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SclerodermaPhase 2SLSIINCT00883129

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

A Phase 2 study testing Mycophenolate mofetil and Cyclophosphamide in people with Scleroderma and Interstitial Lung Disease, run by Michael Roth at 14 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Scleroderma, Interstitial Lung Disease
What is being tested?
Mycophenolate mofetil and Cyclophosphamide
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
142 participants
Where
14 sitesUnited States
Study dates
Sep 2009to Nov 2015
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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])
Show all 22Show fewer
  • 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)

Trial locations and contacts

14 sites in 1 country.

14 sites in 1 country

United States14 sites

  • University of Michigan Medical School

    Ann Arbor, Michigan, 48109

  • Johns Hopkins University School of Medicine

    Baltimore, Maryland, 21205

  • Boston University School of Medicine

    Boston, Massachusetts, 02118

  • Medical University of South Carolina

    Charleston, South Carolina, 29425

  • Feinberg School of Medicine, Northwestern University

    Chicago, Illinois, 60611

  • University of Illinois at Chicago, College of Medicine

    Chicago, Illinois, 60612

  • National Jewish Health

    Denver, Colorado, 80206

  • University of Texas Medical School at Houston

    Houston, Texas, 77225

  • David Geffen School of Medicine at UCLA

    Los Angeles, California, 90095

  • University of Minnesota

    Minneapolis, Minnesota, 55454

  • University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School

    New Brunswick, New Jersey, 08854

  • University of Utah

    Salt Lake City, Utah, 84132

  • University of California, San Francisco

    San Francisco, California, 94143

  • Georgetown University School of Medicine

    Washington D.C., District of Columbia, 20057

Other trials in United States

About this study

Official title: 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.

Read the 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.

Keywords
Systemic Sclerosis, Mycophenolate Mofetil, Cyclophosphamide, High Resolution Computerized Tomography, Pulmonary Function, Dyspnea, Health Related Quality of Life
Medical subject headings
Scleroderma, Diffuse, Lung Diseases, Interstitial, Scleroderma, Systemic, Dyspnea

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Mycophenolate mofetilDrug

    Also called CellCept

    24 months of oral mycophenolate mofetil, up to a maximal dose of 1.5 grams twice daily as tolerated

  • CyclophosphamideDrug

    Also called Cytoxan

    12 months of oral cyclophosphamide, up to a maximal dose of 2 mg/kg daily as tolerated

  • PlaceboDrug

    Also called Sugar Pill

    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.

Study groups in NCT00883129
Study groupRoleWhat they receive
Mycophenolate ArmExperimentalParticipants will receive oral mycophenolate mofetil for 2 years.
Receives: Drug: Mycophenolate mofetil
Cyclophosphamide ArmExperimentalParticipants will receive oral cyclophosphamide for 1 year, followed by placebo for 1 year.
Receives: Drug: Cyclophosphamide; Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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: Measured at study Baseline and Months 3, 6, 12, 15, 18, 21, and 24

Secondary outcomes (8)

  1. 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: Measured at study entry and Months 6, 12, 18, and 24

  2. 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: Measured at study entry and Months 3, 6, 12, 15, 18, 21, and 24

  3. 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: Measured at baseline and Month 24

  4. 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: Measured at Months 6, 12, 18, and 24

  5. 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: Measured at study entry and Months 3, 6, 9, 12, 15, 18, 21, and 24

  6. 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: Measured at baseline and Months 3, 6, 9, 12, 15, 18, 21, and 24

  7. Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death

    Measured: Measured throughout the 2-year study

  8. 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

    Measured: Continuous assessment from randomization to 24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Apr 2009 (estimated)
  2. Study startSep 2009
  3. Primary completionJan 2015
  4. Study completionNov 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
142 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00883129
Sponsor's protocol ID
632
Other IDs
R01HL089901, R01HL089758
Acronym
SLSII
Status last verified
Feb 2017
First submitted
16 Apr 2009
Last updated
10 Feb 2017
Data monitoring committee
Yes
Individual data sharing
No

Publications

  • 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.

    PubMed 18620121

  • 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. doi: 10.1002/sim.2749.

    PubMed 17124698

  • 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):762-771. doi: 10.1111/j.1541-0420.2007.00952.x. Epub 2007 Dec 20.

    PubMed 18162112

  • 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.

    PubMed 19197956

  • 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. Epub 2009 Mar 13.

    PubMed 19286849

  • 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. Epub 2010 Nov 3.

    PubMed 21050542

  • 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.

    PubMed 21531236

  • 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.

    PubMed 21547897

  • 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.

    PubMed 21618205

  • 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. Epub 2011 Sep 17.

    PubMed 21927793

  • 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):614-621. doi: 10.1378/chest.11-0801.

    PubMed 22156609

  • 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. doi: 10.1056/NEJMoa055120.

    PubMed 16790698

  • 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. doi: 10.1002/art.20787.

    PubMed 15692967

  • 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. doi: 10.1002/art.22580.

    PubMed 17469162

  • 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. doi: 10.1136/ard.2007.069518. Epub 2007 May 7.

    PubMed 17485423

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Mycophenolate mofetil and Cyclophosphamide in people with Scleroderma and Interstitial Lung Disease, run by Michael Roth at 14 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Feb 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 14 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 10 Feb 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the 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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00883129, which also lists 31 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Feb 2017.

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