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

Aortic Stenosis Clinical Trial

— ASPEN  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01275339
• Other study ID #: 10-1334b
• Status: Terminated
• Phase: Phase 4
• Start date: December 2012
• Est. completion date: April 14, 2017

Study information

• Verified date: April 2019
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 10
• Est. completion date: April 14, 2017
• Est. primary completion date: April 14, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Aortic Stenosis
• Aortic Valve Stenosis
• Constriction, Pathologic
• Hypertrophy
• LV Remodeling, Hypertrophy

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	Washington University School of Medicine	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Washington University School of Medicine

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Baseline, 12 weeks, and 6 months
Secondary	Change in Myocardial Fibrosis (ECV) on MRI		6 months
Secondary	Change in Other Echocardiographic Indices of Diastolic Function	E/e' and deceleration time	12 weeks and 6 months
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	6 and 12 weeks and 6 months
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	12 weeks and 6 months
Secondary	Change in LV Hypertrophic Remodeling	Relative wall thickness, LV chamber dimensions, and wall thickness	12 weeks and 6 months
Secondary	Change in Novel Echocardiographic Indices of Diastolic Function	LV stiffness, viscoelasticity, and a load independent index of diastolic filling	12 weeks and 6 months
Secondary	Change in 6 Minute Walk Distance		6 and 12 weeks and 6 months
Secondary	Change in Circulating Neurohormonal Markers	BNP and systemic markers of collagen turnover and oxidative stress	6 and 12 weeks and 6 months
Secondary	Change in Quality of Life	Assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ)	6 and 12 weeks and 6 months
Secondary	Change in Pulmonary Artery Pressure and Pulmonary Vascular Resistance as Assessed by Echo		12 weeks and 6 months
Secondary	Change in Systemic Blood Pressure		6 and 12 weeks and 6 months
Secondary	Change in RV Function	TAPSE, s' tissue Doppler, and Tei index	12 weeks and 6 months
Secondary	Change in AS Severity	Aortic valve area, transvalvular pressure gradients	12 weeks and 6 months