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

Interstitial Lung Disease Clinical Trial

— SLSII  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00883129
• Other study ID #: 632
• Secondary ID: R01HL089901R01HL
• Status: Completed
• Phase: Phase 2
• First received: April 16, 2009
• Last updated: February 6, 2017
• Start date: September 2009
• Est. completion date: November 2015

Study information

• Verified date: February 2017
• Source: University of California, Los Angeles
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 142
• Est. completion date: November 2015
• Est. primary completion date: January 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Interstitial Lung Disease
• Lung Diseases
• Lung Diseases, Interstitial
• Scleroderma
• Scleroderma, Diffuse
• Scleroderma, Localized
• Scleroderma, Systemic

Intervention

Drug:
• Mycophenolate mofetil
24 months of oral mycophenolate mofetil, up to a maximal dose of 1.5 grams twice daily as tolerated
• Cyclophosphamide
12 months of oral cyclophosphamide, up to a maximal dose of 2 mg/kg daily as tolerated
• 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.

Locations

Country	Name	City	State
United States	University of Michigan Medical School	Ann Arbor	Michigan
United States	Johns Hopkins University School of Medicine	Baltimore	Maryland
United States	Boston University School of Medicine	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Feinberg School of Medicine, Northwestern University	Chicago	Illinois
United States	University of Illinois at Chicago, College of Medicine	Chicago	Illinois
United States	National Jewish Health	Denver	Colorado
United States	University of Texas Medical School at Houston	Houston	Texas
United States	David Geffen School of Medicine at UCLA	Los Angeles	California
United States	University of Minnesota	Minneapolis	Minnesota
United States	University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School	New Brunswick	New Jersey
United States	University of Utah	Salt Lake City	Utah
United States	University of California, San Francisco	San Francisco	California
United States	Georgetown University School of Medicine	Washington	District of Columbia

Sponsors (3)

Lead Sponsor	Collaborator
Michael Roth	Hoffmann-La Roche, National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (21)

Au K, Mayes MD, Maranian P, Clements PJ, Khanna D, Steen VD, Tashkin D, Roth MD, Elashoff R, Furst DE. Course of dermal ulcers and musculoskeletal involvement in systemic sclerosis patients in the scleroderma lung study. Arthritis Care Res (Hoboken). 2010 — View Citation

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): differe — View Citation

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. — View Citation

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. — View Citation

Furst DE, Tseng CH, Clements PJ, Strange C, Tashkin DP, Roth MD, Khanna D, Li N, Elashoff R, Schraufnagel DE; Scleroderma Lung Study.. Adverse events during the Scleroderma Lung Study. Am J Med. 2011 May;124(5):459-67. doi: 10.1016/j.amjmed.2010.12.009. — View Citation

Goldin J, Elashoff R, Kim HJ, Yan X, Lynch D, Strollo D, Roth MD, Clements P, Furst DE, Khanna D, Vasunilashorn S, Li G, Tashkin DP. Treatment of scleroderma-interstitial lung disease with cyclophosphamide is associated with less progressive fibrosis on s — View Citation

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 symptom — View Citation

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. doi: 10.3899/jrheum.080633. — View Citation

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 — View Citation

Khanna D, Tseng CH, Farmani N, Steen V, Furst DE, Clements PJ, Roth MD, Goldin J, Elashoff R, Seibold JR, Saggar R, Tashkin DP. Clinical course of lung physiology in patients with scleroderma and interstitial lung disease: analysis of the Scleroderma Lung Study Placebo Group. Arthritis Rheum. 2011 Oct;63(10):3078-85. doi: 10.1002/art.30467. — View Citation

Khanna D, Tseng CH, Furst DE, Clements PJ, Elashoff R, Roth M, Elashoff D, Tashkin DP; for Scleroderma Lung Study Investigators.. Minimally important differences in the Mahler's Transition Dyspnoea Index in a large randomized controlled trial--results fro — View Citation

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 — View Citation

Kim HG, Tashkin DP, Clements PJ, Li G, Brown MS, Elashoff R, Gjertson DW, Abtin F, Lynch DA, Strollo DC, Goldin JG. A computer-aided diagnosis system for quantitative scoring of extent of lung fibrosis in scleroderma patients. Clin Exp Rheumatol. 2010 Sep-Oct;28(5 Suppl 62):S26-35. — View Citation

Kim HJ, Brown MS, Elashoff R, Li G, Gjertson DW, Lynch DA, Strollo DC, Kleerup E, Chong D, Shah SK, Ahmad S, Abtin F, Tashkin DP, Goldin JG. Quantitative texture-based assessment of one-year changes in fibrotic reticular patterns on HRCT in scleroderma lung disease treated with oral cyclophosphamide. Eur Radiol. 2011 Dec;21(12):2455-65. doi: 10.1007/s00330-011-2223-2. — View Citation

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. doi: 10.1016/j.acra.2008.03.011. — View Citation

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. doi: 10.1002/bimj.200810491. — View Citation

Roth MD, Tseng CH, Clements PJ, Furst DE, Tashkin DP, Goldin JG, Khanna D, Kleerup EC, Li N, Elashoff D, Elashoff RM; Scleroderma Lung Study Research Group.. Predicting treatment outcomes and responder subsets in scleroderma-related interstitial lung disease. Arthritis Rheum. 2011 Sep;63(9):2797-808. doi: 10.1002/art.30438. — View Citation

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 inters — View Citation

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, Mubar — View Citation

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, Muba — View Citation

Theodore AC, Tseng CH, Li N, Elashoff RM, Tashkin DP. Correlation of cough with disease activity and treatment with cyclophosphamide in scleroderma interstitial lung disease: findings from the Scleroderma Lung Study. Chest. 2012 Sep;142(3):614-21. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death		Measured throughout the 2-year study
Secondary	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