Corona Virus Infection
Conditions
Brief summary
This is a phase 3, randomized, double-blind, placebo-controlled multicenter study to evaluate the efficacy and safety of colchicine in adult patients diagnosed with COVID-19 infection and have at least one high-risk criterion. Approximately 6000 subjects meeting all inclusion and no exclusion criteria will be randomized to receive either colchicine or placebo tablets for 30 days.
Detailed description
The primary objective of this study is to determine whether short-term treatment with colchicine reduces the rate of death and lung complications related to COVID-19. The secondary objective is to determine the safety of treatment with colchicine in this patient population. Approximately 6000 patients will be enrolled to receive either colchicine or placebo (1:1 allocation ratio) for 30 days. Follow-up assessments will occur at 15 and 30 days following randomization for evaluation of the occurrence of any trial endpoints or other adverse events. Safety and efficacy will be based on data from randomized patients. An independent data and safety monitoring board (DSMB) will periodically review study results as well as the overall conduct of the study, and will make recommendations to the study Executive Steering Committee (ESC) to continue, stop or modify the study protocol.
Interventions
DRUGColchicine
Patients in this arm will receive study medication colchicine 0.5 mg per os (PO) twice daily for the first 3 days and then once daily for the last 27 days. If a dose is missed, it should not be replaced.
DRUGPlacebo oral tablet
Patients will receive the placebo 0.5 mg per os (PO) twice daily for the first 3 days and then once daily for the last 27 days. If a dose is missed, it should not be replaced.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Bill and Melinda Gates Foundation
The Government of Quebec
Dacima Software Inc.
Montreal Heart Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
This will be a randomized, double-blind, placebo-controlled, multi-center study. Following signature of the informed consent form, approximately 6000 subjects meeting all inclusion and no exclusion criteria will be randomized to receive either colchicine or placebo (1:1 allocation ratio) for 30 days. Follow-up phone or video assessments will occur at 15 and 30 days following randomization for evaluation of the occurrence of any trial endpoints or other adverse events.
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Males and females, at least 40 years of age, capable and willing to provide informed consent; 2. Patient must have received a diagnosis of COVID-19 infection within the last 24 hours; 3. Outpatient setting (not currently hospitalized or under immediate consideration for hospitalization); 4. Patient must possess at least one of the following high-risk criteria: 70 years or more of age, obesity (BMI ≥ 30 kg/m2), diabetes mellitus, uncontrolled hypertension (systolic blood pressure ≥150 mm Hg), known respiratory disease (including asthma or chronic obstructive pulmonary disease), known heart failure, known coronary disease, fever of ≥38.4°C within the last 48 hours, dyspnea at the time of presentation, bicytopenia, pancytopenia, or the combination of high neutrophil count and low lymphocyte count; 5. Female patient is either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile, or is of childbearing potential and practicing at least one method of contraception and preferably two complementary forms of contraception including a barrier method (e.g. male or female condoms, spermicides, sponges, foams, jellies, diaphragm, intrauterine device (IUD)) throughout the study and for 30 days after study completion; 6. Patient must be able and willing to comply with the requirements of this study protocol.
Exclusion criteria
1. Patient currently hospitalized or under immediate consideration for hospitalization; 2. Patient currently in shock or with hemodynamic instability; 3. Patient with inflammatory bowel disease (Crohn's disease or ulcerative colitis), chronic diarrhea or malabsorption; 4. Patient with pre-existent progressive neuromuscular disease; 5. Estimated Glomerular filtration rate (eGFR), using the MDRD equation for all subjects being considered for enrollment, with a cut-off of \< 30 mL/m in/1.73m2; 6. Patient with a history of cirrhosis, chronic active hepatitis or severe hepatic disease; 7. Female patient who is pregnant, or breast-feeding or is considering becoming pregnant during the study or for 6 months after the last dose of study medication; 8. Patient currently taking colchicine for other indications (mainly chronic indications represented by Familial Mediterranean Fever or gout); 9. Patient with a history of an allergic reaction or significant sensitivity to colchicine; 10. Patient undergoing chemotherapy for cancer; 11. Patient is considered by the investigator, for any reason, to be an unsuitable candidate for the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization. | 30 days post randomization | The primary endpoint will be the composite of death or hospitalization due to COVID-19 infection in the 30 days following randomization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Deaths in the 30 Days Following Randomization. | 30 days post randomization | The secondary endpoint consisted of two components of the composite primary endpoint and included death in the 30 days following randomization. |
| Number of Participants Who Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization. | 30 days post randomization | The secondary endpoint consisted of two components of the composite primary endpoint and included hospitalization due to COVID-19 infection in the 30 days following randomization. |
| Number of Participants Who Required Mechanical Ventilation in the 30 Days Following Randomization. | 30 days post randomization | The secondary endpoint is the need for mechanical ventilation in the 30 days following randomization. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization in the Subgroup of Patients With PCR-confirmed COVID-19. | 30 Days post randomization | In the prespecified analysis of the 4159 patients with Covid-19 confirmed by PCR, the primary endpoint (composite of death or hospitalization due to Covid-19 infection in the 30 Days following randomization) was compared between the two treatment groups. |
| Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Sex | 30 Days post randomization | NIH-required analysis. The primary endpoint will be the composite of death or hospitalization due to COVID-19 infection in the 30 days following randomization by Sex. |
| Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Race | 30 Days post randomization | NIH-required analysis. The primary endpoint will be the composite of death or hospitalization due to COVID-19 infection in the 30 days following randomization by Race. |
| Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Ethnicity. | 30 Days post randomization | NIH-required analysis. The primary endpoint will be the composite of death or hospitalization due to COVID-19 infection in the 30 days following randomization by Ethnicity. |
Countries
Brazil, Canada, Greece, South Africa, Spain, United States
Participant flow
Pre-assignment details
18 patients were not included: * 11 study medication was not delivered at home; * 7 ineligible or condition deteriorated before study medication was delivered.
