Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617000203358
Ethics application status
Approved
Date submitted
19/01/2017
Date registered
8/02/2017
Date last updated
8/02/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
The CO-POC trial
COlchicine for the prevention of Peri-Operative Complications: A prospective randomised placebo controlled, double blinded study to assess the role of colchicine in decreasing myocardial injury during cardiac surgery
Scientific title
COlchicine for the prevention of Peri-Operative Complications: A prospective randomised placebo controlled, double blinded study to assess the role of colchicine in decreasing myocardial injury during cardiac surgery
Secondary ID [1] 289426 0
Nil known
Universal Trial Number (UTN)
U1111-1184-2384
Trial acronym
CO-POC
Linked study record
VISION Study registration number: NCT01842568

Health condition
Health condition(s) or problem(s) studied:
Myocardial injury 299102 0
Coronary artery bypass surgery 299103 0
Post-pericardiotomy syndrome 299104 0
Post-operative atrial fibrillation 299105 0
Post-operative effusions 299106 0
Condition category
Condition code
Cardiovascular 299132 299132 0 0
Coronary heart disease
Surgery 301434 301434 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will be randomized to receive either a placebo or colchicine commenced between 24 and 72 hours prior to surgery, decided at the clinical discretion of the treating physician. and continued for 1 month after surgery. Colchicine/placebo will be given as 0.5 mg once daily without a loading dose. Colchicine/placebo will be provided by gastric tube in unconscious postoperative patients in intensive care units. Adherence will be determined on the basis of counts of pills in dispensed boxes with a target of at least 80% adherence. Blood samples will be taken prior to and up to 3 days after coronary artery bypass surgery. They will then have one routine follow-up at 6 weeks to have a physical examination, an ECG and an echocardiogram.
Intervention code [1] 295015 0
Treatment: Drugs
Comparator / control treatment
Patients will be randomized to receive placebo (Formulation: LACTOSE (SUPER-TAB), MAIZE STARCH, POVIDONE K, MAGNESIUM STEARATE) or colchicine 0.5 mg once daily. This will be commenced between 24 and 72 hours before surgery and continued for 1 month after surgery. Participants will be randomly assigned to treatment groups by a central computer–based automated sequence. All participants and trial investigators will be blinded to randomized treatment.
Control group
Placebo

Outcomes
Primary outcome [1] 298605 0
Incidence of significant post-operative myocardial injury defined as high sensitivity troponin I (hs-cTnI) levels > 10 x the upper limit of normal assessed from plasma samples.
Timepoint [1] 298605 0
Serial rise in Troponin I from pre-operatively, to 6-12 hours and day 1,2 & 3 post cardiac surgery.
Secondary outcome [1] 324702 0
The extent of post-operative myocardial injury defined as a) peak plasma hs-cTnI levels in the first 72 hours after surgery, b) mean plasma hs-cTnI levels in the first 72 hours after surgery and c) the area under the curve for hs-cTnI release within the first 72 hours after surgery.
Timepoint [1] 324702 0
Serial rise in Troponin I from pre-operatively, to 6-12 hours and day 1,2 & 3 post cardiac surgery
Secondary outcome [2] 324703 0
Incidence of post-pericardiotomy syndrome (PPS):

The diagnosis of PPS will be based on the presence of two or more of the following criteria
(1) Fever without alternative causes lasting beyond the first post-operative week
(2) Pleuritic chest pain
(3) Friction rub
(4) Pericardial effusion, and/or
(5) Pleural effusion
Timepoint [2] 324703 0
Within 3 months of cardiac surgery
Secondary outcome [3] 330944 0
The need for pericardial or pleural drainage

Clinically significant effusions will be the defined as those requiring drainage.
A semi quantitative assessment of pericardial effusion will also be documented
1. A small effusion will be considered as an echo-free space (anterior plus posterior) of less than 10 mm
2. A moderate effusion will be an echo-free pericardial space of 10 to 20 mm, and
3. A large effusion will be an echo-free space more than 20 mm.
Pericardial effusion echo-free spaces will be measured at the onset of the QRS complex (end of diastole). The study will also assess the presence or absence of pleural effusion and the need for thoracentesis.
Timepoint [3] 330944 0
Within 3 months of cardiac surgery
Secondary outcome [4] 330945 0
The incidence of new onset atrial fibrillation within 30 days of cardiac surgery in patients in sinus rhythm pre-operatively.

Postoperative atrial fibrillation will be defined as atrial fibrillation lasting for more than 30 seconds. Continuous electrocardiographic monitoring will be adopted for as long as the patient is in the intensive care facility. Twelve lead ECGs are recommended daily and more frequently at the discretion of the treating physicians for symptoms or clinically suspected arrhythmia. Clinical data (e.g., onset time, symptoms, treatments, and duration) and confirmatory rhythm strips or 12- lead ECGs will be collected for all postoperative arrhythmias of at least 30 seconds' duration.
Timepoint [4] 330945 0
Within 30 days of cardiac surgery
Secondary outcome [5] 330946 0
All cause death
Timepoint [5] 330946 0
30 days and 1 year post cardiac surgery
Secondary outcome [6] 330947 0
The combined incidence of the need for pericardiocentesis or thoracentesis, coronary heart disease related readmissions, major vascular complications (myocardial infarction or stroke) and mortality will be obtained prospectively and by review of medical records.
Timepoint [6] 330947 0
1 year post cardiac surgery
Secondary outcome [7] 330948 0
Quality of life measured by EQ-5D questionnaire
Timepoint [7] 330948 0
1 year post cardiac surgery

