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
  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 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.


Condition Intervention Phase
Aortic Stenosis
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 Aortic Valve Replacement (ASPEN-AVR): A Pilot Study

Resource links provided by NLM:


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

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Enrollment: 1
Study Start Date: January 2011
Study Completion Date: April 2012
Primary Completion Date: April 2011 (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 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
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 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.

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  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: NCT01272388

Locations
United States, Missouri
Washington University School of Medicine
St. Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
Investigators
Principal Investigator: Brian R. Lindman, MD 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: NCT01272388     History of Changes
Other Study ID Numbers: 10-1334a
Study First Received: January 6, 2011
Last Updated: December 18, 2012
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:
Constriction, Pathologic
Aortic Valve Stenosis
Pathological Conditions, Anatomical
Heart Valve Diseases
Heart Diseases
Cardiovascular Diseases
Ventricular Outflow Obstruction
Tadalafil
Vasodilator Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents

ClinicalTrials.gov processed this record on September 22, 2014