Comparison of Therapeutic Regimens for Scleroderma Interstitial Lung Disease (The Scleroderma Lung Study II) - Full Text View

Sponsor:	National Heart, Lung, and Blood Institute (NHLBI)
Collaborator:	Hoffmann-La Roche
Information provided by:	National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier:	NCT00883129

Purpose

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.

Condition	Intervention	Phase
Scleroderma Interstitial Lung Disease	Drug: Mycophenolate mofetil Drug: Cyclophosphamide Drug: Placebo	Phase II

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Active Control, Parallel Assignment, Safety/Efficacy Study
Official Title:	Mycophenolate vs. Oral Cyclophosphamide in Scleroderma Interstitial Lung Disease (Scleroderma Lung Study II)

Resource links provided by NLM:

MedlinePlus related topics: Breathing Problems

Drug Information available for: Cyclophosphamide Mycophenolate mofetil hydrochloride Mycophenolate Mofetil

U.S. FDA Resources

Further study details as provided by National Heart, Lung, and Blood Institute (NHLBI):

Primary Outcome Measures:

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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

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 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
Fibrosis score, as measured by thoracic high resolution computerized tomography [ Time Frame: Measured at study entry and Month 24 ] [ Designated as safety issue: No ]
Breathlessness, as assessed by the Mahler Modified Dyspnea Index [ Time Frame: Measured at study entry and Months 6, 12, 18, and 24 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
Toxicity, as measured by adverse events, serious adverse events, and death [ Time Frame: Measured throughout the 2-year study ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	150
Study Start Date:	September 2009
Estimated Study Completion Date:	May 2014
Estimated Primary Completion Date:	May 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Mycophenolate Arm: Experimental Participants will receive oral mycophenolate mofetil for 2 years.	Drug: Mycophenolate mofetil 24 months of oral mycophenolate mofetil, up to a maximal dose of 1.5 grams twice daily as tolerated
Cyclophosphamide Arm: Experimental Participants will receive oral cyclophosphamide for 1 year, followed by placebo for 1 year.	Drug: Cyclophosphamide 12 months of oral cyclophosphamide, up to a maximal dose of 2 mg/kg daily as tolerated 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.

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, Rodnam 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

Ages Eligible for Study:	18 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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 80 percent of predicted value
Onset of the first non-Raynaud manifestation of SSc in the 5 years before study entry
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

Exclusion Criteria:

FVC less than 45 percent of predicted value
Carbon monoxide diffusing capacity (DLCO) (HBg-corrected) less than 40 percent of predicted value
FEV1/FVC ratio less than 65 percent
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
Pregnant (documented by urine pregnancy test) and/or breastfeeding
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)

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00883129

Contacts

Contact: Grace Ibrahim	310-206-0396	gibrahim@mednet.ucla.edu
Contact: Sara Spencer, RN	310-206-4112	sspencer@mednet.ucla.edu

Locations

United States, California
David Geffen School of Medicine at UCLA	Recruiting
Los Angeles, California, United States, 90095
University of California, San Francisco	Recruiting
San Francisco, California, United States, 94143
United States, Colorado
National Jewish Health	Recruiting
Denver, Colorado, United States, 80206
United States, District of Columbia
Georgetown University School of Medicine	Not yet recruiting
Washington, District of Columbia, United States, 20057
United States, Illinois
Feinberg School of Medicine, Northwestern University	Recruiting
Chicago, Illinois, United States, 60611
University of Illinois at Chicago, College of Medicine	Not yet recruiting
Chicago, Illinois, United States, 60612
United States, Maryland
Johns Hopkins University School of Medicine	Recruiting
Baltimore, Maryland, United States, 21205
United States, Massachusetts
Boston University School of Medicine	Not yet recruiting
Boston, Massachusetts, United States, 02118
United States, Michigan
University of Michigan Medical School	Not yet recruiting
Ann Arbor, Michigan, United States, 48109
United States, New Jersey
University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School	Recruiting
New Brunswick, New Jersey, United States, 08854
United States, South Carolina
Medical University of South Carolina	Recruiting
Charleston, South Carolina, United States, 29425
United States, Texas
University of Texas Medical School at Houston	Not yet recruiting
Houston, Texas, United States, 77225

Sponsors and Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

Hoffmann-La Roche

Investigators

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

More Information

Publications:

Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, Arriola E, Silver R, Strange C, Bolster M, Seibold JR, Riley DJ, Hsu VM, Varga J, Schraufnagel DE, Theodore A, Simms R, Wise R, Wigley F, White B, Steen V, Read C, Mayes M, Parsley E, Mubarak K, Connolly MK, Golden J, Olman M, Fessler B, Rothfield N, Metersky M; Scleroderma Lung Study Research Group. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006 Jun 22;354(25):2655-66.

Khanna D, Clements PJ, Furst DE, Chon Y, Elashoff R, Roth MD, Sterz MG, Chung J, FitzGerald JD, Seibold JR, Varga J, Theodore A, Wigley FM, Silver RM, Steen VD, Mayes MD, Connolly MK, Fessler BJ, Rothfield NF, Mubarak K, Molitor J, Tashkin DP; Scleroderma Lung Study Group. Correlation of the degree of dyspnea with health-related quality of life, functional abilities, and diffusing capacity for carbon monoxide in patients with systemic sclerosis and active alveolitis: results from the Scleroderma Lung Study. Arthritis Rheum. 2005 Feb;52(2):592-600.

Khanna D, Yan X, Tashkin DP, Furst DE, Elashoff R, Roth MD, Silver R, Strange C, Bolster M, Seibold JR, Riley DJ, Hsu VM, Varga J, Schraufnagel DE, Theodore A, Simms R, Wise R, Wigley F, White B, Steen V, Read C, Mayes M, Parsley E, Mubarak K, Connolly MK, Golden J, Olman M, Fessler B, Rothfield N, Metersky M, Clements PJ; Scleroderma Lung Study Group. Impact of oral cyclophosphamide on health-related quality of life in patients with active scleroderma lung disease: results from the scleroderma lung study. Arthritis Rheum. 2007 May;56(5):1676-84.

Clements PJ, Roth MD, Elashoff R, Tashkin DP, Goldin J, Silver RM, Sterz M, Seibold JR, Schraufnagel D, Simms RW, Bolster M, Wise RA, Steen V, Mayes MD, Connelly K, Metersky M, Furst DE; Scleroderma Lung Study Group. Scleroderma lung study (SLS): differences in the presentation and course of patients with limited versus diffuse systemic sclerosis. Ann Rheum Dis. 2007 Dec;66(12):1641-7. Epub 2007 May 7.

Tashkin DP, Elashoff R, Clements PJ, Roth MD, Furst DE, Silver RM, Goldin J, Arriola E, Strange C, Bolster MB, Seibold JR, Riley DJ, Hsu VM, Varga J, Schraufnagel D, Theodore A, Simms R, Wise R, Wigley F, White B, Steen V, Read C, Mayes M, Parsley E, Mubarak K, Connolly MK, Golden J, Olman M, Fessler B, Rothfield N, Metersky M, Khanna D, Li N, Li G; Scleroderma Lung Study Research Group. Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. Am J Respir Crit Care Med. 2007 Nov 15;176(10):1026-34. Epub 2007 Aug 23.

Strange C, Bolster MB, Roth MD, Silver RM, Theodore A, Goldin J, Clements P, Chung J, Elashoff RM, Suh R, Smith EA, Furst DE, Tashkin DP; Scleroderma Lung Study Research Group. Bronchoalveolar lavage and response to cyclophosphamide in scleroderma interstitial lung disease. Am J Respir Crit Care Med. 2008 Jan 1;177(1):91-8. Epub 2007 Sep 27.

Goldin JG, Lynch DA, Strollo DC, Suh RD, Schraufnagel DE, Clements PJ, Elashoff RM, Furst DE, Vasunilashorn S, McNitt-Gray MF, Brown MS, Roth MD, Tashkin DP; Scleroderma Lung Study Research Group. High-resolution CT scan findings in patients with symptomatic scleroderma-related interstitial lung disease. Chest. 2008 Aug;134(2):358-67. Epub 2008 Jul 18.

Kim HJ, Li G, Gjertson D, Elashoff R, Shah SK, Ochs R, Vasunilashorn F, Abtin F, Brown MS, Goldin JG. Classification of parenchymal abnormality in scleroderma lung using a novel approach to denoise images collected via a multicenter study. Acad Radiol. 2008 Aug;15(8):1004-16.

Elashoff RM, Li G, Li N. An approach to joint analysis of longitudinal measurements and competing risks failure time data. Stat Med. 2007 Jun 30;26(14):2813-35.

Elashoff RM, Li G, Li N. A joint model for longitudinal measurements and survival data in the presence of multiple failure types. Biometrics. 2008 Sep;64(3):762-71. Epub 2007 Dec 20.

Li N, Elashoff RM, Li G. Robust joint modeling of longitudinal measurements and competing risks failure time data. Biom J. 2009 Feb;51(1):19-30.

Hant FN, Ludwicka-Bradley A, Wang HJ, Li N, Elashoff R, Tashkin DP, Silver RM; Scleroderma Lung Study Research Group. Surfactant protein D and KL-6 as serum biomarkers of interstitial lung disease in patients with scleroderma. J Rheumatol. 2009 Apr;36(4):773-80. Epub 2009 Mar 13.

Li N, Elashoff RM, Li G. Robust joint modeling of longitudinal measurements and competing risks failure time data. Biom J. 2009 Feb;51(1):19-30.

Responsible Party:	David Geffen School of Medicine at UCLA ( Donald P. Tashkin, MD )
Study ID Numbers:	632, R01 HL089758-01A1, R01 HL089901-01A1, MOCSLID-SLSII
Study First Received:	April 16, 2009
Last Updated:	September 4, 2009
ClinicalTrials.gov Identifier:	NCT00883129 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Heart, Lung, and Blood Institute (NHLBI):

Systemic Sclerosis
Mycophenolate Mofetil
Cyclophosphamide
High Resolution Computerized Tomography

Pulmonary Function
Dyspnea
Health Related Quality of Life

Additional relevant MeSH terms:

Lung Diseases, Interstitial
Lung Diseases
Scleroderma, Localized
Molecular Mechanisms of Pharmacological Action
Skin Diseases
Immunologic Factors
Antineoplastic Agents
Physiological Effects of Drugs
Mycophenolic Acid
Enzyme Inhibitors
Cyclophosphamide

Antibiotics, Antineoplastic
Immunosuppressive Agents
Pharmacologic Actions
Respiratory Tract Diseases
Therapeutic Uses
Myeloablative Agonists
Connective Tissue Diseases
Mycophenolate mofetil
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Alkylating Agents

ClinicalTrials.gov processed this record on February 08, 2010