Exercise Induced Pulmonary Hypertension in Systemic Sclerosis and Treatment With Ambrisentan

Sponsor
University of California, Los Angeles (Other)
Overall Status
Completed
CT.gov ID
NCT01051960
Collaborator
Gilead Sciences (Industry)
12
1
1
22
0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the clinical characteristics and hemodynamic profiles that predict exercise induced pulmonary hypertension in 15 patients with systemic sclerosis. The study also aims to determine the effectiveness of Ambrisentan for subjects with exercise induced Pulmonary Arterial Hypertension (PAH) with scleroderma

Condition or Disease Intervention/Treatment Phase
Phase 4

Detailed Description

The current literature addresses therapies for patients with resting PAH only, diagnosed by right heart catheterization. However, the World Health Organization (WHO) also recognizes and defines exercise induced pulmonary arterial hypertension (ex-PAH), which may precede the development of resting PAH. The natural progression of PAH, especially during exercise, has not been well delineated. An exercise hemodynamic study previously showed that in normal healthy subjects the mean pulmonary pressure does not exceed 30mmHg even at maximal cardiac outputs. A prior study evaluated exercise Doppler echocardiography systemic sclerosis patients with normal resting echocardiograms, finding an abnormal response which was defined as an estimated right ventricular systolic pressure greater than 40 mmHg. In the same study, 6.6% of the patients progressed to resting PAH over the followup period of 12 months. Limited data is available regarding the prevalence of ex-PAH in systemic sclerosis using right heart catheterization.

Study Design

Study Type:
Interventional
Actual Enrollment :
12 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Exercise Induced Pulmonary Hypertension in Systemic Sclerosis and Treatment With Ambrisentan: A Prospective Single Center, Open Label, Pilot Study
Actual Study Start Date :
Mar 1, 2009
Actual Primary Completion Date :
Jun 1, 2010
Actual Study Completion Date :
Jan 1, 2011

Arms and Interventions

Arm Intervention/Treatment
Experimental: ambrisentan

ambrisentan dosed at either 5mg or 10mg orally once per day

Drug: Ambrisentan
Ambrisentan 5mg or 10mg once daily
Other Names:
  • Letairis
  • Outcome Measures

    Primary Outcome Measures

    1. Change in Exercise Pulmonary Hemodynamics From Baseline to Week 24 [24 weeks]

      We defined ePH (exercise PH) as an mPAP of 30 mmHg, PCWP of 18 mm Hg, and a transpulmonary gradient (TPG) of 15 mm Hg, where TPG equals mPAP minus PCWP. We defined ePVH (exercise pulmonary venous hypertension) as an mPAP of 30 mm Hg, PCWP of 18 mm Hg, and a TPG of 15 mm Hg. We defined eoPH (exercise out of proportion) as an mPAP of 30 mm Hg, PCWP of 18 mm Hg, and a TPG of 15 mm Hg (4). Our hypothesis was that SSc patients with normal exercise physiology and ePVH have a different patho-physiology compared to patients with pulmonary vascular disease (ePH and eoPH).

    Secondary Outcome Measures

    1. Change in Distance Walked in Six Minutes From Baseline to 24 Week [24 weeks]

      ATS guideline based assessment with known minimally clinically important difference

    2. Quality of Life (QOL) Based on SF36 and HAQ-DI [24 weeks]

      Number of participants exceeding minimally important difference estimates on changes in quality of life as assessed by SF-36 (short form 36) quality of life index with mental and physical component scores, or by HAQ-DI (health assessment questionnaire disability index) limitations that may be related to musculoskeletal limitations

    3. HAQ-DI (Health Assessment Questionnaire Disability Index) [24 weeks]

      Assessing limitations that may be related to musculoskeletal limitations, the HAQ-DI assesses the difficulty a participant has had in the past week in 8 domains of daily living activities: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and other activities. Each activity category consists of 2-3 items in which level of difficulty is scored from 0 to 3 with 0=no difficulty, 1=some difficulty, 2=much difficulty, and 3=unable to do. The 8 domain scores are averaged into a total HAQ-DI score ranging from 0 (no disability) to 3 (completely disabled).

