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

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT02481258
• Collaborator: Sanofi (Industry), National Institutes of Health (NIH) (NIH)
• Enrollment: 35
• Location: 1
• Arms: 2
• Duration (Months): 54
• Patients Per Site Per Month: 0.6

Study Details

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.

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.

Study Design

• Study Type: Interventional
• 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: Jun 1, 2015
• Actual Primary Completion Date: Jul 1, 2018
• Actual Study Completion Date: Dec 1, 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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: 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.

3. 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).

4. Change in Plasma Tumor Necrosis Factor Alpha [Baseline, 6 months]

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

5. 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: 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• Sanofi
• National Institutes of Health (NIH)

Investigators

• Principal Investigator: Jordan D Miller, PhD, Mayo Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 8, 2014

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

None provided.

• Responsible Party: Jordan D. Miller, Ph.D., SAC II, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT02481258
• Other Study ID Numbers: 14-006469; TR 000954
• First Posted: Jun 25, 2015
• Last Update Posted: Jan 22, 2021
• Last Verified: Jan 1, 2021

• Keywords provided by Jordan D. Miller, Ph.D., SAC II, Mayo Clinic: Stenosis; Aortic Valve; Aorta; Calcified; Calcific; Calcification
• Additional relevant MeSH terms: Aortic Valve Stenosis; Calcinosis; Constriction, Pathologic; 5-chloro-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide

Study Results

Participant Flow

Pre-assignment Detail	Patients were required to complete initial testing for valve calcium and function (in addition to other tests/screening characteristics) prior to enrollment.

Arm/Group Title	Ataciguat (HMR1766)	Matching Placebo
Arm/Group Description	200mg taken daily for 6 months Ataciguat (HMR1766)	Taken Daily for 6 months Placebo Comparator: Matching Placebo
Period Title: Overall Study
STARTED	12	11
COMPLETED	12	11
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Ataciguat (HMR1766)	Matching Placebo	Total
Arm/Group Description	200mg taken daily for 12 months Ataciguat (HMR1766)	Taken Daily for 12 months Placebo Comparator: Matching Placebo	Total of all reporting groups
Overall Participants	12	11	23
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	74 (4)	72 (8)	73 (6)
Sex: Female, Male (Count of Participants)
Female	5 41.7%	3 27.3%	8 34.8%
Male	7 58.3%	8 72.7%	15 65.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	12 100%	11 100%	23 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	12 100%	11 100%	23 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ataciguat (HMR1766)	Matching Placebo
Arm/Group Description	200mg taken daily for 12 months Ataciguat (HMR1766)	Taken Daily for 12 months Placebo Comparator: Matching Placebo
Measure Participants	12	12
Mean (Standard Error) [Arbitrary Units]	65 (45)	215 (58)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ataciguat (HMR1766), Matching Placebo
	Comments	The statistical analysis was done using an ANCOVA analysis adjusting for the baseline aortic valve calcium levels.
	Type of Statistical Test	Equivalence
	Comments	Power calculations were based on a two-sample t-test. A priori calculations to detect an effect size of 0.57 units indicated that that 50 patients per arm were needed to have 80% power. The actual effect size observed in the present study was 0.86.
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	ANCOVA
	Comments

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

One placebo sample was not obtained/available for analysis, thereby reducing the number of data points from 11 to 10.

Arm/Group Title	Ataciguat (HMR1766)	Matching Placebo
Arm/Group Description	200mg taken daily for 6 months Ataciguat (HMR1766)	Taken Daily for 6 months Placebo Comparator: Matching Placebo
Measure Participants	12	10
Mean (Standard Error) [pg/ml]	2.3 (1.6)	-0.2 (0.4)

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ataciguat (HMR1766)	Matching Placebo
Arm/Group Description	200mg taken daily for 6 months Ataciguat (HMR1766)	Taken Daily for 6 months Placebo Comparator: Matching Placebo
Measure Participants	12	11
Mean (Standard Error) [change in cm^2]	-0.07 (0.03)	-0.129 (0.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ataciguat (HMR1766), Matching Placebo
	Comments
	Type of Statistical Test	Equivalence
	Comments	Power calculations were based on a two-sample t-tests assuming initial recruitment of 50 subjects.
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	Our a priori threshold for statistical significance was p < 0.05.
	Method	ANCOVA
	Comments

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ataciguat (HMR1766)	Matching Placebo
Arm/Group Description	200mg taken daily for 6 months Ataciguat (HMR1766)	Taken Daily for 6 months Placebo Comparator: Matching Placebo
Measure Participants	12	11
Mean (Standard Error) [percent]	0.6 (1.5)	-2.8 (1.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ataciguat (HMR1766), Matching Placebo
	Comments	The statistical analysis was done using an ANCOVA analysis adjusting for the baseline aortic valve calcium levels.
	Type of Statistical Test	Equivalence
	Comments	Power calculations were based on a two-sample t-test.
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	Our a priori threshold for statistical significance was p < 0.05.
	Method	ANCOVA
	Comments

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

One placebo sample was not obtained/available for analysis, thereby reducing the number of data points from 11 to 10.

