Safety and Efficacy Trial to Treat Diastolic Heart Failure Using Ambrisentan

• Sponsor: University of Texas Southwestern Medical Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00840463
• Collaborator: Gilead Sciences (Industry)
• Enrollment: 4
• Location: 1
• Arms: 2
• Duration (Months): 60
• Patients Per Site Per Month: 0.1

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Hypertension; Heart Failure With Preserved Ejection Fraction	Drug: Ambrisentan; Other: Placebo	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 4 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Diagnostic
• Official Title: Safety and Efficacy Trial Using Ambrisentan for Pulmonary Hypertension Associated With Congestive Heart Failure With Preserved Left Ventricular Ejection Fraction
• Study Start Date: Jan 1, 2009
• Actual Primary Completion Date: Sep 1, 2013
• Actual Study Completion Date: Jan 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1	Drug: 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).; Other Names: Letairis
Placebo Comparator: 2	Other: Placebo; Sugar pill; Other Names: The placebo will look identical to the Ambrisentan tablets

Outcome Measures

Primary Outcome Measures

1. 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]

2. 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 Outcome Measures

1. 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.

2. 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.

3. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Catheterization

2. Elevated pulmonary arterial pressure (PA mean >25mmHg)

3. Elevated pulmonary vascular resistance (>240 dynes.cm.sec-5) or transpulmonary gradient (>12 mmHg)

4. Elevated LVEDP (>15mmHg, but ≤23 mmHg)

5. Evidence of left ventricular diastolic dysfunction: LA>4.0, LVH or diastolic dysfunction by mitral filling pattern

6. Echocardiogram: Normal or mildly reduced LV ejection fraction (greater than or equal to 40%)

7. Symptomatic chronic HF (WHO functional class II-IV)

8. Baseline walk distance 100 to 400 meters

9. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UT Southwestern Medical Center	Dallas	Texas	United States	75390-8550

Sponsors and Collaborators

• University of Texas Southwestern Medical Center
• Gilead Sciences

Investigators

• Principal Investigator: Kelly M Chin, MD, UT Southwestern Medical Center
• Principal Investigator: Fernando Torres, MD, UT Southwestern Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT00840463
• Other Study ID Numbers: IN-US-300-0126
• First Posted: Feb 10, 2009
• Last Update Posted: May 19, 2020
• Last Verified: May 1, 2020

• Keywords provided by University of Texas Southwestern Medical Center: Pulmonary Hypertension; Diastolic Heart Failure
• Additional relevant MeSH terms: Hypertension, Pulmonary; Hypertension; Heart Failure; Ambrisentan

Study Results

Participant Flow

Recruitment Details	Recruitment occurred through the UTSW clinics. Recruitment difficulties arose and the study was halted due to poor recruitment

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	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).	Placebo: Sugar pill
Period Title: Overall Study
STARTED	3	1
COMPLETED	2	1
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Ambrisentan	Placebo	Total
Arm/Group Description	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).	Placebo: Sugar pill	Total of all reporting groups
Overall Participants	3	1	4
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	1 33.3%	1 100%	2 50%
>=65 years	2 66.7%	0 0%	2 50%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	62	50	59.5
Sex: Female, Male (Count of Participants)
Female	2 66.7%	1 100%	3 75%
Male	1 33.3%	0 0%	1 25%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	3 100%	1 100%	4 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	3 100%	1 100%	4 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	3 100%	1 100%	4 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	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).	Placebo: Sugar pill
Measure Participants	2	1
Mean (Full Range) [wood units]	-0.75	2.81

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	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).	Placebo: Sugar pill
Measure Participants	3	1
Free from clinically significant AE	2 66.7%	1 100%
Developed clinically significant AE	1 33.3%	0 0%

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	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).	Placebo: Sugar pill
Measure Participants	2	1
Mean (Full Range) [meters]	-22	53

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	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).	Placebo: Sugar pill
Measure Participants	3	1
Improved	0 0%	0 0%
Stable	3 100%	1 100%
Worsened	0 0%	0 0%

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	Ambrisentan	Placebo
Arm/Group Description	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).	Placebo: Sugar pill
Measure Participants	2	1
Mean (Full Range) [score on a scale]	12.5	0

Adverse Events

Arm/Group Title	Ambrisentan		Placebo
Arm/Group Description	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).		Placebo: Sugar pill
All Cause Mortality
	Ambrisentan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/1 (0%)
Serious Adverse Events
	Ambrisentan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		0/1 (0%)
Cardiac disorders
Admission for heart failure	1/3 (33.3%)	1	0/1 (0%)	0
Other (Not Including Serious) Adverse Events
	Ambrisentan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		1/1 (100%)
Cardiac disorders
Edema	2/3 (66.7%)	2	0/1 (0%)	0
Chest pain or tightness	2/3 (66.7%)	2	0/1 (0%)	0
Musculoskeletal and connective tissue disorders
Gout	1/3 (33.3%)	1	1/1 (100%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.