    4. St. George's Respiratory Questionnaire [24 weeks]

      To assess overall health, daily life, and perceived well-being in patients with underlying lung disease, the SGRQ is a health-related quality of life questionnaire divided into 3 components : symptoms, activity and impact. The total score (summed weights) can range from 0 to 100 with a lower score denoting a better health status.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 80 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Systemic Sclerosis diagnosed by the American College of Rheumatology consensus statement including any of the following:
    • Limited

    • Diffuse

    • Sine Scleroderma

    1. Patients must be willing and able to undergo right heart catheterization with lower extremity cycle ergometry

    2. Mean pulmonary artery pressure (mPAP) > 30mmHg with exercise; PCWP ≤ 15mmHg on RHC at rest

    3. Men and women, ages 18 years of age or older

    4. Standard adjunctive medications will be allowed concurrently in this study at the discretion of the treating pulmonologist and rheumatologist, including digoxin, diuretics, anticoagulants (e.g. warfarin), stable immunosuppression or other anti-fibrotic therapy for at least one month prior to enrollment

    Exclusion Criteria:
    1. Resting PAH (mPAP > 25mmHg) on right heart catheterization

    2. Other known causes of PAH including prior venous thromboembolism, HIV infection, chronic liver disease with portal hypertension, left ventricular systolic dysfunction (e.g. LVEF < 40%), and congenital causes of PAH

    3. Severe hepatic disease precluding the use of ambrisentan (AST/ALT ≥3x ULN).

    4. Women who are pregnant or breastfeeding.

    5. Concurrent therapy with a prostanoid or prostanoid analogue, PDE5 inhibitors, or enrolled in another active clinical study.

    6. Use of any prostacyclin or endothelial receptor antagonist (ERA) within 30 days before study entry.

    7. Bed or wheel chair bound or a baseline 6-Minute Walk distance (6MWD) less than 150 meters.

    8. Childbearing capable women who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period.

    9. New York Heart Association (NYHA) Classification: Class IV

    10. Renal dysfunction (serum creatinine >2.5mg/dL).

    11. Uncontrolled sleep apnea.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 David Geffen School of Medicine, University of California, Los Angeles Los Angeles California United States 90095

    Sponsors and Collaborators

    • University of California, Los Angeles
    • Gilead Sciences

    Investigators

    • Principal Investigator: Rajeev Saggar, MD, University of California, Los Angeles
    • Principal Investigator: Dinesh Khanna, MD, University of California, Los Angeles

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    University of California, Los Angeles
    ClinicalTrials.gov Identifier:
    NCT01051960
    Other Study ID Numbers:
    • 10-000567
    First Posted:
    Jan 20, 2010
    Last Update Posted:
    Nov 2, 2020
    Last Verified:
    Oct 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Keywords provided by University of California, Los Angeles
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details 15 participants were screened, and 12 were eligible and enrolled in the study
    Pre-assignment Detail
    Arm/Group Title Ambrisentan
    Arm/Group Description ambrisentan dosed at either 5mg or 10mg orally once per day Ambrisentan: Ambrisentan 5mg or 10mg once daily
    Period Title: Overall Study
    STARTED 12
    COMPLETED 11
    NOT COMPLETED 1

    Baseline Characteristics

    Arm/Group Title Ambrisentan
    Arm/Group Description ambrisentan dosed at either 5mg or 10mg orally once per day Ambrisentan: Ambrisentan 5mg or 10mg once daily
    Overall Participants 12
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    47.6
    (19.4)
    Sex: Female, Male (Count of Participants)
    Female
    11
    91.7%
    Male
    1
    8.3%
    Region of Enrollment (participants) [Number]
    United States
    12
    100%

