Comparison of Therapeutic Regimens for Scleroderma Interstitial Lung Disease (The Scleroderma Lung Study II)

Study Overview
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Brief Summary
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Scleroderma is a rare, long-term autoimmune disease in which normal tissue is replaced with dense, thick fibrous tissue. Normally, the immune system helps defend the body against disease and infection. In people with scleroderma, the immune system triggers fibroblast cells to produce too much of the protein collagen. The extra collagen becomes deposited in the skin and organs, causing hardening and thickening that is similar to the scarring process. Although scleroderma most often affects the skin, it also can affect other parts of the body, including the lungs, and in its most severe forms scleroderma can be life-threatening. Scleroderma-related interstitial lung disease is one example of a life-threatening scleroderma condition. In people with symptomatic scleroderma-related interstitial lung disease, scarring occurs in the delicate lung tissue, compromising lung function. The purpose of this study is to determine whether people with symptomatic scleroderma-related interstitial lung disease experience more respiratory benefits from treatment with a 2-year course of mycophenolate mofetil or treatment with a 1-year course of oral cyclophosphamide.

Detailed Description
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Interstitial lung disease describes a condition in which the lung tissue has become scarred or inflamed. Interstitial lung disease caused by scleroderma, specifically seen as progressive pulmonary fibrosis, occurs in approximately 40 percent of patients with scleroderma and has emerged as the leading overall cause of death. In a previous study, the Scleroderma Lung Study I (SLS I), investigators evaluated a 1-year cyclophosphamide (CYC) treatment for people with scleroderma-related interstitial lung disease. The study results demonstrated statistically significant improvements in forced vital capacity, total lung capacity, dyspnea, Rodnan skin scores, and several measures of quality of life. However, when patients were followed for another year after completing their CYC therapy, the beneficial effects of CYC waned and were no longer significant by the 24-month follow-up. Preliminary information suggests that an alternative immunosuppressive medication, mycophenolate mofetil (MMF), may be effective in treating this disease, be given for longer periods, and result in fewer side effects. This study, the Scleroderma Lung Study II (SLS II), will compare the safety and efficacy of a 2-year treatment with MMF versus a 1-year treatment with CYC. Specifically, investigators will determine whether MMF produces similar or better improvements in lung capacity and fewer side effects throughout the entire 2-year period. Participation will include about 21 study visits over a 2-year period. Eligible participants will be randomly assigned to receive either MMF twice daily for 2 years or CYC once daily for 1 year, followed by placebo for 1 year. Blood and urine samples will be collected every 2 weeks for the first 2 months and then once a month for the remainder of the study. Every 3 months, participants will attend study visits that will include pulmonary function tests, blood and urine sampling, a physical exam, and questionnaires about current health and medications. At the final study visit, participants will also undergo a high resolution computerized tomography (HRCT) scan and possibly a punch biopsy.

Official Title
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Mycophenolate vs. Oral Cyclophosphamide in Scleroderma Interstitial Lung Disease (Scleroderma Lung Study II)

Conditions
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Scleroderma, Interstitial Lung Disease

