Aortic Stenosis and PhosphodiEsterase iNhibition With No Planned Aortic Valve Replacement (ASPEN-NoAVR): 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 iNhibition With No Planned Aortic Valve Replacement (ASPEN-NoAVR): A Pilot Study |
- Change in LV mass on MRI [ Time Frame: Baseline to 12 weeks ] [ Designated as safety issue: No ]
- Change in LV diastolic function as measured by a load-independent index of filling [ Time Frame: Baseline to 12 weeks ] [ Designated as safety issue: No ]
- Change in myocardial fibrosis on MRI [ Time Frame: Baseline to 12 weeks ] [ Designated as safety issue: No ]
- Change in LV systolic function as assessed by 3D multiparametric strain (MRI), LV longitudinal systolic strain (speckle tracking echo), and stress-corrected midwall fractional shortening. [ Time Frame: Baseline to 12 weeks ] [ Designated as safety issue: No ]
- Safety and tolerability [ Time Frame: 6 weeks and 12 weeks ] [ Designated as safety issue: Yes ]The following with be reported: 1) number of subjects with adverse events; 2) change in mean systemic pressure from baseline to 12 weeks; 3) side effects of the medication; and 4) number of subjects that needed to withdraw from the study because they could not tolerate the medication.
- Change in 6 minute walk [ Time Frame: Baseline to 6 and 12 weeks ] [ Designated as safety issue: No ]
- Change in quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) [ Time Frame: Baseline to 6 and 12 weeks ] [ Designated as safety issue: No ]
- Change in pulmonary artery pressure in all subjects and those with baseline pulmonary hypertension [ Time Frame: Baseline to 6 and 12 weeks ] [ Designated as safety issue: No ]
- Change in RV function in all subjects and those with baseline RV dysfunction [ Time Frame: Baseline to 6 and 12 weeks ] [ Designated as safety issue: No ]
- Change in systemic markers of collagen turnover and oxidative stress [ Time Frame: Baseline to 12 weeks ] [ Designated as safety issue: No ]
- Evaluate changes in the endpoints between the active drug and placebo groups based on presence/absence of diabetes [ Time Frame: Baseline to 12 weeks ] [ Designated as safety issue: No ]
| Estimated Enrollment: | 21 |
| Study Start Date: | January 2011 |
| Estimated Study Completion Date: | December 2012 |
| Estimated Primary Completion Date: | December 2012 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
| Active Comparator: Tadalafil |
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 (12 weeks). 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 |
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 (12 weeks). 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), preserved ejection fraction, and no planned aortic valve replacement will be eligible for this randomized, double-blind, placebo-controlled, pilot study. 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 2:1 to tadalafil vs. placebo. An MRI will also be performed during this randomization visit. After 6 and 12 weeks on drug or placebo, subjects will have the same baseline testing repeated. At 12 weeks, an MRI will be repeated.
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 ≤ 1.2 cm2)
- Left ventricular hypertrophy
- EF ≥ 50%
- 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: Tara Hohn, MHS | (314) 286-0502 | thohn@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: Tara Hohn, MHS 314-286-0502 thohn@dom.wustl.edu | |
| Principal Investigator: | Brian R. Lindman, MD | Washington University School of Medicine |
More Information
No publications provided
| Responsible Party: | Brian R. Lindman, MD, 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: | August 2, 2011 |
| 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 October 18, 2012
