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Aortic Stenosis and PhosphodiEsterase iNhibition With Aortic Valve Replacement (ASPEN-AVR): A Pilot Study

This study has been terminated.
(We designed a different pilot trial based on data obtained after this study started - the 2 studies were too overlapping to continue both.)
Sponsor:
Information provided by (Responsible Party):
Brian Lindman, MD, Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT01272388
First received: January 6, 2011
Last updated: December 18, 2012
Last verified: December 2012

January 6, 2011
December 18, 2012
January 2011
April 2011   (final data collection date for primary outcome measure)
  • Change in quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
  • Change in LV diastolic function as measured by a load-independent index of filling [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
Same as current
Complete list of historical versions of study NCT01272388 on ClinicalTrials.gov Archive Site
  • Change in 6 minute walk [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
  • Change in LV systolic function as measured by global longitudinal strain (speckle tracking echo) and stress-corrected midwall fractional shortening [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
  • Safety and tolerability [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]
  • Change in pulmonary artery pressure in all subjects and those with baseline pulmonary hypertension [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
  • Change in RV function in all subjects and those with baseline RV dysfunction [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
  • Change in systemic markers of collagen turnover and oxidative stress [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
  • Differences in tissue measures of NO-cGMP signaling and oxidative stress [ Time Frame: 4 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: 4 weeks ] [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
Aortic Stenosis and PhosphodiEsterase iNhibition With Aortic Valve Replacement (ASPEN-AVR): A Pilot Study
Aortic Stenosis and PhosphodiEsterase iNhibition With Aortic Valve Replacement (ASPEN-AVR): A Pilot Study

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 PDE5 inhibition influences NO-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 upregulate NO-cGMP signaling, reduce oxidative stress, and have a favorable impact on LV structure and function as well as pulmonary artery pressures and quality of life. In this pilot study, the investigators anticipate that short-term administration of tadalafil to patients with AS will be safe and well-tolerated.

Patients with severe symptomatic AS who will undergo elective aortic valve replacement will be eligible for this randomized, double-blind, placebo-controlled, pilot study. Prior to randomization, subjects will have testing including: 6 minute walk, quality of life questionnaire, blood draw, and an echocardiogram. If an initial monitored dose of tadalafil is tolerated, participants will be randomized 2:1 to tadalafil vs. placebo. After 4 weeks on drug or placebo, subjects will have the same baseline testing repeated. At the time of aortic valve replacement surgery, the aortic valve and a small piece of LV myocardium will be taken for several analyses.

Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Aortic Stenosis
  • 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 the surgical date (~4 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:
    • Cialis
    • Adcirca
  • 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 the surgical date (~4 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 daily is not tolerated, then the dose will be decreased back to 1 pill daily.
  • Active Comparator: Tadalafil
    Intervention: Drug: Tadalafil
  • Placebo Comparator: Placebo
    Intervention: Drug: Placebo
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
1
April 2012
April 2011   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Patients with severe aortic stenosis (AVA < 1.0 cm2)
  • Left ventricular hypertrophy
  • EF ≥ 45%
  • NYHA functional class ≥ 2
  • Ambulatory (able to perform a 6 minute walk test)
  • 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
  • Creatinine clearance < 30 mL/min
  • 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)
  • Cirrhosis
  • Pulmonary fibrosis
  • 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
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01272388
10-1334a
Yes
Brian Lindman, MD, Washington University School of Medicine
Washington University School of Medicine
Not Provided
Principal Investigator: Brian R. Lindman, MD Washington University School of Medicine
Washington University School of Medicine
December 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP