Scleroderma, Systemic
Conditions
Keywords
Scleroderma, Systemic
Brief summary
Researchers from the Division of Pulmonary and Critical Care Medicine at University of California, San Francisco (UCSF) are conducting a study to evaluate whether mycophenolate mofetil (an immunosuppressive medication, trade named CellCept) is safe and effective for preventing the lung damage from scleroderma from getting worse.
Detailed description
The proposed study is designed to evaluate the safety and efficacy of mycophenolate mofetil (CellCept) for the treatment of symptomatic pulmonary alveolitis due to systemic sclerosis (SSc). This study utilizes a prospective, open-label, experimental design. Primary Hypothesis: The alveolitis in patients with SSc, as defined by decreased forced vital capacity (FVC), bronchoalveolar lavage (BAL), and High Resolution Chest Tomography (HRCT) is responsive to 1 year of daily mycophenolate mofetil therapy. Secondary Hypothesis: Quality of life, six-minute walk and single-breath diffusing capacity for carbon monoxide (DLCO) improve in patients with SSc mediated alveolitis after therapy with mycophenolate mofetil. This response to therapy is associated with a change in the inflammatory cytokine profile present in BAL fluid.
Interventions
DRUGMycophenolate mofetil
Sponsors
Roche Pharma AG
University of California, San Francisco
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* To participate in this study, patients must first undergo a BAL and HRCT. To be eligible to undergo HRCT and BAL (under the purview of this trial), prospective patients must meet the following criteria: * Aged 21-70. * Negative pregnancy test (with a sensitivity of at least 50 mIU/mL) for females of child-bearing potential * All patients must fulfill the criteria for SSc by American College of Rheumatology (ACR) criteria (Subcommittee for Scleroderma Criteria 1980). * FVC \< 85% of predicted. * SSc for no more than 7 years with onset defined as the date of the first non-Raynaud manifestation. * 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). * Abnormal DLCO and abnormalities on the plain chest radiograph are not required, although a normal DLCO would be unusual in the face of significant ventilatory restriction due to SSc lung disease. * To be eligible to take study medication, the patient must meet not only the criteria above, but also must have ≥ 3.0% neutrophils or ≥ 2.0% eosinophils in screening BAL fluid and/or ground glass opacification on HRCT. * Women of childbearing potential should have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 1 week before beginning therapy. CellCept therapy will not be initiated until a report of a negative pregnancy test has been obtained. * Effective contraception must be used before beginning CellCept therapy, during therapy, and for 6 weeks following discontinuation of therapy, even where there has been a history of infertility, unless due to hysterectomy. Two reliable forms of contraception must be used simultaneously unless abstinence is the chosen method. If pregnancy does occur during treatment, the physician and patient should discuss the desirability of continuing the pregnancy.
Exclusion criteria
* FVC \< 45% of predicted or DLCO (corrected for hemoglobin \[Hgb\] but not for alveolar volume) \< 35% of predicted (suggestive of severe, probably irreparable, disease). * Leukopenia (white blood cell count \< 4000) or thrombocytopenia (platelet count \< 100,000). * Serum creatinine ≥ 2.0 mg/dl. * Pregnancy, breast feeding, unreliability, drug abuse, or chronic debilitating disease. * Uncontrolled congestive heart failure. * Active infection of the lung, or elsewhere, whose management would be compromised by mycophenolate mofetil. * Prior treatment for alveolitis with mycophenolate mofetil or prior or current treatment for alveolitis with: D-penicillamine, methotrexate, colchicine, Potaba, or azathioprine. * Other serious concomitant medical illness (e.g., cancer). * Forced expiratory volume in 1 second (FEV1)/FVC ratio \< 65%. * If of childbearing potential, failure regularly to be employing two reliable means of contraception (i.e., condom, abstinence, intrauterine device (IUD), tubal ligation, vasectomy) * Pulmonary hypertension (defined as an estimated systolic blood pressure (SBP) ≥ 35 mmHg measured by echocardiogram). * Smoking of cigars, pipes, or cigarettes during the past 6 months. * Clinically significant abnormalities on chest x-ray or HRCT scan other than interstitial lung disease (e.g., lung mass, evidence of active pulmonary infection). * Use of prednisone (or equivalent) in doses \> 10 mg per day. * Does not have ≥ 