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Safety and Efficacy Trial to Treat Diastolic Heart Failure Using Ambrisentan

Primary Purpose

Pulmonary Hypertension, Heart Failure With Preserved Ejection Fraction

Status
Terminated
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Ambrisentan
Placebo
Sponsored by
University of Texas Southwestern Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Pulmonary Hypertension focused on measuring Pulmonary Hypertension, Diastolic Heart Failure

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Catheterization

    1. Elevated pulmonary arterial pressure (PA mean >25mmHg)
    2. Elevated pulmonary vascular resistance (>240 dynes.cm.sec-5) or transpulmonary gradient (>12 mmHg)
    3. Elevated LVEDP (>15mmHg, but ≤23 mmHg)
  2. Evidence of left ventricular diastolic dysfunction: LA>4.0, LVH or diastolic dysfunction by mitral filling pattern
  3. Echocardiogram: Normal or mildly reduced LV ejection fraction (greater than or equal to 40%)
  4. Symptomatic chronic HF (WHO functional class II-IV)
  5. Baseline walk distance 100 to 400 meters
  6. 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:

  1. Use of endothelin receptor antagonist, prostacyclin or PDE-5 inhibitor within 4 weeks of enrollment
  2. Exercise capacity limited by other illness (other lung disease, arthritis, mobility limitations)
  3. Uncontrolled systemic hypertension
  4. Uncontrolled atrial fibrillation
  5. Severe valvular disease
  6. Pregnant females- females of child bearing potential will need to use contraceptive agent barrier given the teratogenicity associated with ERA's
  7. Uncontrolled OSA

Sites / Locations

  • UT Southwestern Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

1

2

Arm Description

Outcomes

Primary Outcome Measures

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]
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

Secondary Outcome Measures

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.
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.
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

Full Information

First Posted
February 6, 2009
Last Updated
May 15, 2020
Sponsor
University of Texas Southwestern Medical Center
Collaborators
Gilead Sciences
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1. Study Identification

Unique Protocol Identification Number
NCT00840463
Brief Title
Safety and Efficacy Trial to Treat Diastolic Heart Failure Using Ambrisentan
Official Title
Safety and Efficacy Trial Using Ambrisentan for Pulmonary Hypertension Associated With Congestive Heart Failure With Preserved Left Ventricular Ejection Fraction
Study Type
Interventional

2. Study Status

Record Verification Date
May 2020
Overall Recruitment Status
Terminated
Why Stopped
Poor enrolment
Study Start Date
January 2009 (undefined)
Primary Completion Date
September 2013 (Actual)
Study Completion Date
January 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Texas Southwestern Medical Center
Collaborators
Gilead Sciences

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Hypertension, Heart Failure With Preserved Ejection Fraction
Keywords
Pulmonary Hypertension, Diastolic Heart Failure

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
4 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Active Comparator
Arm Title
2
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Ambrisentan
Other Intervention Name(s)
Letairis
Intervention Description
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).
Intervention Type
Other
Intervention Name(s)
Placebo
Other Intervention Name(s)
The placebo will look identical to the Ambrisentan tablets
Intervention Description
Sugar pill
Primary Outcome Measure Information:
Title
Change in Pulmonary Vascular Resistance (Wood Units)
Description
The primary efficacy outcome will be Pulmonary Vascular Resistance.PVR will be calculated as [(PA mean - wedge) / Cardiac Output]
Time Frame
Baseline and Four months
Title
Safety Assessment-Number of Subjects Who Are Free and Those Who Developed Clinically Significant Adverse Events (CSAEs)
Description
Freedom from clinically significant adverse events will be measure by determining the number free from CSAEs and those who developed CSAEs
Time Frame
4 months
Secondary Outcome Measure Information:
Title
Change in 6 Minute Walk Distance
Description
subjects complete the 6 minute walk test to determine how far (in meters) they are able to walk in 6 minutes.
Time Frame
Baseline and Four months
Title
Change in Functional Class
Description
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.
Time Frame
basline and 4 months
Title
Change in Short Form-36 Physical Functioning
Description
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
Time Frame
baseline 4 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kelly M Chin, MD
Organizational Affiliation
UT Southwestern Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Fernando Torres, MD
Organizational Affiliation
UT Southwestern Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
UT Southwestern Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390-8550
Country
United States

12. IPD Sharing Statement

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Safety and Efficacy Trial to Treat Diastolic Heart Failure Using Ambrisentan

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