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

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ClinicalTrials.gov Identifier: NCT01093885
Recruitment Status : Completed
First Posted : March 26, 2010
Results First Posted : November 29, 2018
Last Update Posted : November 29, 2018
Sponsor:
Collaborator:
Gilead Sciences
Information provided by (Responsible Party):
University of Pennsylvania

Tracking Information
First Submitted Date  ICMJE March 24, 2010
First Posted Date  ICMJE March 26, 2010
Results First Submitted Date  ICMJE October 16, 2017
Results First Posted Date  ICMJE November 29, 2018
Last Update Posted Date November 29, 2018
Study Start Date  ICMJE February 2010
Actual Primary Completion Date July 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 26, 2018)
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 [ Time Frame: Baseline and 12 months ]
Using validated clinical response measurements such as the modified Rodnan skin score (MRSS) we will determine whether combination therapy will effect morbidity in systemic sclerosis. The modified Rodnan skin score has a range from 0-51 with higher numbers being worse skin involvement.
Original Primary Outcome Measures  ICMJE
 (submitted: March 24, 2010)
The primary objective of this study is to determine 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. [ Time Frame: Baseline, Month 1, 3, 6, 9, and Month 12. ]
Using validated clinical response measurements such as the modified Rodnan skin score (MRSS) and scleroderma health assessment questionnaire (SHAQ), we will determine whether combination therapy will effect morbidity in systemic sclerosis.
Change History Complete list of historical versions of study NCT01093885 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 26, 2018)
Systemic Sclerosis Quality of Life Assessed by the SF-36. [ Time Frame: Baseline vs Month 12. ]
The SF-36 form is a patient reported survey of patient health. The comparison status was analyzed between baseline and 12 months. The SF-36 has a range of 0-100 with higher numbers suggestive of better patient health
Original Secondary Outcome Measures  ICMJE
 (submitted: March 24, 2010)
Secondary objectives will examine systemic sclerosis as it relates to visceral organ involvement based on the Medsger severity scale as well as quality of life as assessed by the Scleroderma health assessment questionnaire (SHAQ) and SF-36. [ Time Frame: Baseline, Month 1, 3, 6, 9, and 12 month. ]
Using validated clinical response measurements such as the modified Rodnan skin score (MRSS)and scleroderma health assessment questionnaire (SHAQ), we will determine whether combination therapy will effect morbidity in systemic sclerosis.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Ambrisentan With Antifibrotic Agent Combination Therapy in Diffuse Systemic Sclerosis
Official Title  ICMJE An Open Label Study of Ambrisentan With Antifibrotic Agent Combination Therapy in Treatment of Diffuse Systemic Sclerosis
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Intervention Model: Single Group Assignment
Intervention Model Description:
Single arm open label study.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Systemic Sclerosis
  • Scleroderma
Intervention  ICMJE Drug: Ambrisentan

Drug is dispensed in tablet form. Ambrisentan with anti-fibrotic to assess benefit on skin

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.

Other Names:
  • LETAIRIS (ambrisentan) tablets for oral use
  • Initial U.S. Approval: 2007
Study Arms  ICMJE open label: medication Ambrisentan

Open label study of Ambrisentan.

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.

** Dose escalation was attempted however none of the patients were able to increase. Therefore all subjects remained on 5 mg daily throughout the study. 12 patients on mycophenolate mofetil, 2 on mycophenolic acid and one on methotrexate

Intervention: Drug: Ambrisentan
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 24, 2010)
15
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE July 2016
Actual Primary Completion Date July 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 19 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01093885
Other Study ID Numbers  ICMJE Ambrj55501.
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of Pennsylvania
Study Sponsor  ICMJE University of Pennsylvania
Collaborators  ICMJE Gilead Sciences
Investigators  ICMJE
Principal Investigator: Chris Derk, MD, MSc University of Pennsylvania
PRS Account University of Pennsylvania
Verification Date November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP