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Trial registered on ANZCTR
Registration number
ACTRN12614000093684
Ethics application status
Approved
Date submitted
20/01/2014
Date registered
24/01/2014
Date last updated
22/03/2021
Date data sharing statement initially provided
10/05/2019
Date results information initially provided
10/05/2019
Type of registration
Prospectively registered
Titles & IDs
Public title
"The LoDoCo2 Trial":Low Dose Colchicine for secondary prevention of cardiovascular disease.
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Scientific title
The LoDoCo2 Trial: A randomised controlled trial on the effect of low dose Colchicine for secondary prevention of cardiovascular disease in patients with established, stable coronary artery disease
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Secondary ID [1]2820280
Nil
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Universal Trial Number (UTN)
U1111-1139-8608
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Trial acronym
LoDoCo2
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Cardiovascular death 2884760
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Myocardial infarction2909860
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Ischemic Stroke 3145020
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Ischemia-driven coronary revascularization 3145030
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Condition category
Condition code
Cardiovascular28882228882200
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Coronary heart disease
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Colchicine 0.5mg tablet taken orally each day for the duration of the trial, It is expected that some participants randomized earlier in the trial will receive treatment for up to 5 years, whereas others randomized later in the trial will be on the trial medication for a minimum of 1 year. LoDoCo2 is an event driven intention to treat trial: participation continues until the requisite number of primary events have occurred and with the requirement of a minimal follow-up of 1 year.
Adherence will be determined by questionnaire every 6 months at the time of collection of the new supply of the trial medication, No serum levels of colchicine metabolites are being measured
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Intervention code [1]2866160
Treatment: Drugs
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Intervention code [2]2866170
Prevention
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Comparator / control treatment
Placebo [Glucose] tablet taken orally each day for the duration of the trial
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Control group
Placebo
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Outcomes
Primary outcome [1]2889600
The time to the first occurrence of any of the elements of the composite of cardiovascular death, myocardial infarction, ischemic stroke, and ischemia-driven coronary revascularisation.
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Timepoint [1]2889600
Minimum follow up of 1 year for each individual. Expected maximum follow up of 5 years for some participants. Estimated median follow up of 3 years or 331 primary outcome events
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Secondary outcome [1]3014420
the composite of cardiovascular death, myocardial infarction or ischemic stroke
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Timepoint [1]3014420
Minimum follow up of 1 year for each individual. Expected maximum follow up of 5 years for some participants. Estimated median follow up of 3 years or 331 primary outcome events
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Secondary outcome [2]3014430
the composite of myocardial infarction or ischemia-driven coronary revascularization
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Timepoint [2]3014430
Minimum follow up of 1 year for each individual. Expected maximum follow up of 5 years for some participants. Estimated median follow up of 3 years or 331 primary outcome events
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Secondary outcome [3]3014440
the composite of cardiovascular death or myocardial infarction
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Timepoint [3]3014440
Minimum follow up of 1 year for each individual. Expected maximum follow up of 5 years for some participants. Estimated median follow up of 3 years or 331 primary outcome events
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Secondary outcome [4]3014450
Ischemia-driven coronary revascularization
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Timepoint [4]3014450
Minimum follow up of 1 year for each individual. Expected maximum follow up of 5 years for some participants. Estimated median follow up of 3 years or 331 primary outcome events
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Secondary outcome [5]3750060
Myocardial infarction
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Timepoint [5]3750060
Minimum follow up of 1 year for each individual. Expected maximum follow up of 5 years for some participants. Estimated median follow up of 3 years or 331 primary outcome events
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Secondary outcome [6]3750070
Ischemic stroke
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Timepoint [6]3750070
Minimum follow up of 1 year for each individual. Expected maximum follow up of 5 years for some participants. Estimated median follow up of 3 years or 331 primary outcome events
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Secondary outcome [7]3750080
Death from any cause
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Timepoint [7]3750080
Minimum follow up of 1 year for each individual. Expected maximum follow up of 5 years for some participants. Estimated median follow up of 3 years or 331 primary outcome events
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Secondary outcome [8]3931370
Cardiovascular Death
