Aortic Stenosis and PhosphodiEsterase iNhibition With Aortic Valve Replacement (ASPEN-AVR): A Pilot Study

NCT01272388 | Terminated Phase 4 Results DMC

• 1 other identifier: 10-1334a
• Study Type: interventional
• Target: 1
• 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 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.

Conditions

Aortic Stenosis

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Quality of Life as Assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ)

  KCCQ overall summary score is reported. Scale is 0-100 (higher value is better).

  Baseline and 4 weeks

Secondary Outcomes (1)

• 6 Minute Walk Distance

  Baseline and 4 weeks

Study Arms (2)

Tadalafil

ACTIVE COMPARATOR

Drug: Tadalafil

Placebo

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 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.

Also known as: Cialis, Adcirca

Tadalafil

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 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.

Placebo

Eligibility Criteria

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

You may qualify if:

• 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
• 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
• 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

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; Hypertension, Pulmonary; Hypertrophy, Left Ventricular

Interventions

Tadalafil

Condition Hierarchy (Ancestors)

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

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

314-747-3617

Study Officials

• Brian R. Lindman, MD

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

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: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Study Record Dates

• First Submitted: January 6, 2011
• First Posted: January 7, 2011
• Study Start: January 1, 2011
• Primary Completion: April 1, 2011
• Study Completion: April 1, 2012
• Last Updated: September 12, 2018
• Results First Posted: September 12, 2018

Record last verified: 2018-09

Locations

US (1)