Arm/Group Title	Ataciguat (HMR1766)	Matching Placebo
Arm/Group Description	200mg taken daily for 6 months Ataciguat (HMR1766)	Taken Daily for 6 months Placebo Comparator: Matching Placebo
Measure Participants	12	10
Mean (Standard Error) [pg/ml]	1.9 (2.3)	2.8 (1.9)

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ataciguat (HMR1766)	Matching Placebo
Arm/Group Description	200mg taken daily for 6 months Ataciguat (HMR1766)	Taken Daily for 6 months Placebo Comparator: Matching Placebo
Measure Participants	12	11
Mean (Standard Error) [change in mm Hg]	1.8 (0.85)	3.6 (0.9)

Adverse Events

Time Frame	Adverse event data were acquired during the periods of patient enrollment (from 6 months to a maximum of 12 months of treatment duration). The total study duration was 3 years.
Adverse Event Reporting Description	Our definitions of AE and SAE do not differ from those provided on clinicaltrials.gov. For this study, adverse events were identified through regularly scheduled follow-up phone calls by study staff.
Arm/Group Title	Ataciguat (HMR1766)		Matching Placebo
Arm/Group Description	200mg taken daily for 6 months Ataciguat (HMR1766)		Taken Daily for 6 months Placebo Comparator: Matching Placebo
All Cause Mortality
	Ataciguat (HMR1766)		Matching Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)
Serious Adverse Events
	Ataciguat (HMR1766)		Matching Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/12 (8.3%)		1/12 (8.3%)
Cardiac disorders
Hospitalization due progression of disease	0/12 (0%)	0	1/12 (8.3%)	1
Hepatobiliary disorders
Elevated Liver Enzymes	1/12 (8.3%)	1	0/12 (0%)	0
Other (Not Including Serious) Adverse Events
	Ataciguat (HMR1766)		Matching Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/12 (75%)		10/12 (83.3%)
Blood and lymphatic system disorders
Nosebleed	0/12 (0%)	0	1/12 (8.3%)	1
Low Hemoglobin	1/12 (8.3%)	1	0/12 (0%)	0
Cardiac disorders
Bradycardia	1/12 (8.3%)	1	0/12 (0%)	0
Chest Pain/Tightness	2/12 (16.7%)	2	1/12 (8.3%)	1
Gastrointestinal disorders
Diarrhea	2/12 (16.7%)	2	0/12 (0%)	0
Odor in urine	1/12 (8.3%)	1	0/12 (0%)	0
Flatulence	1/12 (8.3%)	1	0/12 (0%)	0
Constipation	1/12 (8.3%)	1	0/12 (0%)	0
Indigestion	0/12 (0%)	0	1/12 (8.3%)	1
Dry Mouth	1/12 (8.3%)	1	0/12 (0%)	0
Hepatobiliary disorders
Cholesterol lab values out of range	0/12 (0%)	0	1/12 (8.3%)	1
Infections and infestations
Fever	0/12 (0%)	0	1/12 (8.3%)	1
Cough (related to cold/flu)	1/12 (8.3%)	1	1/12 (8.3%)	1
Metabolism and nutrition disorders
Hypoglycemia	0/12 (0%)	0	1/12 (8.3%)	1
Hyperglycemia	0/12 (0%)	0	1/12 (8.3%)	1
Musculoskeletal and connective tissue disorders
Lower back pain	1/12 (8.3%)	1	0/12 (0%)	0
Ankle Edema	2/12 (16.7%)	2	1/12 (8.3%)	1
Fall (study unrelated)	1/12 (8.3%)	1	0/12 (0%)	0
Muscle Cramps/Aches	0/12 (0%)	0	2/12 (16.7%)	2
Arm Pain	1/12 (8.3%)	1	0/12 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate Cancer (study unrelated)	1/12 (8.3%)	1	0/12 (0%)	0
Nervous system disorders
Headache	0/12 (0%)	0	2/11 (18.2%)	2
Dizziness/Lightheadedness	2/12 (16.7%)	6	3/12 (25%)	3
Tired/Fatigue	3/12 (25%)	3	1/12 (8.3%)	1
Mood Changes	1/12 (8.3%)	1	1/12 (8.3%)	1
Hot Flashes	1/12 (8.3%)	1	0/12 (0%)	0
Nausea	1/12 (8.3%)	1	1/12 (8.3%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/12 (25%)	4	2/12 (16.7%)	2
Runny Nose (Common Cold)	1/12 (8.3%)	1	0/12 (0%)	0
Skin and subcutaneous tissue disorders
Rash/Dry Skin	3/12 (25%)	3	0/12 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.