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

NCT01275339 | Terminated Phase 4 Results DMC

• 1 other identifier: 10-1334b
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

Aortic Stenosis; LV Remodeling, Hypertrophy

Keywords

Aortic valve stenosis; Tadalafil; Phosphodiesterase inhibitors; Hypertension, pulmonary; Hypertrophy, left ventricular

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (13)

• Change in Myocardial Fibrosis (ECV) on MRI

  6 months

• Change in Other Echocardiographic Indices of Diastolic Function

  12 weeks and 6 months

• Safety and Tolerability

  6 and 12 weeks and 6 months

• Change in Indices of Systolic Function

  12 weeks and 6 months

• Change in LV Hypertrophic Remodeling

  12 weeks and 6 months

Study Arms (4)

Tadalafil in Diabetic Cohort

ACTIVE COMPARATOR

Drug: Tadalafil

Placebo in Diabetic Cohort

PLACEBO COMPARATOR

Drug: Placebo

Tadalafil in Non-Diabetic Cohort

ACTIVE COMPARATOR

Drug: Tadalafil

Placebo in Non-Diabetic Cohort

PLACEBO COMPARATOR

Drug: Placebo

Interventions

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.

Also known as: Cialis, Adcirca

Tadalafil in Diabetic Cohort; Tadalafil in Non-Diabetic Cohort

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.

Placebo in Diabetic Cohort; Placebo in Non-Diabetic Cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• years of age and older
• Able and willing to comply with all the requirements for the study

You may not qualify if:

• 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

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

MeSH Terms

Conditions

Aortic Valve Stenosis; Hypertrophy; Hypertension, Pulmonary; Hypertrophy, Left Ventricular

Interventions

Tadalafil

Condition Hierarchy (Ancestors)

Aortic Valve Disease; Heart Valve Diseases; Heart Diseases; Cardiovascular Diseases; Ventricular Outflow Obstruction; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases; Cardiomegaly

Intervention Hierarchy (Ancestors)

Carbolines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indole Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 3-Ring

Results Point of Contact

• Title: Brian R. Lindman, MD
• Organization: Washington University School of Medicine

brlindman@wustl.edu

615-936-5949

Study Officials

• Brian R. Lindman, MD, MSCI

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 6, 2011
• First Posted: January 12, 2011
• Study Start: December 1, 2012
• Primary Completion: April 14, 2017
• Study Completion: April 14, 2017
• Last Updated: April 17, 2019
• Results First Posted: April 17, 2019

Record last verified: 2019-04

Locations

US (1)