Study of Ambrisentan With Antifibrotic Agent Combination Therapy in Diffuse Systemic Sclerosis
| Status: | Completed |
|---|---|
| Conditions: | Skin and Soft Tissue Infections, Neurology, Dermatology |
| Therapuetic Areas: | Dermatology / Plastic Surgery, Neurology |
| Healthy: | No |
| Age Range: | 19 - 90 |
| Updated: | 12/1/2018 |
| Start Date: | February 2010 |
| End Date: | July 2016 |
An Open Label Study of Ambrisentan With Antifibrotic Agent Combination Therapy in Treatment of Diffuse Systemic Sclerosis
Systemic sclerosis is a chronic autoimmune connective tissue disorder with no universally
accepted disease modifying regimen. Recruiting patients for systemic sclerosis treatment
studies is difficult due to the limited availability of such patients and furthermore the use
of a placebo arm is often deemed unethical due to the poor survival of diffuse systemic
sclerosis patients.
Long-term controlled trials examining functional outcomes and survival from novel therapeutic
agents for systemic sclerosis are often difficult to undertake because of costs, rarity of
the disease and ethical issues with the use of a true placebo. Open label single center
studies while inferior to multicenter placebo controlled studies, have helped establish the
benefits of certain pharmaceutical agents in systemic sclerosis, and while not universally
accepted as disease modifying agents, have been used with some success to treat systemic
sclerosis.
The hypothesis on which we are basing this study is that an endothelin receptor antagonist
and disease modifying agent with antifibrotic properties will have additive influence on
fibrosis, inhibit cellular and humoral hyperactivity and interfere with smooth muscle
proliferation in the vessel wall. The combination of these two agents will also be the first
regimen to address the heterogeneity of scleroderma manifestations including ILD, pulmonary
arterial hypertension and skin manifestations
accepted disease modifying regimen. Recruiting patients for systemic sclerosis treatment
studies is difficult due to the limited availability of such patients and furthermore the use
of a placebo arm is often deemed unethical due to the poor survival of diffuse systemic
sclerosis patients.
Long-term controlled trials examining functional outcomes and survival from novel therapeutic
agents for systemic sclerosis are often difficult to undertake because of costs, rarity of
the disease and ethical issues with the use of a true placebo. Open label single center
studies while inferior to multicenter placebo controlled studies, have helped establish the
benefits of certain pharmaceutical agents in systemic sclerosis, and while not universally
accepted as disease modifying agents, have been used with some success to treat systemic
sclerosis.
The hypothesis on which we are basing this study is that an endothelin receptor antagonist
and disease modifying agent with antifibrotic properties will have additive influence on
fibrosis, inhibit cellular and humoral hyperactivity and interfere with smooth muscle
proliferation in the vessel wall. The combination of these two agents will also be the first
regimen to address the heterogeneity of scleroderma manifestations including ILD, pulmonary
arterial hypertension and skin manifestations
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.
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
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