Clinical trial NCT05637398: Colchicine in Patients With Heart Failure and Preserved Left Ventricular Ejection Fraction
Official title: Colchicine in Patients With Heart Failure and Preserved Left Ventricular Ejection Fraction
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: HFpEF - Heart Failure With Preserved Ejection Fraction
Colchicine
Lead sponsor: I.M. Sechenov First Moscow State Medical University
Sponsor class: OTHER
First posted: 2022-12-05
Enrollment: 40
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Heart failure with preserved left ventricular ejection fraction (HFpEF) is a syndrome associated with high morbidity and mortality rates. Systemic low-grade inflammation is acknowledged to be a fundamental pathophysiological mechanism of HFpEF. Interventions targeting inflammatory pathway is understudied in HFpEF. Colchicine is a safe and well tolerated anti-inflammatory drug, which interferes with several steps in the inflammatory process. The drug has been extensively studied in different cardiovascular pathologies except HFpEF. We assume that colchicine decreases inflammation and reduces sST2 levels in HFpEF.

Detailed description: HFpEF is a syndrome associated with high morbidity and mortality rates. The underlying mechanisms of the syndrome are not fully understood. Systemic low-grade inflammation is acknowledged to be a fundamental pathophysiological mechanism of HFpEF, which facilitates cardiomyocyte stiffness and myocardial fibrosis development. However, anti-inflammatory treatment approaches are largely under studied. Colchicine is a safe and well tolerated anti-inflammatory drug, which interferes with several steps in the inflammatory process, resulting in suppression of a number of pro-inflammatory pathways and cytokines release, including IL-1, hsCRP. The drug has been extensively studied in patients with coronary artery disease (COLCOT, LoDoCo2) and showed significant reduction in risk of cardio-vascular events, as well as inflammation. Post-hoc analysis of in the CANTOS study investigated the effect of monoclonal antibody targeting interleukin-1β in patients with prior myocardial infarction, showed a reduction in heart failure (HF) hospitalization of patients with elevations in high-sensitivity C-reactive protein (hsCRP). There is no data available regarding the effect of Colchicine on HFpEF patients. Soluble suppression of tumourigenicity 2 (sST2), a member of the interleukin (IL)-1 receptor family, which is not restricted to inflammation, but is also expressed in cardiomyocytes, fibroblast and endothelial cells of cardiac microvessels in response to myocardial stress antagonizing cardioprotective effects of IL-33/ST2 system. In HFpEF, sST2 associated with worse clinical signs and symptoms, co-morbidities, biomarkers of fibrosis and neurohormonal activation. Elevated levels of sST2 are acknowledged as a predictor of worse prognosis in both HF with reduced ejection fraction (HFrEF) and HFpEF. We assume that colchicine decreases inflammation and reduces sST2 levels in HFpEF.

Eligibility criteria: Inclusion Criteria:

* 40 years of age, male and female
* Left ventricular ejection fraction (LVEF) ≥ 50%
* Symptoms and signs of heart failure
* N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml at baseline (patients in atrial fibrillation at baseline NT-proBNP ≥ 600 pg/ml), left atrial volume index (LAVI) \>34 mL/m2 or a left ventricular mass index (LVMI) =115 g/m2 for males and =95 g/m2 for females
* body mass index (BMI) \> 30kg/m2 or diabetes mellitus

Exclusion Criteria:

* Hypertrophic cardiomyopathy, constrictive pericarditis, or cardiac amyloidosis
* Acute decompensation of HF in the last 1 month
* Valvular heart disease
* Prior history of LVEF below 50%
* Acute myocardial infarction in the last 3 months, cardiac surgery or cerebrovascular accident within the recent 6 months
* Any active or chronic inflammatory diseases or infections
* Patients with indication for colchicine therapy or history of colchicine intolerance
* Severe hepatic (alanine aminotransferase N3 upper limit of normal or renal dysfunction (estimated glomerular filtration rate \<45 mL/min per 1.73m2)
* Severe nervous system diseases
* History of any malignancy or suffering from cancer
* Lack of informed consent

Primary outcomes:
measure: Change in Soluble suppression of tumourigenicity 2 (sST2,ng/ml)
timeFrame: from baseline to 12 weeks of treatment
Secondary outcomes:
measure: Change in high-sensitivity C-reactive protein (hsCRP, mg/l )
timeFrame: from baseline to 12 weeks of treatment
measure: Change in N-terminal pro-brain natriuretic peptide (NTproBNP, ng,ml)
timeFrame: from baseline to 12 weeks of treatment
measure: Change in E/e' (average)
timeFrame: from baseline to 12 weeks of treatment
measure: Change in Left ventricular global longitudinal strain (LVGLS,%)
timeFrame: from baseline to 12 weeks of treatment
measure: Left atrial reservoir strain (LA reservoir strain ,%)
timeFrame: from baseline to 12 weeks of treatment
measure: Drug discontinuation
timeFrame: during 12 weeks of treatment
measure: Incidence of side effects
timeFrame: during 12 weeks of treatment
measure: Change in insulin-like growth factor-binding protein 7 (IGFBP-7, ng/ml)
timeFrame: from baseline to 12 weeks of treatment
measure: Change in procollagen type I carboxy-terminal propeptide (PICP, ng/ml)
timeFrame: from baseline to 12 weeks of treatment
measure: Change in C-terminal telopeptide of collagen type I (CITP,ng/ml)
timeFrame: from baseline to 12 weeks of treatment
Other outcomes:
Locations:
city: Moscow
country: Russian Federation
facility: A Shchendrygina
city: Moscow
country: Russian Federation
facility: Anastasia Shchendrygina
Study officials:
affiliation: Sechenov Univerity
name: Anastasia Shchendrygina
role: PRINCIPAL_INVESTIGATOR
References: