Clinical trial NCT00883129: Comparison of Therapeutic Regimens for Scleroderma Interstitial Lung Disease (The Scleroderma Lung Study II)
Official title: Mycophenolate vs. Oral Cyclophosphamide in Scleroderma Interstitial Lung Disease (Scleroderma Lung Study II)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Scleroderma
Interstitial Lung Disease
Keywords: Systemic Sclerosis
Mycophenolate Mofetil
Cyclophosphamide
High Resolution Computerized Tomography
Pulmonary Function
Dyspnea
Health Related Quality of Life
Lead sponsor: University of California, Los Angeles
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Hoffmann-La Roche
First posted: 2009-04-17
Enrollment: 142
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.

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)

Primary outcomes:
measure: Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value
timeFrame: Measured at study Baseline and Months 3, 6, 12, 15, 18, 21, and 24
Secondary outcomes:
measure: Total Lung Capacity (TLC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value
timeFrame: Measured at study entry and Months 6, 12, 18, and 24
measure: Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value
timeFrame: Measured at study entry and Months 3, 6, 12, 15, 18, 21, and 24
measure: Fibrosis Score, as Measured by Thoracic High Resolution Computerized Tomography (HRCT)
timeFrame: Measured at baseline and Month 24
measure: Transitional Dyspnea Index Score
timeFrame: Measured at Months 6, 12, 18, and 24
measure: Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI)
timeFrame: Measured at study entry and Months 3, 6, 9, 12, 15, 18, 21, and 24
measure: Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS)
timeFrame: Measured at baseline and Months 3, 6, 9, 12, 15, 18, 21, and 24
measure: Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death
timeFrame: Measured throughout the 2-year study
measure: Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure.
timeFrame: Continuous assessment from randomization to 24 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: David Geffen School of Medicine at UCLA
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Denver
country: United States
facility: National Jewish Health
state: Colorado
city: Washington
country: United States
facility: Georgetown University School of Medicine
state: District of Columbia
city: Chicago
country: United States
facility: Feinberg School of Medicine, Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Illinois at Chicago, College of Medicine
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine
state: Maryland
city: Boston
country: United States
facility: Boston University School of Medicine
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical School
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: New Brunswick
country: United States
facility: University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School
state: New Jersey
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Houston
country: United States
facility: University of Texas Medical School at Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: University of California, Los Angeles
name: Donald P. Tashkin, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: UCLA School of Public Health
name: Robert M. Elashoff, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Los Angeles
name: Michael D. Roth, MD
role: PRINCIPAL_INVESTIGATOR
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