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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02481258
Recruitment Status : Completed
First Posted : June 25, 2015
Results First Posted : January 18, 2020
Last Update Posted : January 18, 2020
Sponsor:
Collaborators:
Sanofi
National Institutes of Health (NIH)
Information provided by (Responsible Party):
Jordan D. Miller, Ph.D., Mayo Clinic

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.

Condition or disease Intervention/treatment Phase
Aortic Valve Stenosis Drug: Ataciguat (HMR1766) Other: Placebo Comparator: Matching Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 35 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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 Start Date : June 2015
Actual Primary Completion Date : July 1, 2018
Actual Study Completion Date : December 1, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Minerals

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



Primary Outcome Measures :
  1. Changes in Aortic Valve Calcium Levels [ Time Frame: 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 Outcome Measures :
  1. Change in Levels of Plasma Interleukin-6 and Plasma Tumor Necrosis Factor Alpha [ Time Frame: 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.

  2. Change in Aortic Valve Function [ Time Frame: 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.

  3. Change in Left Ventricular Function [ Time Frame: 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).



Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02481258


Locations
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United States, Minnesota
Mayo Clinic in Rochester
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
Sanofi
National Institutes of Health (NIH)
Investigators
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Principal Investigator: Jordan D Miller, PhD Mayo Clinic
  Study Documents (Full-Text)

Documents provided by Jordan D. Miller, Ph.D., Mayo Clinic:
Additional Information:
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Responsible Party: Jordan D. Miller, Ph.D., SAC II, Mayo Clinic
ClinicalTrials.gov Identifier: NCT02481258    
Other Study ID Numbers: 14-006469
TR 000954 ( Other Identifier: National Center for Advancing Translational Sciences )
First Posted: June 25, 2015    Key Record Dates
Results First Posted: January 18, 2020
Last Update Posted: January 18, 2020
Last Verified: January 2020
Keywords provided by Jordan D. Miller, Ph.D., Mayo Clinic:
Stenosis
Aortic Valve
Aorta
Calcified
Calcific
Calcification
Additional relevant MeSH terms:
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Aortic Valve Stenosis
Calcinosis
Constriction, Pathologic
Pathological Conditions, Anatomical
Calcium Metabolism Disorders
Metabolic Diseases
Heart Valve Diseases
Heart Diseases
Cardiovascular Diseases
Ventricular Outflow Obstruction
5-chloro-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide
Enzyme Activators
Molecular Mechanisms of Pharmacological Action