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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00883129
First Posted: April 17, 2009
Last Update Posted: February 10, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Hoffmann-La Roche
Information provided by (Responsible Party):
Michael Roth, University of California, Los Angeles
April 16, 2009
April 17, 2009
November 6, 2016
February 10, 2017
February 10, 2017
September 2009
January 2015   (Final data collection date for primary outcome measure)
Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value [ Time Frame: Measured at study Baseline and Months 3, 6, 12, 15, 18, 21, and 24 ]
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.
Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value [ Time Frame: Measured at study entry and Months 3, 6, 12, 15, 18, 21, and 24 ]
Complete list of historical versions of study NCT00883129 on ClinicalTrials.gov Archive Site
  • Total Lung Capacity (TLC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value [ Time Frame: Measured at study entry and Months 6, 12, 18, and 24 ]
    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.
  • Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value [ Time Frame: Measured at study entry and Months 3, 6, 12, 15, 18, 21, and 24 ]
    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.
  • Fibrosis Score, as Measured by Thoracic High Resolution Computerized Tomography (HRCT) [ Time Frame: Measured at baseline and Month 24 ]
    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.
  • Transitional Dyspnea Index Score [ Time Frame: Measured at Months 6, 12, 18, and 24 ]
    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.
  • Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI) [ Time Frame: Measured at study entry and Months 3, 6, 9, 12, 15, 18, 21, and 24 ]
    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.
  • Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS) [ Time Frame: Measured at baseline and Months 3, 6, 9, 12, 15, 18, 21, and 24 ]
    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.
  • Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death [ Time Frame: 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. [ Time Frame: Continuous assessment from randomization to 24 months ]
    The number of participants who remained in the study at the listed time points are reported
  • Total Lung Capacity (TLC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value [ Time Frame: Measured at study entry and Months 3, 6, 12, 15, 18, 21, and 24 ]
  • Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value [ Time Frame: Measured at study entry and Months 3, 6, 12, 15, 18, 21, and 24 ]
  • Fibrosis score, as measured by thoracic high resolution computerized tomography [ Time Frame: Measured at study entry and Month 24 ]
  • Breathlessness, as assessed by the Mahler Modified Dyspnea Index [ Time Frame: Measured at study entry and Months 6, 12, 18, and 24 ]
  • Health-related quality of life (HRQoL) and Health Utility, as assessed by validated questionnaires [ Time Frame: 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 [ Time Frame: Measured at study entry and Months 3, 6, 9, 12, 15, 18, 21, and 24 ]
  • Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death [ Time Frame: Measured throughout the 2-year study ]
Not Provided
Not Provided
 
Comparison of Therapeutic Regimens for Scleroderma Interstitial Lung Disease (The Scleroderma Lung Study II)
Mycophenolate vs. Oral Cyclophosphamide in Scleroderma Interstitial Lung Disease (Scleroderma Lung Study II)
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.

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.

Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
  • Scleroderma
  • Interstitial Lung Disease
  • Drug: Mycophenolate mofetil
    24 months of oral mycophenolate mofetil, up to a maximal dose of 1.5 grams twice daily as tolerated
    Other Name: CellCept
  • Drug: Cyclophosphamide
    12 months of oral cyclophosphamide, up to a maximal dose of 2 mg/kg daily as tolerated
    Other Name: Cytoxan
  • Drug: Placebo
    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.
    Other Name: Sugar Pill
  • Experimental: Mycophenolate Arm
    Participants will receive oral mycophenolate mofetil for 2 years.
    Intervention: Drug: Mycophenolate mofetil
  • Experimental: Cyclophosphamide Arm
    Participants will receive oral cyclophosphamide for 1 year, followed by placebo for 1 year.
    Interventions:
    • Drug: Cyclophosphamide
    • Drug: Placebo

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
142
November 2015
January 2015   (Final data collection date for primary outcome measure)

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)
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT00883129
632
R01HL089901 ( U.S. NIH Grant/Contract )
R01HL089758 ( U.S. NIH Grant/Contract )
Yes
Not Provided
Plan to Share IPD: No
Michael Roth, University of California, Los Angeles
Michael Roth
  • National Heart, Lung, and Blood Institute (NHLBI)
  • Hoffmann-La Roche
Principal Investigator: Donald P. Tashkin, MD University of California, Los Angeles
Principal Investigator: Robert M. Elashoff, PhD UCLA School of Public Health
Principal Investigator: Michael D. Roth, MD University of California, Los Angeles
University of California, Los Angeles
February 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP