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Effect of Bosentan on Skin Fibrosis in Patients With Systemic Sclerosis

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00318175
First Posted: April 26, 2006
Last Update Posted: September 10, 2007
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by:
Heinrich-Heine University, Duesseldorf
  Purpose
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.

Condition Intervention Phase
Systemic Scleroderma Skin Fibrosis Hand Functionality Drug: Bosentan (Tracleer) Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Study to Assess the Effect of Bosentan on the Treatment of Skin Fibrosis in Patients With Systemic Sclerosis (BTSF)

Resource links provided by NLM:


Further study details as provided by Heinrich-Heine University, Duesseldorf:

Primary Outcome Measures:
  • 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:
  • 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.

Estimated Enrollment: 10
Study Start Date: June 2006
Study Completion Date: May 2007
Detailed Description:
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.
  Eligibility

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00318175


Locations
Germany
Heinrich-Heine-University of Duesseldorf, Department of Dermatology
Duesseldorf, NRW, Germany, 40225
Sponsors and Collaborators
Heinrich-Heine University, Duesseldorf
Investigators
Principal Investigator: Annegret Kuhn, MD Heinrich-Heine-University of Duesseldorf, Department of Dermatology
  More Information

Publications:
ClinicalTrials.gov Identifier: NCT00318175     History of Changes
Other Study ID Numbers: AMG 002
2005-000798-23
First Submitted: April 24, 2006
First Posted: April 26, 2006
Last Update Posted: September 10, 2007
Last Verified: September 2007

Keywords provided by Heinrich-Heine University, Duesseldorf:
Systemic Scleroderma
Dermal Sclerosis
Bosentan
Endothelin Receptor Antagonist
Rodnan Skin Score

Additional relevant MeSH terms:
Scleroderma, Systemic
Scleroderma, Diffuse
Sclerosis
Fibrosis
Pathologic Processes
Connective Tissue Diseases
Skin Diseases
Bosentan
Endothelin Receptor Antagonists
Antihypertensive Agents
Molecular Mechanisms of Pharmacological Action