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Trial registered on ANZCTR


Registration number
ACTRN12615000861550
Ethics application status
Approved
Date submitted
22/07/2015
Date registered
18/08/2015
Date last updated
11/11/2020
Date data sharing statement initially provided
18/03/2019
Date results information initially provided
18/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The Australian COPS trial - COlchicine in Patients with acute coronary Syndromes
Scientific title
In patients who present with acute coronary syndromes, does addition of low-dose colchicine to standard medical therapy, compared to standard medical therapy alone, reduce the major adverse cardiovascular events at 12 months?
Secondary ID [1] 287133 0
Nil known
Universal Trial Number (UTN)
U1111-1169-9214
Trial acronym
The Australian COPS trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ischaemic heart disease 295679 0
Condition category
Condition code
Cardiovascular 295953 295953 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will receive oral colchicine 0.5mg tablets twice daily for 1 month followed by oral colchicine 0.5mg once daily for 11 months, in addition to the standard medical therapy for ischaemic heart disease.

Medication adherence will be assessed indirectly by pill counts. Participants will be asked to count the number of pills remain in their medication bottles during scheduled telephone interviews.
Intervention code [1] 292392 0
Treatment: Drugs
Comparator / control treatment
Participants will receive placebo (microcrystalline cellulose) tablets twice daily for 1 month followed by once daily for 11 months, in addition to the standard medical therapy for ischaemic heart disease.

Medication adherence will be assessed indirectly by pill counts. Participants will be asked to count the number of pills remain in their medication bottles during scheduled telephone interviews.
Control group
Placebo

Outcomes
Primary outcome [1] 295637 0
Composite of major adverse cardiovascular events (MACE) which include: (a) Acute coronary syndrome, (b) Ischaemic-driven revascularization, (c) Death from any cause, and (d) Non-cardioembolic ischaemic stroke The primary outcome will be assessed via medical records and telephone interviews.
Timepoint [1] 295637 0
12 months
Secondary outcome [1] 316051 0
Rates of recurrent acute coronary syndrome, assessed via medical records and telephone interviews
Timepoint [1] 316051 0
12 months
Secondary outcome [2] 316052 0
Rates of ischaemic-driven revascularization, assessed via medical records and telephone interviews
Timepoint [2] 316052 0
12 months
Secondary outcome [3] 316053 0
Cardiac-related mortality, assessed via medical records, primary physicians or telephone follow-up with participant's family
Timepoint [3] 316053 0
12 months
Secondary outcome [4] 316436 0
Rates of non-cardioembolic ischaemic stroke, assessed via medical records and telephone interviews
Timepoint [4] 316436 0
12 months
Secondary outcome [5] 316437 0
Health-related quality of life, assessed using EuroQol 5-Dimensions 5-Level (EQ-5D-5L) and Seattle Angina questionnaires, during initial hospital admission and at 12 months
Timepoint [5] 316437 0
12 months
Secondary outcome [6] 372155 0
Death from any cause, assessed via medical records, primary physicians or telephone follow-up with participant's family
Timepoint [6] 372155 0
12 months

Eligibility
Key inclusion criteria
- Age between 18 to 85 years old
- Patients who are admitted to the hospital with acute coronary syndromes (also known as a heart attack) - defined by elevated troponin with ischaemic symptoms or ECG changes
- Presence of coronary artery disease on coronary angiogram – defined by >30% luminal stenosis in epicardial vessel of >2.5mm luminal diameter, which is managed with PCI or medical therapy
- Able to provide written informed consent
Minimum age
18 Years
Maximum age
85 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Coronary artery disease requiring surgical revascularization
- Pre-existing long-term colchicine use for other medical conditions
- Pre-existing, or plan for, administration of other immunosuppressant therapy
- Severe liver impairment – defined by elevated serum ALT and/or AST levels twice the upper limit of normal AND total serum bilirubin level twice the upper limit of normal OR coagulopathy (INR>1.5)
- Severe renal insufficiency – defined by eGFR<30mL/min/1.73m2
- Pre-existing use of strong CYP3A4 or P-glycoprotein inhibitors (eg. cyclosporine, antiretroviral drugs, antifungals, erythromycin and clarithromycin) and no other alternative medical therapy can be used
- Known active malignancy
- Known allergy or hypersensitivity to colchicine
- Pregnant and lactating woman or woman with childbearing potential without effective birth control methods

