Clinical trial NCT01093885: Study of Ambrisentan With Antifibrotic Agent Combination Therapy in Diffuse Systemic Sclerosis
Official title: An Open Label Study of Ambrisentan With Antifibrotic Agent Combination Therapy in Treatment of Diffuse Systemic Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Systemic Sclerosis
Scleroderma
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: Gilead Sciences
First posted: 2010-03-26
Enrollment: 15
Sex: ALL
Minimum age (years): 19
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Single arm open label study.
Primary purpose: TREATMENT

Brief summary: 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

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: The Benefit That an Antifibrotic Agent and Ambrisentan Combination Have on the Cutaneous Involvement of Patients With Early Diffuse Systemic Sclerosis by Utilizing the MRSS
timeFrame: Baseline and 12 months
Secondary outcomes:
measure: Systemic Sclerosis Quality of Life Assessed by the SF-36.
timeFrame: Baseline vs Month 12.
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: University of Pennsylvania Health System
state: Pennsylvania
Study officials:
affiliation: University of Pennsylvania
name: Chris Derk, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Schorpion A, Shenin M, Neubauer R, Derk CT. A prospective, open-label, non-comparative study of ambrisentan with anti-fibrotic agent combination therapy in the treatment of diffuse systemic sclerosis. BMC Rheumatol. 2018 May 15;2:13. doi: 10.1186/s41927-018-0021-z. eCollection 2018.