Lung Diseases, Pulmonary Fibrosis, Scleroderma, Systemic, Systemic Scleroderma
Conditions
Keywords
Lung Diseases, Pulmonary Fibrosis, Systemic Scleroderma, Scleroderma, systemic
Brief summary
To evaluate the efficacy and safety of cyclophosphamide versus placebo for the prevention and progression of symptomatic pulmonary disease in patients with systemic sclerosis.
Detailed description
BACKGROUND: Systemic sclerosis is a connective tissue disease of unknown etiology characterized by microvascular injury and excessive fibrosis of the skin and viscera. In the United States, 5,000 to 10,000 new cases are diagnosed annually. Approximately 80 percent of these persons will eventually develop some degree of lung involvement, and restrictive lung disease (interstitial fibrosis) is now the leading cause of morbidity and mortality in systemic sclerosis. An inflammatory alveolitis is thought to be the precursor of interstitial pulmonary fibrosis in systemic sclerosis. An effective treatment for SSc interstitial lung disease has yet to be identified. Cyclophosphamide (CYC) is already being widely used by rheumatologists desperate to do something to halt rapidly declining lung function in SSC patients. Thus, the time is ripe to perform a placebo-controlled trial of CYC in this disease. Pulmonary scleroderma strikes all races and is most prevalent among women during their child-bearing, child-rearing, and working years. A positive outcome from this trial, demonstrating that oral cyclophosphamide has a beneficial effect on pulmonary fibrosis, would be of great importance by offering a scientific basis for treatment. Similarly, a negative result, demonstrating no benefit from cyclophosphamide therapy, would also be important in avoiding hazardous and expensive therapy that is now being used widely. DESIGN NARRATIVE: Multicenter, placebo-controlled, randomized, double-blind. Subjects are recruited at 12 clinical centers and randomized to 2 mg/kg/day of cyclophosphamide or placebo. Follow-up visits for pulmonary assessments occur every three months for two years after treatment. If patients fail the cyclophosphamide treatment, they will be offered azathioprine for the remainder of the 24 month trial. The primary endpoint of the study is change in forced vital capacity at the end of 12 months of treatment. Secondary endpoints include quality of life, activity, and dyspnea indices, and carbon monoxide diffusing capacity. Recruitment ends in December, 2003.
Interventions
DRUGCyclophosphamide
Cyclophosphamide (Cytoxan, Bristol-Myers Squibb) was initiated with a dose of 1 mg per kilogram of body weight per day (to the nearest 25 mg). The doses were increased monthly by one capsule up to 2 mg per kilogram.
DRUGPlacebo
Matching gelcaps 25 mgs
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
The University of Texas Health Science Center, Houston
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with limited or diffuse systemic scleroderma if they had evidence of active alveolitis on examination of bronchoalveolar-lavage (BAL) fluid (defined as neutrophilia of ≥3 percent, eosinophilia of ≥2 percent, or both)on thoracic high-resolution computed tomography (CT), any ground-glass opacity, 2. Onset of the first symptom of scleroderma other than Raynaud's phenomenon within the previous seven years, 3. An FVC between 45 and 85 percent of the predicted value 4. Grade 2 exertional dyspnea according to the baseline instrument of the Mahler Dyspnea Index (as measured with the use of the magnitude-of-task component).
Exclusion criteria
1. A single-breath carbon monoxide diffusing capacity (DlCO) that was less than 30 percent of the predicted value, 2. A history of smoking within the preceding six months, other clinically significant pulmonary abnormalities, 3. Clinically significant pulmonary hypertension requiring drug therapy. 4. Patients taking prednisone at a dose of more than 10 mg per day, those who had previously been treated for more than four weeks with oral cyclophosphamide or had received two or more intravenous doses, 5. Patients who recently received other potentially disease-modifying medications.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Forced Vital Capacity | 12 months | The primary end point was the forced vital capacity (FVC, expressed as a percentage of the predicted value) at 12 months, after adjustment for the baseline FVC. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Lung Capacity | 12 months | expressed as a percentage of the predicted value |
| DLCO | 12 months | diffusing capacity of the lungs for carbon monoxide |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cylophosphamide Cyclophosphamide (Cytoxan, Bristol-Myers Squibb) was initiated with a dose of 1 mg per kilogram of body weight per day (to the nearest 25 mg). The doses were increased monthly by one capsule up to 2 mg per kilogram.
Cyclophosphamide: Cyclophosphamide (Cytoxan, Bristol-Myers Squibb) was initiated with a dose of 1 mg per kilogram of body weight per day (to the nearest 25 mg). The doses were increased monthly by one capsule up to 2 mg per kilogram. | 79 |
| Placebo Matching gel caps at a dose of 25 mg
Placebo: Matching gelcaps 25 mgs | 79 |
| Total | 158 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 3 |
| Overall Study | Lack of Efficacy | 3 | 5 |
| Overall Study | Withdrawal by Subject | 20 | 16 |
Baseline characteristics
| Characteristic | Cylophosphamide | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 48.2 Years STANDARD_DEVIATION 1.4 | 47.5 Years STANDARD_DEVIATION 1.4 | 47.9 Years STANDARD_DEVIATION 1 |
| Sex: Female, Male Female | 60 Participants | 51 Participants | 111 Participants |
| Sex: Female, Male Male | 19 Participants | 28 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 20 / 79 | 4 / 79 |
| serious Total, serious adverse events | 5 / 79 | 5 / 79 |
Outcome results
Primary
Forced Vital Capacity
The primary end point was the forced vital capacity (FVC, expressed as a percentage of the predicted value) at 12 months, after adjustment for the baseline FVC.
Time frame: 12 months
Population: The Number of Participants Analyzed is not consistent with the Participant Flow for the following reason: a number of the patients who withdrew, had treatment failure, or died had completed at least the six-month visit--for these patients, a generalized estimating-equation regression model was fitted, and data missing at 12 months were imputed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cylophosphamide | Forced Vital Capacity | 66.6 % of predicted | Standard Error 1.7 |
| Placebo | Forced Vital Capacity | 65.6 % of predicted | Standard Error 1.6 |
Secondary
DLCO
diffusing capacity of the lungs for carbon monoxide
Time frame: 12 months
Population: The Number of Participants Analyzed is not consistent with the Participant Flow for the following reason: a number of the patients who withdrew, had treatment failure, or died had completed at least the six-month visit--for these patients, a generalized estimating-equation regression model was fitted, and data missing at 12 months were imputed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cylophosphamide | DLCO | 42.8 % of predicted | Standard Error 1.7 |
| Placebo | DLCO | 44.3 % of predicted | Standard Error 2.1 |
Secondary
Total Lung Capacity
expressed as a percentage of the predicted value
Time frame: 12 months
Population: The Number of Participants Analyzed is not consistent with the Participant Flow for the following reason: a number of the patients who withdrew, had treatment failure, or died had completed at least the six-month visit--for these patients, a generalized estimating-equation regression model was fitted, and data missing at 12 months were imputed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cylophosphamide | Total Lung Capacity | 70.5 % of predicted | Standard Error 1.8 |
| Placebo | Total Lung Capacity | 64.7 % of predicted | Standard Error 1.9 |