Colchicine in Belgium in Patients With Coronary Artery Disease After Percutaneous Coronary Intervention

Official title

Colchicine in Belgium in Patients With Coronary Artery Disease

Overview

The main aim of this trial is to determine whether there are fewer cardiovascular events when patients with coronary artery disease take a low dose of colchicine of 0.5 mg daily on top of optimal standard treatment after treatment with PCI, compared with placebo in combination with optimal standard treatment. More specifically, we aim to investigate the benefits of a daily low dose of colchicine in patients with coronary artery disease after treatment with PCI, to confirm that a daily low dose of colchicine helps prevent additional incidents in coronary artery disease, and to identify a subgroup of patients with CAD who are at increased risk for cardiovascular events and could benefit most from colchicine.

Detailed description

This is a prospective, randomised, double-blind, multicenter, placebo-controlled phase III pragmatic superiority trial comparing colchicine 0.5 mg with placebo administered orally once-daily in up to 2770 participants with CAD treated with PCI. Participants will be randomised in a 1:1 ratio to receive either colchicine 0.5 mg or placebo as an adjunct to standard of care. The trial is event driven with trial closure being performed when the targeted number of 566 primary endpoint events has been reached.

Participants will be seen by the site staff 1 month after randomisation and thereafter every 12 months as per standard of care (SOC) and for IMP dispense and compliance, completing questionnaires and outcome event assessment until end of study. After the first month, a telephone visit will be scheduled every 6 months in between two standard of care on-site visits.

Interventions

• Drug Colchicine 0.5 MG Oral Tablet
  Oral intake of 0.5 mg colchicine once daily
• Drug Placebo
  Oral intake of matching placebo once daily

Primary outcome measures

• Time from randomisation to first occurrence of a composite endpoint consisting of: all-cause death, spontaneous (non-procedural) non-fatal myocardial infarction (Type 1, 4B & C), non-fatal stroke, or coronary revascularisation. [Time frame: 44 months]

Secondary outcome measures (8)

• Time from randomisation to first occurrence of a composite of specific cardiovascular endpoints [Time frame: 44 months]
• Time from randomisation to first occurrence of a composite of hard endpoints consisting of: all-cause death, spontaneous (non-procedural) non-fatal myocardial infarction (Type 1, 4B & C), non-fatal stroke [Time frame: 44 months]
• Time from randomisation to first occurrence of breakdown components of primary endpoint and atherosclerosis-related diseases [Time frame: 44 months]
• Time from randomisation to occurrence of first as well as recurrent endpoints consisting of: all-cause death, spontaneous (non-procedural) non-fatal myocardial infarction (Type 1, 4B & C), non-fatal stroke, or coronary revascularisation. [Time frame: 44 months]
• Change from randomisation to year 1 and to end of study of participants reported outcomes (based on ICHOM Standard Set for CAD): Angina Frequency scale [Time frame: 44 months]
• Change from randomisation to year 1 and to end of study of participants reported outcomes (based on ICHOM Standard Set for CAD): Dyspnea [Time frame: 44 months]
• Change from randomisation to year 1 and to end of study of participants reported outcomes (based on ICHOM Standard Set for CAD): Depression. [Time frame: 44 months]
• Change from randomisation to year 1 and to end of study of participants reported outcomes (based on ICHOM Standard Set for CAD): Health-related quality of life. [Time frame: 44 months]

Eligibility criteria

Inclusion criteria

• Age ≥45 years.
• Coronary artery disease treated with PCI and optimal medical therapy, with at least one additional risk factor (based on SMART):

• Age ≥ year
• Diabetes mellitus, on treatment or new diagnosis with HbA1c ≥6.5%
• Current smoking
• Treated hypertension or lood pressure systolic ≥ 4 mmHg or diastolic ≥ mmHg
• Total cholesterol >240 mg/dl untreated, or treated LDL >70 mg/dl
• HDL <40 mg/dl
• hsCRP >2 mg/L AND chronic coronary syndrome (CCS)
• eGFR <60 ml/min (MDRD)
• history of vascular disease:

• CAD (PCI prior to index, CABG, MI)
• stroke (ischemic or hemorrhagic)
• carotid artery revascularisation
• PAD (revascularisation, ABI <0.85 at rest, amputation due to atherosclerotic disease)
• AAA (repair, distal aortic anteroposterior diameter >3.0cm)
• Able to be enrolled/randomized between 2 hour and 5 days post PCI.
• Written informed consent.

