Heart Failure With Preserved Ejection Fraction, Pulmonary Hypertension
Conditions
Keywords
Pulmonary Hypertension, Diastolic Heart Failure
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.
Interventions
DRUGAmbrisentan
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).
OTHERPlacebo
Sugar pill
Sponsors
Gilead Sciences
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pulmonary Vascular Resistance (Wood Units) | Baseline and Four months | 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) | 4 months | Freedom from clinically significant adverse events will be measure by determining the number free from CSAEs and those who developed CSAEs |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in 6 Minute Walk Distance | Baseline and Four months | 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 | basline and 4 months | 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 | baseline 4 months | 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 |
Countries
United States
Participant flow
Recruitment details
Recruitment occurred through the UTSW clinics. Recruitment difficulties arose and the study was halted due to poor recruitment
Participants by arm
| Arm | Count |
|---|---|
| Ambrisentan Ambrisentan: 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). | 3 |
| Placebo Placebo: Sugar pill | 1 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Ambrisentan | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Continuous | 62 years | 50 years | 59.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 1 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 1 Participants | 4 Participants |
| Region of Enrollment United States | 3 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 1 |
| other Total, other adverse events | 3 / 3 | 1 / 1 |
| serious Total, serious adverse events | 1 / 3 | 0 / 1 |
Outcome results
Primary
Change in Pulmonary Vascular Resistance (Wood Units)
The primary efficacy outcome will be Pulmonary Vascular Resistance.PVR will be calculated as \[(PA mean - wedge) / Cardiac Output\]
Time frame: Baseline and Four months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ambrisentan | Change in Pulmonary Vascular Resistance (Wood Units) | -0.75 wood units |
| Placebo | Change in Pulmonary Vascular Resistance (Wood Units) | 2.81 wood units |
Primary
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
Time frame: 4 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ambrisentan | Safety Assessment-Number of Subjects Who Are Free and Those Who Developed Clinically Significant Adverse Events (CSAEs) | Free from clinically significant AE | 2 Participants |
| Ambrisentan | Safety Assessment-Number of Subjects Who Are Free and Those Who Developed Clinically Significant Adverse Events (CSAEs) | Developed clinically significant AE | 1 Participants |
| Placebo | Safety Assessment-Number of Subjects Who Are Free and Those Who Developed Clinically Significant Adverse Events (CSAEs) | Free from clinically significant AE | 1 Participants |
| Placebo | Safety Assessment-Number of Subjects Who Are Free and Those Who Developed Clinically Significant Adverse Events (CSAEs) | Developed clinically significant AE | 0 Participants |
Secondary
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.
Time frame: Baseline and Four months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ambrisentan | Change in 6 Minute Walk Distance | -22 meters |
| Placebo | Change in 6 Minute Walk Distance | 53 meters |
Secondary
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.
Time frame: basline and 4 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ambrisentan | Change in Functional Class | Improved | 0 Participants |
| Ambrisentan | Change in Functional Class | Stable | 3 Participants |
| Ambrisentan | Change in Functional Class | Worsened | 0 Participants |
| Placebo | Change in Functional Class | Improved | 0 Participants |
| Placebo | Change in Functional Class | Stable | 1 Participants |
| Placebo | Change in Functional Class | Worsened | 0 Participants |
Secondary
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
Time frame: baseline 4 months
Population: note that there was no change in the SF-36 score (baseline to month 4) for the placebo arm hence the mean is not meaningful
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ambrisentan | Change in Short Form-36 Physical Functioning | 12.5 score on a scale |
| Placebo | Change in Short Form-36 Physical Functioning | 0 score on a scale |