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The COPS trial is a randomised, double-blind, placebo-controlled study. All ACS patients who are admitted to the hospital and undergo coronary angiography +/- angioplasty will be screened for eligibility. Patients who meet the inclusion and exclusion criteria will be invited to participate in the study. After obtaining informed consent, participants will be registered on a web-based database of which randomisation will be performed. Allocation concealment will be performed by a computer-generated central randomisation system.

Participants will be allocated to receiving standard medical therapy plus placebo (control group) or standard medical therapy plus colchicine (intervention group).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Minimisation using computer-generated software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Summary statistics including mean and standard deviation will be calculated for all baseline characteristics by treatment group. All time-to-event outcomes will be calculated from the date of randomization to the date of the first documented event. If a patient has not experienced an event at the cut-off date for the statistical analysis, the outcome data will be censored at the cut-off date. If the patient has been deemed lost-to-follow-up or has withdrawn from the study, the analysis will include the last date of patient’s assessment. Outcomes for patients that provide no follow-up will be imputed using multiple imputation (refer to Statistical method for the primary endpoint). The cut-off date or study censor date will be determined after the database has been locked for the analysis.

The primary efficacy analysis will be based on the intention-to-treat principle. Each patient will be followed up for a minimum duration of 12 months. A secondary pre-specified on-treatment analysis will also be performed based on patients who are both tolerant and compliant to therapy beyond the first month of randomisation.

There are three data analysis sets in this study:
(1) Full Analysis Set (FAS) which consists of all patients randomised to the study. Analyses will be performed according to treatment arm and the strata utilized at randomization
(2) Per Protocol Set (PPS) which excludes a subset of FAS patients with major protocol deviations (MPDs). Examples of MPDs include but not limited to: study treatment received is different from treatment assigned by randomisation; or stratum assigned by randomisation is different from stratum reported by the investigator. Any other MPDs leading to exclusion from the FAS will be detailed and justified in the final report of the study.
(3) Safety Set (SS) which includes all patients who received at least one dose of study drug.

Statistical method for the primary endpoint:
The primary outcome, will be analysed by time-to-first event survival analysis (log-rank test). The primary analysis will be on an intention-to-treat basis of all randomised patients according to treatment group. Outcomes for participants that provide no follow-up data will be imputed using multiple imputation, redrawing 50 samples. Imputations will be inferred from the following baseline variables: age, diabetes, previous myocardial infarction, previous PCI/CABG, and cardiac biomarkers. The treatment effect will be reported as a hazard ratio, together with a 95% confidence interval. Kaplan-Meier estimates of the MACE at 1, 6 and 12 months, as well as 95% confidence intervals, will be reported in a table by treatment group and also displayed graphically.

A sensitivity analysis of the primary endpoint will also be performed on the PPS using the same methods as described above for the primary analysis.

In addition, supplementary analyses performed on the FAS, Cox Proportional Hazards models incorporating the following covariates: gender, age, hypertension, diabetes, hypercholesterolaemia, smoking history, family history of coronary artery disease, previous myocardial infarction, previous PCI/CABG, previous stroke, and peripheral vascular disease; and their possible interactions with the treatment arms, will be evaluated. The proportional hazards assumption will be checked for all models.

