Safety of Ataciguat in Patients With Moderate Calcific Aortic Valve Stenosis

Study Overview
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Brief Summary
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This study will determine whether Ataciguat (HMR1766) is well-tolerated in patients with mild to moderate calcific aortic valve stenosis. The primary focus of these studies will be on changes in blood pressure and orthostatic tolerance (i.e., ability to stand up without passing out), and determining whether treatment with Ataciguat results in significant reductions in blood pressure in this patient population.

Official Title
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A Phase Ib Randomized, Placebo-controlled, Double-blinded Study Evaluating the Safety of Ataciguat (HMR1766) in Patients With Moderate Calcific Aortic Valve Stenosis

Conditions
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Aortic Valve Stenosis

Intervention / Treatment
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* Drug: Ataciguat
* Drug: 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 arbitrary units from chest CT Ejection fraction >50% Exclusion Criteria: History of orthostatic intolerance or symptomatic hypotension 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 nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate signaling (sildenafil, nitrates, etc.) History of orthostatic intolerance Concomitant participation in other trials at Mayo Clinic or elsewhere.

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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo gel capsule, dosage matches number of Ataciguat capsules for each respective dose, capsules taken once daily with breakfast for 14 consecutive days. | Drug: Placebo<br> <br> * Other names: Placebo gel capsule of identical composition to Active group, but does not have active compound.;|
| Active Comparator: Ataciguat<br>Ataciguat, orally administered gel capsule, 50, 100, or 200 mg, once per day with breakfast for 14 consecutive days | Drug: Ataciguat<br> <br> * Other names: HMR1766;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients experiencing orthostatic hypotension | The primary objective of the current study is to determine whether Ataciguat (HMR1766) is well-tolerated by patients with moderate calcific aortic valve stenosis. In this particular patient population, incidence of orthostatic intolerance/symptomatic hypotension is a potential concern. | Baseline - 14 days | 
| The change in blood pressure following the transition from sitting to standing | The primary objective of the current study is to determine whether Ataciguat (HMR1766) is well-tolerated by patients with moderate calcific aortic valve stenosis. In this particular patient population, incidence of orthostatic intolerance/symptomatic hypotension is a potential concern. Transitioning from sitting to standing is a functional test that will allow us to examine the effects of Ataciguat on blood pressure regulation in response to a relevant orthostatic stress. | Baseline - 14 days | 
| The change in blood pressure following progressive head-up tilt | The primary objective of the current study is to determine whether Ataciguat (HMR1766) is well-tolerated by patients with moderate calcific aortic valve stenosis. In this particular patient population, incidence of orthostatic intolerance/symptomatic hypotension is a potential concern. Tilt table testing will allow us to examine the effects of Ataciguat on blood pressure regulation in response to a tightly controlled orthostatic stress. | Baseline - 14 days | 
| Subject self-reports of light-headedness/orthostatic intolerance during the standing test and the head-up tilt testing | The primary objective of the current study is to determine whether Ataciguat (HMR1766) is well-tolerated by patients with moderate calcific aortic valve stenosis. In this particular patient population, incidence of orthostatic intolerance/symptomatic hypotension is a potential concern. Evaluating subject perceptions of light-headedness/orthostatic intolerance will help us to understand the relationship between changes in blood pressure and changes in symptoms in this patient population before and after treatment with Ataciguat. | Baseline - 14 days |