Effect of Bosentan on Skin Fibrosis in Patients With Systemic Sclerosis

Study Overview
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Brief Summary
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Endothelin-1 is a potent vasoconstrictor and binds to two receptors, ET-A and ET-B, which are variable expressed on endothelial cells, smooth muscle cells, and fibroblasts. Furthermore, endothelin-1 has been found to be released in vitro by scleroderma fibroblasts and could contribute to the development of dermal fibrosis in systemic sclerosis. Bosentan is a dual receptor antagonist, that competes with the binding of endothelin-1 to both receptors and has already been approved for the treatment of pulmonary arterial hypertension in Europe, the US, and some other countries. The purpose of this study is to evaluate the effect of bosentan treatment on skin fibrosis and functionality in patients with systemic sclerosis.

Detailed Description
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Systemic sclerosis (SSc) is a polymorphic disorder with an unknown cause characterized by fibrosis of the skin, blood vessels, and visceral organs. The degree of skin involvement is a very important outcome measure in patients with this disease. The pathogenesis of SSc involves immunologic mechanisms, vascular damage, and excessive accumulation of extracellular matrix component in the skin. One reason for these changes is meant to be an increased release of endothelin-1, a peptide which has vasoconstrictor effects and possesses mitogenic activity on cultured vascular smooth muscle cells and fibroblasts, cell types that are involved in SSc pathogenesis. Interestingly, endothelin-1 levels are raised in patients with SSc and Raynaud´s disease, particularly, in the subset of patients with diffuse cutaneous SSc who have widespread dermal sclerosis. However, skin fibrosis in SSc is a poorly studied, rare condition for which there are no approved therapies. Bosentan is a dual endothelin receptor antagonist, that competes with the binding of endothelin-1 to both receptors (ET-A and AT-B). It was recently shown to be effective in the treatment of idiopathic as well as pulmonary arterial hypertension (PAH) in SSc, but it has also been proved in two multicenter randomized prospective placebo-controlled double-blind studies in Europe and the US (RAPIDS-1 and RAPIDS-2) that there is a beneficial effect of bosentan in preventing digital ulcers in these patients. Furthermore,it has been suggested that bosentan has also a positive effect on skin fibrosis. In this study, skin fibrosis will be measured using 20-MHz-ultrasound, the Rodnan Skin Score, and investigation of the fist closure of each patient during treatment with bosentan over 24 weeks.

Official Title
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Study to Assess the Effect of Bosentan on the Treatment of Skin Fibrosis in Patients With Systemic Sclerosis (BTSF)

Conditions
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Hand Functionality, Systemic Scleroderma, Skin Fibrosis

Intervention / Treatment
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* Drug: Bosentan (Tracleer)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with systemic sclerosis (diffuse SSc, limited SSc) ACR criteria fulfilled Current areas of skin fibrosis due to SSc Women postmenopausal or negative pre-treatment pregnancy test as well as a reliable method of contraception during study treatment and for at least 3 months after study treatment termination Signed informed consent Exclusion Criteria: Severe PAH or interstitial lung disease (WHO class III and IV) Skin fibrosis and digital ulcers (DUs) due to conditions other than SSc Systolic BP < 85 mmHg Hemoglobin concentration < 75% of the lower limit of the normal range AST and/or ALT values greater than 3 times the upper limit of normal Moderate to severe hepatic impairment Severe malabsorption, severe organ failure or any life threatening condition Breast feeding Treatment with any of the following drugs: glibenclamide (glyburide), cyclosporine A, and tacrolimus 1 week prior to study participation Treatment with parenteral prostanoids 3 months prior to study participation Treatment with inhaled, subcutaneous or oral prostanoids 1 month prior to registration Systemic antibiotics to treat infection of DUs 2 weeks prior to study participation Current treatment with phosphodiesterase inhibitors such as sildenafil, except for intermittent treatment of male erectile dysfunction Patient with conditions that prevent compliance with the protocol or adhering to therapy Patient who received an investigational product within 1 month preceding screening Known hypersensitivity to bosentan or any of the excipients

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Bosentan (Tracleer)|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurable reduction of skin thickening using 20 MHz-ultrasound and the Rodnan Skin Score after treatment with study medication over 24 weeks in patients with systemic sclerosis. |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of bosentan on hand functionality measured by SHAQ, UK-functional score, and fist closure as well as on nitrosylated serum protein levels in the plasma of patients with systemic scleroderma. |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Systemic Scleroderma, Dermal Sclerosis, Bosentan, Endothelin Receptor Antagonist, Rodnan Skin Score