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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
10/05/2019
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.
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
Secondary ID [1] 282028 0
Nil
Universal Trial Number (UTN)
U1111-1139-8608
Trial acronym
LoDoCo2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cardiovascular events [cardiovascular death, ACS including non fatal myocardial infarction and unstable angina, out of hospital cardiac arrest] in patients with proven but stable coronary heart disease 288476 0
Ischemic stroke in patients with proven but stable coronary disease 290986 0
Condition category
Condition code
Cardiovascular 288822 288822 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
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 likely be on the trial medication for 2 years. In an intention to treat trial, participation continues until the requisite number of primary events have occurred or earlier, should a participant choose to cease the trial medication or the DSMB suggest that the trial be ceased for any other reason
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
Intervention code [1] 286616 0
Treatment: Drugs
Intervention code [2] 286617 0
Prevention
Comparator / control treatment
Placebo [Glucose] tablet taken orally each day for the 3 to 4 year duration of the trial
Control group
Placebo

Outcomes
Primary outcome [1] 288960 0
The time to the first occurrence of the composite of cardiovascular death, non-fatal acute coronary syndrome or non-fatal ischemic stroke
Timepoint [1] 288960 0
Expected minimum follow up of 2 years 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
Secondary outcome [1] 301442 0
Time to the first occurrence of the composite of sudden cardiac death, non-fatal out of hospital cardiac arrest, myocardial infarction or unstable angina irrespective of revascularization, or atherosclerotic ischemic stroke (the composite endpoint of the first LoDoCo trial)
Timepoint [1] 301442 0
Expected minimum follow up of 2 years 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
Secondary outcome [2] 301443 0
Time to first occurrence of either non-fatal myocardial infarction or unstable angina related to stent disease or graft failure
Timepoint [2] 301443 0
Expected minimum follow up of 2 years 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
Secondary outcome [3] 301444 0
other cardiovascular endpoints including new onset atrial fibrillation, deep vein thrombosis, pulmonary embolism as evidenced from the patient record
Timepoint [3] 301444 0
Expected minimum follow up of 2 years 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
Secondary outcome [4] 301445 0
safety measures including rate of intolerance or serious adverse events including rhabdomyolysis as evidenced by the patient records. Rhabdomyolysis determined by acute onset of severe myo-necrosis evident by marked elevation in serum creatinine kinase
Timepoint [4] 301445 0
Expected minimum follow up of 2 years 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

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
Minimum age
35 Years
Maximum age
82 Years
Gender
Both males and females
Can healthy volunteers participate?
No
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.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A simple randomisation table will be created by a computerised sequence generation.
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
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 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 and futility
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
LoDoCo2 is an event-driven trial powered to detect a 30% reduction (HR 0.7) in the primary composite of cardiovascular death, non-fatal acute coronary syndrome and non-fatal ischemic stroke. This effect size is beyond the upper limit of the confidence interval of the HR of the initial LoDoCo trial (HR 0.33, 95% CI 0.18 - 0.59) but still clinically meaningful. Based upon these assumptions, and an expected annual primary event rate of 3.5% in the control group, it is estimated that 331 primary events will need to accrue in order to detect such an effect with >90% power (two sided alpha level of 0.05). The trial aims at ~6000 screened patients, leading to 5.500 randomised (divided over both continents) and an expected mean follow-up of 3 years

Data analysis:
Summary statistics Summary statistics, including mean and standard deviation will be calculated for all baseline characteristics by treatment arm. All time to event outcomes will be calculated in days by subtracting the date of randomisation from either: 1) the date of event or death; or 2) the trial termination date for those patients not experiencing the defined event. The primary efficacy analysis will be based on the intention-to-treat principle. The intention-to-treat analysis will include all randomised subjects who had taken at least 1 tablet of their trial medication* and all events during the time from randomisation to the trial termination. The trial end-date will be set at the date when the last participant recruited into the trial has been followed for 12 months unless terminated before by the DSMB. The time-to-first-event for all outcomes will be presented using a Kaplan–Meier plot. The primary efficacy outcome will be analysed using a Cox proportional hazards model including treatment group coded as control or colchicine. Other outcomes will be analysed similarly. In addition, the primary analysis can be stratified by baseline characteristics

Recruitment
Recruitment status
Active, not 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)
WA
Recruitment postcode(s) [1] 6428 0
6000 - Perth Gpo
Recruitment outside Australia
Country [1] 9000 0
Netherlands
State/province [1] 9000 0
Utrecht

Funding & Sponsors
Funding source category [1] 288477 0
Government body
Name [1] 288477 0
National Health and Medical Research Coucil of Australia
Address [1] 288477 0
16 Marcus Clarke St
Canberra ACT 2601

