Exercise Induced Pulmonary Hypertension in Systemic Sclerosis and Treatment With Ambrisentan
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
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:
|
Outcome Measures
Primary Outcome Measures
- 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
- Change in Distance Walked in Six Minutes From Baseline to 24 Week [24 weeks]
ATS guideline based assessment with known minimally clinically important difference
- 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
- 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).
- 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
Inclusion Criteria:
- Systemic Sclerosis diagnosed by the American College of Rheumatology consensus statement including any of the following:
-
Limited
-
Diffuse
-
Sine Scleroderma
-
Patients must be willing and able to undergo right heart catheterization with lower extremity cycle ergometry
-
Mean pulmonary artery pressure (mPAP) > 30mmHg with exercise; PCWP ≤ 15mmHg on RHC at rest
-
Men and women, ages 18 years of age or older
-
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:
-
Resting PAH (mPAP > 25mmHg) on right heart catheterization
-
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
-
Severe hepatic disease precluding the use of ambrisentan (AST/ALT ≥3x ULN).
-
Women who are pregnant or breastfeeding.
-
Concurrent therapy with a prostanoid or prostanoid analogue, PDE5 inhibitors, or enrolled in another active clinical study.
-
Use of any prostacyclin or endothelial receptor antagonist (ERA) within 30 days before study entry.
-
Bed or wheel chair bound or a baseline 6-Minute Walk distance (6MWD) less than 150 meters.
-
Childbearing capable women who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period.
-
New York Heart Association (NYHA) Classification: Class IV
-
Renal dysfunction (serum creatinine >2.5mg/dL).
-
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.- 10-000567
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
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 |
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 |
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%
|
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)
|
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
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 |
rsaggar@mednet.ucla.edu |
- 10-000567