Intervention / Treatment
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* Drug: Mycophenolate mofetil
* Drug: Cyclophosphamide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The presence of either 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) scleroderma, as determined by American College of Rheumatology criteria Dyspnea on exertion (grade 2 on the Magnitude of Task component of the Mahler Modified Dyspnea Index) FVC less than or equal to 80 percent of predicted value at screening and less than or equal to 85 percent predicted at baseline Onset of the first non-Raynaud manifestation of SSc within the prior 84 months Presence of any ground glass opacification on thoracic high resolution computerized tomography (HRCT) Repeat FVC at the baseline visit (Visit 2) within 10 percent of the FVC measured at screening and less than or equal to 85 percent predicted. Exclusion Criteria: FVC less than 45 percent of predicted value at either screening or baseline Carbon monoxide diffusing capacity (DLCO) (HBg-corrected) less than 30 percent of predicted value and less than 40 percent of predicted when documentation of pulmonary artery pressures by echocardiogram, right heart catheterization or magnetic resonance imaging identifies clinically significant pulmonary hypertension. All participants with a DLCO less than 40 percent predicted must have documentation of pulmonary artery pressures in order to be considered for inclusion. FEV1/FVC ratio less than 65 percent at either screening or baseline Clinically significant abnormalities on HRCT not attributable to scleroderma Diagnosis of clinically significant resting pulmonary hypertension requiring treatment, as ascertained before study evaluation or as part of a standard of care clinical assessment performed outside of the study protocol Persistent unexplained hematuria (more than 10 red blood cells per high-power field [RBCs/hpf]) History of persistent leukopenia (white blood cell count less than 4000) or thrombocytopenia (platelet count less than 150,000) Clinically significant anemia (less than 10g/dl) Baseline liver function test (LFTs) or bilirubin more than 1.5 times the upper limit of normal, other than that due to Gilbert's disease Concomitant and present use of captopril Serum creatinine more than 2.0mg/dL Uncontrolled congestive heart failure Pregnancy (documented by urine pregnancy test) and/or breast feeding Prior use of oral CYC or MMF for more than 8 weeks or the receipt of more than two intravenous doses of CYC in the past Use of CYC and/or MMF in the 30 days before random assignment Active infection (lung or elsewhere) whose management would be compromised by CYC or MMF Other serious concomitant medical illness (e.g., cancer), chronic debilitating illness (other than scleroderma), or unreliability or drug abuse that might compromise the patient's participation in the study Current use, or use within the 30 days prior to random assignment, of prednisone (or equivalent) in doses of more than 10 mg/day If of child bearing potential (a female participant <55 years of age who has not been postmenopausal for > 5 years and who has not had a hysterectomy and/or oophorectomy), failure to employ two reliable means of contraception (which may include surgical sterilization, barrier methods, spermicidals, intrauterine devices, and/or hormonal contraception). Use of contraindicated medications; more information on this criterion can be found in the study protocol Smoking of cigars, pipes, or cigarettes in the 6 months before study entry Use of medications with putative disease-modifying properties within the past month (e.g., D-penicillamine, azathioprine, methotrexate, Potaba)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mycophenolate Arm<br>Participants will receive oral mycophenolate mofetil for 2 years. | Drug: Mycophenolate mofetil<br>* 24 months of oral mycophenolate mofetil, up to a maximal dose of 1.5 grams twice daily as tolerated<br>* Other names: CellCept;|
| Experimental: Cyclophosphamide Arm<br>Participants will receive oral cyclophosphamide for 1 year, followed by placebo for 1 year. | Drug: Cyclophosphamide<br>* 12 months of oral cyclophosphamide, up to a maximal dose of 2 mg/kg daily as tolerated<br>* Other names: Cytoxan;Drug: Placebo<br>* 12 months of placebo will be delivered to participants in the Cyclophosphamide arm during the second year in order to maintain the blind with the Mycophenolate arm, which receives drug for the entire 2 years.<br>* Other names: Sugar Pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | The primary outcome is the course over time from baseline to 24 months for the FVC %-predicted. The FVC %-predicted represents the adjusted volume of air (adjusted as a percentage of the expected normal valued based on the participant's age, height, gender and ethnicity) that can be forcibly exhaled from the lungs after taking the deepest breath possible. The FVC %-predicted is reduced in patients with interstitial lung disease and is used as a measure of lung involvement and disease severity. | Measured at study Baseline and Months 3, 6, 12, 15, 18, 21, and 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Lung Capacity (TLC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | The TLC represents the total volume of air within the lung after taking the deepest breath possible and the TLC %-predicted represents the TLC expressed as a percentage of the expected normal valued based on the participant's age, height, gender and ethnicity. The TLC %-predicted is reduced in patients with interstitial lung disease and is used as a measure of disease severity. | Measured at study entry and Months 6, 12, 18, and 24 | 
| Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | The DLCO is a pulmonary function test that measures the capacity for the lung to carry out gas exchange between the inhaled breath and the pulmonary capillary blood vessels and the DLCO %-predicted represents the DLCO expressed as a percentage of the expected normal valued based on the participant's age, height, gender and ethnicity. The DLCO %-predicted is reduced in patients with interstitial lung disease and is used as a measure of disease severity. | Measured at study entry and Months 3, 6, 12, 15, 18, 21, and 24 | 
| Fibrosis Score, as Measured by Thoracic High Resolution Computerized Tomography (HRCT) | Imaging of the whole lung (WL) is performed using a volumetric high resolution computerized tomography (HRCT) scan, which is then analyzed using a computer algorithm to determine the percentage of overall pixels exhibiting features characteristic for quantitative lung fibrosis (QLF). Higher percentages for QLF-WL therefore represent greater involvement by lung fibrosis. | Measured at baseline and Month 24 | 
| Transitional Dyspnea Index Score | Change in breathlessness was assessed using the Transitional Dyspnea Index, which compares current symptoms to those at baseline. Total score ranges from - 9 to + 9. The lower the score, the more deterioration in severity of dyspnea. | Measured at Months 6, 12, 18, and 24 | 
| Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI) | The HAQ-DI asks questions related to 8 activity domains (dressing, arising, eating, walking, hygiene, reach, grip, and common daily activities) with the patient's capacity to carry out each activity scored from 0 to 3. Scores across all domains are averaged and a higher score represents greater disability. | Measured at study entry and Months 3, 6, 9, 12, 15, 18, 21, and 24 | 
| Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS) | Skin thickness is quantified using the modified Rodnan measurement method (mRSS), with a scale that ranges from 0 (no skin involvement) to a maximum of 51. The reported skin score is determined by a clinical assessment of skin thickness, which is performed by a trained reader, and represents the sum of individual assessments that are made in each of 17 body areas. Each area is given a score in the range of 0-3 (0 = normal; 1= mild thickness; 2 = moderate; 3 = severe thickness). A higher score represents more severe skin involvement. | Measured at baseline and Months 3, 6, 9, 12, 15, 18, 21, and 24 | 
| Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death |  | Measured throughout the 2-year study | 
| Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure. | The number of participants who remained in the study at the listed time points are reported | Continuous assessment from randomization to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Systemic Sclerosis, Mycophenolate Mofetil, Cyclophosphamide, High Resolution Computerized Tomography, Pulmonary Function, Dyspnea, Health Related Quality of Life