Colchicine in HFpEF

• Status: Not yet recruiting
• Trial end date: 2024-12-01
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Montreal Heart Institute
• Treatments: Colchicine

Criteria

Inclusion Criteria:

• Patients ≥ 40 and < 80 years of age;

• Chronic symptomatic HFpEF defined as follows: left ventricular ejection fraction (LVEF) > or = 45% by echocardiography within 6 months prior to screening visit;

• Stable clinically and therapeutically for at least 1 month before enrolment; *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);

• an NT-proBNP of ≥600 pg/ml if in sinus rhythm, and ≥1800 pg/ml if in atrial fibrillation;

• and at least one of the following criteria defining chronic enhanced inflammatory milieu:

1. Obesity, defined as body mass index (BMI) > 30kg/m2,

2. Diabetes mellitus,

3. Evidence of pathological systemic inflammation including: high hs-CRP levels (hs-CRP>5mg/L), or the combination of high neutrophil count and low lymphocyte count (Neutrophil to Lymphocyte Ratio >3).

Exclusion Criteria:

• Patients > 80 years of age;

• Any prior echocardiographic measurement of LVEF <45%;

• Presence of clinical, biological or echocardiography signs of cardiac amyloidosis;

• Presence of hemodynamically significant valvular heart disease in the opinion of the investigator;

• Presence of active infection within the 3 months prior to enrolment;

• 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 baseline visit or an elective PCI within 30 days prior to baseline visit;

• Current acute decompensated HF requiring augmented therapy with diuretic agents, vasodilator agents, and/or inotropic drugs;

• Changes in diuretics and / or renin-angiotensin-aldosterone system (RAAS) inhibitors regimen within 30 days prior to 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;

• Women of child-bearing potential;

• 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);

• Patients currently under long-term anti-inflammatory medication for a chronic condition (steroids, NSAIDS);

• Patient considered by the investigator, for any reason, to be an unsuitable candidate for the study.