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

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

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.

Study Overview

• Status: Completed
• Conditions: Aortic Valve Stenosis
• Intervention / Treatment: Drug: Ataciguat (HMR1766); Other: Placebo Comparator: Matching Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 46 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

1. Age > 50 years
2. Male or female sex
3. Aortic valve area greater than 1.0 cm2 but less than 2.0 cm2
4. Aortic valve calcium levels greater than 300 AU from chest CT
5. Ejection fraction >50%

Exclusion Criteria

1. Orthostatic intolerance or symptomatic hypotension prior to study or during study visits
2. Positive pregnancy test during screening visit
3. Nitrate use or α-antagonist medication use within 24 hours
4. Systolic blood pressure <110 mm Hg
5. Mean systemic arterial pressure <75 mm Hg
6. Severe mitral or aortic regurgitation
7. Retinal or optic nerve problems
8. Recent (≤30 days) acute coronary syndrome
9. Oxygen saturation <90% on room air
10. Congenital valve disease
11. Hepatic dysfunction/elevated liver enzymes
12. Prescription of drugs known to alter NO-sGC-cGMP signaling (sildenafil, nitrates, etc.)
13. Prescription of Warfarin (Coumadin) for chronic anticoagulation
14. Concomitant participation in other trials at Mayo Clinic or elsewhere
15. Use of phenytoin or related compounds for any indication
16. Chronic midazolam treatment for any indication
17. Use of monoamine oxidase inhibitors for any indication
18. Use of anti-diabetic drugs in the sulfonylurea family

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: Sanofi; National Institutes of Health (NIH)
• Investigators: Principal Investigator: Jordan D Miller, PhD, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Actual): July 1, 2018
• Study Completion (Actual): December 1, 2019

Study Registration Dates

• First Submitted: June 23, 2015
• First Submitted That Met QC Criteria: June 23, 2015
• First Posted (Estimate): June 25, 2015

Study Record Updates

• Last Update Posted (Actual): January 22, 2021
• Last Update Submitted That Met QC Criteria: January 4, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Stenosis; Aorta; Aortic Valve; Calcification; Calcified; Calcific
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Metabolic Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction; Calcium Metabolism Disorders; Aortic Valve Stenosis; Constriction, Pathologic; Calcinosis; Molecular Mechanisms of Pharmacological Action; Enzyme Activators; 5-chloro-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide
• Other Study ID Numbers: 14-006469; TR 000954 (Other Identifier: National Center for Advancing Translational Sciences)