Statistical methods for the secondary endpoints:
Fine and Gray competing risks regression will be used to compare the effects of treatment arms for the following competing risks:
· Acute coronary syndrome
· Ischaemic-driven revascularization
· Non-cardioembolic ischaemic stroke
· Death from any cause
· Death due to cardiovascular disease

Cumulative incidences, and their 95% confidence intervals will be reported.

Health-related quality of life will be compared between groups using baseline-adjusted linear regression.

Sample size justification:
We postulate that the control group will have a combined event rate of approximately 20% over 3 years in the control group versus 10% in the treatment group based on previous literature. The 20% and 10% per 3 year event rate translates to 3.45% and 7.16% annual event rates. On this basis we estimate that a sample size of 1009 patients provides 80% power at 5% significance to detect this difference, using a log-rank test. We expect to see 49 events in the cohort. This corresponds to a hazard ratio of 2.1170 and assumes participant attrition of 10% over the period of the study.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,TAS,VIC

Funding & Sponsors
Funding source category [1] 291692 0
Hospital
Name [1] 291692 0
St. Vincent's Hospital Melbourne
Address [1] 291692 0
41 Victoria Parade, Fitzroy VIC 3065
Country [1] 291692 0
Australia
Primary sponsor type
Hospital
Name
St. Vincent's Hospital Melbourne
Address
41 Victoria Parade, Fitzroy VIC 3065
Country
Australia
Secondary sponsor category [1] 290367 0
Hospital
Name [1] 290367 0
Peninsula Health
Address [1] 290367 0
2 Hastings Road, Frankston VIC 3199
Country [1] 290367 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293313 0
St Vincent’s Hospital (Melbourne) Human Research Ethics Committee
Ethics committee address [1] 293313 0
41 Victoria Parade, Fitzroy VIC 3065
Ethics committee country [1] 293313 0
Australia
Date submitted for ethics approval [1] 293313 0
19/05/2015
Approval date [1] 293313 0
26/08/2015
Ethics approval number [1] 293313 0
HREC/15/SVHM/44

Summary
Brief summary
The COPS trial is a prospective multicentre randomised study to examine the effect of adding low-dose colchicine to standard medical therapy in patients who have had a heart attack. A total of 1009 participants will be recruited from hospitals across Australia over the study period. Participants will be randomised to either (a) standard medical therapy or (b) standard medical therapy plus low-dose oral colchicine. Participants will be followed up for 12 months for predefined major adverse cardiovascular outcomes via telephone interviews.

We hypothesise that the addition of colchicine to standard medical therapy will reduce long-term major adverse cardiovascular events in patients who have had a heart attack.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 58950 0
Prof Jamie Layland
Address 58950 0
St. Vincent's Hospital Melbourne
Cardiac Investigation Unit
Level 1, Building A
41 Victoria Parade, Fitzroy VIC 3065
Country 58950 0
Australia
Phone 58950 0
+613 9231 2211
Fax 58950 0
Email 58950 0
jlayland@phcn.vic.gov.,au
Contact person for public queries
Name 58951 0
Prof Jamie Layland
Address 58951 0
St. Vincent's Hospital Melbourne
Cardiac Investigation Unit
Level 1, Building A
41 Victoria Parade, Fitzroy VIC 3065
Country 58951 0
Australia
Phone 58951 0
+613 9231 2211
Fax 58951 0
Email 58951 0
jlayland@phcn.vic.gov.au
Contact person for scientific queries
Name 58952 0
Prof Jamie Layland
Address 58952 0
St. Vincent's Hospital Melbourne
Cardiac Investigation Unit
Level 1, Building A
41 Victoria Parade, Fitzroy VIC 3065
Country 58952 0
Australia
Phone 58952 0
+613 9231 2211
Fax 58952 0
Email 58952 0
jlayland@phcn.vic.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Study protocol
How or where can supporting documents be obtained?
Type [1] 2672 0
Study protocol
Citation [1] 2672 0
Link [1] 2672 0
Email [1] 2672 0
Other [1] 2672 0
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary