Colchicine in HFpEF

Study Overview
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Brief Summary
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Heart failure is a growing epidemic that affects up to 500,000 individuals in Canada, with 50,000 new cases being diagnosed each year. Half of these will have HF with preserved ejection fraction (HFpEF). HFpEF has been associated with high rates of morbidity, mortality, and health care expenditures. Its pathophysiology remains poorly understood, and positive medication trial results to date have been rare. Inflammation is strongly associated with a profibrotic activation in HFpEF, which is in turn associated with the severity and prognosis of the disease. Colchicine is a potent anti-inflammatory drug which properties relate to the suppression of tubulin polymerization and inflammasome inhibition, thus reducing the production of IL-1β and IL-18. The investigators thus propose a pilot study of 6 months follow-up duration that will test the efficacy and safety of 2 dosing regimens of colchicine (vs. placebo) in patients with HFpEF.

Official Title
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A Biomarker Study Assessing the Effects of Colchicine on Inflammation and Extra-Cellular Matrix Turnover in Patients With Heart Failure and Preserved Ejection Fraction.

Conditions
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Heart Failure, Inflammation, Colchicine

Intervention / Treatment
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* Drug: Colchicine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients ≥ 40 years of age; Chronic symptomatic HFpEF defined as follows: left ventricular ejection fraction (LVEF) > or = 45% within 6 months prior to screening visit (regardless of the imaging modality); No recent change in RAAS inhibitors regimen for at least 1 month before enrolment (excluding changes in oral diuretics); NYHA functional class II to IV; Evidence of structural heart disease defined by at least 1 of the following echocardiography findings: LV hypertrophy (i.e. septal or posterior wall thickness ≥1.1 cm) or left atrial enlargement (i.e., width ≥3.8 cm, length ≥5.0 cm, area ≥20 cm2, volume ≥55 ml, or volume index ≥29 ml/m2); Patients with a diagnosis of acute heart failure (treated with intravenous diuretics) within 12 months before screening; or an NT-proBNP of ≥300 pg/ml if in sinus rhythm, and ≥900 pg/ml if in atrial fibrillation within 30 days before screening (if multiple measurements, consider the highest); At least one of the following criteria defining chronic enhanced inflammatory milieu: Obesity, defined as body mass index (BMI) > 30kg/m2, Type 2 diabetes according to Diabetes Canada definition (http://guidelines.diabetes.ca/cpg/chapter3), and regardless of therapy, Evidence of pathological systemic inflammation including: high hs-CRP levels (hs-CRP>2mg/L), or the combination of high neutrophil count and low lymphocyte count (Neutrophil to Lymphocyte Ratio >3) within 30 days before screening (if multiple measurements, consider the higher), Subjects with the capacity to provide informed consent. Exclusion Criteria: Any prior measurement of LVEF <40%; Patients with a diagnosis of hypertrophic or infiltrative cardiomyopathy; Presence of hemodynamically significant valvular heart disease in the opinion of the investigator; Presence of active infection within the 3 months prior to visit 1 needing antibiotics (excluding COVID-19); Acute decompensated HF, acute coronary syndrome (including myocardial infarction), cardiac surgery, other major cardiovascular surgery, or urgent percutaneous coronary intervention (PCI) within the 3 months prior to visit 1; Elective PCI within 30 days prior to visit 1; Known or clinically judged significant (i.e., angina with CCS class >2/4) epicardial coronary artery disease (CAD) that has not been revascularized (revascularized CAD is defined by a history of myocardial infraction, percutaneous intervention, or coronary artery bypass grafting); Changes renin-angiotensin-aldosterone system (RAAS) inhibitors regimen within 30 days prior to screening visit; History of hypersensitivity to colchicine; Life-threatening or uncontrolled dysrhythmia, including symptomatic or sustained ventricular tachycardia and atrial fibrillation or atrial flutter with a resting ventricular rate >120 beats per minute; Any surgical or medical condition that in the opinion of the investigator may place the patient at higher risk from his/her participation in the study or is likely to prevent the patient from complying with the requirements of the study or completing the study; Evidence of hepatic disease as determined by any 1 of the following: serum glutamate oxaloacetate transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) values exceeding 3× the upper limit of normal, bilirubin>1.5 mg/dL (>25.65 μmol/L) at baseline visit; or patient with a history of cirrhosis, chronic active hepatitis or severe hepatic disease; Patients with estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 as calculated by the Modification in Diet in Renal Disease (MDRD) formula at baseline visit; History or presence of any other disease with a life expectancy of <1 year; Patient with inflammatory bowel disease (Crohn's disease or ulcerative colitis) or patient with chronic diarrhea; Patient with pre-existent progressive neuromuscular disease; 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 enrolment; Patients currently under long-term steroid medication for a chronic condition, or steroid medication within 30 days before screening; Patient is considered by the investigator, for any reason, to be an unsuitable candidate for the study. Positive pregnancy test result at the screening visit, and females of childbearing potential who do not agree to use adequate method of contraception for the duration of the study; acceptable means of birth control include: implantable contraceptives, injectable contraceptives, oral contraceptives, transdermal contraceptives, intrauterine devices, male or female condoms with spermicide, abstinence, or a sterile sexual partner.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Colchicine 0.5 mg die<br>Colchicine 0.5 mg die | Drug: Colchicine<br>* Patients meeting all inclusion criteria and no exclusion criteria will be randomly assigned to receive either colchicine (0.5mg once daily), colchicine (0.5mg twice daily) or matched placebo (1:1:1 allocation ratio), in addition to standard of care.<br>|
| Active Comparator: Colchicine 0.5 mg bid<br>Colchicine 0.5 mg bid | Drug: Colchicine<br>* Patients meeting all inclusion criteria and no exclusion criteria will be randomly assigned to receive either colchicine (0.5mg once daily), colchicine (0.5mg twice daily) or matched placebo (1:1:1 allocation ratio), in addition to standard of care.<br>|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Patients meeting all inclusion criteria and no exclusion criteria will be randomly assigned to receive either colchicine (0.5mg once daily), colchicine (0.5mg twice daily) or matched placebo (1:1:1 allocation ratio), in addition to standard of care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in hs-CRP (C reactive protein) | The primary endpoint will be the change from baseline to 6 months in hs-CRP (mg/L), a circulating biomarker of inflammation. | Change from baseline to 6 months in hs-CRP | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in circulating biomarkers of hemodynamic stress | Change in circulating biomarkers of hemodynamic stress (N-terminal pro-brain natriuretic peptide (NT-proBNP, in pg/mL)) | Change from baseline to 6 months in other biomarkers | 
| Change in circulating biomarkers of myocardial injury | Change in circulating biomarkers of myocardial injury (hs-TnT, Troponin, in ng/L) | Change from baseline to 6 months in other biomarkers | 
| Change in left ventricular (LV) diastolic function | Change in a combination of echocardiography-based measures assessing left ventricular (LV) diastolic function | Change from baseline to 6 months in LV diastolic function | 
| Change in functional status and symptoms | Change in functional status and New York Heart Association (NYHA) class | Change from baseline to 6 months in functional status and symptoms |