A Study Evaluating the Effects of Ataciguat (HMR1766) on Aortic Valve Calcification - Clinical Trial for Aortic Valve Stenosis | NCT02481258

Back to results

Primary Purpose

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Ataciguat (HMR1766)

Placebo Comparator: Matching Placebo

About this trial

This is an interventional treatment trial for Aortic Valve Stenosis focused on measuring Stenosis, Aortic Valve, Aorta, Calcified, Calcific, Calcification

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Mayo Clinic in Rochester

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Ataciguat (HMR1766)

Matching Placebo

Arm Description

200mg taken daily for 12 months

Taken Daily for 12 months

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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.

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.

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).

Change in Plasma Tumor Necrosis Factor Alpha

Determine whether long-term treatment with ataciguat reduces levels of circulating inflammatory cytokines.

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.

Full Information

NCT ID

NCT02481258

First Posted

June 23, 2015

Last Updated

January 4, 2021

Sponsor

Mayo Clinic

Collaborators

Sanofi, National Institutes of Health (NIH)

1. Study Identification

Unique Protocol Identification Number

NCT02481258

Brief Title

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

Acronym

CAVS

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2021

Overall Recruitment Status

Completed

Study Start Date

June 2015 (undefined)

Primary Completion Date

July 1, 2018 (Actual)

Study Completion Date

December 1, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Mayo Clinic

Collaborators

Sanofi, National Institutes of Health (NIH)

4. Oversight

Data Monitoring Committee

No

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Aortic Valve Stenosis

Keywords

Stenosis, Aortic Valve, Aorta, Calcified, Calcific, Calcification

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

35 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Ataciguat (HMR1766)

Arm Type

Experimental

Arm Description

200mg taken daily for 12 months

Arm Title

Matching Placebo

Arm Type

Placebo Comparator

Arm Description

Taken Daily for 12 months

Intervention Type

Drug

Intervention Name(s)

Ataciguat (HMR1766)

Intervention Type

Other

Intervention Name(s)

Placebo Comparator: Matching Placebo

Primary Outcome Measure Information:

Title

Changes in Aortic Valve Calcium Levels

Description

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).

Time Frame

baseline, 6 mos

Secondary Outcome Measure Information:

Title

Change in Levels of Plasma Interleukin-6

Description

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.

Time Frame

baseline, 6 mos

Title

Change in Aortic Valve Function: Aortic Valve Area

Description

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.

Time Frame

baseline, 6 mos

Title

Change in Left Ventricular Function

Description

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).

Time Frame

baseline, 6 mos

Title

Change in Plasma Tumor Necrosis Factor Alpha

Description

Determine whether long-term treatment with ataciguat reduces levels of circulating inflammatory cytokines.

Time Frame

Baseline, 6 months

Title

Change in Aortic Valve Function: Transvalvular Pressure Gradient

Description

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.

Time Frame

baseline, 6 mos

10. Eligibility

Sex

All

Minimum Age & Unit of Time

50 Years

Accepts Healthy Volunteers

No

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jordan D Miller, PhD

Organizational Affiliation

Mayo Clinic

Official's Role

Principal Investigator

Facility Information:

Facility Name

Mayo Clinic in Rochester

City

Rochester

State/Province

Minnesota

ZIP/Postal Code

55905

Country

United States

12. IPD Sharing Statement

Links:

URL

https://www.mayo.edu/research/clinical-trials

Description

Mayo Clinic Clinical Trials

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

Aortic Valve Stenosis

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial