Colchicine Cardiovascular Outcomes Trial (COLCOT) (COLCOT)

• ClinicalTrials.gov Identifier: NCT02551094
• Recruitment Status: Completed
• First Posted: September 16, 2015
• Results First Posted: October 19, 2020
• Last Update Posted: October 19, 2020
• Sponsor: Montreal Heart Institute
• Information provided by (Responsible Party): Montreal Heart Institute

Tracking Information

• First Submitted Date: August 26, 2015
• First Posted Date: September 16, 2015
• Results First Submitted Date: July 17, 2020
• Results First Posted Date: October 19, 2020
• Last Update Posted Date: October 19, 2020
• Actual Study Start Date: December 4, 2015
• Actual Primary Completion Date: July 17, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 23, 2020)

First Event of Cardiovascular Death, Resuscitated Cardiac Arrest, Acute Myocardial Infarction, Stroke, or Urgent Hospitalization for Angina Requiring Coronary Revascularization [ Time Frame: From randomization to occurence of first event, assessed up to 3.5 years ]

The descriptive statistics are the number of participants having at least one of the composites of the primary endpoint.

Original Primary Outcome Measures (submitted: September 14, 2015)

• Cardiovascular death [ Time Frame: approximately 3 to 4 years ]
  number of days from randomization
• resuscitated cardiac arrest [ Time Frame: approximately 3 to 4 years ]
  number of days from randomization
• acute myocardial infarction [ Time Frame: approximately 3 to 4 years ]
  number of days from randomization
• stroke [ Time Frame: approximately 3 to 4 years ]
  number of days from randomization
• hospitalization for angina requiring coronary revascularization [ Time Frame: approximately 3 to 4 years ]
  number of days from randomization

Current Secondary Outcome Measures (submitted: September 23, 2020)

• Death (Total Mortality) [ Time Frame: From randomization to death, assessed up to 3.5 years ]
  The descriptive statistics are the number of participants having deceased.
• Cardiovascular Death [ Time Frame: From randomization to death, assessed up to 3.5 years ]
  The descriptive statistics are presented as the number of participants having had a cardiovascular death.
• Resuscitated Cardiac Arrest [ Time Frame: From randomization to event, assessed up to 3.5 years ]
  The descriptive statistics are presented as the number of participants having had resuscitated cardiac arrest
• Myocardial Infarction [ Time Frame: From randomization to event, assessed up to 3.5 years ]
  The descriptive statistics are presented as the number of participants having had myocardial infarction.
• Stroke [ Time Frame: From randomization to event, assessed up to 3.5 years ]
  The descriptive statistics are presented as the number of participants having had a stroke.
• Urgent Hospitalization for Angina Requiring Coronary Revascularization [ Time Frame: From randomization to event, assessed up to 3.5 years ]
  The descriptive statistics are presented as the number of participants having had urgent hospitalization for angina requiring coronary revascularization.
• First Event of Cardiovascular Death, Resuscitated Cardiac Arrest, Acute MI or Stroke. [ Time Frame: From randomization to occurence of first event, assessed up to 3.5 years ]
  The descriptive statistics are presented as the number of participants having had a first event of cardiovascular death, resuscitated cardiac arrest, acute MI or stroke.

Original Secondary Outcome Measures (submitted: September 14, 2015)

• total mortality [ Time Frame: approximately 3 to 4 years ]
  number of days from composite of cardiovascular death
• total mortality [ Time Frame: approximately 3 to 4 years ]
  number of days from composite of resuscitated cardiac arrest
• total mortality [ Time Frame: approximately 3 to 4 years ]
  number of days from composite of acute myocardial infarction
• total mortality [ Time Frame: approximately 3 to 4 years ]
  number of days from composite of stroke

Current Other Pre-specified Outcome Measures (submitted: September 23, 2020)

• First Event of Deep Venous Thrombosis or Pulmonary Embolus [ Time Frame: From randomization to occurence of first event, assessed up to 3.5 years ]
  The descriptive statistics are presented as the number of participants having had a first event of deep venous thrombosis or pulmonary embolus.
• Atrial Fibrillation [ Time Frame: From randomization to event, assessed up to 3.5 years ]
  The descriptive statistics are presented as the number of participants having had atrial fibrillation.
• Heart Failure Hospitalization [ Time Frame: From randomization to event, assessed up to 3.5 years ]
  The descriptive statistics are presented as the number of participants having had heart failure hospitalization.
• Coronary Revascularization [ Time Frame: From randomization to event, assessed up to 3.5 years ]
  The descriptive statistics are presented as the number of participants having had coronary revascularization.

Original Other Pre-specified Outcome Measures (submitted: September 14, 2015)

• deep venous thrombosis [ Time Frame: approximately 3 to 4 years ]
  number of days from randomization
• pulmonary embolus [ Time Frame: approximately 3 to 4 years ]
  number of days from randomization
• atrial fibrillation [ Time Frame: approximately 3 to 4 years ]
  number of days from randomization
• heart failure hospitalization [ Time Frame: approximately 3 to 4 years ]
  number of days from randomization
• coronary revascularization [ Time Frame: approximately 3 to 4 years ]
  number of days from randomization

Descriptive Information

• Brief Title: Colchicine Cardiovascular Outcomes Trial (COLCOT)
• Official Title: Colchicine Cardiovascular Outcomes Trial (COLCOT)
• Brief Summary: The study evaluates whether long-term treatment with colchicine reduces rates of cardiovascular events in patients after myocardial infarction. Patients who have suffered a documented acute myocardial infarction within the last 30 days, are treated according to the national guidelines and after having completed any planned percutaneous revascularization procedures associated with their initial infarction will receive either colchicine (0.5 mg per day) or matching placebo (1:1 allocation ratio) for an estimated 2 years period or until the target of 301 primary endpoints has been reached.
• Detailed Description: Atherosclerosis is the most common cause of myocardial infarction, stroke and peripheral arterial disease. Research has clearly demonstrated that inflammation plays a key role in the initiation, progression and manifestations of atherosclerosis. Atherosclerotic lesions begin as an accumulation of lipid-laden cells (primarily macrophages) beneath the endothelium, and progress with the further accumulation of cells, connective-tissue elements, lipids and debris through immunological and inflammatory activation. Neutrophils and other inflammatory cells have been shown to invade culprit atherosclerotic lesions in acute coronary syndromes. It is likely that the inflammatory process is responsible for the high rate of cardiovascular events despite significant advances in the treatment of risk factors such as hypercholesterolemia and hypertension. It is vital to improve our understanding of the inflammatory nature of atherosclerotic disease and modify the inflammatory process with targeted therapies. Prospective cohort studies have consistently shown that high sensitivity C-reactive protein (hs-CRP) and several other biomarkers of inflammation are independently associated with increasing risk of future cardiovascular events in different populations. This together with animal models showing that reduced inflammation has anti-atherosclerotic effects, create the impetus to test the hypothesis that treatment of the underlying inflammatory process will contribute to improved cardiovascular clinical outcomes. Colchicine is an inexpensive, yet potent, anti-inflammatory drug approved for acute use in patients with gout and chronic use in patients with Familial Mediterranean Fever. The mechanism of action is through the inhibition of tubulin polymerization and potentially also through effects on cellular adhesion molecules and inflammatory chemokines. Colchicine may also have direct anti-inflammatory effects by inhibiting key inflammatory signaling networks known as the inflammasome and pro-inflammatory cytokines. Through the disruption of the cytoskeleton, colchicine is believed to suppress secretion of cytokines and chemokines as well as in vitro platelet aggregation. Considerable work has highlighted the potential of colchicine in the treatment of cardiovascular diseases mediated by pro-inflammatory processes. More recently colchicine has been evaluated for its effect on cardiovascular events in patients with coronary artery disease (CAD).
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention

Condition

• Coronary Artery Disease
• Myocardial Infarction

Intervention

• Drug: colchicine
  0.5 mg tablet taken once a day
  Other Name: no other name
• Drug: colchicine placebo
  sugar pill manufactured to mimic colchicine 0.5 mg tablet
  Other Name: no other name

Study Arms

• Active Comparator: colchicine
  0.5 mg tablet of colchicine taken once a day
  Intervention: Drug: colchicine
• Placebo Comparator: colchicine placebo
  0.5 mg tablet of placebo taken once a day
  Intervention: Drug: colchicine placebo