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Timepoint [8]3931370
Minimum follow up of 1 year for each individual. Expected maximum follow up of 5 years for some participants. Estimated median follow up of 3 years or 331 primary outcome events
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Eligibility
Key inclusion criteria
Patients with coronary heart disease diagnosed by coronary angiography or CT coronary angiogram who are clinically stable [no cardiovascular related hospital admission in the prior 6 months] and Patients with CABG>10 years ago, unless evidence of graft failure or the need for angioplasty since surgery
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Minimum age
35Years
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Maximum age
82Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
1] Serious Non-Cardiac Co-morbidity; including prior history of myopathy, leucopenia or thrombocytopenia , renal dysfunction with eGFR <50mL/min or serum Creatinine>150mmol/l, advanced liver disease, severe intestinal disease, advanced cancer 2] history of noncompliance with medical therapy or known to be poor clinic attendee, 3] A need for regular drugs known to be potent CYP inhibitors (e.g., ketaconazole or clarithromycin), 4] Other advanced Cardiac Disease; Advanced valvular heart disease, Severe LV dysfunction or symptomatic heart failure or Severe Pulmonary hypertension, 5] Women of child bearing age; 6] Current on-going use of long term colchicine therapy for any other reason, 6] Known intolerance to colchicine, 7] Enrollment in a competing trial, 8] Unwilling or unable to be consented for inclusion into the study for any reason.
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Study design
Purpose of the study
Prevention
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealmentprocedures)
Enrollment: By usual Cardiologist at the time of routine review. Open label run in period: Participants who are enrolled in the study will trial open label colchicine for 30 days to determine their tolerance to therapy. During this time the Cardiologist and the participant know that active treatment is being administered Randomization: Only patients who are tolerant of therapy will be randomised into the study. Randomisation will be double blinded. The names of participants who are tolerant to therapy will be allocated to either study arm by the holder of the allocation schedule who is off site at the central administrative office located in the Heart Research Insistuite.
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Methods used to generate the sequence in which subjects will be randomised (sequencegeneration)
A simple randomisation table will be created by a computerised sequence generation.
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Masking / blinding
Blinded (masking used)
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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
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Intervention assignment
Parallel
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Other design features
Update
1] 30 day run in period of open label therapy to determine tolerance to therapy. 2] Only participants who are tolerant of therapy and willing to continue in the study will be randomized. 3] Participants may withdraw at any time and may re-enter the trial later if they choose. 4] Caring physicians can decide whether the trial medication should be ceased if there is clinical concern about possible effects of therapy. 5] Doctors and participants are warned to avoid clarithromycin (Australia and The Netherlands) and Verapamil and Azithromycin (The Netherlands) during the trial but if required to temporarily cease the TM 6] An interim analysis is planned when 75% of the requisite number of events have occurred to examine drug safety
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Phase
Phase 3
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Type of endpoint/s
Safety/efficacy
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Statistical methods / analysis
The sample size determination for the study was event-driven, i.e. based on a requirement for the number of patients reaching the primary efficacy endpoint. Design assumptions included a 10% drop-out rate after the open label run-in phase, a per annum rate for the composite primary endpoint in the control group of 2.6% and a hazard ratio of 0.70. It was estimated that the occurrence of at least 331 composite primary endpoints would provide the trial with 90% power to statistically detect the expected treatment benefit at a two-sided significance level of 0.05. Based on these assumptions the sample size was set at 5447 randomized participants. In accordance with the intent-to-treat principle outlined in the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for human use – the ICH Harmonised Tripartite Guideline Statistical Principles for Clinical Trials E9, the primary analyses for efficacy will be based on time to first event for the primary composite end-point in all randomized patients who took at least 1 tablet of their assigned trial medication using events adjudicated by the Clinical Events Committee. In addition, a per protocol analysis for the primary outcome in patients who remained compliant with the trial medication through the duration of the trial will be conducted. The occurrence of the primary endpoint over time will be depicted with Kaplan-Meier curves. The hazard ratio (HR), its 95% confidence interval (CI) and the corresponding P – value will be derived from a Cox proportional hazards model with a factor for treatment group (colchicine versus control). P < 0.05 for the primary endpoint will be considered statistically significant. Secondary endpoints will be analyzed in a similar fashion using HRs and 95% CIs derived from a Cox proportional hazards model. The testing of the primary and secondary endpoints will be assessed in a closed testing procedure to preserve alpha as specified in the statistical analysis plan.
