EiPAH: An Open-Label Uncontrolled Study of the Safety and Efficacy of Ambrisentan in Participants With Exercise-Induced Pulmonary Arterial Hypertension (PAH)

Sponsor
Brigham and Women's Hospital (Other)
Overall Status
Completed
CT.gov ID
NCT01338636
Collaborator
Gilead Sciences (Industry)
30
1
1
92
0.3

Study Details

Study Description

Brief Summary

The purpose of this study is assess whether ambrisentan can help people with exercise- induced pulmonary arterial hypertension (EIPAH). The investigators also want to find out if ambrisentan is safe to take without causing excessive side effects.

Condition or Disease Intervention/Treatment Phase
Phase 4

Detailed Description

EIPAH population: These participants may provide a unique window into the pathogenesis of PAH. Our data suggest that these participants may represent an early phase of PAH with an abnormal vascular response.

The study includes an assessment of the potential impact of ambrisentan on the exercise capacity Advanced Level-3 cardiopulmonary exercise test (CPET) and the World Health Organization functional class (WHO FC).

Study Design

Study Type:
Interventional
Actual Enrollment :
30 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
An Open-Label Uncontrolled Study of the Safety and Efficacy of Ambrisentan in Patients With Exercise Induced Pulmonary Arterial Hypertension
Study Start Date :
Sep 1, 2008
Actual Primary Completion Date :
Feb 1, 2016
Actual Study Completion Date :
May 1, 2016

Arms and Interventions

Arm Intervention/Treatment
Other: Exercise-induced PAH

Open-label ambrisentan

Drug: Ambrisentan
5 mg orally every day for 4 weeks. At Week 4, if ambrisentan 5 mg was tolerated, the dose was increased to 10 mg every day for the remainder of the 24-week period.
Other Names:
  • Letairis
  • Outcome Measures

    Primary Outcome Measures

    1. Changes From Baseline in Peak Exercise Mean Pulmonary Artery Pressure (mPAP), Transpulmonary Pressure Gradient (TPG), and Pulmonary Capillary Wedge Pressure (PCWP) [Baseline to Week 24]

      mPAP is measure of the blood pressure found in the main artery of the lung. TPG is the difference between mean pulmonary arterial pressure and left atrial pressure. PCWP is the pressure measured by wedging a pulmonary catheter with an inflated balloon into a small pulmonary arterial branch.

    2. Change From Baseline in Peak Exercise Pulmonary Vascular Resistance (PVR) [Baseline to Week 24]

      PVR is the resistance offered by the pulmonary circulatory system.

    3. Change From Baseline in Peak Exercise Pulmonary Vascular Compliance (PVC ) [Baseline to Week 24]

      PVC is a measure of a pulmonary vein's ability to expand.

    4. Change From Baseline in Peak Exercise Cardiac Output (CO) [Baseline to Week 24]

      CO is the amount of blood pumped by the heart per minute.

    5. Change From Baseline in Peak Exercise Maximum Oxygen Uptake (VO2max) [Baseline to Week 24]

      VO2max is the measurement of the maximum amount of oxygen that an individual can utilize during intense or maximal exercise.

    Secondary Outcome Measures

    1. Change From Baseline in 6-minute Walk Distance (6MWD) [Baseline to Week 24]

      6MWD is the distance walked by the participant in 6 minutes.

    2. Borg Dyspnea Scale Score [Baseline and Week 24]

      The Borg Dyspnea Scale measures how breathless the participant feels. Scores range from 0 (no shortness of breath) to 10 (more short of breath than ever experienced). (minimum score 0, maximum score 10 with 10 being worsening outcome)

    3. World Health Organization Functional Class (WHO FC) [Baseline and Week 24]

      The WHO FC categorizes cardiac disability using four classes, ranging from Class 1 (without limitation of physical activity) to Class 4 (inability to carry on any physical activity without discomfort).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • The participant provides written informed consent before the commencement of any study related procedure.

    • The participant is 18 years of age or older.

    • If a female participant of child-bearing potential, the participant must agree to use 2 forms of contraceptive therapy, including at least 1 barrier method, throughout the study and follow-up. (Women who are surgically sterile or those post-menopausal for at least 2 years are not considered to be of childbearing potential.)

    • The participant has findings of either exercise induced PAH on an Advanced Level-3 CPET performed within the last 6-months and is a New York Heart Association (NYHA) Class I or II.

