Not provided
Not provided
Not provided
Not provided
Difficulty enrolling patients and PI moved institutions.
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Tadalafil in Diabetic Cohort | Active Comparator |
| |
| Placebo in Diabetic Cohort | Placebo Comparator |
| |
| Tadalafil in Non-Diabetic Cohort | Active Comparator |
| |
| Placebo in Non-Diabetic Cohort | Placebo Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tadalafil | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline, 12 weeks, and 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Myocardial Fibrosis (ECV) on MRI | 6 months | |
| Change in Other Echocardiographic Indices of Diastolic Function | E/e' and deceleration time | 12 weeks and 6 months |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Brian R. Lindman, MD, MSCI | Washington University School of Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Washington University School of Medicine | St Louis | Missouri | 63110 | United States |
Not provided
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Tadalafil in Diabetic Cohort | 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. |
| FG001 | Placebo in Diabetic Cohort | 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. |
| FG002 | Tadalafil in Non-Diabetic Cohort | 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. |
| FG003 | Placebo in Non-Diabetic Cohort | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
There were a small number of subjects enrolled in this trial before it was terminated. There was block randomization and none got assigned to the Diabetic placebo cohort. Only 2 diabetics were enrolled and they were both randomized to tadalafil.
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Tadalafil in Diabetic Cohort | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | There were 0 enrolled that were randomized to placebo in the diabetic cohort; the total number enrolled in the study was small, so this happened randomly. | Posted | Mean | Full Range | cm/sec | Baseline, 12 weeks, and 6 months |
|
6 months
In that arm of the study, no patients were enrolled.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Tadalafil in Diabetic Cohort | 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. |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| shortness of breath | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Shortness of breath developed during the intervention period |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Brian R. Lindman, MD | Washington University School of Medicine | 615-936-5949 | brlindman@wustl.edu |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 1, 2012 | Apr 8, 2019 | Prot_SAP_000.pdf |
Not provided
| ID | Term |
|---|---|
| D001024 | Aortic Valve Stenosis |
| D006984 | Hypertrophy |
| D006976 | Hypertension, Pulmonary |
| D017379 | Hypertrophy, Left Ventricular |
| ID | Term |
|---|---|
| D000082862 | Aortic Valve Disease |
| D006349 | Heart Valve Diseases |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D000068581 | Tadalafil |
| ID | Term |
|---|---|
| D002243 | Carbolines |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
|
|
| Placebo | Drug | 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. |
|
| 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 | 6 and 12 weeks and 6 months |
| 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 | 12 weeks and 6 months |
| Change in LV Hypertrophic Remodeling | Relative wall thickness, LV chamber dimensions, and wall thickness | 12 weeks and 6 months |
| Change in Novel Echocardiographic Indices of Diastolic Function | LV stiffness, viscoelasticity, and a load independent index of diastolic filling | 12 weeks and 6 months |
| Change in 6 Minute Walk Distance | 6 and 12 weeks and 6 months |
| Change in Circulating Neurohormonal Markers | BNP and systemic markers of collagen turnover and oxidative stress | 6 and 12 weeks and 6 months |
| Change in Quality of Life | Assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) | 6 and 12 weeks and 6 months |
| Change in Pulmonary Artery Pressure and Pulmonary Vascular Resistance as Assessed by Echo | 12 weeks and 6 months |
| Change in Systemic Blood Pressure | 6 and 12 weeks and 6 months |
| Change in RV Function | TAPSE, s' tissue Doppler, and Tei index | 12 weeks and 6 months |
| Change in AS Severity | Aortic valve area, transvalvular pressure gradients | 12 weeks and 6 months |
| Withdrawal by Subject |
|
| BG001 | Placebo in Diabetic Cohort | 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. |
| BG002 | Tadalafil in Non-Diabetic Cohort | 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. |
| BG003 | Placebo in Non-Diabetic Cohort | 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. |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG001 | Placebo in Diabetic Cohort | 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. |
| OG002 | Tadalafil in Non-Diabetic Cohort | 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. |
| OG003 | Placebo in Non-Diabetic Cohort | 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. |
|
|
| Secondary | Change in Myocardial Fibrosis (ECV) on MRI | Not Posted | 6 months | Participants |
| Secondary | Change in Other Echocardiographic Indices of Diastolic Function | E/e' and deceleration time | Not Posted | 12 weeks and 6 months | Participants |
| Secondary | 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 | Not Posted | 6 and 12 weeks and 6 months | Participants |
| Secondary | 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 | Not Posted | 12 weeks and 6 months | Participants |
| Secondary | Change in LV Hypertrophic Remodeling | Relative wall thickness, LV chamber dimensions, and wall thickness | Not Posted | 12 weeks and 6 months | Participants |
| Secondary | Change in Novel Echocardiographic Indices of Diastolic Function | LV stiffness, viscoelasticity, and a load independent index of diastolic filling | Not Posted | 12 weeks and 6 months | Participants |
| Secondary | Change in 6 Minute Walk Distance | Not Posted | 6 and 12 weeks and 6 months | Participants |
| Secondary | Change in Circulating Neurohormonal Markers | BNP and systemic markers of collagen turnover and oxidative stress | Not Posted | 6 and 12 weeks and 6 months | Participants |
| Secondary | Change in Quality of Life | Assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) | Not Posted | 6 and 12 weeks and 6 months | Participants |
| Secondary | Change in Pulmonary Artery Pressure and Pulmonary Vascular Resistance as Assessed by Echo | Not Posted | 12 weeks and 6 months | Participants |
| Secondary | Change in Systemic Blood Pressure | Not Posted | 6 and 12 weeks and 6 months | Participants |
| Secondary | Change in RV Function | TAPSE, s' tissue Doppler, and Tei index | Not Posted | 12 weeks and 6 months | Participants |
| Secondary | Change in AS Severity | Aortic valve area, transvalvular pressure gradients | Not Posted | 12 weeks and 6 months | Participants |
| 0 |
| 2 |
| 0 |
| 2 |
| 1 |
| 2 |
| EG001 | Placebo in Diabetic Cohort | 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. | 0 | 0 | 0 | 0 | 0 | 0 |
| EG002 | Tadalafil in Non-Diabetic Cohort | 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. | 0 | 4 | 0 | 4 | 2 | 4 |
| EG003 | Placebo in Non-Diabetic Cohort | 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. | 0 | 4 | 0 | 4 | 2 | 4 |
|
| orthopnea | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Occurred during follow-up |
|
| lightheadedness | Cardiac disorders | Systematic Assessment | Occurred during follow-up |
|
| fall | Musculoskeletal and connective tissue disorders | Systematic Assessment | Unrelated to study drug as blood pressure was fine beforehand |
|
| dilated aorta | Vascular disorders | Systematic Assessment | Identified in follow-up although it may have been present at baseline |
|
| unsteady | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| nausea | Gastrointestinal disorders | Systematic Assessment |
|
Not provided
Not provided
| D014694 |
| Ventricular Outflow Obstruction |
| D020763 | Pathological Conditions, Anatomical |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D006973 | Hypertension |
| D014652 | Vascular Diseases |
| D006332 | Cardiomegaly |
| D026121 |
| Indole Alkaloids |
| D007211 | Indoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006575 | Heterocyclic Compounds, 3-Ring |