3.0% neutrophils or ≥ 2.0% eosinophils on screening BAL fluid and does not have ground glass opacification on HRCT. * Unable to take oral medication. * Not able to comply with study procedures in the opinion of the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Forced Vital Capacity (FVC) | Baseline, 12 months | compare pre- and post-therapy FVC (post- minus pre-). Forced vital capacity (FVC) is the volume of air (liters) that can forcibly be blown out after full inspiration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Bronchoalveolar Lavage (BAL) Components (Neutrophils, Eosinophils) | Baseline, 12 months | BAL samples were colleected from the affected lobe (as determined by lung CT scans) before beginning and after completing study therapy. |
| Change in Shortness of Breath (Self-reported) | Baseline, 12 months | Participants reported frequency of shortness of breath experienced with exertion |
| Mean Change in Six Minute Walk Distance | 12 months | Comparison of 6-minute walk distance before beginning and after completing study therapy |
| Mean Change in Diffusion Capacity of the Lung for Carbon Monoxide (DLCO) | 12 months | DLCO was measured before beginning and after completion of study therapy |
Countries
United States
Participant flow
Recruitment details
8 patients were screened at one clinical site (UCSF) in the United States
Pre-assignment details
One patient screened for enrollment did not meet eligibility criteria
Participants by arm
| Arm | Count |
|---|---|
| Treatment Study subjects receive standard mycophenolate dosing. | 7 |
| Total | 7 |
Baseline characteristics
| Characteristic | Treatment |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants |
| Age Continuous | 52.57 years STANDARD_DEVIATION 7.52 |
| Region of Enrollment United States | 7 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 1 / 7 |
| serious Total, serious adverse events | 1 / 7 |
Outcome results
Primary
Mean Change From Baseline in Forced Vital Capacity (FVC)
compare pre- and post-therapy FVC (post- minus pre-). Forced vital capacity (FVC) is the volume of air (liters) that can forcibly be blown out after full inspiration.
Time frame: Baseline, 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment | Mean Change From Baseline in Forced Vital Capacity (FVC) | 0.1786 Liters | Standard Deviation 0.1613 |
Comparison: H(0): post-pre FVC (liters) = 0p-value: 0.02695% CI: [0.0294, 0.3277]t-test, 2 sided
Secondary
Change in Shortness of Breath (Self-reported)
Participants reported frequency of shortness of breath experienced with exertion
Time frame: Baseline, 12 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment | Change in Shortness of Breath (Self-reported) | Patient-reported less shortness of breath | 6 participants |
| Treatment | Change in Shortness of Breath (Self-reported) | Patient-reported no change in shortness of breath | 1 participants |
| Treatment | Change in Shortness of Breath (Self-reported) | Patient-reported increased shortness of breath | 0 participants |
Secondary
Mean Change in Bronchoalveolar Lavage (BAL) Components (Neutrophils, Eosinophils)
BAL samples were colleected from the affected lobe (as determined by lung CT scans) before beginning and after completing study therapy.
Time frame: Baseline, 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Mean Change in Bronchoalveolar Lavage (BAL) Components (Neutrophils, Eosinophils) | Mean change in neutrophil count | -3 Cells/uL | Standard Deviation 8.1 |
| Treatment | Mean Change in Bronchoalveolar Lavage (BAL) Components (Neutrophils, Eosinophils) | Mean change in eosinophil count | -6.3 Cells/uL | Standard Deviation 16.4 |
Comparison: H(0): Post-pre neutrophil count = 0p-value: 0.365295% CI: [-10.49, 4.4945]t-test, 2 sided
Comparison: H(0): post-pre eosinophil count = 0p-value: 0.348595% CI: [-21.41, 8.8426]t-test, 2 sided
Secondary
Mean Change in Diffusion Capacity of the Lung for Carbon Monoxide (DLCO)
DLCO was measured before beginning and after completion of study therapy
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment | Mean Change in Diffusion Capacity of the Lung for Carbon Monoxide (DLCO) | 1.86 Liters | Standard Deviation 1.5 |
Comparison: H(0): Post-pre DLCO = 0p-value: 0.016795% CI: [0.4758, 3.2527]t-test, 2 sided
Secondary
Mean Change in Six Minute Walk Distance
Comparison of 6-minute walk distance before beginning and after completing study therapy
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment | Mean Change in Six Minute Walk Distance | 264.3 Feet | Standard Deviation 194.7 |
Comparison: H(0): post-pre walk distance = 0p-value: 0.011595% CI: [84.256, 444.32]t-test, 2 sided