Safety and Efficacy Trial to Treat Diastolic Heart Failure Using Ambrisentan

Study Overview
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Brief Summary
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This is a randomized study of ambrisentan that will last 16 weeks. The study will include patients with diastolic heart failure and pulmonary hypertension. Patients will be randomized (1:1) to ambrisentan or placebo. The ambrisentan or matching placebo will be started at 2.5 mg by mouth daily and increased to 5mg and then 10mg daily, if tolerated. Patients will be seen at least monthly for 16 weeks. Adverse reactions will be reviewed and the required monthly laboratory tests (liver function testing and pregnancy testing, if applicable), will be performed. Patients will also complete an exercise test (six minute walk distance) and a quality of life survey at the baseline, week 4 and week 16 visit. An echocardiogram and a right heart catheterization and left ventricular end diastolic pressure measurement will be performed at the 16 week visit. The primary end-point is safety, and secondary end-points include the catheterization results, echocardiogram results, the walk distance and the quality of life survey. The expected completion of the study is 18 months from initiation. Ambrisentan is an FDA approved drug for PAH, but not for CHF.

Detailed Description
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Hypothesis: patients with pulmonary hypertension secondary to diastolic congestive heart failure (CHF) treated with ambrisentan for 16 weeks will have improved hemodynamics, increased exercise capacity and improved functional class with an acceptable safety profile, compared with placebo treated patients. Objectives: to evaluate the safety and efficacy of ambrisentan treatment in patients with pulmonary hypertension due to diastolic CHF. Efficacy will be assessed by improvement in hemodynamics (PVR(Pulmonary Vascular Resistance): primary efficacy endpoint), six minute walk distance (6MWD), World Health Organization (WHO) functional class and quality of life after 16 weeks of treatment with ambrisentan. Safety of ambrisentan will be compared to placebo. Concomitant Medication: Treatment with standard medications for CHF including diuretics and optimal blood pressure control with antihypertensive medications will be allowed throughout the study period. Diuretics adjustment will also be allowed and encouraged based on the planned diuretic management protocol. Approved medications for CHF in general are allowed as well, though it should be noted that there are no medications shown to have benefit in diastolic CHF. Patients may not be on an endothelin antagonist or sildenafil.

Official Title
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Safety and Efficacy Trial Using Ambrisentan for Pulmonary Hypertension Associated With Congestive Heart Failure With Preserved Left Ventricular Ejection Fraction

Conditions
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Pulmonary Hypertension, Heart Failure With Preserved Ejection Fraction

Intervention / Treatment
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* Drug: Ambrisentan
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Catheterization Elevated pulmonary arterial pressure (PA mean >25mmHg) Elevated pulmonary vascular resistance (>240 dynes.cm.sec-5) or transpulmonary gradient (>12 mmHg) Elevated LVEDP (>15mmHg, but ≤23 mmHg) Evidence of left ventricular diastolic dysfunction: LA>4.0, LVH or diastolic dysfunction by mitral filling pattern Echocardiogram: Normal or mildly reduced LV ejection fraction (greater than or equal to 40%) Symptomatic chronic HF (WHO functional class II-IV) Baseline walk distance 100 to 400 meters Age 18 - 80 (increased from 70) Maximal treatment of diastolic dysfunction as noted by the treating physicians with no change in medical therapy for one month prior to entry Exclusion Criteria: Use of endothelin receptor antagonist, prostacyclin or PDE-5 inhibitor within 4 weeks of enrollment Exercise capacity limited by other illness (other lung disease, arthritis, mobility limitations) Uncontrolled systemic hypertension Uncontrolled atrial fibrillation Severe valvular disease Pregnant females- females of child bearing potential will need to use contraceptive agent barrier given the teratogenicity associated with ERA's Uncontrolled OSA

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br> | Drug: Ambrisentan<br>* Subjects will be initiated at 2.5 mg per day and increased to 5mg daily in 2 weeks and then 10mg daily if clinically tolerated (edema is controlled and symptoms are stable).<br>* Other names: Letairis;|
| Placebo Comparator: 2<br> | Other: Placebo<br>* Sugar pill<br>* Other names: The placebo will look identical to the Ambrisentan tablets;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Pulmonary Vascular Resistance (Wood Units) | The primary efficacy outcome will be Pulmonary Vascular Resistance.PVR will be calculated as [(PA mean - wedge) / Cardiac Output] | Baseline and Four months | 
| Safety Assessment-Number of Subjects Who Are Free and Those Who Developed Clinically Significant Adverse Events (CSAEs) | Freedom from clinically significant adverse events will be measure by determining the number free from CSAEs and those who developed CSAEs | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 6 Minute Walk Distance | subjects complete the 6 minute walk test to determine how far (in meters) they are able to walk in 6 minutes. | Baseline and Four months | 
| Change in Functional Class | Change in functional class from baseline to month 4. This is graded from WHO FC I to FC IV. Assessment will be completed by an investigator on the study at every visit. | basline and 4 months | 
| Change in Short Form-36 Physical Functioning | Change between baseline and follow-up in the physical functioning items of the SF-36 questionnaire. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. The eight sections are: vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, and mental health | baseline 4 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Hypertension, Diastolic Heart Failure