Country [1] 288477 0
Australia
Funding source category [2] 296767 0
Commercial sector/Industry
Name [2] 296767 0
Aspen Pharamcare Australia
Address [2] 296767 0
34-36 Chandos St
St Leonards
NSW 2065
Country [2] 296767 0
Australia
Funding source category [3] 296768 0
Commercial sector/Industry
Name [3] 296768 0
GenesisCare
Address [3] 296768 0
3/140 Mount Bay Rd
Perth
Western Australia
6000
Country [3] 296768 0
Australia
Funding source category [4] 296769 0
Government body
Name [4] 296769 0
ZonMW
Address [4] 296769 0
Laan van Nieuw Oost-Indië 334,
2593 CE
Den Haag
Country [4] 296769 0
Netherlands
Funding source category [5] 296770 0
Charities/Societies/Foundations
Name [5] 296770 0
Withering Stichting Nederland
Address [5] 296770 0
Moreelsepark 1

3511 EP
Utrech
Country [5] 296770 0
Netherlands
Funding source category [6] 296771 0
Commercial sector/Industry
Name [6] 296771 0
Teva
Address [6] 296771 0
Diakenhuisweg 39-45
2033 AP
Haarlem
Country [6] 296771 0
Netherlands
Funding source category [7] 296772 0
Commercial sector/Industry
Name [7] 296772 0
Disphar
Address [7] 296772 0
Disphar International BV
Tolweg 15
3741 LM
Baarn


Country [7] 296772 0
Netherlands
Funding source category [8] 296773 0
Commercial sector/Industry
Name [8] 296773 0
Tiofarma
Address [8] 296773 0
Hermanus Boerhaavestraat 1,
3261 ME
Oud-Beijerland
Country [8] 296773 0
Netherlands
Primary sponsor type
Other
Name
Heart Research Institute, Sir Charles Gairdner Hospital
Address
QE2 Medical Center
Hospital Avenue
Nedlands 6009
Western Australia
Country
Australia
Secondary sponsor category [1] 295756 0
Other Collaborative groups
Name [1] 295756 0
Dutch Network for Cardiovascular Research (WCN)
Address [1] 295756 0
Utrecht
P.O. Box 19008
3501 DA Utrecht
The Netherlands
Country [1] 295756 0
Netherlands

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297995 0
Sir Charles Gairdner Group HREC
Ethics committee address [1] 297995 0
Level 2 A Block
Hospital Ave
Nedlands
WA 6009
Ethics committee country [1] 297995 0
Australia
Date submitted for ethics approval [1] 297995 0
25/11/2013
Approval date [1] 297995 0
27/02/2014
Ethics approval number [1] 297995 0
2013-236
Ethics committee name [2] 297996 0
Medical Reseach Ethics Committees United
Ethics committee address [2] 297996 0
Postbus 2500
3430 EM Niewegein
Ethics committee country [2] 297996 0
Netherlands
Date submitted for ethics approval [2] 297996 0
01/07/2016
Approval date [2] 297996 0
18/08/2016
Ethics approval number [2] 297996 0
R16.027/LoDoCo2

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, non-fatal acute coronary syndrome or non-fatal ischemic stroke
Trial website
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
Public notes

Contacts
Principal investigator
Name 38142 0
Prof Peter L Thompson
Address 38142 0
Heart Research Institute of Western Australia
Floor 2 Harry Perkins Institute
Sir Charles Gairdner Hospital,
Perth 6009
Western Australia
Country 38142 0
Australia
Phone 38142 0
+61 407970090
Fax 38142 0
Email 38142 0
peter.thompson@health.wa.gov.au
Contact person for public queries
Name 38143 0
Prof Peter L Thompson
Address 38143 0
Heart Research Institute of Western Australia
Floor 2 Harry Perkins Institute
Sir Charles Gairdner Hospital,
Perth 6009
Western Australia
Country 38143 0
Australia
Phone 38143 0
+61 407970090
Fax 38143 0
Email 38143 0
peter.thompson@health.wa.gov.au
Contact person for scientific queries
Name 38144 0
Dr Mark Nidorf
Address 38144 0
Heart Care Western Australia
3/140 Mounts Bay Rd
Perth 6000
Western Australia
Country 38144 0
Australia
Phone 38144 0
+61 413145410
Fax 38144 0
Email 38144 0
smnidorf@gmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All collected coded data
When will data be available (start and end dates)?
6 months after publication
No end-date
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
Available for what types of analyses?
To be determined
How or where can data be obtained?
Written request to the LoDoCo2 Steering Committee
What supporting documents are/will be available?
Study protocol
Clinical study report
Ethical approval
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