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

Sponsor
University of Pennsylvania (Other)
Overall Status
Completed
CT.gov ID
NCT01093885
Collaborator
Gilead Sciences (Industry)
15
Enrollment
1
Location
1
Arm
76.9
Duration (Months)
0.2
Patients Per Site Per Month

Study Details

Study Description

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

Condition or DiseaseIntervention/TreatmentPhase
N/A

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 Design

Study Type:
Interventional
Actual Enrollment :
15 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Intervention Model Description:
Single arm open label study.Single arm open label study.
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
An Open Label Study of Ambrisentan With Antifibrotic Agent Combination Therapy in Treatment of Diffuse Systemic Sclerosis
Study Start Date :
Feb 1, 2010
Actual Primary Completion Date :
Jul 1, 2016
Actual Study Completion Date :
Jul 1, 2016

Arms and Interventions

ArmIntervention/Treatment
Other: 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

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
  • Outcome Measures

    Primary Outcome Measures

    1. 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 [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.

    Secondary Outcome Measures

    1. Systemic Sclerosis Quality of Life Assessed by the SF-36. [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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    19 Years to 90 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1University of Pennsylvania Health SystemPhiladelphiaPennsylvaniaUnited States19104

    Sponsors and Collaborators

    • University of Pennsylvania
    • Gilead Sciences

    Investigators

    • Principal Investigator: Chris Derk, MD, MSc, University of Pennsylvania

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    University of Pennsylvania
    ClinicalTrials.gov Identifier:
    NCT01093885
    Other Study ID Numbers:
    • Ambrj55501.
    First Posted:
    Mar 26, 2010
    Last Update Posted:
    Nov 29, 2018
    Last Verified:
    Nov 1, 2018

    Study Results

    Participant Flow

    Recruitment DetailsRecruitment took place in the clinic over a 5 year period
    Pre-assignment DetailNone of the patients were able to increase the dosage of ambrisentan from the initial dose of 5 mg to 10 mg.
    Arm/Group TitleOpen Label: Medication Ambrisentan
    Arm/Group DescriptionOpen 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. 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.
    Period Title: Overall Study
    STARTED15
    COMPLETED10
    NOT COMPLETED5

    Baseline Characteristics

    Arm/Group TitleOpen Label: Medication Ambrisentan
    Arm/Group DescriptionOpen 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. 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.
    Overall Participants15
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    47.6
    (10.7)
    Sex: Female, Male (Count of Participants)
    Female
    10
    66.7%
    Male
    5
    33.3%
    Region of Enrollment (Count of Participants)
    United States
    15
    100%
    Extent of skin sclerosis (units on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [units on a scale]
    21
    (7.4)

    Outcome Measures

    1. Primary Outcome
    TitleThe Benefit That an Antifibrotic Agent and Ambrisentan Combination Have on the Cutaneous Involvement of Patients With Early Diffuse Systemic Sclerosis by Utilizing the MRSS
    DescriptionUsing 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.
    Time FrameBaseline and 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleOpen Label: Medication Ambrisentan
    Arm/Group DescriptionOpen 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. 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.
    Measure Participants15
    mRss mean for group at study entry
    21
    (7.4)
    mRss mean for group at end of Study- to 12 months
    13
    (11.2)
    2. Secondary Outcome
    TitleSystemic Sclerosis Quality of Life Assessed by the SF-36.
    DescriptionThe 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
    Time FrameBaseline vs Month 12.

    Outcome Measure Data

    Analysis Population Description
    15 subjects enrolled, 5 subjects withdrew. Data analyzed was only for the 10 subjects who completed the 12 month visit and had both a baseline and a 12 month SF-36 form completed
    Arm/Group TitleOpen Label: Medication Ambrisentan
    Arm/Group DescriptionOpen 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. 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.
    Measure Participants10
    SF-36 mean for group at study entry
    62
    (23.3)
    SF-36 mean of group at study end -12 months
    65.9
    (25.7)

    Adverse Events

    Time Frame1 year
    Adverse Event Reporting Description Serious Adverse Events Other Adverse Events
    Arm/Group TitleOpen Label: Medication Ambrisentan
    Arm/Group DescriptionOpen 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. 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.
    All Cause Mortality
    Open Label: Medication Ambrisentan
    Affected / at Risk (%)# Events
    Total0/15 (0%)
    Serious Adverse Events
    Open Label: Medication Ambrisentan
    Affected / at Risk (%)# Events
    Total4/15 (26.7%)
    Blood and lymphatic system disorders
    Anemia1/15 (6.7%) 1
    Gastrointestinal disorders
    Adynamic ileus1/15 (6.7%) 1
    Product Issues
    Lower Extremity Swelling1/15 (6.7%) 1
    Skin and subcutaneous tissue disorders
    Pruritis1/15 (6.7%) 1
    Other (Not Including Serious) Adverse Events
    Open Label: Medication Ambrisentan
    Affected / at Risk (%)# Events
    Total15/15 (100%)
    Cardiac disorders
    Hypertension1/15 (6.7%) 1
    Ankle Swelling4/15 (26.7%) 4
    Hypotension1/15 (6.7%) 1
    Eye disorders
    Cataract Removal1/15 (6.7%) 1
    Gastrointestinal disorders
    Gastrointestinal illness3/15 (20%) 3
    Increased Reflux1/15 (6.7%) 1
    General disorders
    Hot flashes1/15 (6.7%) 1
    Facial Flushing1/15 (6.7%) 1
    Dizziness2/15 (13.3%) 2
    Fatigue1/15 (6.7%) 1
    Mouth Ulcers1/15 (6.7%) 1
    Immune system disorders
    Flu1/15 (6.7%) 1
    Infections and infestations
    Sore throat1/15 (6.7%) 1
    Urinary Tract Infection1/15 (6.7%) 3
    Nasal congestion3/15 (20%) 3
    Musculoskeletal and connective tissue disorders
    Shoulder Pain1/15 (6.7%) 1
    Bilateral Flank Pain1/15 (6.7%) 1
    Bilateral Finger Swelling1/15 (6.7%) 1
    Bilateral Wrist Swelling1/15 (6.7%) 1
    Bursitis1/15 (6.7%) 1
    Leg Cramps1/15 (6.7%) 1
    Left Upper Quadrant Pain1/15 (6.7%) 1
    Joint Pain1/15 (6.7%) 1
    Right Shoulder Weakness1/15 (6.7%) 1
    Right Hip Weakness1/15 (6.7%) 1
    Nervous system disorders
    Headache1/15 (6.7%) 1
    Respiratory, thoracic and mediastinal disorders
    Shortness of Breath1/15 (6.7%) 1
    Skin and subcutaneous tissue disorders
    Rash2/15 (13.3%) 2
    Basal Cell Skin cancer1/15 (6.7%) 1

    Limitations/Caveats

    Dose escalation was attempted however none of the patients were able to increase. Therefore all subjects remained on 5 mg daily throughout the study.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/TitleDr. Chris Derk
    OrganizationUniversity of Pennsylvania Health System
    Phone215-662-2792
    Emailchris.derk@uphs.upenn.edu
    Responsible Party:
    University of Pennsylvania
    ClinicalTrials.gov Identifier:
    NCT01093885
    Other Study ID Numbers:
    • Ambrj55501.
    First Posted:
    Mar 26, 2010
    Last Update Posted:
    Nov 29, 2018
    Last Verified:
    Nov 1, 2018