Alveolitis, Systemic Sclerosis
Conditions
Keywords
active alveolitis in systemic sclerosis
Brief summary
The purpose of this study is to assess the safety and tolerability of imatinib (gleevec) in subjects who have systemic sclerosis. Imatinib has been approved by the FDA for the treatment of newly diagnosed adult patients with CML (newly diagnosed adult patients and for the treatment of patients with an accelerated phase. Imatinib is also approved for the treatment of patients with a certain type of gastrointestinal cancer (called stromal tumors) but it has not been approved to treat systemic sclerosis. Imatinib works by interfering with an enzyme called tyrosine phosphatase resulting in suppression of the immune system. It als interferes with a protein called platelet derived growth factor receptor (PDGFr) that has been linked to increased fibrosis.
Detailed description
Systemic sclerosis is a rare, progressive disease that leads to hardening and tightening of the skin and connective tissues. It usually begins with a few dry patches of skin on the hands or face that begin getting thicker and harder. These patches then spread to other areas of the skin. In some cases, systemic sclerosis also affects the blood vessels an internal organs. Systemic sclerosis is one of a group of arthritic conditions called connective tissue disorders, a person's antibodies are directed against their own tissues.
Interventions
DRUGImatinib
All subjects will receive gleevec. Subjects will have a clinic visit every 2 weeks for the first 20 weeks and then they will have one every 4 weeks for the remainder of the study. Gleevec will be taken by mouth everyday. It will be increased to a maximum of 600 mg every day. It will be increased 100 mg at each visit for the first 12 weeks. Your participation may last up to 1 year and participants will have approximately 18 clinic visits.
Sponsors
Novartis Pharmaceuticals
University of California, Los Angeles
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. All patients must fulfill the criteria for SSc by ACR criteria 2. Age of entry into the study ≥ 18 yrs 3. FVC \<85% of predicted. 4. Able to complete the 6MWT with a walking distance ≥ 150 m 5. Patients must have dyspnea on exertion (grade ≥ 2 on the Magnitude of Task component of the Mahler Modified Dyspnea Index). 6. SSc for ≤ 10 years, with onset defined as the date of the first non-Raynaud manifestation typical of systemic sclerosis. 7. Patients may have limited (cutaneous thickening distal but not proximal to elbows and knees, with or without facial involvement) or diffuse (cutaneous thickening proximal to elbows and knees, often involving the chest or abdomen) cutaneous SSc (Medsger 1995). 8. Patients must show some evidence of alveolitis as defined by an HRCT of the lung which shows ground glass opacification as a radiographic marker of alveolitis or finely reticulated fibrosis or they must have alveolitis by BAL ( ≥ 3% PMN's or ≥ 2% eosinophils). 9. Female patients of childbearing potential must have negative pregnancy test within 7 days before initiation of study drug dosing. 10. Patients must be able to provide written voluntary informed consent.
Exclusion criteria
1. FVC ≤ 50% of predicted or DLCO (corrected for Hgb but not for alveolar volume) ≤ 35% of predicted (suggesting severe probably irreparable disease and/or significant pulmonary vascular involvement by SSc). 2. FEV1/FVC ratio \<65% (to exclude significant airflow obstruction) 3. Clinically significant abnormalities on HRCT not attributable to SSc (e.g., lung mass, extensive scarring due to previous infection, etc.) 4. Clinically significant pulmonary hypertension documented on right heart catheterization (i.e., right ventricular systolic pressure of \>50 mm Hg and/or mean PAP ≥30 mm Hg) pulmonary pressure or echocardiographic evidence of PAH (if echo cardiographic systolic pressure ≥ 55 mmHg) or FVC/DLCO ratio \>1.6 on pulmonary function testing 5. Persistent unexplained hematuria (\>10 RBCs/hpf). 6. History of persistent leukopenia (white blood cell count \<3500), neutropenia (absolute neutrophil count \< 1500) or thrombocytopenia (platelet count \<100,000). 7. Clinically significant anemia (\<9.0 gm/dl) 8. Serum creatinine \>ULN. 9. Pregnancy (documented by urine pregnancy test), breast feeding 10. If of child-bearing potential, failure regularly to employ a reliable means of contraception 11. Active infection of the lung or elsewhere, whose management would be compromised by Imatinib 12. Unreliability, drug abuse (including active alcoholism) 13. Any chronic, debilitating illness (other than SSc) 14. Smoking of cigars, pipes or cigarettes during the past 6 months 15. Baseline liver function tests (ALT or AST or bilirubin \>1.5 x upper limit of normal 16. Previous use of prednisone \> 10 mg per day. If on prednisone ≤10 mg/d, dose must have been stable for \> 1 month. 