Aortic Valve Stenosis
Conditions
Keywords
Stenosis, Aortic Valve, Aorta, Calcified, Calcific, Calcification
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.
Interventions
OTHERPlacebo Comparator: Matching Placebo
Sponsors
Sanofi
National Institutes of Health (NIH)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Aortic Valve Calcium Levels | baseline, 6 mos | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in Levels of Plasma Interleukin-6 | baseline, 6 mos | 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 | baseline, 6 mos | 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. 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 2. 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 | baseline, 6 mos | 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 | Baseline, 6 months | Determine whether long-term treatment with ataciguat reduces levels of circulating inflammatory cytokines. |
| Change in Aortic Valve Function: Transvalvular Pressure Gradient | baseline, 6 mos | 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. 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 2. mean transvalvular pressure gradient over time (calculated from the blood velocity trace using the Bernoulli equation) in subjects receiving HMR1766 or placebo capsules. |
Countries
United States
Participant flow
Pre-assignment details
Patients were required to complete initial testing for valve calcium and function (in addition to other tests/screening characteristics) prior to enrollment.
Participants by arm
| Arm | Count |
|---|---|
| Ataciguat (HMR1766) 200mg taken daily for 12 months
Ataciguat (HMR1766) | 12 |
| Matching Placebo Taken Daily for 12 months
Placebo Comparator: Matching Placebo | 11 |
| Total | 23 |
Baseline characteristics
| Characteristic | Ataciguat (HMR1766) | Matching Placebo | Total |
|---|---|---|---|
| Age, Continuous | 74 years STANDARD_DEVIATION 4 | 72 years STANDARD_DEVIATION 8 | 73 years STANDARD_DEVIATION 6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 11 Participants | 23 Participants |
| Region of Enrollment United States | 12 Participants | 11 Participants | 23 Participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Male | 7 Participants | 8 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 9 / 12 | 10 / 12 |
| serious Total, serious adverse events | 1 / 12 | 1 / 12 |
Outcome results
Primary
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).
Time frame: baseline, 6 mos
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ataciguat (HMR1766) | Changes in Aortic Valve Calcium Levels | 65 Arbitrary Units | Standard Error 45 |
| Matching Placebo | Changes in Aortic Valve Calcium Levels | 215 Arbitrary Units | Standard Error 58 |
Comparison: The statistical analysis was done using an ANCOVA analysis adjusting for the baseline aortic valve calcium levels.p-value: 0.05ANCOVA
Secondary
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: 1. 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 2. 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ataciguat (HMR1766) | Change in Aortic Valve Function: Aortic Valve Area | -0.07 change in cm^2 | Standard Error 0.03 |
| Matching Placebo | Change in Aortic Valve Function: Aortic Valve Area | -0.129 change in cm^2 | Standard Error 0.04 |
p-value: >0.05ANCOVA
Secondary
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: 1. 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 2. 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ataciguat (HMR1766) | Change in Aortic Valve Function: Transvalvular Pressure Gradient | 1.8 change in mm Hg | Standard Error 0.85 |
| Matching Placebo | Change in Aortic Valve Function: Transvalvular Pressure Gradient | 3.6 change in mm Hg | Standard Error 0.9 |
Secondary
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).
Time frame: baseline, 6 mos
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ataciguat (HMR1766) | Change in Left Ventricular Function | 0.6 percent | Standard Error 1.5 |
| Matching Placebo | Change in Left Ventricular Function | -2.8 percent | Standard Error 1.6 |
Comparison: The statistical analysis was done using an ANCOVA analysis adjusting for the baseline aortic valve calcium levels.p-value: >0.05ANCOVA
Secondary
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.
Time frame: baseline, 6 mos
Population: One placebo sample was not obtained/available for analysis, thereby reducing the number of data points from 11 to 10.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ataciguat (HMR1766) | Change in Levels of Plasma Interleukin-6 | 2.3 pg/ml | Standard Error 1.6 |
| Matching Placebo | Change in Levels of Plasma Interleukin-6 | -0.2 pg/ml | Standard Error 0.4 |
Secondary
Change in Plasma Tumor Necrosis Factor Alpha
Determine whether long-term treatment with ataciguat reduces levels of circulating inflammatory cytokines.
Time frame: Baseline, 6 months
Population: One placebo sample was not obtained/available for analysis, thereby reducing the number of data points from 11 to 10.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ataciguat (HMR1766) | Change in Plasma Tumor Necrosis Factor Alpha | 1.9 pg/ml | Standard Error 2.3 |
| Matching Placebo | Change in Plasma Tumor Necrosis Factor Alpha | 2.8 pg/ml | Standard Error 1.9 |