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Aortic StenosisPhase 4ASPENNCT01275339

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

A Phase 4 study testing Tadalafil in people with Aortic Stenosis and LV Remodeling, Hypertrophy, run by Washington University School of Medicine at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Aortic Stenosis, LV Remodeling, Hypertrophy
What is being tested?
Tadalafil
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
10 participants
Where
1 siteUnited States
Study dates
Dec 2012to 14 Apr 2017
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 10Show fewer
  • Ambulatory
  • Normal sinus rhythm
  • 18 years of age and older
  • Able and willing to comply with all the requirements for the study

Who cannot join

  • 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
Show all 17Show fewer
  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Washington University School of Medicine

    St Louis, Missouri, 63110

Other trials in United States

About this study

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.

Read the 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.

Being tested
Tadalafil, Placebo
Keywords
Aortic valve stenosis, Tadalafil, Phosphodiesterase inhibitors, Hypertension, pulmonary, Hypertrophy, left ventricular
Medical subject headings
Aortic Valve Stenosis, Hypertrophy, Hypertension, Pulmonary, Hypertrophy, Left Ventricular

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TadalafilDrug

    Also called Cialis, Adcirca

    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.

  • PlaceboDrug

    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.

Study groups in NCT01275339
Study groupRoleWhat they receive
Tadalafil in Diabetic CohortActive comparatorNot described
Receives: Drug: Tadalafil
Placebo in Diabetic CohortPlacebo comparatorNot described
Receives: Drug: Placebo
Tadalafil in Non-Diabetic CohortActive comparatorNot described
Receives: Drug: Tadalafil
Placebo in Non-Diabetic CohortPlacebo comparatorNot described
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Baseline, 12 weeks, and 6 months

Secondary outcomes (13)

  1. Change in Myocardial Fibrosis (ECV) on MRI

    Measured: 6 months

  2. Change in Other Echocardiographic Indices of Diastolic Function

    E/e' and deceleration time

    Measured: 12 weeks and 6 months

  3. 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

    Measured: 6 and 12 weeks and 6 months

  4. 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

    Measured: 12 weeks and 6 months

  5. Change in LV Hypertrophic Remodeling

    Relative wall thickness, LV chamber dimensions, and wall thickness

    Measured: 12 weeks and 6 months

  6. Change in Novel Echocardiographic Indices of Diastolic Function

    LV stiffness, viscoelasticity, and a load independent index of diastolic filling

    Measured: 12 weeks and 6 months

  7. Change in 6 Minute Walk Distance

    Measured: 6 and 12 weeks and 6 months

  8. Change in Circulating Neurohormonal Markers

    BNP and systemic markers of collagen turnover and oxidative stress

    Measured: 6 and 12 weeks and 6 months

  9. Change in Quality of Life

    Assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ)

    Measured: 6 and 12 weeks and 6 months

  10. Change in Pulmonary Artery Pressure and Pulmonary Vascular Resistance as Assessed by Echo

    Measured: 12 weeks and 6 months

  11. Change in Systemic Blood Pressure

    Measured: 6 and 12 weeks and 6 months

  12. Change in RV Function

    TAPSE, s' tissue Doppler, and Tei index

    Measured: 12 weeks and 6 months

  13. Change in AS Severity

    Aortic valve area, transvalvular pressure gradients

    Measured: 12 weeks and 6 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Jan 2011 (estimated)
  2. Study startDec 2012
  3. Primary completion14 Apr 2017
  4. Study completion14 Apr 2017

Why it stopped: Difficulty enrolling patients and PI moved institutions.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
10 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01275339
Sponsor's protocol ID
10-1334b
Acronym
ASPEN
Status last verified
Apr 2019
First submitted
6 Jan 2011
Last updated
17 Apr 2019
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Tadalafil in people with Aortic Stenosis and LV Remodeling, Hypertrophy, run by Washington University School of Medicine at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 17 Apr 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 17 Apr 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Diastolic Function as Measured by Tissue Doppler e' (time frame: Baseline, 12 weeks, and 6 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01275339.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Apr 2019.

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