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Trial registered on ANZCTR


Registration number
ACTRN12616000400460
Ethics application status
Approved
Date submitted
7/03/2016
Date registered
29/03/2016
Date last updated
7/04/2020
Date data sharing statement initially provided
18/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The effect of Colchicine on Cardiovascular Outcomes in Acute Coronary Syndrome Study (The COLCARDIO-ACS Study)
Scientific title
The COLCARDIO-ACS Study - Colchicine Cardiovascular Outcomes in Acute Coronary Syndrome Study
Secondary ID [1] 288702 0
None
Universal Trial Number (UTN)
U1111-1180-4572
Trial acronym
COLCARDIO-ACS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute coronary syndrome 297922 0
Ischaemic heart disease 297923 0
Atherosclerosis 297924 0
Condition category
Condition code
Cardiovascular 298086 298086 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Colchicine 0.5 mg daily for a median of 3 years. This will be administered orally.

ACS patients will be provisionally consented in hospital and asked to return for a hs-CRP blood test between 4-6 weeks post-ACS. Patients with hs-CRP >2mg/L will be registered into the study and commenced on optimal medical therapy as per local guidelines. All patients will complete an initial 2-week run-in period with colchicine (0.5mg) to identify any compliance/adherence issues, before returning for the randomisation visit.

Patients will be randomised to receive blinded study drug (0.5mg colchicine or matching placebo) via a secure website. Randomisation will stratify by hs-CRP level, statin dose (to prevent any confounding effects of the possible anti-inflammatory actions of statins and LDLc achieved), MI site, age, gender and study site.

Post-randomisation follow-up will occur at 3 months, 12 months, 24 months, 36 months, and annually thereafter. This will include clinical assessment, questionnaires, and blood tests.

Adherence will also be assessed at the routine follow-up intervals (3, 12, 24, 36 months) by way of asking the patient directly. We will also receive regular updates from the dispensing hospital pharmacy about whether patients have collected their alloted supply of colchicine or placebo and at what time intervals.

The median of 3 years was based on our power calculation which sought to elicit a statistically significant difference between the two groups and refute the null hypothesis, and based on other trials which have reported cardiovascular outcomes post ACS in groups treated with statins and other secondary preventative therapies. Furthermore, the landmark LoDoCo trial looking at low dose colchicine in a stable angina population had a median 3 year follow-up period so we seek to replicate this in our trial.
Intervention code [1] 294126 0
Treatment: Drugs
Comparator / control treatment
Placebo. These will be small, inert sugar pills.
Control group
Placebo

Outcomes
Primary outcome [1] 305446 0
Composite MACE outcome - CV death, ACS, urgent revascularisation, non-fatal stroke.

This outcome will be assessed using patient questionnaires, regular follow-up and self reported events or hospitalisations, reporting of events by family members or other contacts, review of patient medical records and admission summaries, and correspondence from GPs and other specialists. The patient questionnaire is uniquely designed specifically for this study and is not validated in other trials.
Timepoint [1] 305446 0
Median 3 years follow-up

At routine follow-up with patients - 3 months, 12 months, 24 months, 36 months.
Secondary outcome [1] 322134 0
Non-fatal stroke

This outcome will be assessed using patient questionnaires, regular follow-up and self reported events or hospitalisations, reporting of events by family members or other contacts, review of patient medical records and admission summaries, and correspondence from GPs and other specialists. The patient questionnaire is uniquely designed specifically for this study and is not validated in other trials.
Timepoint [1] 322134 0
3 years median follow-up

At routine follow-up with patients - 3 months, 12 months, 24 months, 36 months.
Secondary outcome [2] 322135 0
Cardiovascular mortality - death due to any cardiac cause (e.g. myocardial infarction, heart failure, arrhythmia, sudden cardiac death)

This outcome will be assessed using reporting of events by family members or other contacts, review of patient medical records and admission summaries, and correspondence from GPs and other specialists.
Timepoint [2] 322135 0
3 years median follow-up

At routine follow-up with patients - 3 months, 12 months, 24 months, 36 months.
Secondary outcome [3] 322136 0
Urgent revascularization (PCI or CABG)

This outcome will be assessed using patient questionnaires, regular follow-up and self reported events or hospitalisations, reporting of events by family members or other contacts, review of patient medical records and admission summaries, and correspondence from GPs and other specialists. The patient questionnaire is uniquely designed specifically for this study and is not validated in other trials.
Timepoint [3] 322136 0
3 years median follow-up

At routine follow-up with patients - 3 months, 12 months, 24 months, 36 months.
Secondary outcome [4] 345269 0
ACS including myocardial infarction (MI) - specifically Type 1 MI only (3rd universal definition).

