full manuscript requested us initially to communicate publically only a minimal amount of results and without p-values. Because of the requests of multiple governments, the journal editors then allowed us to make public the entire manuscript, which was done on January 26 in Biomedical Archives.
4- The primary endpoint of death or hospitalization for the 4488 patients showed a reduction of 21% in favor of colchicine with a p-value of 0.08. In the context of the pandemic where no therapy is currently available to prevent hospitalizations, we believe that the benefits of a safe, inexpensive and orally administered medication are clinically important. The consistency of the results for the composite primary endpoint, its components and the secondary endpoints for both the overall population and that with PCR-confirmed COVID is clinically persuasive in our opinion. We also believe that a p-value whether below or above 0.05, should be interpreted in light of the context and the totality of the data. In December 2020, FDA, Norman Stockbridge MD PhD declared that "The idea of dichotomizing the success of studies by a P value being less than or greater than 0.05 has no basis in law, either natural or federal or in regulations, and it is barely mentioned in guidance". Dr. Stockbridge pointed out examples where the agency has approved drugs despite a neutral primary endpoint finding, such as enalapril on the basis of SOLVD-Prevention's secondary endpoint benefits and bivalirudin (angiomax) on the basis of post-hoc pooling of the BAT studies. An application discussed at FDA in December 2020 centered on the PARAGON-HF trial, which had a P-value of 0.06 for its primary aim of reducing HF hospitalization and death from cardiovascular causes with sacubitril/valsartan versus valsartan alone in those with a left ventricular EF of 45% or higher (RR 0.87, P=0.06). The advisory panel nevertheless voted almost unanimously (12 "yes" to one "no") for expansion of the indication for sacubitril/valsartan beyond the currently-approved heart failure with reduced ejection fraction (HFrEF). In COLCORONA, the analysis of the 4159 patients with PCR-confirmed COVID was pre-specified in the statistical analysis plan (Section 6.4.4) because it was considered critical. Indeed, there was in the early stages of the pandemic a shortage of PCR tests that prevented confirmation of the diagnosis in 329 patients. In the 4159 patients with PCR-confirmed COVID, colchicine induced a significant 25% reduction in the composite primary endpoint of death or hospitalization, as well as a >25% reduction in hospitalizations. There were consistent effects for the other endpoints, including a reduction in pneumonias. We believe that COLCORONA shows that colchicine reduces the composite of death and hospitalization in patients with PCR-confirmed COVID.
5- The number needed to treat (NNT) for patients with PCR-confirmed COVID in COLCORONA is 71 for the primary endpoint of death or hospitalization. We believe that a NNT of 71 is acceptable in the context of a pandemic, for a drug like colchicine that is inexpensive and safe. We have published last year the cost-effectiveness analysis of colchicine (Samuel M and Tardif JC, Eur Heart J Qual Care Clin Outcomes. 2020 May 14) from our COLCOT study of 4745 patients, which showed that colchicine therapy was an economically dominant strategy. Table 3 of our COLCORONA manuscript shows the event rates for different groups of patients. These results suggest a NNT of 29 for patients with diabetes, 31 for patients aged 70 years and above, 53 for patients with respiratory disease, and 25 for patients with coronary disease or heart failure.
6- Although the 25% reduction of the primary composite endpoint of hospitalization or death and the 25% reduction in hospitalizations alone were statistically significant for colchicine in patients with PCR-confirmed COVID, we agree that the point estimate suggesting a large risk reduction for death was not statistically significant.
7- We would have preferred for all patients to undergo a PCR test to confirm the diagnosis of COVID-19. However, there was a shortage of reagents and PCR tests in several regions when we started the trial in March 2020. We therefore allowed a diagnosis based on an epidemiological link with a household member who had a positive nasopharyngeal PCR test result for patients with symptoms compatible with COVID-19, or by a clinical algorithm in a symptomatic patient without an obvious alternative cause as per official guidelines at the time. Because of our concerns related to the lack of PCR confirmation in 7% of the patients, we pre-specified in the statistical analysis plan signed in November 2020 by our head biostatistician and steering committee chairman that we would also evaluate the 93% of patients (ultimately 4159 patients) in whom COVID was confirmed by naso-pharyngeal PCR testing.
8- The imbalance in pulmonary emboli (11 vs 2) was possibly a chance finding. In COLCORONA, there was no report of deep venous thrombosis; there was 1 MI in the placebo group and 0 MI in the colchicine group. In COLCOT (Tardif JC et al, NEJM 2019) and LoDoCO2 (Nidorf SM et al NEJM), there was no significant difference in deep venous thrombosis or pulmonary emboplus between the colchicine and placebo groups.
In COLCORONA, despite that apparent imbalance in pulmonary emboli, the numbers of hospitalizations, use of mechanical ventilation and deaths were lower in the colchicine group than in the placebo group.
In addition, D-dimer levels were reduced in the colchicine group compared to controls in the GRECCO study of COVID-19 patients published recently (Deftereos et al, JAMA Network Open 2020).
Finally, we have recently shown that colchicine reduced the area of histological lung injury by 61% and markedly improved oxygenation in an experimental model of acute respiratory distress syndrome (Dupuis J and Tardif JC, Plos One 2020).
9- There are several clinical studies that support the positive results of COLCORONA. In addition to observational studies, the smaller GRECCO randomized trial showed statistically significant benefits of colchicine compared to control (Deftereos et al, JAMA Network Open 2020).
10- In terms of the hypothesis underlying COLCORONA, there is accumulating evidence suggesting that some patients with COVID-19 suffer from the inflammatory storm. SARS-CoV-1, which is closely related to the SARS-CoV-2 virus responsible for COVID-19, has been shown several years ago to activate the NLRP3 inflammasome. Given that colchicine reduces the activity of the inflammasome, we hypothesized that colchicine would reduce complications of COVID-19 by preventing or reducing the inflammatory syndrome.
11- Finally, low-dose colchicine is a safe medication, as revealed in the 10,000 patients followed for2 years in COLCOT and LoDoCO2 randomized trials (both published in NEJM). In COLCOT, 99% received statins and no clinically-relevant interaction was observed. In addition, the number of serious adverse events was lower in the colchicine group than the placebo group in COLCORONA. Finally, colchicine should not be administered with erythromycine or clarithromycine, but colchicine can be administered with azithromycine.
On behalf of the COLCORONA Investigators,
Jean-Claude Tardif CM, MD, FRCPC, FCCS, FACC, FAHA, FESC, FCAHS
Director, MHI Research Center
Professor of medicine
Canada Research Chair in translational and personalized medicine
University of Montreal endowed research chair in atherosclerosis
Montreal Heart Institute
This clinical trial is supported by