Aortic Stenosis and PhosphodiEsterase Type 5 iNhibition (ASPEN): A Pilot Study

Study Overview
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Brief Summary
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Currently, aortic stenosis (AS) is considered a surgical disease with no medical therapy available to improve any clinical outcomes, including symptoms, time to surgery, or long-term survival. Thus far, randomized studies involving statins have not been promising with respect to slowing progressive valve stenosis. Beyond the valve, two common consequences of aortic stenosis are hypertrophic remodeling of the left ventricle (LV) and pulmonary venous hypertension; each of these has been associated with worse heart failure symptoms, increased operative mortality, and worse long-term outcomes. Whether altering LV structural abnormalities, improving LV function, and/or reducing pulmonary artery pressures with medical therapy would improve clinical outcomes in patients with AS has not been tested. Animal models of pressure overload have demonstrated that phosphodiesterase type 5 (PDE5) inhibition influences nitric oxide (NO) - cyclic guanosine monophosphate (cGMP) signaling in the LV and favorably impacts LV structure and function, but this has not been tested in humans with AS. Studies in humans with left-sided heart failure and pulmonary venous hypertension have shown that PDE5 inhibition improves functional capacity and quality of life, but patients with AS were not included in those studies. The investigators hypothesize that PDE5 inhibition with tadalafil will have a favorable impact on LV structure and function as well as pulmonary artery pressures. In this pilot study, the investigators anticipate that short-term administration of tadalafil to patients with AS will be safe and well-tolerated.

Detailed Description
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Subjects with moderately severe to severe aortic stenosis (AS), left ventricular hypertrophy (LVH), diastolic dysfunction, preserved ejection fraction, and no planned aortic valve replacement over the next 6 months will be eligible for this randomized, double-blind, placebo-controlled, pilot study. There will be a diabetic cohort (n=32) and non-diabetic cohort (n=24); each cohort will be randomized 1:1 to tadalafil vs. placebo. During a baseline study visit, the following will be obtained: clinical data, 6 minute walk, quality of life questionnaire, blood draw, and an echocardiogram. A 3-day run-in will occur to initially assess tolerability and compliance. If the drug is tolerated during this run-in period, participants will be randomized. An MRI will also be performed during this randomization visit. Follow-up study visits and testing will occur at 6 and 12 weeks and 6 months.

Official Title
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Aortic Stenosis and PhosphodiEsterase Type 5 iNhibition (ASPEN): A Pilot Study

Conditions
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Aortic Stenosis, LV Remodeling, Hypertrophy

