Study of Ambrisentan With Antifibrotic Agent Combination Therapy in Diffuse Systemic Sclerosis
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 Disease | Intervention/Treatment | Phase |
|---|---|---|
| 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
Arms and Interventions
| Arm | Intervention/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:
|
Outcome Measures
Primary Outcome Measures
- 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
- 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
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
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Pennsylvania Health System | Philadelphia | Pennsylvania | United States | 19104 |
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.- Ambrj55501.
Study Results
Participant Flow
| Recruitment Details | Recruitment took place in the clinic over a 5 year period |
|---|---|
| Pre-assignment Detail | None of the patients were able to increase the dosage of ambrisentan from the initial dose of 5 mg to 10 mg. |
| Arm/Group Title | Open Label: Medication Ambrisentan |
|---|---|
| Arm/Group Description | 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. 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 | |
| STARTED | 15 |
| COMPLETED | 10 |
| NOT COMPLETED | 5 |
Baseline Characteristics
| Arm/Group Title | Open Label: Medication Ambrisentan |
|---|---|
| Arm/Group Description | 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. 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 Participants | 15 |
| 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
| Title | 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 |
|---|---|
| Description | 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. |
| Time Frame | Baseline and 12 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Open Label: Medication Ambrisentan |
|---|---|
| Arm/Group Description | 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. 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 Participants | 15 |
| mRss mean for group at study entry |
21
(7.4)
|
| mRss mean for group at end of Study- to 12 months |
13
(11.2)
|
| Title | Systemic Sclerosis Quality of Life Assessed by the SF-36. |
|---|---|
| Description | 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 |
| Time Frame | Baseline 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 Title | Open Label: Medication Ambrisentan |
|---|---|
| Arm/Group Description | 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. 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 Participants | 10 |
| 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 Frame | 1 year | |
|---|---|---|
| Adverse Event Reporting Description | Serious Adverse Events Other Adverse Events | |
| Arm/Group Title | Open Label: Medication Ambrisentan | |
| Arm/Group Description | 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. 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 | |
| Total | 0/15 (0%) | |
Serious Adverse Events |
||
| Open Label: Medication Ambrisentan | ||
| Affected / at Risk (%) | # Events | |
| Total | 4/15 (26.7%) | |
| Blood and lymphatic system disorders | ||
| Anemia | 1/15 (6.7%) | 1 |
| Gastrointestinal disorders | ||
| Adynamic ileus | 1/15 (6.7%) | 1 |
| Product Issues | ||
| Lower Extremity Swelling | 1/15 (6.7%) | 1 |
| Skin and subcutaneous tissue disorders | ||
| Pruritis | 1/15 (6.7%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| Open Label: Medication Ambrisentan | ||
| Affected / at Risk (%) | # Events | |
| Total | 15/15 (100%) | |
| Cardiac disorders | ||
| Hypertension | 1/15 (6.7%) | 1 |
| Ankle Swelling | 4/15 (26.7%) | 4 |
| Hypotension | 1/15 (6.7%) | 1 |
| Eye disorders | ||
| Cataract Removal | 1/15 (6.7%) | 1 |
| Gastrointestinal disorders | ||
| Gastrointestinal illness | 3/15 (20%) | 3 |
| Increased Reflux | 1/15 (6.7%) | 1 |
| General disorders | ||
| Hot flashes | 1/15 (6.7%) | 1 |
| Facial Flushing | 1/15 (6.7%) | 1 |
| Dizziness | 2/15 (13.3%) | 2 |
| Fatigue | 1/15 (6.7%) | 1 |
| Mouth Ulcers | 1/15 (6.7%) | 1 |
| Immune system disorders | ||
| Flu | 1/15 (6.7%) | 1 |
| Infections and infestations | ||
| Sore throat | 1/15 (6.7%) | 1 |
| Urinary Tract Infection | 1/15 (6.7%) | 3 |
| Nasal congestion | 3/15 (20%) | 3 |
| Musculoskeletal and connective tissue disorders | ||
| Shoulder Pain | 1/15 (6.7%) | 1 |
| Bilateral Flank Pain | 1/15 (6.7%) | 1 |
| Bilateral Finger Swelling | 1/15 (6.7%) | 1 |
| Bilateral Wrist Swelling | 1/15 (6.7%) | 1 |
| Bursitis | 1/15 (6.7%) | 1 |
| Leg Cramps | 1/15 (6.7%) | 1 |
| Left Upper Quadrant Pain | 1/15 (6.7%) | 1 |
| Joint Pain | 1/15 (6.7%) | 1 |
| Right Shoulder Weakness | 1/15 (6.7%) | 1 |
| Right Hip Weakness | 1/15 (6.7%) | 1 |
| Nervous system disorders | ||
| Headache | 1/15 (6.7%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||
| Shortness of Breath | 1/15 (6.7%) | 1 |
| Skin and subcutaneous tissue disorders | ||
| Rash | 2/15 (13.3%) | 2 |
| Basal Cell Skin cancer | 1/15 (6.7%) | 1 |
Limitations/Caveats
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/Title | Dr. Chris Derk |
|---|---|
| Organization | University of Pennsylvania Health System |
| Phone | 215-662-2792 |
| chris.derk@uphs.upenn.edu |
- Ambrj55501.