17. All other medication with putative disease-modifying properties (e.g., D-penicillamine, cyclophosphamide, azathioprine, methotrexate, colchicine, Potaba) must be discontinued 1 month prior to beginning study medication. 18. Patient is \< 5 years since she/he had a primary malignancy except: if the other primary malignancy is not currently clinically significant nor requiring active intervention, or if other primary malignancy is a basal cell skin cancer or a cervical carcinoma in situ. Existence of any other malignant disease is not allowed except after consultation with the PI. 19. Patient with Grade III/IV cardiac problems as defined by the New York Heart Association Criteria. (i.e., congestive heart failure, myocardial infarction within 6 months of study) 20. Patient has a severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes, chronic renal disease, or active uncontrolled infection). 21. Patient has known chronic liver disease (i.e., chronic active hepatitis and cirrhosis). 22. Patient has a known diagnosis of human immunodeficiency virus (HIV) infection. 23. Use of contraindicated medications at baseline.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-related Adverse Events | Baseline vs. Endpoint (1 year) | Treatment-related adverse events requiring discontinuation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in FVC (Forced Vital Capacity) | Baseline vs. Endpoint (1 year) | Measures the amount of air breathed out as a percent of predicted. |
| Change in TLC (Total Lung Capacity) | Baseline vs. Endpoint (1 year) | No measures of dispersion was available for TLC as data were lost. This describes the total lung capacity as a percent of predicted. |
| Change in DLco | Baseline vs. Endpoint (1 year) | DLCO (diffusing capacity or transfer factor of the lung for carbon monoxide (CO)) is the extent to which oxygen passes from the air sacs of the lungs into the blood. Commonly, it refers to the test used to determine this parameter. |
| Change in Modified Rodnan Skin Score (MRSS) | Baseline vs. Endpoint | No measures of dispersion was available as data were lost. The range of this measure is 0 to 51 and measures the extent of skin thickening with higher numbers representing thickening. |
Countries
United States
Participant flow
Recruitment details
University setting convenience samples.
Pre-assignment details
1-year, Phase I/IIa, Open-label trial
Participants by arm
| Arm | Count |
|---|---|
| Imatinib Systemic Sclerosis patients administered oral 600 mg imatinib once per day for up to one year. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 7 |
| Overall Study | Lost to Follow-up | 1 |
Baseline characteristics
| Characteristic | Imatinib |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Age, Continuous | 46.1 years STANDARD_DEVIATION 14.2 |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 10 / 20 |
| serious Total, serious adverse events | 3 / 20 |
Outcome results
Primary
Treatment-related Adverse Events
Treatment-related adverse events requiring discontinuation.
Time frame: Baseline vs. Endpoint (1 year)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib | Treatment-related Adverse Events | 5 participants |
Secondary
Change in DLco
DLCO (diffusing capacity or transfer factor of the lung for carbon monoxide (CO)) is the extent to which oxygen passes from the air sacs of the lungs into the blood. Commonly, it refers to the test used to determine this parameter.
Time frame: Baseline vs. Endpoint (1 year)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Imatinib | Change in DLco | 1.46 Percent predicted |
Secondary
Change in FVC (Forced Vital Capacity)
Measures the amount of air breathed out as a percent of predicted.
Time frame: Baseline vs. Endpoint (1 year)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imatinib | Change in FVC (Forced Vital Capacity) | 1.74 Percent predicted | Standard Deviation 2.1 |
Secondary
Change in Modified Rodnan Skin Score (MRSS)
No measures of dispersion was available as data were lost. The range of this measure is 0 to 51 and measures the extent of skin thickening with higher numbers representing thickening.
Time frame: Baseline vs. Endpoint
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Imatinib | Change in Modified Rodnan Skin Score (MRSS) | 3.9 units on a scale |
Secondary
Change in TLC (Total Lung Capacity)
No measures of dispersion was available for TLC as data were lost. This describes the total lung capacity as a percent of predicted.
Time frame: Baseline vs. Endpoint (1 year)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Imatinib | Change in TLC (Total Lung Capacity) | 4.17 Percent predicted |