Placebo Controlled Trial of Bosentan in Scleroderma Patients

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the drug Bosentan improves exercise tolerance in scleroderma patients.

Detailed Description
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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: Stress echocardiography identifies early pulmonary vascular disease by detecting exercise-induced pulmonary hypertension in patients with systemic sclerosis. 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).

Official Title
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Placebo Controlled Trial of Bosentan vs Placebo in NYHA Class I/II Scleroderma Patients With Exercise Induced Pulmonary Hypertension

Conditions
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Systemic Scleroderma, Pulmonary Hypertension

Intervention / Treatment
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* Drug: Bosentan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 Normal Mean Pulmonary Arterial Pressure (PAP) at rest Mean PAP > 30 with exercise Wedge Pressure < 18 Entry criteria for participating in the exercise echocardiogram study (Georegtown IRB 03-363) Diffusing Capacity (DLCO) <60 with a Forced Vital Capacity (FVC) >60%, or FVC/DLCO > 1.6, or 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bosentan<br> | Drug: Bosentan<br>* 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<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* 62.5 mg PO Bid for 1 month, followed by 125 mg PO Bid thereafter, for a total of 16 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | This will be determined after 16 weeks on the study medication. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-minute Walk Distance | The distance walked during a 6-minute walk test. | 16 weeks | 
| Brain Natriuretic Peptide (BNP) Level | Serum BNP level to evaluate Brain Natriuretic Peptide (BNP) level | 16 weeks | 
| Endothelin-1(ET-1) Level | From saved serum to determine Endothelian-1 (ET-1) levels in patients | 16 weeks | 
| 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). | 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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scleroderma, systemic sclerosis, bosentan, pulmonary hypertension, PHAROS, PHROS, exercise echocardiogram