Exclusion criteria

• Women who are pregnant, breastfeeding, or of childbearing potential who are not using an effective method of contraception. Or women who intend to donate oocytes.
• Men who plan to father children during the study period or who are unwilling to use effective forms of contraception. Or men who intend to donate sperm.
• Any contraindication or known intolerance to colchicine.
• Chronic use of -or need for- colchicine.
• Auto-immune disease or other condition requiring current or planned chronic systemic steroids, immunosuppressant or biologic drug targeting the immune system (for example, TNF blockers, anakinra, rituximab, abatacept, tocilizumab etc.).
• Creatinine clearance <30 mL/min/1.73 m2.
• Cirrhosis Child-Pugh stadium B and C, or acute severe liver disease
• Neuromuscular disease or non-transient CK levels > 5 x ULN (unless due to MI).
• History of cancer or lymphoproliferative disease within the last 3 years, other than successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma, or localized cervix carcinoma in situ.
• Current or planned use of any strong inhibitor of CYP3A4 or p-glycoprotein: macrolide antibiotics (clarithromycin, telithromycin), azole antifungal agents (ketoconazole, voriconazole, fluconazole, itraconazole), cyclosporine, HIV medication (ritonavir, lopinavir, tipranavir, atazanavir, darunavir, indinavir, saquinavir).
• Chronic diarrhea, or inflammatory owel disease (Crohn's disease or ulcerative colitis).
• Drug or alcohol abuse.
• Planned cardiovascular intervention known on the day of screening.
• Currently enrolled in another investigational trial.
• Considered to be an unsuitable candidate by the investigator.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Prevention

Study locations

Belgium · 19 centers

• Algemeen Stedelijk Ziekenhuis Campus Aalst — Aalst
• Het Ziekenhuisnetwerk Antwerpen — Antwerp
• Universitair Ziekenhuis Antwerpen — Antwerp
• Imelda — Bonheiden
• AZ Sint-Jan Brugge-Oostende AV — Bruges
• Humani Charleroi — Charleroi
• Grand Hôpital de Charleroi — Charleroi
• Ziekenhuis Oost Limburg — Genk
• … and 11 more centers

Publications

• Fiolet ATL, Opstal TSJ, Mosterd A, Eikelboom JW, Jolly SS, Keech AC, Kelly P, Tong DC, Layland J, Nidorf SM, Thompson PL, Budgeon C, Tijssen JGP, Cornel JH. Efficacy and safety of low-dose colchicine in patients with coronary disease: a systematic review and meta-analysis of randomized trials. Eur Heart J. 2021 Jul 21;42(28):2765-2775. doi: 10.1093/eurheartj/ehab115. PMID 33769515
• Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, Pinto FJ, Ibrahim R, Gamra H, Kiwan GS, Berry C, Lopez-Sendon J, Ostadal P, Koenig W, Angoulvant D, Gregoire JC, Lavoie MA, Dube MP, Rhainds D, Provencher M, Blondeau L, Orfanos A, L'Allier PL, Guertin MC, Roubille F. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019 Dec 26;381(26):2497-2505. d PMID 31733140
• Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ, The SHK, Xu XF, Ireland MA, Lenderink T, Latchem D, Hoogslag P, Jerzewski A, Nierop P, Whelan A, Hendriks R, Swart H, Schaap J, Kuijper AFM, van Hessen MWJ, Saklani P, Tan I, Thompson AG, Morton A, Judkins C, Bax WA, Dirksen M, Alings M, Hankey GJ, Budgeon CA, Tijssen JGP, Cornel JH, Thompson PL; LoDoCo2 Trial Investigators. Colc PMID 32865380
• Tong DC, Quinn S, Nasis A, Hiew C, Roberts-Thomson P, Adams H, Sriamareswaran R, Htun NM, Wilson W, Stub D, van Gaal W, Howes L, Collins N, Yong A, Bhindi R, Whitbourn R, Lee A, Hengel C, Asrress K, Freeman M, Amerena J, Wilson A, Layland J. Colchicine in Patients With Acute Coronary Syndrome: The Australian COPS Randomized Clinical Trial. Circulation. 2020 Nov 17;142(20):1890-1900. doi: 10.1161/C PMID 32862667
• Dorresteijn JA, Visseren FL, Wassink AM, Gondrie MJ, Steyerberg EW, Ridker PM, Cook NR, van der Graaf Y; SMART Study Group. Development and validation of a prediction rule for recurrent vascular events based on a cohort study of patients with arterial disease: the SMART risk score. Heart. 2013 Jun;99(12):866-72. doi: 10.1136/heartjnl-2013-303640. Epub 2013 Apr 10. PMID 23574971
• Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013 Jan 29;61(4):404-410. doi: 10.1016/j.jacc.2012.10.027. Epub 2012 Dec 19. PMID 23265346
• De Cock E, Kautbally S, Timmermans F, Bogaerts K, Hanet C, Desmet W, Gurne O, Vranckx P, Hiltrop N, Dujardin K, Vanduynhoven P, Vermeersch P, Pirlet C, Hermans K, Van Reet B, Ferdinande B, Aminian A, Dewilde W, Guedes A, Simon F, De Roeck F, De Vroey F, Jukema JW, Sinnaeve P, Buysschaert I. Low-dose colchicine for the prevention of cardiovascular events after percutaneous coronary intervention: Ra PMID 39233210

Identifiers

NCT: NCT06095765 · ONZ-2023-0237 · KCE-INV-21-1324 · 2023-505028-74-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