Publications *

• Bouabdallaoui N, Tardif JC, Waters DD, Pinto FJ, Maggioni AP, Diaz R, Berry C, Koenig W, Lopez-Sendon J, Gamra H, Kiwan GS, Blondeau L, Orfanos A, Ibrahim R, Gregoire JC, Dube MP, Samuel M, Morel O, Lim P, Bertrand OF, Kouz S, Guertin MC, L'Allier PL, Roubille F. Time-to-treatment initiation of colchicine and cardiovascular outcomes after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT). Eur Heart J. 2020 Nov 7;41(42):4092-4099. doi: 10.1093/eurheartj/ehaa659.
• 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. doi: 10.1056/NEJMoa1912388. Epub 2019 Nov 16.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 15, 2018): 4745
• Original Estimated Enrollment (submitted: September 14, 2015): 4500
• Actual Study Completion Date: July 17, 2019
• Actual Primary Completion Date: July 17, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Males and females of at least 18 years of age capable and willing to provide informed consent
• Patient must have suffered a documented acute myocardial infarction within the last 30 days
• Patient must be treated according to national guidelines (including anti-platelet therapy, statin, renin-angiotensin-aldosterone system inhibitor (preferably angiotensin-converting enzyme) and beta-blocker when indicated)
• Patient must have completed any planned percutaneous revascularization procedures associated with his or her qualifying myocardial infarction
• Female patient is either not of childbearing potential, defined as postmenopausal for at least one year or surgically sterile, or is of childbearing potential and practicing at least one method of contraception and preferably two complementary forms of contraception
• Patient is judged to be in good general health as determined by the principal investigator
• Patient must be able and willing to comply with the requirements of this study protocol

Exclusion Criteria:

• Patient with a poorly controlled medical condition, such as New York Heart Association Class III-IV heart failure, a left ventricular ejection fraction of less than 35%, recent stroke (within the past 3 months), or any other condition which in the opinion of the investigator, would put the patient at risk if participating in this study
• Patient with a Type 2 index MI (secondary to ischemic imbalance)
• Patient with a prior coronary artery bypass graft within the past 3 years, or planned
• Patient currently in cardiogenic shock or with hemodynamic instability
• Patient with a history of cancer or lymphoproliferative disease within the last 3 years other than a successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma and or localized carcinoma in situ of the cervix
• Patient with inflammatory bowel disease (Crohn's disease or ulcerative colitis) or patient with chronic diarrhea
• Patient with pre-existent progressive neuromuscular disease or patient with creatine phosphokinase level greater than 3 times the upper limit of normal (unless due to myocardial infarction which is allowed) as measured within the past 30 days and determined to be non-transient through repeat testing
• Patient with any of the following as measured within the past 30 days, and determined to be non-transient through repeat testing: hemoglobin less than 115 grams/L, white blood cell count less than 3.0 X 10(9)/L,platelet count less than 110 X 10(9)/L, alanine aminotransferase greater than 3 times the upper limit of normal, total bilirubin greater than 2 times the upper limit of normal (unless due to Gilbert syndrome, which is allowed), creatinine greater than 2 times the upper limit of normal
• Patient with a history of cirrhosis, chronic active hepatitis or sever hepatic disease
• Female patient who is pregnant, or breast-feeding or is considering becoming pregnant during the study or for 6 months after the last dose of study medication
• Patient with a history of clinically significant drug or alcohol abuse in the last year
• Patient is currently using or plan to begin chronic systemic steroid therapy (oral or intravenous) during the study (topical or inhaled steroids are allowed)
• Patient currently taking colchicine for other indications (mainly chronic indications represented by Familial Mediterranean Fever or gout); there is no wash-out period required for patients who have been treated with colchicine and stopped treatment prior to enrollment
• Patient with history of an allergic reaction or significant sensitivity to colchicine
• Patient who has used an investigational chemical agent less than 30 days or 5 half-lives prior to the screening visit (whichever is longer)
• Patient is considered by he investigator, for any reason, to be an unsuitable candidate for the study

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada

Administrative Information

• NCT Number: NCT02551094
• Other Study ID Numbers: MHIPS-003
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Montreal Heart Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: Montreal Heart Institute
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Jean-Claude Tardif, MD; Montreal Heart Institute
• Study Director: Andreas Orfanos, MD; Montreal Health Innovations Coordinating Centre

• PRS Account: Montreal Heart Institute
• Verification Date: September 2020