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Recruitment
Recruitment status
Completed
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Date of first participant enrolment
Anticipated
17/02/2014
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Actual
14/09/2014
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Date of last participant enrolment
Anticipated
31/10/2018
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Actual
3/12/2018
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Date of last data collection
Anticipated
1/05/2020
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Actual
17/02/2020
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Sample size
Target
5500
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Accrual to date
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Final
5522
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Recruitment in Australia
Recruitment state(s)
WA
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Recruitment postcode(s) [1]64280
6000 - Perth Gpo
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Recruitment outside Australia
Country [1]90000
Netherlands
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State/province [1]90000
Funding & Sponsors
Funding source category [1]2884770
Government body
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Name [1]2884770
National Health and Medical Research Coucil of Australia
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Country [1]2884770
Australia
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Funding source category [2]2967670
Commercial sector/Industry
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Name [2]2967670
Aspen Pharamcare Australia
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Country [2]2967670
Australia
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Funding source category [3]2967680
Commercial sector/Industry
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Name [3]2967680
GenesisCare
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Country [3]2967680
Australia
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Funding source category [4]2967690
Government body
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Name [4]2967690
ZonMW
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Country [4]2967690
Netherlands
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Funding source category [5]2967700
Charities/Societies/Foundations
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Name [5]2967700
Withering Stichting Nederland
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Country [5]2967700
Netherlands
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Funding source category [6]2967710
Commercial sector/Industry
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Name [6]2967710
Teva
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Country [6]2967710
Netherlands
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Funding source category [7]2967720
Commercial sector/Industry
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Name [7]2967720
Disphar
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Country [7]2967720
Netherlands
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Funding source category [8]2967730
Commercial sector/Industry
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Name [8]2967730
Tiofarma
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Country [8]2967730
Netherlands
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Funding source category [9]3038660
Charities/Societies/Foundations
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Name [9]3038660
Nederlandse Hartstichting
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Country [9]3038660
Netherlands
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Primary sponsor type
Other
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Name
Heart Research Institute, Sir Charles Gairdner Hospital
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Address
QE2 Medical Center
Hospital Avenue
Nedlands 6009
Western Australia
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Country
Australia
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Secondary sponsor category [1]2957560
Other Collaborative groups
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Name [1]2957560
Dutch Network for Cardiovascular Research (WCN)
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Address [1]2957560
Utrecht
P.O. Box 19008
3501 DA Utrecht
The Netherlands
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Country [1]2957560
Netherlands
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]2979950
Sir Charles Gairdner Group HREC
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Ethics committee address [1]2979950
Level 2 A Block
Hospital Ave
Nedlands
WA 6009
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Ethics committee country [1]2979950
Australia
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Date submitted for ethics approval [1]2979950
25/11/2013
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Approval date [1]2979950
27/02/2014
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Ethics approval number [1]2979950
2013-236
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Ethics committee name [2]2979960
Medical Reseach Ethics Committees United
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Ethics committee address [2]2979960
Postbus 2500 3430 EM Nieuwegein
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Ethics committee country [2]2979960
Netherlands
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Date submitted for ethics approval [2]2979960
01/07/2016
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Approval date [2]2979960
18/08/2016
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Ethics approval number [2]2979960
R16.027/LoDoCo2
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Summary
Brief summary
The primary objective of this study is to evaluate clinical efficacy of treatment with colchicine 0.5mg once daily as compared to placebo in patients with stable coronary artery disease on the incidence of first occurrence of the composite of cardiovascular death, myocardial infarction, ischemic stroke or ischemia-driven coronary revascularisation.