Participants by arm
| Arm | Count |
|---|---|
| Colchicine Patients in this arm will receive study medication colchicine 0.5 mg per os (PO) twice daily for the first 3 days and then once daily for the last 27 days. If a dose is missed, it should not be replaced. | 2,235 |
| Placebo Patients will receive the placebo 0.5 mg per os (PO) twice daily for the first 3 days and then once daily for the last 27 days. If a dose is missed, it should not be replaced. | 2,253 |
| Total | 4,488 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Admitted to Hospital and Intubated | 1 | 0 |
| Overall Study | Death | 5 | 9 |
| Overall Study | Lost to Follow-up | 4 | 8 |
| Overall Study | Withdrawal by Subject | 33 | 47 |
Baseline characteristics
| Characteristic | Colchicine | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 53.0 years | 54.0 years | 54.0 years |
| Body Mass Index (BMI) | 30.0 kg/m^2 STANDARD_DEVIATION 6.2 | 30.0 kg/m^2 STANDARD_DEVIATION 6.3 | 30.0 kg/m^2 STANDARD_DEVIATION 6.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 327 Participants | 349 Participants | 676 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1869 Participants | 1872 Participants | 3741 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 39 Participants | 32 Participants | 71 Participants |
| History of Diabetes No | 1791 Participants | 1803 Participants | 3594 Participants |
| History of Diabetes Yes | 444 Participants | 450 Participants | 894 Participants |
| History of Respiratory Disease No | 1652 Participants | 1647 Participants | 3299 Participants |
| History of Respiratory Disease Not Reported | 0 Participants | 1 Participants | 1 Participants |
| History of Respiratory Disease Yes | 583 Participants | 605 Participants | 1188 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 5 Participants | 9 Participants | 14 Participants |
| Race (NIH/OMB) Asian | 23 Participants | 20 Participants | 43 Participants |
| Race (NIH/OMB) Black or African American | 114 Participants | 116 Participants | 230 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 7 Participants | 7 Participants | 14 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 5 Participants | 5 Participants |
| Race (NIH/OMB) White | 2084 Participants | 2092 Participants | 4176 Participants |
| Region of Enrollment Brazil | 79 participants | 82 participants | 161 participants |
| Region of Enrollment Canada | 1817 participants | 1830 participants | 3647 participants |
| Region of Enrollment Greece | 1 participants | 1 participants | 2 participants |
| Region of Enrollment South Africa | 0 participants | 2 participants | 2 participants |
| Region of Enrollment Spain | 94 participants | 94 participants | 188 participants |
| Region of Enrollment United States | 244 participants | 244 participants | 488 participants |
| Sex: Female, Male Female | 1238 Participants | 1183 Participants | 2421 Participants |
| Sex: Female, Male Male | 997 Participants | 1070 Participants | 2067 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 2,195 | 9 / 2,217 |
| other Total, other adverse events | 524 / 2,195 | 328 / 2,217 |
| serious Total, serious adverse events | 108 / 2,195 | 139 / 2,217 |
Outcome results
Primary
Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization.
The primary endpoint will be the composite of death or hospitalization due to COVID-19 infection in the 30 days following randomization.
Time frame: 30 days post randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Colchicine | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization. | 104 Participants |
| Placebo | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization. | 131 Participants |
p-value: 0.08195.1% CI: [0.61, 1.03]Chi-squared
Secondary
Number of Deaths in the 30 Days Following Randomization.
