Colchicine and Inflammation in Aortic Stenosis

Study Overview
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Brief Summary
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Aortic stenosis (AS) is the most common valvular heart disease in the developed world. Once symptomatic, untreated patients have a poor prognosis with five-year survival rate of 25%. Once at an advanced stage, AS will lead to the development of left ventricle hypertrophy, and eventually heart failure and death. At-present, there is no effective medical therapy for aortic stenosis. Current management of patients with AS consists of 'watchful waiting'. Valve replacement is needed when these patients (often acutely) become symptomatic. Recent studies have shown that inflammatory processes with similarities to atherosclerosis play an important role in AS. Therefore, we hypothesize that treatment with anti-inflammatory therapy, in the form of colchicine, could reduce the progression of AS. If positive, this trial will be the first to provide a potential therapeutic option for millions of people world-wide with AS.

Official Title
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Does Colchicine Reduce Progression of Aortic Valve Stenosis?

Conditions
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Aortic Valve Disease, Aortic Valve Stenosis, Aortic Valve Calcification, Inflammation, Calcification, Cardiovascular Diseases

Intervention / Treatment
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* Drug: Colchicine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criterion: • Asymptomatic moderate aortic valve stenosis on recent (<6 months) echocardiography (based on peak velocity, mean gradient, aortic valve area). The severity of AS will be quantified according to current EACVI / ASE guidelines. Exclusion Criteria: Heavily calcified aortic valve on echocardiography (defined as grade 4 calcification: extensive thickening/calcification of all cusps as described in the articles by Rosenhek et al.); a planned aortic valve replacement in the next six months; severe mitral valve stenosis (MVA < 1cm2); severe mitral or aortic valve regurgitation; rheumatic aortic valve disease; bicuspid aortic valve; valvular disease due to history of chest radiation; left ventricular dysfunction (LVEF < 35%); renal impairment (eGFR <30 ml/min/1.73m2); patients aged <50 and >80 years; pre-existing chronic gastro-intestinal complaints which may obscure signs of colchicine intolerance; child-bearing potential without the use of contraception; use of CYP3A4 (e.g. verapamil) or P-glycoprotein inhibitors; use of bisphosphonate or denosumab; chronic use of immunosuppressants or anti-inflammatory drugs including colchicine and NSAID's (excl. acetylsalicylic acid); active or chronic liver disease; the presence of a pacemaker or internal cardiac defibrillator; life expectancy <2 years.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 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: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Colchicine<br>75 patients will receive colchicine tablets | Drug: Colchicine<br>* ATC: M04AC01<br>|
| Placebo Comparator: Placebo<br>75 patients will receive placebo tablets | Drug: Placebo<br>* Placebo tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in aortic valve calcium score | Change in aortic valve calcium score measured by computed tomography aortic valve calcification (CT-AVC). | Baseline and 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Aortic valve 18F-NaF uptake | Difference in aortic valve 18F-NaF uptake of the aortic valve using positron emission tomography (PET) between baseline and end of study. | Baseline and 24 months | 
| Change in echocardiographic parameter for aortic stenosis | Determined by change in peak velocity (m/s) | Baseline, 12 months and 24 months | 
| Adverse Outcomes | Determine the effect of colchicine on calcified aortic stenosis related adverse outcomes (cardiac death, myocardial infarction, stroke, (hospitalization for) heart failure and aortic valve replacement). | Baseline and 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aortic Stenosis, Inflammation