Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001408875
Ethics application status
Approved
Date submitted
13/08/2021
Date registered
20/10/2021
Date last updated
4/04/2024
Date data sharing statement initially provided
20/10/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
The effect of Colchicine on Cardiovascular Outcomes in Stroke Study (The CASPER Study)
Scientific title
Colchicine After Stroke Event to Prevent Event Recurrence (CASPER): A randomised trial to evaluate the efficacy of oral Colchicine in high-risk patients with atherosclerosis-associated inflammation post-Stroke
Secondary ID [1] 304696 0
None
Universal Trial Number (UTN)
Trial acronym
CASPER
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Atherosclerosis 322683 0
Ischemic Stroke 322684 0
Transient Ischemic Attack 322685 0
Condition category
Condition code
Cardiovascular 320294 320294 0 0
Diseases of the vasculature and circulation including the lymphatic system
Stroke 321207 321207 0 0
Ischaemic
Neurological 321208 321208 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Oral Colchicine 0.5 mg tablet taken daily for median of 3 years. Eligible and consenting participants will be registered and then commenced on Run-In treatment consisting of 1 oral tablet (0.5mg of colchicine) a day for 28 days additional to standard of care. The Run-In treatment will be dispensed to participants in a single blinded manner. Upon completion of the Run-In treatment participants will be asked to return to site for a safety and compliance check before being randomised to receive either oral Colchicine 0.5mg taken daily or matched oral Placebo tablet taken daily for a median of 3 years.
Intervention code [1] 321070 0
Treatment: Drugs
Comparator / control treatment
Matched oral Placebo tablet taken daily for median 3 years. These tablets will be sugar pills with no active medicine.
Control group
Placebo

Outcomes
Primary outcome [1] 328147 0
Major Adverse Cardiovacular Event (MACE) outcome – non-fatal stroke, Acute Coronory Sydrome (ACS) – including myocardial infarction (MI), urgent revascularisation and Cardiovacsular (CV) death.

The outcome will assess incidence using, 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.
Timepoint [1] 328147 0
Follow-up visits during the study treatment period are planned at 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, 36 months (primary timepoint) and annually until end of study.
Secondary outcome [1] 397831 0
Non-fatal stroke

The outcome will assess incidence using 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.
Timepoint [1] 397831 0
Follow-up visits during the study treatment period are planned at 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, 36 months and annually until end of study.
Secondary outcome [2] 397832 0
Cardiovascular death – death due to any cardiac cause (e.g. myocardial infarction, heart failure, arrhythmia and sudden cardiac death)

The outcome will assess incidence 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] 397832 0
Follow-up visits during the study treatment period are planned at 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, 36 months and annually until end of study.
Secondary outcome [3] 397833 0
Urgent revascularisation

The outcome will assess incidence using, 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.
Timepoint [3] 397833 0
Follow-up visits during the study treatment period are planned at 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, 36 months and annually until end of study.
Secondary outcome [4] 397834 0
Acute Coronary Syndrome (including non-fatal myocardial infarction)

The outcome will assess incidence using, 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.
Timepoint [4] 397834 0
Follow-up visits during the study treatment period are planned at 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, 36 months and annually until end of study.
Secondary outcome [5] 397835 0
All-cause mortality

The outcome will assess incidence 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] 397835 0
Follow-up visits during the study treatment period are planned at 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, 36 months and annually until end of study.
Secondary outcome [6] 397836 0
Change in hs-CRP assessed from blood tests
Timepoint [6] 397836 0
Baseline visit and then follow-up visits during the study treatment period are planned at 3 months, 12 months, 36 months.
Secondary outcome [7] 397837 0
Quality of Life assessed as a composite of EuroQoL EQ-5D-5L, WHODAS 2.0 and PROMIS-GH scores,
Timepoint [7] 397837 0
Baseline visit and then follow-up visits during the study treatment period are planned at 6 months, 24 months, 36 months and annually until the end of study.
Secondary outcome [8] 397838 0
Number of days alive and not in hospital

This outcome will be assessed using 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.
Timepoint [8] 397838 0
Follow-up visits during the study treatment period are planned at 3 months, 12 months, 24 months, 36 months and end of study.

Eligibility
Key inclusion criteria
1. Presentation with an ischaemic stroke without major disability (MRS less than or equal to 3 - at time of registration [4-52 weeks]) OR clinical TIA with brain imaging evidence of acute infarction and commenced on OMT
2. hs-CRP greater than or equal to 1.0mg/L (at time of registration) 4 to 52 weeks post-stroke event
3. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Suspected cardio-embolic stroke/ TIA, that is probably caused by
a. Identified atrial fibrillation (permanent or paroxysmal),
b. Other identified cardiac source (intra-cardiac thrombus, endocarditis, metallic heart valve, low ejection fraction <30%),
c. Stroke/ TIA caused by dissection, endo-carditis, paradoxical embolism, drug use, venous thrombosis, within 48 hours after carotid or cardiac surgery,
2. Hypercoagulability states,
3. Migraines related to the index stroke or TIA/ Migrainous Strokes, or inherited cerebrovascular disorders.
4. Any known intolerance to Colchicine
5. Pre-existing Colchicine treatment for greater than 7 days within the last 3 months
6. Current active myopathy with creatine kinase (CK) >3x upper limit of normal.
7. Severe liver disease or aminotransferase level >3 x upper limit of normal, within the last 3 months
8. Persistent Blood dyscrasia (white cell count or platelet count <lower limit of normal), within the last 3 months
9. Estimated glomerular filtration rate (eGFR) <30 ml/min per 1.73m2 at time of registration
10. Prior or current therapy with a strong CYP3A4 inhibitor or inducer or calcineurin inhibitor
11. Active autoimmune disease or chronic inflammatory bowel disease (defined as any disease requiring long-term or frequent immunosuppression)
12. Any other conditions that would not make it possible to participate in the trial