This outcome will be assessed using patient questionnaires, regular follow-up and self reported events or hospitalisations, reporting of events by family members or other contacts, review of patient medical records and admission summaries, and correspondence from GPs and other specialists. The patient questionnaire is uniquely designed specifically for this study and is not validated in other trials.

Timepoint [4] 345269 0
3 years median follow-up

At routine follow-up with patients - 3 months, 12 months, 24 months, 36 months.
Secondary outcome [5] 345270 0
All-cause death

This outcome will be assessed using reporting of events by family members or other contacts, review of patient medical records and admission summaries, and correspondence from GPs and other specialists.
Timepoint [5] 345270 0
3 years median follow-up

At routine follow-up with patients - 3 months, 12 months, 24 months, 36 months.
Secondary outcome [6] 345271 0
Number of days alive and not in hospital

This outcome will be assessed using patient questionnaires, regular follow-up and self reported events or hospitalisations, reporting of events by family members or other contacts, review of patient medical records and admission summaries, and correspondence from GPs and other specialists. The patient questionnaire is uniquely designed specifically for this study and is not validated in other trials.
Timepoint [6] 345271 0
3 years median follow-up

At routine follow-up with patients - 3 months, 12 months, 24 months, 36 months.
Secondary outcome [7] 345272 0
Quality of life as demonstrated by EuroQoL and WHODAS

This is a composite outcome.

Timepoint [7] 345272 0
3 years median follow-up

At routine follow-up with patients - 3 months, 12 months, 24 months, 36 months.
Secondary outcome [8] 345273 0
Change in hs-CRP on treatment from time of study entry

This outcome will be assessed using serum assays at baseline, 3 months, 12 months, 24 months, and 36 months.
Timepoint [8] 345273 0
3 years median follow-up

At routine follow-up with patients - Baseline, 3 months, 12 months, 24 months, 36 months.

Eligibility
Key inclusion criteria
Age >= 18
Hs-CRP >= 2mg/L (4-6 weeks post ACS)
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Colchicine treatment for another cause e.g. gout
Severe liver disease
Renal insufficiency with CrCl < 45 ml/min
Calcineurin inhibitor treatment
Allergy/hypersensitivity to colchicine
Haematological malignancy or antineoplastic therapy
Thrombocytopenia or leucopenia
Pregnancy, lactating women, women at risk of pregnancy
Strong CYP3A4 inhibitors
Chronic inflammatory bowel disease

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)
This is a randomised (1:1), placebo-controlled, double-blind multi-centre superiority trial of 3000 patients. We will blind the participants to their intervention. We will also blind the investigators and data collectors (who will see participants at regular follow-up) to whether the participant they are seeing is in the treatment or placebo group. This blinding process will remain intact over the entire course of the study (from allocation to final follow-up after one year post treatment commencement). The method of allocation concealment will be central computerised randomisation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer-generated
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering 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)
Safety/efficacy
Statistical methods / analysis
Our power calculation is based on existing evidence which examined recurrent event rates post ACS in patients. Large trials identified at least a 20% event rate over 3 years in ACS survivors, even when not stratified by hsCRP. Thus, in the control arm of our study, we have assumed a conservative 20% event rate. In statin therapy trials in patients post-ACS, there was a relative risk reduction (RRR) of at least 33% in patients with hsCRP > 2 mg/L. We have taken a conservative RRR of 25%, resulting in an estimated 15% event rate in the treatment arm. Allowing for a 10% loss to follow-up and 10% non-compliance rate, and 90% power, this means we will need to recruit 3000 patients (1500 in each arm) in total.

All analyses will use the intention to treat principle. Time to event outcomes will be compared using Kaplan-Meier curves and Cox regression analyses. Continuous outcomes will be assessed for normality and analysed with suitable linear models.

Recruitment
Recruitment status
Not yet recruiting
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,WA
Recruitment hospital [1] 5398 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 10603 0
Concord Repatriation Hospital - Concord
Recruitment hospital [3] 10604 0
Westmead Hospital - Westmead
Recruitment hospital [4] 10605 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [5] 10606 0
Dubbo Base Hospital - Dubbo
Recruitment hospital [6] 10607 0
Orange Health Service - Orange
Recruitment hospital [7] 10608 0
Bathurst Base Hospital - Bathurst
Recruitment hospital [8] 10609 0
Royal Perth Hospital - Perth
Recruitment postcode(s) [1] 12849 0
2050 - Camperdown
Recruitment postcode(s) [2] 22320 0
2139 - Concord
Recruitment postcode(s) [3] 22321 0
2145 - Westmead
Recruitment postcode(s) [4] 22322 0
2065 - St Leonards
Recruitment postcode(s) [5] 22323 0
2830 - Dubbo
Recruitment postcode(s) [6] 22324 0
2800 - Orange
Recruitment postcode(s) [7] 22325 0
2795 - Bathurst
Recruitment postcode(s) [8] 22326 0
6000 - Perth
Recruitment outside Australia
Country [1] 10263 0
Chile
State/province [1] 10263 0
Santiago
Country [2] 10264 0
United Kingdom
State/province [2] 10264 0
Edinburgh, Scotland

Funding & Sponsors
Funding source category [1] 293060 0
Charities/Societies/Foundations
Name [1] 293060 0
Perpetual IMPACT Philanthropy
Address [1] 293060 0
Angel Place, Level 12
123 Pitt St
Sydney NSW 2000
Country [1] 293060 0
Australia
Funding source category [2] 305402 0
Government body
Name [2] 305402 0
National Health and Medical Research Council (NHMRC)
Address [2] 305402 0
16 Marcus Clarke Street
Canberra ACT 2601
Country [2] 305402 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
NHMRC CTC
Medical Foundation Building
Level 6, 92-94 Parramatta Road
Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 291839 0
None
Name [1] 291839 0
Address [1] 291839 0
Country [1] 291839 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294569 0
Sydney Local Health District (RPAH Zone)
Ethics committee address [1] 294569 0
Research Ethics and Governance Office
Royal Prince Alfred Hospital
RPAH Medical Centre
Suite 210A, 100 Carillon Ave
Newtown NSW 2042
Ethics committee country [1] 294569 0
Australia
Date submitted for ethics approval [1] 294569 0
18/01/2018
Approval date [1] 294569 0
24/08/2018
Ethics approval number [1] 294569 0
X18-0004

Summary
Brief summary
Inflammation plays a pivotal role in atherosclerosis, offering new opportunities for the prevention and treatment of coronary artery disease.

Colchicine is a commonly used anti-inflammatory medication approved for the treatment of gout, Familial Mediterranean Fever, and acute/recurrent pericarditis. There is an increasing body of evidence in the medical literature supporting a beneficial role of long term colchicine therapy in prevention of cardiovascular disease, via modulation of inflammatory cytokine production and tubulin-mediated mitosis inhibition. This includes both primary prevention in patients treated with colchicine for gout or Familial Mediterranean Fever, and secondary prevention in patients with stable coronary artery disease who are also being treated with statins and anti-platelet agents.

Low-dose colchicine use has also been proven to be safe, well tolerated, and is inexpensive and readily available.

The aim of this project is to assess the effect of colchicine (0.5 mg/day) in addition to optimal medical therapy on cardiovascular outcomes in ACS patients with evidence of persistent coronary inflammation (based on hsCRP). We hypothesise that addition of colchicine to optimal medical therapy in patients post-ACS, who have biomarker evidence of persistent inflammation will reduce recurrent cardiovascular events.
Trial website
None
Trial related presentations / publications
None
Public notes
None

Contacts
Principal investigator
Name 64194 0
A/Prof Sanjay Patel
Address 64194 0
Department of Cardiology, Royal Prince Alfred Hospital, Missenden Road
Camperdown NSW 2050
Country 64194 0
Australia
Phone 64194 0
+61427886689, +61295163456
Fax 64194 0
+61295163934
Email 64194 0
sanjay.patel599@gmail.com
Contact person for public queries
Name 64195 0
A/Prof Colcardio-ACS Trial Coordinator
Address 64195 0
NHMRC Clinical Trials Centre,
Medical Foundation Building,
Level 4, 92-94 Parramatta Road
Camperdown NSW 2050
Country 64195 0
Australia
Phone 64195 0
+61 02 9562 5000
Fax 64195 0
+61 02 9562 5094
Email 64195 0
colarcario-acs@ctc.usyd.edu.au
Contact person for scientific queries
Name 64196 0
A/Prof Sanjay Patel
Address 64196 0
Department of Cardiology, Royal Prince Alfred Hospital, Missenden Road
Camperdown NSW 2050
Country 64196 0
Australia
Phone 64196 0
+61427886689, +61295163456
Fax 64196 0
+61295163934
Email 64196 0
sanjay.patel599@gmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual participant data will not be made available; only aggregates/means/statistical summaries.
What supporting documents are/will be available?
No other documents available
Summary results
No Results