Intervention / Treatment
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* Drug: Tadalafil
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with moderate to severe aortic stenosis (AVA < 1.5 cm2) Left ventricular hypertrophy Diastolic dysfunction as evidenced by tissue Doppler e' (average of septal and lateral) ≤ 7 cm/s EF ≥ 50% None or minimal symptoms related to aortic stenosis (NYHA ≤ 2) The subject and treating physician are not planning on a valve replacement procedure to occur during the next 6 months Ambulatory Normal sinus rhythm 18 years of age and older Able and willing to comply with all the requirements for the study Exclusion Criteria: Need for ongoing nitrate medications SBP < 110mmHg or MAP < 75mmHg Moderately severe or severe mitral regurgitation Moderately severe or severe aortic regurgitation Contraindication to MRI Creatinine clearance < 30 mL/min Cirrhosis Pulmonary fibrosis Increased risk of priapism Retinal or optic nerve problems or unexplained visual disturbance If a subject requires ongoing use of an alpha antagonist typically used for benign prostatic hyperplasia (BPH) (prazosin, terazosin, doxazosin, or tamsulosin), SBP < 120 mmHg or MAP < 80 mmHg is excluded Need for ongoing use of a potent CYP3A inhibitor or inducer (ritonavir, ketoconazole, itraconazole, rifampin) Current or recent (≤ 30 days) acute coronary syndrome O2 sat < 90% on room air Females that are pregnant or believe they may be pregnant Any condition which the PI determines will place the subject at increased risk or is likely to yield unreliable data Unwilling to provide informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tadalafil in Diabetic Cohort<br> | Drug: Tadalafil<br>* Active drug will be encapsulated to look identical to the placebo pill. Subjects will take a single oral dose of tadalafil once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 20 mg (1 pill) daily for 3 days before having the dose increased to 40 mg (2 pills) once daily. If the increase to 40mg daily is not tolerated, then the dose will be decreased back to 20mg daily.<br>* Other names: Adcirca;|
| Placebo Comparator: Placebo in Diabetic Cohort<br> | Drug: Placebo<br>* The placebo pill will be encapsulated to look identical to the active drug pill. Subjects will take a single oral dose of placebo once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 1 pill daily for 3 days before having the dose increased to 2 pills once daily. If the increase to 2 pills is not tolerated, then the dose will be decreased back to 1 pill daily.<br>|
| Active Comparator: Tadalafil in Non-Diabetic Cohort<br> | Drug: Tadalafil<br>* Active drug will be encapsulated to look identical to the placebo pill. Subjects will take a single oral dose of tadalafil once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 20 mg (1 pill) daily for 3 days before having the dose increased to 40 mg (2 pills) once daily. If the increase to 40mg daily is not tolerated, then the dose will be decreased back to 20mg daily.<br>* Other names: Adcirca;|
| Placebo Comparator: Placebo in Non-Diabetic Cohort<br> | Drug: Placebo<br>* The placebo pill will be encapsulated to look identical to the active drug pill. Subjects will take a single oral dose of placebo once daily from the time of randomization until study completion (6 months). Subjects will begin by taking 1 pill daily for 3 days before having the dose increased to 2 pills once daily. If the increase to 2 pills is not tolerated, then the dose will be decreased back to 1 pill daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diastolic Function as Measured by Tissue Doppler e' | Measurement of e' (average of septal and lateral) on echo at each of the time points specified. | Baseline, 12 weeks, and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Myocardial Fibrosis (ECV) on MRI |  | 6 months | 
| Change in Other Echocardiographic Indices of Diastolic Function | E/e' and deceleration time | 12 weeks and 6 months | 
| Safety and Tolerability | The following with be reported - frequency of the following: hypotension (SBP < 90 mmHg), symptomatic hypotension (symptoms of presyncope or syncope associated with SBP <90), syncope, hospitalization for a cardiac reason, myocardial infarction, new onset or worsening heart failure, and new sustained arrhythmia requiring intervention | 6 and 12 weeks and 6 months | 
| Change in Indices of Systolic Function | Stroke volume, EF, LV twist, and stress-corrected midwall shortening by echo and 3D multiparametric strain and EF by MRI | 12 weeks and 6 months | 
| Change in LV Hypertrophic Remodeling | Relative wall thickness, LV chamber dimensions, and wall thickness | 12 weeks and 6 months | 
| Change in Novel Echocardiographic Indices of Diastolic Function | LV stiffness, viscoelasticity, and a load independent index of diastolic filling | 12 weeks and 6 months | 
| Change in 6 Minute Walk Distance |  | 6 and 12 weeks and 6 months | 
| Change in Circulating Neurohormonal Markers | BNP and systemic markers of collagen turnover and oxidative stress | 6 and 12 weeks and 6 months | 
| Change in Quality of Life | Assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) | 6 and 12 weeks and 6 months | 
| Change in Pulmonary Artery Pressure and Pulmonary Vascular Resistance as Assessed by Echo |  | 12 weeks and 6 months | 
| Change in Systemic Blood Pressure |  | 6 and 12 weeks and 6 months | 
| Change in RV Function | TAPSE, s' tissue Doppler, and Tei index | 12 weeks and 6 months | 
| Change in AS Severity | Aortic valve area, transvalvular pressure gradients | 12 weeks and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aortic valve stenosis, Tadalafil, Phosphodiesterase inhibitors, Hypertension, pulmonary, Hypertrophy, left ventricular