    Outcome Measures

    1. Primary Outcome
    Title Change in Exercise Pulmonary Hemodynamics From Baseline to Week 24
    Description We defined ePH (exercise PH) as an mPAP of 30 mmHg, PCWP of 18 mm Hg, and a transpulmonary gradient (TPG) of 15 mm Hg, where TPG equals mPAP minus PCWP. We defined ePVH (exercise pulmonary venous hypertension) as an mPAP of 30 mm Hg, PCWP of 18 mm Hg, and a TPG of 15 mm Hg. We defined eoPH (exercise out of proportion) as an mPAP of 30 mm Hg, PCWP of 18 mm Hg, and a TPG of 15 mm Hg (4). Our hypothesis was that SSc patients with normal exercise physiology and ePVH have a different patho-physiology compared to patients with pulmonary vascular disease (ePH and eoPH).
    Time Frame 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Ambrisentan
    Arm/Group Description ambrisentan dosed at either 5mg or 10mg orally once per day Ambrisentan: Ambrisentan 5mg or 10mg once daily
    Measure Participants 11
    Mean (Standard Deviation) [mmHg]
    37.4
    (8.3)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ambrisentan
    Comments Whether change from baseline to 24-weeks is significantly different from zero
    Type of Statistical Test Other
    Comments comparison of means
    Statistical Test of Hypothesis p-Value .0008
    Comments significant at p<0.05
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Final Values)
    Estimated Value -93.0
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Change in Distance Walked in Six Minutes From Baseline to 24 Week
    Description ATS guideline based assessment with known minimally clinically important difference
    Time Frame 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Ambrisentan
    Arm/Group Description ambrisentan dosed at either 5mg or 10mg orally once per day Ambrisentan: Ambrisentan 5mg or 10mg once daily
    Measure Participants 11
    Mean (Standard Deviation) [meters]
    44.5
    (10.3)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ambrisentan
    Comments change from baseline to 24 weeks
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.00007
    Comments
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Final Values)
    Estimated Value 44.5
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Quality of Life (QOL) Based on SF36 and HAQ-DI
    Description Number of participants exceeding minimally important difference estimates on changes in quality of life as assessed by SF-36 (short form 36) quality of life index with mental and physical component scores, or by HAQ-DI (health assessment questionnaire disability index) limitations that may be related to musculoskeletal limitations
    Time Frame 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Ambrisentan
    Arm/Group Description ambrisentan dosed at either 5mg or 10mg orally once per day Ambrisentan: Ambrisentan 5mg or 10mg once daily
    Measure Participants 11
    Count of Participants [Participants]
    0
    0%
    4. Secondary Outcome
    Title HAQ-DI (Health Assessment Questionnaire Disability Index)
    Description Assessing limitations that may be related to musculoskeletal limitations, the HAQ-DI assesses the difficulty a participant has had in the past week in 8 domains of daily living activities: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and other activities. Each activity category consists of 2-3 items in which level of difficulty is scored from 0 to 3 with 0=no difficulty, 1=some difficulty, 2=much difficulty, and 3=unable to do. The 8 domain scores are averaged into a total HAQ-DI score ranging from 0 (no disability) to 3 (completely disabled).
    Time Frame 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Ambrisentan
    Arm/Group Description ambrisentan dosed at either 5mg or 10mg orally once per day Ambrisentan: Ambrisentan 5mg or 10mg once daily
    Measure Participants 12
    Mean (Standard Deviation) [score on a scale]
    1.12
    (0.02)
    5. Secondary Outcome
    Title St. George's Respiratory Questionnaire
    Description To assess overall health, daily life, and perceived well-being in patients with underlying lung disease, the SGRQ is a health-related quality of life questionnaire divided into 3 components : symptoms, activity and impact. The total score (summed weights) can range from 0 to 100 with a lower score denoting a better health status.
    Time Frame 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Ambrisentan
    Arm/Group Description ambrisentan dosed at either 5mg or 10mg orally once per day Ambrisentan: Ambrisentan 5mg or 10mg once daily
    Measure Participants 12
    Mean (Standard Deviation) [score on a scale]
    13.2
    (11.7)

    Adverse Events

    Time Frame 24 weeks
    Adverse Event Reporting Description
    Arm/Group Title Ambrisentan
    Arm/Group Description ambrisentan dosed at either 5mg or 10mg orally once per day Ambrisentan: Ambrisentan 5mg or 10mg once daily
    All Cause Mortality
    Ambrisentan
    Affected / at Risk (%) # Events
    Total 0/12 (0%)
    Serious Adverse Events
    Ambrisentan
    Affected / at Risk (%) # Events
    Total 1/12 (8.3%)
    Blood and lymphatic system disorders
    edema 1/12 (8.3%) 1
    Other (Not Including Serious) Adverse Events
    Ambrisentan
    Affected / at Risk (%) # Events
    Total 12/12 (100%)
    Blood and lymphatic system disorders
    Edema 5/12 (41.7%) 5
    Gastrointestinal disorders
    Constipation 1/12 (8.3%) 1
    Fecal incontinence 1/12 (8.3%) 1
    General disorders
    Joint and body pain 1/12 (8.3%) 1
    Headache 1/12 (8.3%) 1
    Hepatobiliary disorders
    Elevated liver function tests 1/12 (8.3%) 1
    Immune system disorders
    Allergic reaction 1/12 (8.3%) 1
    Musculoskeletal and connective tissue disorders
    Pulled muscle 1/12 (8.3%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bronchoalveolar carcinoma 1/12 (8.3%) 1
    Respiratory, thoracic and mediastinal disorders
    Upper respiratory symptoms 2/12 (16.7%) 2
    Nasal Congestion 5/12 (41.7%) 5
    Skin and subcutaneous tissue disorders
    Tinea Corporis 1/12 (8.3%) 1

    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 Rajan Saggar, MD
    Organization University of California, Los Angeles
    Phone (310) 794-9718
    Email rsaggar@mednet.ucla.edu
    Responsible Party:
    University of California, Los Angeles
    ClinicalTrials.gov Identifier:
    NCT01051960
    Other Study ID Numbers:
    • 10-000567
    First Posted:
    Jan 20, 2010
    Last Update Posted:
    Nov 2, 2020
    Last Verified:
    Oct 1, 2020