A Study Evaluating the Effects of Ataciguat (HMR1766) on Aortic Valve Calcification

Study Overview
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Brief Summary
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The primary objective of the current study is to determine whether Ataciguat (HMR1766) slows progression of valve calcification in patients with moderate calcific aortic valve stenosis. Secondary and tertiary objectives are to determine whether Ataciguat slows progression of aortic valve function, reduces systemic inflammation, and prevents left ventricular dysfunction in patients with moderate calcific aortic valve stenosis.

Detailed Description
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Patients with Moderate Calcific Aortic Valve Stenosis may be eligible for enrollment in this study. Participation lasts 12 months, which includes a total of 3 study visits (baseline/screening visit, 6 month follow up visit and 12 month follow up visit). During each visit, a blood sample will be taken along with other research related tests (Orthostatic Tolerance Standing Test, CT Scan, Echocardiogram, DEXA Scan). Qualifying Participants will be supplied with 6 months worth of study medication or placebo during visits 1 (baseline/screening visit) and 2 (6 month follow up visit) in which they will take at home daily with food. On visit 3 (12 month follow up visit), any remaining study medication or placebo will be returned to study staff.

Official Title
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A Phase II Randomized, Placebo-Controlled, Double-Blinded Study Evaluating the Effects of Ataciguat (HMR1766) on Aortic Valve Calcification in Patients With Moderate Calcific Aortic Valve Stenosis

Conditions
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Aortic Valve Stenosis

Intervention / Treatment
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* Drug: Ataciguat (HMR1766)
* Other: Placebo Comparator: Matching Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age > 50 years Male or female sex Aortic valve area greater than 1.0 cm2 but less than 2.0 cm2 Aortic valve calcium levels greater than 300 AU from chest CT Ejection fraction >50% Exclusion Criteria Orthostatic intolerance or symptomatic hypotension prior to study or during study visits Positive pregnancy test during screening visit Nitrate use or α-antagonist medication use within 24 hours Systolic blood pressure <110 mm Hg Mean systemic arterial pressure <75 mm Hg Severe mitral or aortic regurgitation Retinal or optic nerve problems Recent (≤30 days) acute coronary syndrome Oxygen saturation <90% on room air Congenital valve disease Hepatic dysfunction/elevated liver enzymes Prescription of drugs known to alter NO-sGC-cGMP signaling (sildenafil, nitrates, etc.) Prescription of Warfarin (Coumadin) for chronic anticoagulation Concomitant participation in other trials at Mayo Clinic or elsewhere Use of phenytoin or related compounds for any indication Chronic midazolam treatment for any indication Use of monoamine oxidase inhibitors for any indication Use of anti-diabetic drugs in the sulfonylurea family

Ages Eligible for Study
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Minimum Age: 50 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ataciguat (HMR1766)<br>200mg taken daily for 12 months | Drug: Ataciguat (HMR1766)<br> <br> |
| Placebo Comparator: Matching Placebo<br>Taken Daily for 12 months | Other: Placebo Comparator: Matching Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Aortic Valve Calcium Levels | This will be done using computed tomography (CT) scanning to evaluate aortic valve calcium levels, which is considered to be a gold standard for evaluating valvular calcium burden. As measured in Arbitrary Units (AU). | baseline, 6 mos | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Levels of Plasma Interleukin-6 | Determine whether long-term treatment with HMR1766 will result in sustained increases in systemic sGC signaling and reduce levels of circulating inflammatory cytokines in patients with mild to moderate CAVS. This will be done using ELISA-based measurements of interleukin-6 and tumor necrosis factor alpha in venous blood samples. Key comparisons will be between HMR1766-treated and placebo-treated groups, where we will examine the change in inflammatory cytokine levels from baseline in subjects receiving HMR1766 or placebo capsules. | baseline, 6 mos | 
| Change in Aortic Valve Function: Aortic Valve Area | Determine whether long-term treatment with HMR1766 will result in sustained increases in systemic sGC signaling slow progression of aortic valve dysfunction in patients with mild to moderate CAVS. This will be done using echocardiography-based measurements of aortic valve function. Key comparisons will be between HMR1766-treated and placebo-treated groups, where we will examine the change in: aortic valve area over time (calculated from the continuity equation) in subjects receiving HMR1766 or placebo capsules, AVA will be evaluated by both the absolute value and following normalization for body surface area, and mean transvalvular pressure gradient over time (calculated from the blood velocity trace using the Bernoulli equation) in subjects receiving HMR1766 or placebo capsules. | baseline, 6 mos | 
| Change in Left Ventricular Function | Determine whether long-term treatment with HMR1766 will result in sustained increases in systemic sGC signaling slow progression of aortic valve dysfunction in patients with mild to moderate CAVS. This will be done using echocardiography-based measurements of aortic valve function. Key comparisons will be between HMR1766-treated and placebo-treated groups, where we will examine the change in: 1. Left ventricular systolic function (measured by echocardiographic measurement of left ventricular ejection fraction) and 2. Left ventricular diastolic function (measured using the E/A ratio derived from Doppler measurements). | baseline, 6 mos | 
| Change in Plasma Tumor Necrosis Factor Alpha | Determine whether long-term treatment with ataciguat reduces levels of circulating inflammatory cytokines. | Baseline, 6 months | 
| Change in Aortic Valve Function: Transvalvular Pressure Gradient | Determine whether long-term treatment with HMR1766 will result in sustained increases in systemic sGC signaling slow progression of aortic valve dysfunction in patients with mild to moderate CAVS. This will be done using echocardiography-based measurements of aortic valve function. Key comparisons will be between HMR1766-treated and placebo-treated groups, where we will examine the change in: aortic valve area over time (calculated from the continuity equation) in subjects receiving HMR1766 or placebo capsules, AVA will be evaluated by both the absolute value and following normalization for body surface area, and mean transvalvular pressure gradient over time (calculated from the blood velocity trace using the Bernoulli equation) in subjects receiving HMR1766 or placebo capsules. | baseline, 6 mos | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stenosis, Aortic Valve, Aorta, Calcified, Calcific, Calcification