    • The participant has a left ventricular ejection fraction (LVEF) of 55%, obtained by any appropriate method (i.e., echocardiographic assessment (ECHO), radionuclide imaging, or cardiac catheterization)

    • The participant is taking a stable concomitant medication regimen for at least 4 weeks prior to enrollment in the study that is not expected to change during the study period and follow-up. Changes in diuretic and/or nitrate therapy as needed during the study period are acceptable.

    Exclusion Criteria

    • The participant has clinically significant psychiatric, addictive, neurologic disease or any other condition that, in the Investigator's opinion, would compromise his/her ability to give informed consent, participate fully in this study, or prevent adherence to the requirements of the study protocol.

    • The participant has evidence of unstable cardiovascular disease including intermittent atrial fibrillation or unstable angina within the 4 weeks prior to Screening.

    • The participant has diagnosis of exercise induced heart failure with preserved ejection fraction (previously diastolic dysfunction).

    • The participant has amyloidosis, hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy, or constrictive pericarditis.

    • The participant has a history of myocardial infarction, coronary artery bypass graft surgery, or percutaneous cardiac intervention within the last 3 months.

    • The participant has clinically significant valvular heart disease in the opinion of the Investigator.

    • The participant has a history of cerebrovascular accident or transient ischemic attack within the last 3 months.

    • Participant has a serum alanine transaminase (ALT) or aspartate transaminase (AST) lab value that is greater than 1.5x upper limit of normal (ULN) prior to Baseline Visit.

    • Participant has discontinued other endothelial receptor agonist (ERA) treatment (e.g. bosentan) for any adverse event.

    • The participant has, in the opinion of the Investigator, a dependence on alcohol.

    • The participant has, in the opinion of the Investigator, a dependence on illicit drugs.

    • The participant has anemia defined as hemoglobin (Hgb) below 10.0 g/dL.

    • A participant may qualify for the study following diagnosis and treatment of anemia, if the anemia is due to iron and/or vitamin deficiency.

    • The participant has exercise tolerance limited by noncardiac causes (e.g., exercise-induced asthma, chronic obstructive pulmonary disease, malignancy, obesity, musculoskeletal disorder).

    • The participant has uncontrolled systemic hypertension defined as a resting blood pressure of 140/90 mmHg if on no treatment for systemic hypertension or 160/90 mmHg if on 2 systemic hypertension medications. For participants who are receiving treatment for diabetes mellitus, uncontrolled systemic hypertension is defined as ≥ 130/80 mmHg.

    • The participant has the presence, or history, of malignancy that required significant medical intervention within the preceding 3 months and/or is likely to result in death within the next 2 years.

    • The participant has chronic renal impairment or renal insufficiency defined by a serum creatinine 2.5 mg/dL and/or the requirement for dialysis.

    • The participant is lactating, breastfeeding, or pregnant.

    • The participant received any chronic prostacyclin, prostacyclin analogue, ERA, or phosphodiesterase (PDE) inhibitor therapy within the 30 days prior to study entry. The use of PDE inhibitors "as needed" for erectile dysfunction is acceptable as long as the participant is not dosed within 24 hours of an efficacy assessment.

    • The participant has a documented allergy to Lidocaine.

    • Have received any investigational medication within 30 days prior to the start of this study or be scheduled to receive another investigational drug during the course of this study.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Brigham and Women's Hospital Boston Massachusetts United States 02115

    Sponsors and Collaborators

    • Brigham and Women's Hospital
    • Gilead Sciences

    Investigators

    • Principal Investigator: Aaron Waxman, MD, PhD, Brigham and Women's Hospital

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Aaron Waxman MD PhD, Director, Pulmonary Vascular Disease Program, Brigham and Women's Hospital
    ClinicalTrials.gov Identifier:
    NCT01338636
    Other Study ID Numbers:
    • 2008P000687
    First Posted:
    Apr 19, 2011
    Last Update Posted:
    Jan 18, 2022
    Last Verified:
    Jan 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Keywords provided by Aaron Waxman MD PhD, Director, Pulmonary Vascular Disease Program, Brigham and Women's Hospital
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Exercise-induced PAH
    Arm/Group Description Ambrisentan 5 mg orally every day for 4 weeks. At Week 4, if ambrisentan 5 mg was tolerated, the dose was increased to 10 mg every day for the remainder of the 24-week period.
    Period Title: Overall Study
    STARTED 30
    COMPLETED 22
    NOT COMPLETED 8

