Regulatory Decision Summary for Colchicine (*COVCORONA)

Decision issued

No decision was issued by Health Canada. The company cancelled its application before a final decision was issued.

Date of cancellation

2021-06-07

What was the purpose of this submission?

COVCORONA (Colchicine 0.5 mg Film-Coated Tablets) was submitted by Pendopharm under the Interim Order Respecting Clinical Trials for Medical Devices and Drugs Relating to COVID-19. The purpose of this application was to obtain a market authorization for the indication "reduction of complications in adults with coronavirus infections such as COVID-19."

Colchicine is currently authorized in Canada as 0.6 mg tablets for the prophylaxis and treatment of gout flares and Familial Mediterranean Fever (FMF) in adults at doses up to 2.4 mg daily. This application proposed a new tablet strength (0.5 mg) and a new dosing regimen consisting of 0.5 mg twice daily for the first 3 days and then once daily for the next 27 days.

What did the company submit to support its submission?

The proposed indication for colchicine in the reduction of complications in adults with coronavirus infections such as COVID-19 was supported primarily by the efficacy and safety data from the Phase 3 randomised, double-blind, placebo-controlled, multicentre study named "COLCORONA". This study was conducted in non-hospitalized, high-risk patients at least 40 years of age with a recent COVID-19 diagnosis. "High risk" was defined as at least one of the following: age of 70 years or older, obesity (body-mass index of 30 kg/m² or more), diabetes, uncontrolled hypertension (systolic blood pressure ≥150 mm Hg), known respiratory disease, known heart failure, known coronary disease, fever of at least 38.4 °C within the last 48 hours, dyspnea at the time of presentation, bicytopenia, pancytopenia, or the combination of high neutrophil and low lymphocyte counts. The primary endpoint was a composite of death or hospitalisation due to COVID-19 infection in the first 30 days following randomisation. The secondary endpoints consisted of the components of the composite primary endpoint or the need for mechanical ventilation in the 30 days following randomization. Pneumonias, other serious adverse events, and non-serious adverse events were also collected. Patients were eligible for COLCORONA if they had received a diagnosis of COVID-19 infection within 24 hours of enrolment. The diagnosis of COVID-19 was made by local laboratories using Polymerase Chain Reaction (PCR) testing on a nasopharyngeal swab specimen. Given the restrictions in laboratory testing early in the pandemic, a diagnosis was also accepted as an epidemiological link with a household member who had a positive nasopharyngeal test result for patients with symptoms compatible with COVID-19, or by a clinical algorithm in a symptomatic patient without an obvious alternative cause taking into consideration official guidelines. Of the 6,000 participants initially planned, 4,488 patients were eventually enrolled to receive either 0.5 mg colchicine tablets or matching placebo (1:1 allocation ratio) for 30 days (0.5 mg twice daily for the first 3 days and then once daily for the last 27 days). On December 11, 2020, the steering committee chairman informed the data safety monitoring board (DSMB) that the investigators had decided to terminate the study once 75% of the planned patients were recruited and had completed the 30-day follow-up. This decision was made due to logistical issues related to maintaining the central study call centre active 24 hours per day for a prolonged period of time, as well as the need to provide healthcare systems with study results in a timely fashion given the state of the COVID-19 pandemic.

What was the status of the submission when it was cancelled? What was Health Canadas assessment of the submission at the time of cancellation?

In the overall study population (the Intention-to-treat [ITT] population), the proportion of patients with a primary event was lower in the colchicine group (4.7%) compared to the placebo group (5.8%) (for an odds ratio [OR] of 0.79; 95% confidence interval [CI], 0.61-1.03; p = 0.08); however, this difference was not statistically significant and, therefore, the COLCORONA study did not meet its primary endpoint. The results for the secondary endpoints for the overall study population were also not statistically significant. When the subgroup of patients who had a diagnosis of COVID-19 confirmed by PCR test were considered (n = 4,159; 93% of the overall study population), the rates of the composite primary endpoint combining hospitalization and death were 4.6% and 6.0% in the colchicine and placebo groups, respectively, resulting in a statistically significant 25% relative risk reduction (adjusted OR: 0.75; 95% CI, 0.57-0.99; p = 0.04). This result was not considered to be clinically robust as the absolute risk reduction corresponded to 1.4%, which means that 71 patients would need to be treated with colchicine to prevent one event. Overall, no firm conclusion regarding colchicine efficacy in COVID-19 could be drawn based on the COLCORONA study because of the following:
(i) the primary endpoint in the ITT population was not met;
(ii) the hypothesis that the subgroup of patients without PCR-confirmed COVID-19 infection might have another viral infection with similar symptoms and, therefore, would likely represent a different population was not substantiated by evidence; and
(iii) the result for the primary endpoint in the subgroup of patients who had a diagnosis of COVID-19 confirmed by PCR was not statistically and clinically robust.

In the COLCORONA study, adverse events, mainly gastrointestinal in nature, were more frequent in the colchicine treated participants (24.2% vs. 15.5%; p < 0.0001). Diarrhea (13.5% vs. 7.0%), gastrointestinal disorder (5.1% vs. 3.2%), and abdominal pain (1.2% vs. 0.6%) were more common in the colchicine group compared to the placebo group. Rates of serious adverse events were lower with colchicine compared to placebo (4.9% vs. 6.3%). The most frequent serious adverse events were pneumonias (4.1% for placebo vs. 2.9% for colchicine) but none were considered related to the study drug. A significantly higher number of pulmonary embolisms in the colchicine group (0.5% vs. 0.1%; p = 0.01) was observed. Serious and unexpected adverse events considered potentially related to colchicine included dizziness and pancreatitis. A total of 14 deaths occurred during the study, including 5 deaths in the colchicine group and 9 deaths in the placebo group, the majority of which were considered to be related to complications of COVID-19 infection.

Additional evidence related to safety and efficacy of colchicine in COVID-19 provided by the sponsor was from published reports. Unlike the COLCORONA study, the reported studies were relatively small and conducted in hospitalized patients. No firm conclusion regarding colchicine efficacy in COVID-19 could be drawn from this evidence.

Based on the review of submitted evidence, Health Canada was not able to establish a positive benefit-harm balance for the colchicine 0.5 mg tablets in reduction of complications in adults with coronavirus infections such as COVID-19. The sponsor was given an opportunity to provide additional supporting clinical trial evidence. However, on June 7, 2021, the sponsor opted to withdraw the submission from review. Voluntary withdrawal of a submission does not disqualify a sponsor from refiling the application at a later date based on new evidence.

What consequences does the cancellation have for patients accessing the drug under the Special Access Programme (SAP), or via clinical trials?

There is no expected impact for patients using SAP or in clinical trials.

Additional information

*Proposed Brand Name:
COVCORONA