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

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2013 by Washington University School of Medicine
Sponsor:
Information provided by (Responsible Party):
Brian Lindman, MD, Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT01275339
First received: January 6, 2011
Last updated: December 18, 2013
Last verified: December 2013

January 6, 2011
December 18, 2013
December 2012
December 2016   (final data collection date for primary outcome measure)
  • 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 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 ]
Complete list of historical versions of study NCT01275339 on ClinicalTrials.gov Archive Site
  • 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
  • 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 ]
Not Provided
Not Provided
 
Aortic Stenosis and PhosphodiEsterase Type 5 iNhibition (ASPEN): A Pilot Study
Aortic Stenosis and PhosphodiEsterase Type 5 iNhibition (ASPEN): 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 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.

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.

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
  • LV Remodeling, Hypertrophy
  • 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:
    • 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 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 Diabetic Cohort
    Intervention: Drug: Tadalafil
  • Placebo Comparator: Placebo in Diabetic Cohort
    Intervention: Drug: Placebo
  • Active Comparator: Tadalafil in Non-Diabetic Cohort
    Intervention: Drug: Tadalafil
  • Placebo Comparator: Placebo in Non-Diabetic Cohort
    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.
 
Recruiting
56
December 2016
December 2016   (final data collection date for primary outcome measure)

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
Both
18 Years and older
No
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
 
NCT01275339
10-1334b
Yes
Brian Lindman, MD, Washington University School of Medicine
Washington University School of Medicine
Not Provided
Principal Investigator: Brian R. Lindman, MD, MSCI Washington University School of Medicine
Washington University School of Medicine
December 2013

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