Comparison of Therapeutic Regimens for Scleroderma Interstitial Lung Disease (The Scleroderma Lung Study II)
Condition: Scleroderma; Interstitial Lung Disease
MeSH terms: Lung Diseases; Lung Diseases, Interstitial; Scleroderma, Systemic; Scleroderma, Diffuse; Scleroderma, Localized
Intervention: Mycophenolate mofetil; Cyclophosphamide; Placebo
Intervention description: 24 months of oral mycophenolate mofetil, up to a maximal dose of 1.5 grams twice daily as tolerated; 12 months of oral cyclophosphamide, up to a maximal dose of 2 mg/kg daily as tolerated; 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.
Intervention MeSH terms: Mycophenolic Acid; Cyclophosphamide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 142.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Systemic Sclerosis; Mycophenolate Mofetil; Cyclophosphamide; High Resolution Computerized Tomography; Pulmonary Function; Dyspnea; Health Related Quality of Life

Summary:

      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.
    

Eligibility criteria:

        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)