Eligibility
Key inclusion criteria
a) Eligible and have consented to participate in the Vascular Events In Surgery patIents cOhort evaluatioN - Cardiac Surgery study (an observational study of patients undergoing major cardiac surgery: NCT01842568 study), and
b) undergoing isolated coronary artery bypass grafting (CABG)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Known intolerance of colchicine
2) Pre-existing or planned peri-operative colchicine treatment
3) Known myopathy (or elevated creatine kinase> 3 x upper limit of normal)
4) Severe liver disease (or aminotransferase level >1.5 upper limit of normal)
5) Severe blood dyscrasia (white cell count or platelet count < lower limit of normal)
6) Inflammatory bowel disease
7) Estimated glomerular filtration rate <45mL/min per 1.73m2
8) Women of childbearing potential
9) Scheduled for valve and/or aortic surgery in addition to CABG.
10) Therapy with a strong CYP3A4 inhibitor (e.g. cyclosporine, ritonavir, clarithromycin or ketoconazole) or inducer (eg rifampicin)

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)
After the patient meets the inclusion criteria for the study, an off-site representative at the George Institute will allocate the patient to colchicine/placebo based on central randomisation by computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly assigned to treatment groups by a computer–based automated sequence. The random allocation sequence will be implemented by using sequentially numbered containers.
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 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Analyses will be performed by intention to treat. Additional on-treatment analyses will be also performed based on patients who are both tolerant and compliant with colchicine treatment. Mann-Whitney U will be used to compare the groups for continuous variables and the chi square test for categorical variables. Kaplan Meier curves will be used to demonstrate the event free survival and a comparison between groups will be performed using log-rank test.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/03/2017
Actual
Date of last participant enrolment
Anticipated
27/08/2018
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
204
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 5964 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 13386 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 293799 0
Charities/Societies/Foundations
Name [1] 293799 0
Heart Foundation Vanguard Grant
Country [1] 293799 0
Australia
Funding source category [2] 293801 0
Commercial sector/Industry
Name [2] 293801 0
Aspen Pharmacare Australia
Country [2] 293801 0
Australia
Primary sponsor type
Government body
Name
Sydney Local Health District
Address
Level 11, KGV Building
Missenden Road
Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 292633 0
None
Name [1] 292633 0
Address [1] 292633 0
Country [1] 292633 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295233 0
Ethics Review Committee (RPAH Zone) of the Sydney Local Health District
Ethics committee address [1] 295233 0
Level 11, KGV Building
Missenden Road
Camperdown NSW 2050
Ethics committee country [1] 295233 0
Australia
Date submitted for ethics approval [1] 295233 0
29/06/2016
Approval date [1] 295233 0
23/12/2016
Ethics approval number [1] 295233 0
HREC/16/RPAH/398

Summary
Brief summary
AIMS:
The aim of the vanguard Co-POC trial is to assess the safety and feasibility of the trial protocol and to obtain important preliminary data on the effect that colchicine 0.5mg once daily for up to 3 days pre-operatively and 30 days post-operatively has on the incidence and extent of post-operative myocardial injury after coronary artery bypass graft (CABG) surgery.

DESIGN AND METHODS:
The Co-POC vanguard trial is a RCT of colchicine v placebo nested in the Australian VISION Cardiac Surgery cohort. Eligible patients recruited into the VISION Cardiac Surgery study who are undergoing isolated coronary artery bypass graft surgery will be offered the opportunity to participate in the vanguard Co-POC trial. We will recruit 204 patients into this pilot trial (1:1 recruitment).

Patients will be randomised to colchicine 0.5mg once daily or matching placebo. Treatment will be commenced 3 days prior to surgery (but can be commenced up to 24 hours pre-operatively if necessary) and will be continued for 1 month after surgery. Medications will be provided by Aspen Pharmacare Australia according to the US Food and Drug Administration current good manufacturing practice regulations. All concomitant medications will be provided at the discretion of treating clinicians and in keeping with clinical guidelines. Patients will have blood samples collected for hs-cTnI <4 hours pre-operatively and post-operatively at 6-12 hours and on days 1 to 3 (in keeping with the VISION Cardiac Surgery protocol).

Analysis plan: All analyses will be by intention to treat. Groups will be compared using the Mann-Whitney U and chi-square tests as appropriate. Kaplan Meier curves will be used to demonstrate event free survival and groups compared using the log-rank test.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 66638 0
Prof Paul Bannon
Address 66638 0
Department of Cardiothoracic Surgery
Level 6 West
Royal Prince Alfred Hospital
Missenden Road
Camperdown
NSW 2050
Country 66638 0
Australia
Phone 66638 0
+612 9515 8896
Fax 66638 0
+612 9550 6669
Email 66638 0
pgbannon@gmail.com
Contact person for public queries
Name 66639 0
Ms Lisa Turner
Address 66639 0
Department of Cardiothoracic Surgery
Level 6 West
Royal Prince Alfred Hospital
Missenden Road
Camperdown
NSW 2050
Country 66639 0
Australia
Phone 66639 0
+612 9515 8896
Fax 66639 0
+612 9550 6669
Email 66639 0
lisa.turner@email.cs.nsw.gov.au
Contact person for scientific queries
Name 66640 0
Prof Graham Hillis
Address 66640 0
Department of Cardiology
Royal Perth Hospital
Wellington Street
Perth WA 6000
Country 66640 0
Australia
Phone 66640 0
+618 9224 1992
Fax 66640 0
+618 9224 2086
Email 66640 0
graham.hillis@health.wa.gov.au

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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