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Trial website
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Trial related presentations / publications
Nidorf M, Thompson PL. Effect of colchicine (0.5 mg twice daily) on high-sensitivity C-reactive protein independent of aspirin and atorvastatin in patients with stable coronary artery disease. Am J Cardiol. 2007 Mar 15;99(6):805-7. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-Dose Colchicine for Secondary Prevention of Cardiovascular Disease. J Am Coll Cardiol. 2012 Dec 13. doi:pii: S0735-1097(12)05478-2. JACC Jan 13 Nidorf SM, Eikelboom JW, Thompson PL Targeting Cholesterol Crystal-Induced Inflammation for the Secondary Prevention of Cardiovascular Disease Journal of Cardiovascular. Pharmacology and Therapeutics Volume 19 Issue 1 January 2014 pp. 45 - 52. Nidorf SM, Eikelboom JW, Thompson PL Colchicine for Secondary Prevention of Cardiovascular Disease [In Press] Curr Atheroscler Rep (2014) 16:391
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Public notes
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Contacts
Principal investigator
Name381420
Prof Peter L Thompson
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Address381420
Heart Research Institute of Western Australia
Floor 2 Harry Perkins Institute
Sir Charles Gairdner Hospital,
Perth 6009
Western Australia
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Country381420
Australia
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Phone381420
+61 407970090
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Fax381420
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Email381420
[emailprotected]
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Contact person for public queries
Name381430
Prof Peter L Thompson
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Address381430
Heart Research Institute of Western Australia
Floor 2 Harry Perkins Institute
Sir Charles Gairdner Hospital,
Perth 6009
Western Australia
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Country381430
Australia
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Phone381430
+61 407970090
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Fax381430
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Email381430
[emailprotected]
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Contact person for scientific queries
Name381440
Dr Mark Nidorf
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Address381440
GenisisCare 3/140 Mounts Bay Rd Perth 6000 Western Australia
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Country381440
Australia
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Phone381440
+61 413145410
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Fax381440
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Email381440
[emailprotected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
All collected coded data
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When will data be available (start and end dates)?
6 months after publication
No end-date
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Available to whom?
Raw data will not be shared but parties can apply a scientific request for data sharing and data analysis that will be discussed at the publication meeting of the Steering Committee
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Available for what types of analyses?
To be determined
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How or where can data be obtained?
Written request to the LoDoCo2 Steering Committee
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What supporting documents are/will be available?
| Doc. No. | Type | Citation | Link | Other Details | Attachment | |
|---|---|---|---|---|---|---|
| 4967 | Study protocol | n/a | https://www.wcn.life | [emailprotected] | Request the LoDoCo2 steering committee | |
| 4968 | Ethical approval | N/A | https://wcn.life | [emailprotected] | N/A | |
| 4969 | Clinical study report | NA | https://www.wcn.life | [emailprotected] | NA |
Results publications and other study-related documents
Documents added manually
No documents have been uploaded by study researchers.
