Pulmonary Hypertension, Shortness of Breath, Systemic Sclerosis
Conditions
Keywords
Systemic Sclerosis, connective tissue disease, Shortness of breath, Pulmonary Hypertension
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
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.
Interventions
DRUGAmbrisentan
Ambrisentan 5mg or 10mg once daily
Sponsors
Gilead Sciences
University of California, Los Angeles
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
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 2. Patients must be willing and able to undergo right heart catheterization with lower extremity cycle ergometry 3. Mean pulmonary artery pressure (mPAP) \> 30mmHg with exercise; PCWP ≤ 15mmHg on RHC at rest 4. Men and women, ages 18 years of age or older 5. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
15 participants were screened, and 12 were eligible and enrolled in the study
Participants by arm
| Arm | Count |
|---|---|
| Ambrisentan ambrisentan dosed at either 5mg or 10mg orally once per day
Ambrisentan: Ambrisentan 5mg or 10mg once daily | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Ambrisentan |
|---|---|
| Age, Continuous | 47.6 years STANDARD_DEVIATION 19.4 |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 12 |
| other Total, other adverse events | 12 / 12 |
| serious Total, serious adverse events | 1 / 12 |
Outcome results
Primary
Change in Exercise Pulmonary Hemodynamics From Baseline to Week 24
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan | Change in Exercise Pulmonary Hemodynamics From Baseline to Week 24 | 37.4 mmHg | Standard Deviation 8.3 |
Comparison: Whether change from baseline to 24-weeks is significantly different from zerop-value: 0.0008t-test, 2 sided
Secondary
Change in Distance Walked in Six Minutes From Baseline to 24 Week
ATS guideline based assessment with known minimally clinically important difference
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan | Change in Distance Walked in Six Minutes From Baseline to 24 Week | 44.5 meters | Standard Deviation 10.3 |
Comparison: change from baseline to 24 weeksp-value: 0.00007t-test, 2 sided
Secondary
HAQ-DI (Health Assessment Questionnaire Disability Index)
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan | HAQ-DI (Health Assessment Questionnaire Disability Index) | 1.12 score on a scale | Standard Deviation 0.02 |
Secondary
Quality of Life (QOL) Based on SF36 and HAQ-DI
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ambrisentan | Quality of Life (QOL) Based on SF36 and HAQ-DI | 0 Participants |
Secondary
St. George's Respiratory Questionnaire
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan | St. George's Respiratory Questionnaire | 13.2 score on a scale | Standard Deviation 11.7 |