Study of Ambrisentan With Antifibrotic Agent Combination Therapy in Diffuse Systemic Sclerosis

This is an open label, single center study to determine the efficacy and safety of ambrisentan and antifibrotic agent combination in systemic sclerosis. Up to twenty patients will be recruited within the next year who have early diffuse systemic sclerosis and are presently receiving treatment with any of the following antifibrotic agents - cellcept, colchicine, azathioprine, D-penicillamine, methotrexate or cyclophosphamide. Ambrisentan will be added to the present agent and then followed for 12 months.

Patients, male or female, > 18 years with a clinical diagnosis of systemic sclerosis fulfilling the criteria of the American College of Rheumatology (formerly the American Rheumatism Association) classification criteria for systemic sclerosis (24), and diffuse cutaneous involvement based on the criteria of LeRoy et al

A thorough baseline evaluation will determine the extent and severity of systemic sclerosis in the individual patients using laboratory studies and the clinical evaluation. Monthly follow-ups will capture any safety issues related to the combination therapy based again on laboratory studies and clinical evaluation. At the six month and twelve month follow-up a thorough evaluation will again be undertaken to evaluate the extent and severity of the disorder. Event driven follow-ups will also take place to record and establish any safety issues that may arise. Clinical end-points will be the focus of this study.

Dosing of ambrisentan will begin at 5mg daily for the first month. Half the patients will remain at 5mg daily, while the remaining patients will be increased to a maintenance dose of 10mg daily on the fourth week. Subjects will continue their present dose and schedule of disease modifying/antifibrotic medication for the duration of the study.

Inclusion criteria

Patients, male or female, greater than 18 years with a clinical diagnosis of systemic sclerosis fulfilling the criteria of the American College of Rheumatology (formerly the American Rheumatism Association) classification criteria for systemic sclerosis, and diffuse cutaneous involvement based on the criteria of LeRoy et al

• Onset of skin sclerosis less than or equal to 48 months before study entry.
• Extent of skin sclerosis involving the trunk and/or arms and legs proximally to the elbows and/or knees.
• Present regimen consisting of one of the following: cellcept, D-penicillamine, methotrexate or cyclophosphamide.
• Previous history of using an alternative antifibrotic agent prior to present regimen will be permitted.
• Total antifibrotic treatment regimen duration should be less than or equal to 48 months.

Exclusion criteria

• Systemic sclerosis with skin involvement confined to face or acral regions of the body.
• Chemically induced scleroderma.
• Diffuse fasciitis.
• Mixed connective tissue disease and overlap syndromes.
• Pregnancy or nursing.
• Use of non-reliable method of contraception.
• Major surgery in the past month.
• Inability or unwillingness to provide written informed consent.
• Inability or unwillingness to comply with the requirements of the protocol as determined by the investigator.
• Known hypersensitivity or contraindication to ambrisentan