    Baseline Characteristics

    Arm/Group Title Exercise-induced PAH
    Arm/Group Description Ambrisentan 5 mg orally every day for 4 weeks. At Week 4, if ambrisentan 5 mg was tolerated, the dose was increased to 10 mg every day for the remainder of the 24-week period.
    Overall Participants 30
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    60.12
    (9.17)
    Sex: Female, Male (Count of Participants)
    Female
    19
    63.3%
    Male
    11
    36.7%

    Outcome Measures

    1. Primary Outcome
    Title Changes From Baseline in Peak Exercise Mean Pulmonary Artery Pressure (mPAP), Transpulmonary Pressure Gradient (TPG), and Pulmonary Capillary Wedge Pressure (PCWP)
    Description mPAP is measure of the blood pressure found in the main artery of the lung. TPG is the difference between mean pulmonary arterial pressure and left atrial pressure. PCWP is the pressure measured by wedging a pulmonary catheter with an inflated balloon into a small pulmonary arterial branch.
    Time Frame Baseline to Week 24

    Outcome Measure Data

    Analysis Population Description
    The analysis population included evaluable participants who completed the 24-week treatment period.
    Arm/Group Title Exercise-induced PAH
    Arm/Group Description Ambrisentan 5 mg orally every day for 4 weeks. At Week 4, if ambrisentan 5 mg was tolerated, the dose was increased to 10 mg every day for the remainder of the 24-week period.
    Measure Participants 22
    mPAP
    -5.2
    (5.6)
    TPG
    -7.1
    (8.0)
    PCWP
    2.9
    (5.6)
    2. Primary Outcome
    Title Change From Baseline in Peak Exercise Pulmonary Vascular Resistance (PVR)
    Description PVR is the resistance offered by the pulmonary circulatory system.
    Time Frame Baseline to Week 24

    Outcome Measure Data

    Analysis Population Description
    The analysis population included evaluable participants who completed the 24-week treatment period.
    Arm/Group Title Exercise-induced PAH
    Arm/Group Description Ambrisentan 5 mg orally every day for 4 weeks. At Week 4, if ambrisentan 5 mg was tolerated, the dose was increased to 10 mg every day for the remainder of the 24-week period.
    Measure Participants 22
    Mean (Standard Deviation) [Woods units (WU)]
    -0.9
    (0.7)
    3. Primary Outcome
    Title Change From Baseline in Peak Exercise Pulmonary Vascular Compliance (PVC )
    Description PVC is a measure of a pulmonary vein's ability to expand.
    Time Frame Baseline to Week 24

    Outcome Measure Data

    Analysis Population Description
    The analysis population included evaluable participants who completed the 24-week treatment period.
    Arm/Group Title Exercise-induced PAH
    Arm/Group Description Ambrisentan 5 mg orally every day for 4 weeks. At Week 4, if ambrisentan 5 mg was tolerated, the dose was increased to 10 mg every day for the remainder of the 24-week period.
    Measure Participants 22
    Mean (Standard Deviation) [mL/mmHg]
    0.8
    (1.4)
    4. Primary Outcome
    Title Change From Baseline in Peak Exercise Cardiac Output (CO)
    Description CO is the amount of blood pumped by the heart per minute.
    Time Frame Baseline to Week 24

    Outcome Measure Data

    Analysis Population Description
    The analysis population included evaluable participants who completed the 24-week treatment period.
    Arm/Group Title Exercise-induced PAH
    Arm/Group Description Ambrisentan 5 mg orally every day for 4 weeks. At Week 4, if ambrisentan 5 mg was tolerated, the dose was increased to 10 mg every day for the remainder of the 24-week period.
    Measure Participants 22
    Mean (Standard Deviation) [L/min]
    2.3
    (1.4)
    5. Primary Outcome
    Title Change From Baseline in Peak Exercise Maximum Oxygen Uptake (VO2max)
    Description VO2max is the measurement of the maximum amount of oxygen that an individual can utilize during intense or maximal exercise.
    Time Frame Baseline to Week 24

    Outcome Measure Data

    Analysis Population Description
    The analysis population included evaluable participants who completed the 24-week treatment period.
    Arm/Group Title Exercise-induced PAH
    Arm/Group Description Ambrisentan 5 mg orally every day for 4 weeks. At Week 4, if ambrisentan 5 mg was tolerated, the dose was increased to 10 mg every day for the remainder of the 24-week period.
    Measure Participants 22
    Mean (Standard Deviation) [percent predicted]
    4.4
    (2.6)
    6. Secondary Outcome
    Title Change From Baseline in 6-minute Walk Distance (6MWD)
    Description 6MWD is the distance walked by the participant in 6 minutes.
    Time Frame Baseline to Week 24

