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
  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

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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:
  • Cialis
  • Adcirca
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:
  • Cialis
  • Adcirca
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
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01275339

Contacts
Contact: Brian R. Lindman, MD (314) 747-3617 blindman@dom.wustl.edu
Contact: Anna Wittenberg, MPH (314) 286-0502 awittenb@dom.wustl.edu

Locations
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   
Sponsors and Collaborators
Washington University School of Medicine
Investigators
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: December 18, 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
Cardiovascular Diseases
Heart Diseases
Heart Valve Diseases
Pathological Conditions, Anatomical
Ventricular Outflow Obstruction
Tadalafil
Cardiovascular Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Therapeutic Uses
Urological Agents
Vasodilator Agents

ClinicalTrials.gov processed this record on October 20, 2014