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

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01272388
• Collaborator: (none)
• Enrollment: 1
• Location: 1
• Arms: 2
• Duration (Months): 15
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Aortic Stenosis	Drug: Tadalafil; Drug: Placebo	Phase 4

Detailed Description

Patients with severe symptomatic AS who will undergo elective aortic valve replacement will be eligible for this randomized, double-blind, placebo-controlled, pilot study. Prior to randomization, subjects will have testing including: 6 minute walk, quality of life questionnaire, blood draw, and an echocardiogram. If an initial monitored dose of tadalafil is tolerated, participants will be randomized 2:1 to tadalafil vs. placebo. After 4 weeks on drug or placebo, subjects will have the same baseline testing repeated. At the time of aortic valve replacement surgery, the aortic valve and a small piece of LV myocardium will be taken for several analyses.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Aortic Stenosis and PhosphodiEsterase iNhibition With Aortic Valve Replacement (ASPEN-AVR): A Pilot Study
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: Apr 1, 2011
• Actual Study Completion Date: Apr 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Tadalafil	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 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.; Other Names: Cialis Adcirca
Placebo Comparator: Placebo	Drug: 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 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.

Outcome Measures

Primary Outcome Measures

1. Quality of Life as Assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) [Baseline and 4 weeks]

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

Secondary Outcome Measures

1. 6 Minute Walk Distance [Baseline and 4 weeks]

   How far the subject walked in 6 minutes.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 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

• 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

• 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

• Unwilling to provide informed consent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University School of Medicine	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Washington University School of Medicine

Investigators

• Principal Investigator: Brian R. Lindman, MD, Washington University School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Brian Lindman, MD, Assistant Professor of Medicine, Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT01272388
• Other Study ID Numbers: 10-1334a
• First Posted: Jan 7, 2011
• Last Update Posted: Sep 12, 2018
• Last Verified: Sep 1, 2018

• Keywords provided by Brian Lindman, MD, Assistant Professor of Medicine, Washington University School of Medicine: Aortic valve stenosis; Tadalafil; Phosphodiesterase inhibitors; Hypertension, pulmonary; Hypertrophy, left ventricular
• Additional relevant MeSH terms: Aortic Valve Stenosis; Constriction, Pathologic; Tadalafil

Study Results

Participant Flow

Arm/Group Title	Tadalafil	Placebo
Arm/Group Description	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 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.	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 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.
Period Title: Overall Study
STARTED	1	0
COMPLETED	1	0
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Tadalafil	Placebo	Total
Arm/Group Description	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 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.	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 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.	Total of all reporting groups
Overall Participants	1	0	1
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	69	69
Sex: Female, Male (Count of Participants)
Female	1 100%	1 Infinity
Male	0 0%	0 NaN
Region of Enrollment (participants) [Number]
United States	1 100%	1 Infinity

Outcome Measures

1. Primary Outcome

Title	Quality of Life as Assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ)
Description	KCCQ overall summary score is reported. Scale is 0-100 (higher value is better).
Time Frame	Baseline and 4 weeks

Outcome Measure Data

Analysis Population Description

We designed a different pilot trial based on data obtained after this study started - the 2 studies were too overlapping to continue both. We stopped this study after only 1 patient (assigned to tadalafil) was enrolled.

Arm/Group Title	Tadalafil	Placebo
Arm/Group Description	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 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.	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 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.
Measure Participants	1	0
Baseline	87
4 weeks	81.25

2. Secondary Outcome

Title	6 Minute Walk Distance
Description	How far the subject walked in 6 minutes.
Time Frame	Baseline and 4 weeks

Outcome Measure Data

Analysis Population Description

We designed a different pilot trial based on data obtained after this study started - the 2 studies were too overlapping to continue both. We only enrolled one participant (assigned to tadalafil) into the study before stopping the study.

Arm/Group Title	Tadalafil	Placebo
Arm/Group Description	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 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.	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 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.
Measure Participants	1	0
Baseline	1080
4 weeks	860

Adverse Events

Arm/Group Title	Tadalafil		Placebo
Arm/Group Description	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 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.		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 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.
All Cause Mortality
	Tadalafil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/0 (NaN)
Serious Adverse Events
	Tadalafil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		0/0 (NaN)
Musculoskeletal and connective tissue disorders
Back pain	1/1 (100%)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Tadalafil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/1 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.