    Outcome Measure Data

    Analysis Population Description
    The analysis population included evaluable participants who completed the 24-week treatment period.
    Arm/Group Title Exercise-induced PAH
    Arm/Group Description Ambrisentan 5 mg orally every day for 4 weeks. At Week 4, if ambrisentan 5 mg was tolerated, the dose was increased to 10 mg every day for the remainder of the 24-week period.
    Measure Participants 22
    Mean (Standard Deviation) [meters]
    34.8
    (73.2)
    7. Secondary Outcome
    Title Borg Dyspnea Scale Score
    Description The Borg Dyspnea Scale measures how breathless the participant feels. Scores range from 0 (no shortness of breath) to 10 (more short of breath than ever experienced). (minimum score 0, maximum score 10 with 10 being worsening outcome)
    Time Frame Baseline and Week 24

    Outcome Measure Data

    Analysis Population Description
    The analysis population included evaluable participants who completed the 24-week treatment period.
    Arm/Group Title Exercise-induced PAH
    Arm/Group Description Ambrisentan 5 mg orally every day for 4 weeks. At Week 4, if ambrisentan 5 mg was tolerated, the dose was increased to 10 mg every day for the remainder of the 24-week period.
    Measure Participants 22
    Baseline
    5.1
    (2.8)
    Week 24
    3.0
    (0.9)
    8. Secondary Outcome
    Title World Health Organization Functional Class (WHO FC)
    Description The WHO FC categorizes cardiac disability using four classes, ranging from Class 1 (without limitation of physical activity) to Class 4 (inability to carry on any physical activity without discomfort).
    Time Frame Baseline and Week 24

    Outcome Measure Data

    Analysis Population Description
    The analysis population included evaluable participants who completed the 24-week treatment period.
    Arm/Group Title Exercise-induced PAH
    Arm/Group Description Ambrisentan 5 mg orally every day for 4 weeks. At Week 4, if ambrisentan 5 mg was tolerated, the dose was increased to 10 mg every day for the remainder of the 24-week period.
    Measure Participants 22
    Baseline
    2.0
    (0.6)
    Week 24
    1.5
    (0.6)

    Adverse Events

    Time Frame 24 weeks
    Adverse Event Reporting Description
    Arm/Group Title Exercise-induced PAH
    Arm/Group Description Ambrisentan 5 mg orally every day for 4 weeks. At Week 4, if ambrisentan 5 mg was tolerated, the dose was increased to 10 mg every day for the remainder of the 24-week period.
    All Cause Mortality
    Exercise-induced PAH
    Affected / at Risk (%) # Events
    Total / (NaN)
    Serious Adverse Events
    Exercise-induced PAH
    Affected / at Risk (%) # Events
    Total 0/30 (0%)
    Other (Not Including Serious) Adverse Events
    Exercise-induced PAH
    Affected / at Risk (%) # Events
    Total 25/30 (83.3%)
    Cardiac disorders
    Palpitations 1/30 (3.3%)
    Worsening dyspnea on exertion 8/30 (26.7%)
    Gastrointestinal disorders
    Gastrointestinal infection 2/30 (6.7%)
    Metabolism and nutrition disorders
    Peripheral edema 7/30 (23.3%)
    Musculoskeletal and connective tissue disorders
    Joint and body pain 3/30 (10%)
    Jaw pain 1/30 (3.3%)
    Nervous system disorders
    Headache 5/30 (16.7%)
    Dizziness 1/30 (3.3%)
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion 7/30 (23.3%)
    Increased cough 4/30 (13.3%)
    Upper respiratory infection 2/30 (6.7%)
    Skin and subcutaneous tissue disorders
    Rash 2/30 (6.7%)
    Vascular disorders
    Flushing 4/30 (13.3%)
    Nose bleed 1/30 (3.3%)

    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.

    Results Point of Contact

    Name/Title Aaron B. Waxman
    Organization Brigham and Women's Hospital Heart and Vascular Center
    Phone 617-525-9733
    Email abwaxman@partners.org
    Responsible Party:
    Aaron Waxman MD PhD, Director, Pulmonary Vascular Disease Program, Brigham and Women's Hospital
    ClinicalTrials.gov Identifier:
    NCT01338636
    Other Study ID Numbers:
    • 2008P000687
    First Posted:
    Apr 19, 2011
    Last Update Posted:
    Jan 18, 2022
    Last Verified:
    Jan 1, 2022