Back to resultsAortic Stenosis and PhosphodiEsterase Type 5 iNhibition (ASPEN): A Pilot Study (ASPEN)
Primary Purpose
Aortic Stenosis, LV Remodeling, Hypertrophy
Status
Terminated
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Tadalafil
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Aortic Stenosis focused on measuring Aortic valve stenosis, Tadalafil, Phosphodiesterase inhibitors, Hypertension, pulmonary, Hypertrophy, left ventricular
Eligibility 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
Sites / Locations
- Washington University School of Medicine
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Active Comparator
Placebo Comparator
Active Comparator
Placebo Comparator
Arm Label
Tadalafil in Diabetic Cohort
Placebo in Diabetic Cohort
Tadalafil in Non-Diabetic Cohort
Placebo in Non-Diabetic Cohort
Arm Description
Outcomes
Primary Outcome Measures
Diastolic Function as Measured by Tissue Doppler e'
Measurement of e' (average of septal and lateral) on echo at each of the time points specified.
Secondary Outcome Measures
Change in Myocardial Fibrosis (ECV) on MRI
Change in Other Echocardiographic Indices of Diastolic Function
E/e' and deceleration time
Safety and Tolerability
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
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
Relative wall thickness, LV chamber dimensions, and wall thickness
Change in Novel Echocardiographic Indices of Diastolic Function
LV stiffness, viscoelasticity, and a load independent index of diastolic filling
Change in 6 Minute Walk Distance
Change in Circulating Neurohormonal Markers
BNP and systemic markers of collagen turnover and oxidative stress
Change in Quality of Life
Assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ)
Change in Pulmonary Artery Pressure and Pulmonary Vascular Resistance as Assessed by Echo
Change in Systemic Blood Pressure
Change in RV Function
TAPSE, s' tissue Doppler, and Tei index
Change in AS Severity
Aortic valve area, transvalvular pressure gradients
Full Information
NCT ID
NCT01275339
First Posted
January 6, 2011
Last Updated
April 8, 2019
Sponsor
Washington University School of Medicine
1. Study Identification
Unique Protocol Identification Number
NCT01275339
Brief Title
Aortic Stenosis and PhosphodiEsterase Type 5 iNhibition (ASPEN): A Pilot Study
Acronym
ASPEN
Official Title
Aortic Stenosis and PhosphodiEsterase Type 5 iNhibition (ASPEN): A Pilot Study
Study Type
Interventional
2. Study Status
Record Verification Date
April 2019
Overall Recruitment Status
Terminated
Why Stopped
Difficulty enrolling patients and PI moved institutions.
Study Start Date
December 2012 (undefined)
Primary Completion Date
April 14, 2017 (Actual)
Study Completion Date
April 14, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Washington University School of Medicine
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Aortic Stenosis, LV Remodeling, Hypertrophy
Keywords
Aortic valve stenosis, Tadalafil, Phosphodiesterase inhibitors, Hypertension, pulmonary, Hypertrophy, left ventricular
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
10 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Tadalafil in Diabetic Cohort
Arm Type
Active Comparator
Arm Title
Placebo in Diabetic Cohort
Arm Type
Placebo Comparator
Arm Title
Tadalafil in Non-Diabetic Cohort
Arm Type
Active Comparator
Arm Title
Placebo in Non-Diabetic Cohort
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Tadalafil
Other Intervention Name(s)
Cialis, Adcirca
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
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.
Primary Outcome Measure Information:
Title
Diastolic Function as Measured by Tissue Doppler e'
Description
Measurement of e' (average of septal and lateral) on echo at each of the time points specified.
Time Frame
Baseline, 12 weeks, and 6 months
Secondary Outcome Measure Information:
Title
Change in Myocardial Fibrosis (ECV) on MRI
Time Frame
6 months
Title
Change in Other Echocardiographic Indices of Diastolic Function
Description
E/e' and deceleration time
Time Frame
12 weeks and 6 months
Title
Safety and Tolerability
Description
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
Time Frame
6 and 12 weeks and 6 months
Title
Change in Indices of Systolic Function
Description
Stroke volume, EF, LV twist, and stress-corrected midwall shortening by echo and 3D multiparametric strain and EF by MRI
Time Frame
12 weeks and 6 months
Title
Change in LV Hypertrophic Remodeling
Description
Relative wall thickness, LV chamber dimensions, and wall thickness
Time Frame
12 weeks and 6 months
Title
Change in Novel Echocardiographic Indices of Diastolic Function
Description
LV stiffness, viscoelasticity, and a load independent index of diastolic filling
Time Frame
12 weeks and 6 months
Title
Change in 6 Minute Walk Distance
Time Frame
6 and 12 weeks and 6 months
Title
Change in Circulating Neurohormonal Markers
Description
BNP and systemic markers of collagen turnover and oxidative stress
Time Frame
6 and 12 weeks and 6 months
Title
Change in Quality of Life
Description
Assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ)
Time Frame
6 and 12 weeks and 6 months
Title
Change in Pulmonary Artery Pressure and Pulmonary Vascular Resistance as Assessed by Echo
Time Frame
12 weeks and 6 months
Title
Change in Systemic Blood Pressure
Time Frame
6 and 12 weeks and 6 months
Title
Change in RV Function
Description
TAPSE, s' tissue Doppler, and Tei index
Time Frame
12 weeks and 6 months
Title
Change in AS Severity
Description
Aortic valve area, transvalvular pressure gradients
Time Frame
12 weeks and 6 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Brian R. Lindman, MD, MSCI
Organizational Affiliation
Washington University School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Aortic Stenosis and PhosphodiEsterase Type 5 iNhibition (ASPEN): A Pilot Study
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