The secondary endpoint consisted of two components of the composite primary endpoint and included death in the 30 days following randomization.
Time frame: 30 days post randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Colchicine | Number of Deaths in the 30 Days Following Randomization. | 5 Participants |
| Placebo | Number of Deaths in the 30 Days Following Randomization. | 9 Participants |
p-value: 0.29195% CI: [0.19, 1.67]Chi-squared
Secondary
Number of Participants Who Required Mechanical Ventilation in the 30 Days Following Randomization.
The secondary endpoint is the need for mechanical ventilation in the 30 days following randomization.
Time frame: 30 days post randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Colchicine | Number of Participants Who Required Mechanical Ventilation in the 30 Days Following Randomization. | 11 Participants |
| Placebo | Number of Participants Who Required Mechanical Ventilation in the 30 Days Following Randomization. | 21 Participants |
p-value: 0.0895% CI: [0.25, 1.09]Chi-squared
Secondary
Number of Participants Who Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization.
The secondary endpoint consisted of two components of the composite primary endpoint and included hospitalization due to COVID-19 infection in the 30 days following randomization.
Time frame: 30 days post randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Colchicine | Number of Participants Who Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization. | 101 Participants |
| Placebo | Number of Participants Who Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization. | 128 Participants |
p-value: 0.07795% CI: [0.6, 1.03]Chi-squared
Other Pre-specified
Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Ethnicity.
NIH-required analysis. The primary endpoint will be the composite of death or hospitalization due to COVID-19 infection in the 30 days following randomization by Ethnicity.
Time frame: 30 Days post randomization
Population: Data were stratified by ethnicity.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Colchicine | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Ethnicity. | Hispanic or Latino | 20 Participants |
| Colchicine | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Ethnicity. | Not Hispanic or Latino | 82 Participants |
| Colchicine | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Ethnicity. | Not reported or unknown | 2 Participants |
| Placebo | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Ethnicity. | Hispanic or Latino | 24 Participants |
| Placebo | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Ethnicity. | Not Hispanic or Latino | 106 Participants |
| Placebo | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Ethnicity. | Not reported or unknown | 1 Participants |
Other Pre-specified
Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Race
NIH-required analysis. The primary endpoint will be the composite of death or hospitalization due to COVID-19 infection in the 30 days following randomization by Race.
Time frame: 30 Days post randomization
Population: Data were stratified by race.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Colchicine | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Race | Black | 3 Participants |
| Colchicine | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Race | White | 98 Participants |
| Colchicine | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Race | Asian | 1 Participants |
| Colchicine | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Race | More than one race | 0 Participants |
| Colchicine | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Race | Native Hawaiian or other Pacific Islander | 1 Participants |
| Colchicine | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Race | Not reported or unknown | 0 Participants |
| Colchicine | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Race | American Indian or Alaska Native | 1 Participants |
| Placebo | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Race | Not reported or unknown | 0 Participants |
| Placebo | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Race | American Indian or Alaska Native | 2 Participants |
| Placebo | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Race | Asian | 3 Participants |
| Placebo | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Race | Black | 6 Participants |
| Placebo | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Race | Native Hawaiian or other Pacific Islander | 0 Participants |
| Placebo | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Race | White | 120 Participants |
| Placebo | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Race | More than one race | 0 Participants |
Other Pre-specified
Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Sex
NIH-required analysis. The primary endpoint will be the composite of death or hospitalization due to COVID-19 infection in the 30 days following randomization by Sex.
Time frame: 30 Days post randomization
Population: Data were stratified by sex.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Colchicine | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Sex | Male | 58 Participants |
| Colchicine | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Sex | Female | 46 Participants |
| Placebo | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Sex | Male | 90 Participants |
| Placebo | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization by Sex | Female | 41 Participants |
Other Pre-specified
Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization in the Subgroup of Patients With PCR-confirmed COVID-19.
In the prespecified analysis of the 4159 patients with Covid-19 confirmed by PCR, the primary endpoint (composite of death or hospitalization due to Covid-19 infection in the 30 Days following randomization) was compared between the two treatment groups.
Time frame: 30 Days post randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Colchicine | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization in the Subgroup of Patients With PCR-confirmed COVID-19. | 96 Participants |
| Placebo | Number of Participants Who Died or Were Hospitalized Due to COVID-19 Infection in the 30 Days Following Randomization in the Subgroup of Patients With PCR-confirmed COVID-19. | 126 Participants |
p-value: 0.04295% CI: [0.57, 0.99]Regression, Logistic