E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Aortic stenosis (AS) is the most common valvular heart disease in the developed world. The prevalence of aortic sclerosis in the general population is estimated to be 25% at the age of 65 years and severe aortic stenosis is present in 10-15% of the patients aged > 75 years. Once symptomatic, untreated patients have a poor prognosis with a five-year survival rate of 25%. There is no effective medical therapy to stop progression of AS. |
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E.1.1.1 | Medical condition in easily understood language |
Aortic Stenosis (AS) is a disease caused by calcification resulting in narrowing of the Aortic Valve. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The main objective of this study is to determine the effect of colchicine on the progression of moderate AS in asymptomatic patients. |
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E.2.2 | Secondary objectives of the trial |
• To determine the effect of colchicine treatment on aortic valve 18F-NaF uptake as a measure of aortic valve calcification activity. • To study the effect of colchicine treatment on the progression of aortic valve stenosis measured with echocardiography. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• 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.
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E.4 | Principal 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. (see Appendix 1). • Severe mitral valve stenosis (MVA < 1cm2). • Severe mitral or aortic valve regurgitation. • Left ventricular dysfunction (LVEF < 35%). • Bicuspid aortic valve. • Rheumatic aortic valve disease. • Valvular disease due to history of chest radiation. • Patients aged <50 and >80 years. • Pre-existing chronic gastro-intestinal complaints which may obscure signs of colchicine intolerance. • The presence of a pacemaker or internal cardiac defibrillator. • Child-bearing potential without the use of contraception. • Renal impairment (eGFR <30 ml/min/1.73m2). • Active or chronic liver disease. • A planned aortic valve replacement in the next six months. • 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). • Life expectancy <2 years. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in aortic valve calcium score measured by computed tomography aortic valve calcification (CT-AVC) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
24 months after start treatment with colchicine/placebo |
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E.5.2 | Secondary end point(s) |
Difference in aortic valve 18F-NaF uptake of the aortic valve using positron emission tomography (PET) between baseline and end of study. Change in peak velocity (m/s) measured by echocardiography for aortic valve stenosis. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
24 months after start treatment with colchicine/placebo |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
The trial also includes an open-label run-in period prior to randomization. |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 36 |
E.8.9.1 | In the Member State concerned days | |