Documents added automatically
| Source | Title | Year of Publication | DOI |
|---|---|---|---|
| Embase | Inflammation and beyond: new directions and emerging drugs for treating atherosclerosis. | 2017 | https://dx.doi.org/10.1080/14728214.2017.1269743 |
| Embase | Inflammation, Superadded Inflammation, and Out-of-Proportion Inflammation in Atherosclerosis. | 2018 | https://dx.doi.org/10.1001/jamacardio.2018.2760 |
| Embase | Colchicine in cardiac disease: A systematic review and meta-analysis of randomized controlled trials. | 2015 | https://dx.doi.org/10.1186/s12872-015-0068-3 |
| Embase | Does low-density lipoprotein cholesterol induce inflammation? if so, does it matter? Current insights and future perspectives for novel therapies. | 2019 | https://dx.doi.org/10.1186/s12916-019-1433-3 |
| Embase | Why Colchicine Should Be Considered for Secondary Prevention of Atherosclerosis: An Overview. | 2019 | https://dx.doi.org/10.1016/j.clinthera.2018.11.016 |
| Embase | Colchicine Attenuates Inflammation Beyond the Inflammasome in Chronic Coronary Artery Disease A LoDoCo2 Proteomic Substudy. | 2020 | https://dx.doi.org/10.1161/CIRCULATIONAHA.120.050560 |
| Embase | Targeted anti-inflammatory therapy is a new insight for reducing cardiovascular events: A review from physiology to the clinic. | 2020 | https://dx.doi.org/10.1016/j.lfs.2020.117720 |
| Embase | Colchicine in patients with chronic coronary disease. | 2020 | https://dx.doi.org/10.1056/NEJMoa2021372 |
| Embase | Colchicine for acute and chronic coronary syndromes. | 2020 | https://dx.doi.org/10.1136/heartjnl-2020-317108 |
| Embase | Colchicine in the Management of Acute and Chronic Coronary Artery Disease. | 2021 | https://dx.doi.org/10.1007/s11886-021-01560-w |
| Embase | Targeting inflammation in atherosclerosis - from experimental insights to the clinic. | 2021 | https://dx.doi.org/10.1038/s41573-021-00198-1 |
| Embase | Colchicine reduces extracellular vesicle NLRP3 inflammasome protein levels in chronic coronary disease: A LoDoCo2 biomarker substudy. | 2021 | https://dx.doi.org/10.1016/j.atherosclerosis.2021.08.005 |
| Embase | The Effect of Years-Long Exposure to Low-Dose Colchicine on Renal and Liver Function and Blood Creatine Kinase Levels: Safety Insights from the Low-Dose Colchicine 2 (LoDoCo2) Trial. | 2022 | https://dx.doi.org/10.1007/s40261-022-01209-8 |
| Embase | Hearts on Fire: The Role of Inflammation in the Pathogenesis of Atherosclerotic Cardiovascular Disease and How We Can Tend to the Flames. | 2022 | https://dx.doi.org/10.1016/j.cjca.2022.05.023 |
| Embase | Targeting Microtubules for the Treatment of Heart Disease. | 2022 | https://dx.doi.org/10.1161/CIRCRESAHA.122.319808 |
| Embase | Association of Low-Dose Colchicine With Incidence of Knee and Hip Replacements: Exploratory Analyses From a Randomized, Controlled, Double-Blind Trial. | 2023 | https://dx.doi.org/10.7326/M23-0289 |
| Embase | Drivers of mortality in patients with chronic coronary disease in the low-dose colchicine 2 trial. | 2023 | https://dx.doi.org/10.1016/j.ijcard.2022.12.026 |
| Dimensions AI | Cost-effectiveness of low-dose colchicine in patients with chronic coronary disease in the netherlands | 2024 | https://doi.org/10.1093/ehjqcco/qcae021 |
| Dimensions AI | Long-Term Efficacy of Colchicine in Patients With Chronic Coronary Disease: Insights From LoDoCo2 | 2022 | https://doi.org/10.1161/circulationaha.121.058233 |
| Dimensions AI | What’s Old is New Again – A Review of the Current Evidence of Colchicine in Cardiovascular Medicine | 2017 | https://doi.org/10.2174/1573403x12666161014094159 |
| Dimensions AI | Signaling pathways and targeted therapy for myocardial infarction | 2022 | https://doi.org/10.1038/s41392-022-00925-z |
N.B. These documents automatically identified may not have been verified by the study sponsor.
