Pulmonary Hypertension, Systemic Scleroderma
Conditions
Keywords
scleroderma, systemic sclerosis, bosentan, pulmonary hypertension, PHAROS, PHROS, exercise echocardiogram
Brief summary
The purpose of this study is to determine whether the drug Bosentan improves exercise tolerance in scleroderma patients.
Detailed description
Pulmonary hypertension (PAH) is a common and usually fatal form of lung disease in systemic sclerosis (SSc). Multiple drugs have been approved for the treatment of New York Heart Association (NYHA)Class III/IV PAH in scleroderma. Bosentan is an endothelin-1 antagonist which showed significant improvement in distance walked during 12 week clinical trials in PAH patients (7). Therapy for asymptomatic systemic sclerosis patients diagnosed incidentally with PAH (World Health Organization (WHO) Functional Class I) remains controversial. We hypothesize that asymptomatic or minimally symptomatic patients with systemic sclerosis and normal resting pulmonary artery pressures who demonstrate an abnormal rise in pulmonary artery systolic pressure with stress Doppler echocardiography testing represent a subset of patients who already have pulmonary vascular disease and who are at risk for the development of severe PAH. We further hypothesize that early identification and treatment of such patients may retard the progression of that disease. Hypotheses: 1. Stress echocardiography identifies early pulmonary vascular disease by detecting exercise-induced pulmonary hypertension in patients with systemic sclerosis. 2. Treatment of exercise-induced PAH with Bosentan will lead to improved exercise endurance in patients with systemic sclerosis. Subjects will be recruited from those patients who have had an abnormal exercise test as part of an earlier study, Exercise Echocardiograms in Scleroderma (IRB# 03-363).
Interventions
DRUGBosentan
62.5 mg by mouth (PO) twice daily (Bid) for 1 month, followed by 125 mg PO Bid thereafter, for a total of 16 weeks
DRUGPlacebo
62.5 mg PO Bid for 1 month, followed by 125 mg PO Bid thereafter, for a total of 16 weeks
Sponsors
Actelion
Georgetown University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* SSc patients \> 18 with NYHA functional Class I/II symptoms, informed consent, and who are willing to participate in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) long term study (Georgetown IRB 04-227) * Right heart catheterization with 1. Normal Mean Pulmonary Arterial Pressure (PAP) at rest 2. Mean PAP \> 30 with exercise 3. Wedge Pressure \< 18 * Entry criteria for participating in the exercise echocardiogram study (Georegtown IRB 03-363) 1. Diffusing Capacity (DLCO) \<60 with a Forced Vital Capacity (FVC) \>60%, or 2. FVC/DLCO \> 1.6, or 3. a resting Pulmonary Arterial Systolic Pressure (PASP)\> 40mmHg
Exclusion criteria
* Established resting pulmonary hypertension * Congestive heart failure * Diastolic dysfunction * Pregnancy * Inability to adequately walk/exercise * Severe liver disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Exercise Time on the Exercise Echocardiogram Using the Standard Bruce Stress Protocol. | This will be determined after 16 weeks on the study medication. | The total exercise time measured using the exercise echocardiogram is evaluated with the standard Bruce Stress Protocol, and this will be determined after 16 weeks on the study medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 6-minute Walk Distance | 16 weeks | The distance walked during a 6-minute walk test. |
| Brain Natriuretic Peptide (BNP) Level | 16 weeks | Serum BNP level to evaluate Brain Natriuretic Peptide (BNP) level |
| Endothelin-1(ET-1) Level | 16 weeks | From saved serum to determine Endothelian-1 (ET-1) levels in patients |
| Quality of Life (QOL) | 16 weeks | QOL is measured using the Short Form 36 Health Survey (SF-36, which measures health on eight dimensions: general health perception, physical and social functioning, role limitations by physical or emotional problems, mental health, vitality, and bodily pain. For each dimension items are coded, summed, and transformed on to a scale from 0 (worst health) to 100 (best health). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bosentan and Placebo Arms This group consists of subjects on both arms of the study - bosentan and placebo | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Bosentan and Placebo Arms |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 5 |
| serious Total, serious adverse events | 0 / 5 |
Outcome results
Primary
Total Exercise Time on the Exercise Echocardiogram Using the Standard Bruce Stress Protocol.
The total exercise time measured using the exercise echocardiogram is evaluated with the standard Bruce Stress Protocol, and this will be determined after 16 weeks on the study medication.
Time frame: This will be determined after 16 weeks on the study medication.
Secondary
6-minute Walk Distance
The distance walked during a 6-minute walk test.
Time frame: 16 weeks
Population: Outcomes not available, due to early termination of study
Secondary
Brain Natriuretic Peptide (BNP) Level
Serum BNP level to evaluate Brain Natriuretic Peptide (BNP) level
Time frame: 16 weeks
Population: Outcomes not available, due to early termination of study
Secondary
Endothelin-1(ET-1) Level
From saved serum to determine Endothelian-1 (ET-1) levels in patients
Time frame: 16 weeks
Population: Outcomes not available, due to early termination of study
Secondary
Quality of Life (QOL)
QOL is measured using the Short Form 36 Health Survey (SF-36, which measures health on eight dimensions: general health perception, physical and social functioning, role limitations by physical or emotional problems, mental health, vitality, and bodily pain. For each dimension items are coded, summed, and transformed on to a scale from 0 (worst health) to 100 (best health).
Time frame: 16 weeks
Population: Outcomes not available, due to early termination of study