Aortic Stenosis and PhosphodiEsterase Type 5 iNhibition (ASPEN): A Pilot Study
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Aortic Stenosis LV Remodeling, Hypertrophy |
Drug: Tadalafil Drug: Placebo |
Phase 4 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment |
| Official Title: | Aortic Stenosis and PhosphodiEsterase Type 5 iNhibition (ASPEN): A Pilot Study |
- Change in LV mass on MRI [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- Change in diastolic function as measured by tissue Doppler e' [ Time Frame: 12 weeks and 6 months (primary) ] [ Designated as safety issue: No ]
- Change in LV longitudinal peak systolic strain by echo [ Time Frame: 12 weeks and 6 months (primary) ] [ Designated as safety issue: No ]
- Change in myocardial fibrosis (ECV) on MRI [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- Change in other echocardiographic indices of diastolic function [ Time Frame: 12 weeks and 6 months ] [ Designated as safety issue: No ]E/e' and deceleration time
- Safety and tolerability [ Time Frame: 6 and 12 weeks and 6 months ] [ Designated as safety issue: Yes ]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
- Change in indices of systolic function [ Time Frame: 12 weeks and 6 months ] [ Designated as safety issue: No ]Stroke volume, EF, LV twist, and stress-corrected midwall shortening by echo and 3D multiparametric strain and EF by MRI
- Change in LV hypertrophic remodeling [ Time Frame: 12 weeks and 6 months ] [ Designated as safety issue: No ]Relative wall thickness, LV chamber dimensions, and wall thickness
- Change in novel echocardiographic indices of diastolic function [ Time Frame: 12 weeks and 6 months ] [ Designated as safety issue: No ]LV stiffness, viscoelasticity, and a load independent index of diastolic filling
- Change in 6 minute walk distance [ Time Frame: 6 and 12 weeks and 6 months ] [ Designated as safety issue: No ]
- Change in circulating neurohormonal markers [ Time Frame: 6 and 12 weeks and 6 months ] [ Designated as safety issue: No ]BNP and systemic markers of collagen turnover and oxidative stress
- Change in quality of life [ Time Frame: 6 and 12 weeks and 6 months ] [ Designated as safety issue: No ]Assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ)
- Change in pulmonary artery pressure and pulmonary vascular resistance as assessed by echo [ Time Frame: 12 weeks and 6 months ] [ Designated as safety issue: No ]
- Change in systemic blood pressure [ Time Frame: 6 and 12 weeks and 6 months ] [ Designated as safety issue: Yes ]
- Change in RV function [ Time Frame: 12 weeks and 6 months ] [ Designated as safety issue: No ]TAPSE, s' tissue Doppler, and Tei index
- Change in AS severity [ Time Frame: 12 weeks and 6 months ] [ Designated as safety issue: No ]Aortic valve area, transvalvular pressure gradients
| Estimated Enrollment: | 56 |
| Study Start Date: | December 2012 |
| Estimated Study Completion Date: | December 2016 |
| Estimated Primary Completion Date: | December 2016 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
| Active Comparator: Tadalafil in Diabetic Cohort |
Drug: Tadalafil
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.
Other Names:
|
| Placebo Comparator: Placebo in Diabetic Cohort |
Drug: Placebo
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.
|
| Active Comparator: Tadalafil in Non-Diabetic Cohort |
Drug: Tadalafil
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.
Other Names:
|
| Placebo Comparator: Placebo in Non-Diabetic Cohort |
Drug: Placebo
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.
|
Detailed Description:
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.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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
Contacts and Locations| Contact: Brian R. Lindman, MD | (314) 747-3617 | blindman@dom.wustl.edu |
| Contact: Anna Wittenberg, MPH | (314) 286-0502 | awittenb@dom.wustl.edu |
| United States, Missouri | |
| Washington University School of Medicine | Recruiting |
| St. Louis, Missouri, United States, 63110 | |
| Contact: Brian R. Lindman, MD 314-747-3617 blindman@dom.wustl.edu | |
| Contact: Anna Wittenberg, MPH 314-286-0502 awittenb@dom.wustl.edu | |
| Principal Investigator: | Brian R. Lindman, MD, MSCI | Washington University School of Medicine |
More Information
No publications provided
| Responsible Party: | Brian Lindman, MD, Assistant Professor of Medicine, Washington University School of Medicine |
| ClinicalTrials.gov Identifier: | NCT01275339 History of Changes |
| Other Study ID Numbers: | 10-1334b |
| Study First Received: | January 6, 2011 |
| Last Updated: | February 24, 2013 |
| Health Authority: | United States: Institutional Review Board |
Keywords provided by Washington University School of Medicine:
|
Aortic valve stenosis Tadalafil Phosphodiesterase inhibitors Hypertension, pulmonary Hypertrophy, left ventricular |
Additional relevant MeSH terms:
|
Aortic Valve Stenosis Constriction, Pathologic Hypertrophy Heart Valve Diseases Heart Diseases Cardiovascular Diseases Ventricular Outflow Obstruction Pathological Conditions, Anatomical Phosphodiesterase Inhibitors |
Tadalafil Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Phosphodiesterase 5 Inhibitors Vasodilator Agents Cardiovascular Agents Therapeutic Uses |
ClinicalTrials.gov processed this record on May 19, 2013