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-blinded, multi-centre superiority trial of 1500 participants.
All participants, investigators and data collectors (who will see participants at regular follow-up) will be blinded to the allocated treatment (active treatment or placebo). 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 sequence. Randomisation will stratify by statin dose (to prevent confounding effects of the possible anti-inflammatory actions of statins and LDLc achieved), hs-CRP levels, BP, age, sex, lacunar vs large vessel and study site.
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
Efficacy
Statistical methods / analysis
The study is powered on the primary endpoint. Assuming a 28% MACE rate at a median of 3 years follow-up in the placebo arm and 21% event rate in the Colchicine arm (25% RRR, 7% ARR), the study offers 80% power with a two (2) sided pvalue of 0.05 with 1500 participants, allowing for an average aggregate 11% Colchicine non-adherence (or drop-in from placebo) rate .

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 a generalised linear model when appropriate.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
6/02/2023
Actual
3/03/2023
Date of last participant enrolment
Anticipated
31/12/2025
Actual
Date of last data collection
Anticipated
31/12/2027
Actual
Sample size
Target
1500
Accrual to date
11
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 19915 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 23848 0
The Alfred - Melbourne
Recruitment hospital [3] 23849 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [4] 23850 0
Prince of Wales Hospital - Randwick
Recruitment hospital [5] 23851 0
Box Hill Hospital - Box Hill
Recruitment hospital [6] 23852 0
John Hunter Hospital - New Lambton
Recruitment hospital [7] 23853 0
Liverpool Hospital - Liverpool
Recruitment hospital [8] 26361 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [9] 26362 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 34615 0
2050 - Camperdown
Recruitment postcode(s) [2] 39304 0
3004 - Melbourne
Recruitment postcode(s) [3] 39305 0
3050 - Parkville
Recruitment postcode(s) [4] 39306 0
2031 - Randwick
Recruitment postcode(s) [5] 39307 0
3128 - Box Hill
Recruitment postcode(s) [6] 39308 0
2305 - New Lambton
Recruitment postcode(s) [7] 39309 0
2170 - Liverpool
Recruitment postcode(s) [8] 42333 0
4102 - Woolloongabba
Recruitment postcode(s) [9] 42334 0
4029 - Herston

Funding & Sponsors
Funding source category [1] 309063 0
Government body
Name [1] 309063 0
Australian Government Department of Health
Country [1] 309063 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
c/o NHMRC Clinical Trials Centre. Locked Bag 77
Camperdown NSW 1450
Country
Australia
Secondary sponsor category [1] 310009 0
None
Name [1] 310009 0
Address [1] 310009 0
Country [1] 310009 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308941 0
Sydney Local Health District (RPA Zone)
Ethics committee address [1] 308941 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] 308941 0
Australia
Date submitted for ethics approval [1] 308941 0
24/08/2021
Approval date [1] 308941 0
14/10/2021
Ethics approval number [1] 308941 0

Summary
Brief summary
Inflammation is a key component in the cause of ischemic stroke.
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 literature supporting a beneficial role of long-term colchicine therapy in prevention of cardiovascular disease.
Low-dose colchicine use has also been proven to be safe, well tolerated and is inexpensive and readily available.
The aim of this trial is to assess the effect of low-dose colchicine (0.5mg/daily) in addition to optimal medical therapy of cardiovascular outcomes in stroke patients with evidence of persistent coronary inflammation (based on hs-CRP).
We hypothesise that addition of colchicine to optimal medical therapy in patients post-stroke, who have biomarker evidence of persistent inflammation will reduce recurrent cardiovascular events.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 112406 0
Prof Anthony Keech
Address 112406 0
NHMRC Clinical Trials Centre.
Locked Bag 77
Camperdown NSW 1450
Country 112406 0
Australia
Phone 112406 0
+61 02 9562 5319
Fax 112406 0
+61 02 9562 5094
Email 112406 0
[email protected]
Contact person for public queries
Name 112407 0
Ms CASPER Trial Coordinator
Address 112407 0
NHMRC Clinical Trials Centre.
Locked Bag 77
Camperdown NSW 1450
Country 112407 0
Australia
Phone 112407 0
+61 02 9562 5319
Fax 112407 0
+61 02 9562 5094
Email 112407 0
[email protected]
Contact person for scientific queries
Name 112408 0
Prof Anthony Keech
Address 112408 0
NHMRC Clinical Trials Centre.
Locked Bag 77
Camperdown NSW 1450
Country 112408 0
Australia
Phone 112408 0
+61 02 9562 5319
Fax 112408 0
+61 02 9562 5094
Email 112408 0
[email protected]

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?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.