title: Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial.
abstract: 12 months of oral cyclophosphamide has been shown to alter the progression of scleroderma-related interstitial lung disease when compared with placebo. However, toxicity was a concern and without continued treatment the efficacy disappeared by 24 months. We hypothesised that a 2 year course of mycophenolate mofetil would be safer, better tolerated, and produce longer lasting improvements than cyclophosphamide.
  
  
  
  This randomised, double-blind, parallel group trial enrolled patients from 14 US medical centres with scleroderma-related interstitial lung disease meeting defined dyspnoea, pulmonary function, and high-resolution CT (HRCT) criteria. The data coordinating centre at the University of California, Los Angeles (UCLA, CA, USA), randomly assigned patients using a double-blind, double-dummy, centre-blocked design to receive either mycophenolate mofetil (target dose 1500 mg twice daily) for 24 months or oral cyclophosphamide (target dose 2·0 mg/kg per day) for 12 months followed by placebo for 12 months. Drugs were given in matching 250 mg gel capsules. The primary endpoint, change in forced vital capacity as a percentage of the predicted normal value (FVC %) over the course of 24 months, was assessed in a modified intention-to-treat analysis using an inferential joint model combining a mixed-effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data. The study was registered with ClinicalTrials.gov, number NCT00883129.
  
  
  
  Between Sept 28, 2009, and Jan 14, 2013, 142 patients were randomly assigned to either mycophenolate mofetil (n=69) or cyclophosphamide (n=73). 126 patients (mycophenolate mofetil [n=63] and cyclophosphamide [n=63]) with acceptable baseline HRCT studies and at least one outcome measure were included in the primary analysis. The adjusted % predicted FVC improved from baseline to 24 months by 2·19 in the mycophenolate mofetil group (95% CI 0·53-3·84) and 2·88 in the cyclophosphamide group (1·19-4·58). The course of the % FVC did not differ significantly between the two treatment groups based on the prespecified primary analysis using a joint model (p=0·24), indicating that the trial was negative for the primary endpoint. However, in a post-hoc analysis of the primary endpoint, the within-treatment change from baseline to 24 months derived from the joint model showed that the % FVC improved significantly in both the mycophenolate mofetil and cyclophosphamide groups. 16 (11%) patients died (five [7%] mycophenolate mofetil and 11 [15%] cyclophosphamide), with most due to progressive interstitial lung disease. Leucopenia (30 patients vs four patients) and thrombocytopenia (four vs zero) occurred more often in patients given cyclophosphamide than mycophenolate mofetil. Fewer patients on mycophenolate mofetil than on cyclophosphamide prematurely withdrew from study drug (20 vs 32) or met prespecified criteria for treatment failure (zero vs two). The time to stopping treatment was shorter in the cyclophosphamide group (p=0·019).
  
  
  
  Treatment of scleroderma-related interstitial lung disease with mycophenolate mofetil for 2 years or cyclophosphamide for 1 year both resulted in significant improvements in prespecified measures of lung function over the 2 year course of the study. Although mycophenolate mofetil was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than cyclophosphamide was not confirmed. These findings support the potential clinical effectiveness of both cyclophosphamide and mycophenolate mofetil for progressive scleroderma-related interstitial lung disease, and the present preference for mycophenolate mofetil because of its better tolerability and toxicity profile.
  
  
  
  National Heart, Lung and Blood Institute, National Institutes of Health; with drug supply provided by Hoffmann-La Roche and Genentech.
authors.affiliation: Department of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA. Electronic address: dtashkin@mednet.ucla.edu.
authors.forename: Donald P
authors.initials: DP
authors.lastname: Tashkin
authors.affiliation: Department of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Roth
authors.affiliation: Department of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Clements
authors.affiliation: Department of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Furst
authors.affiliation: Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Khanna
authors.affiliation: Department of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Kleerup
authors.affiliation: Department of Radiological Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Goldin
authors.affiliation: Division of Pharmaceutical Services, Ronald Reagan UCLA Medical Center, University of California, Los Angeles, CA, USA.
authors.forename: Edgar
authors.initials: E
authors.lastname: Arriola
authors.affiliation: Department of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Volkmann
authors.affiliation: Department of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kafaja
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Silver
authors.affiliation: Department of Medicine, Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Steen
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Charlie
authors.initials: C
authors.lastname: Strange
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Wise
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Fredrick
authors.initials: F
authors.lastname: Wigley
authors.affiliation: Department of Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Mayes
authors.affiliation: Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Riley
authors.affiliation: Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
authors.forename: Sabiha
authors.initials: S
authors.lastname: Hussain
authors.affiliation: Department of Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Shervin
authors.initials: S
authors.lastname: Assassi
authors.affiliation: Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
authors.forename: Vivien M
authors.initials: VM
authors.lastname: Hsu
authors.affiliation: Department of Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Bela
authors.initials: B
authors.lastname: Patel
authors.affiliation: Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Kristine
authors.initials: K
authors.lastname: Phillips
authors.affiliation: Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Martinez
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Golden
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.
authors.forename: M Kari
authors.initials: MK
authors.lastname: Connolly
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: John
authors.initials: J
authors.lastname: Varga
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Dematte
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Monique E
authors.initials: ME
authors.lastname: Hinchcliff
authors.affiliation: Department of Medicine, National Jewish Health, Denver, CO, USA.
authors.forename: Aryeh
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Department of Medicine, National Jewish Health, Denver, CO, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Swigris
authors.affiliation: Department of Medicine, National Jewish Health, Denver, CO, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Meehan
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Theodore
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Simms
authors.affiliation: Department of Medicine, University of Illinois College of Medicine at Chicago, Chicago, IL, USA.
authors.forename: Suncica
authors.initials: S
authors.lastname: Volkov
authors.affiliation: Department of Medicine, University of Illinois College of Medicine at Chicago, Chicago, IL, USA.
authors.forename: Dean E
authors.initials: DE
authors.lastname: Schraufnagel
authors.affiliation: Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Scholand
authors.affiliation: Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: Frech
authors.affiliation: Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Jerry A
authors.initials: JA
authors.lastname: Molitor
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Highland
authors.affiliation: Department of Medicine, Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Read
authors.affiliation: Departments of Medicine, Biochemistry, and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Fritzler
authors.affiliation: Department of Radiological Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA.
authors.forename: Grace Hyun J
authors.initials: GHJ
authors.lastname: Kim
authors.affiliation: Department of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA.
authors.forename: Chi-Hong
authors.initials: CH
authors.lastname: Tseng
authors.affiliation: Department of Biomathematics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Elashoff
mesh_terms: D000328:Adult; D000368:Aged; D003520:Cyclophosphamide / Q000008:administration & dosage*; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008168:Lung / Q000503:physiopathology; D017563:Lung Diseases, Interstitial / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage*; D012129:Respiratory Function Tests; D012595:Scleroderma, Systemic / Q000150:complications* / Q000503:physiopathology; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D009173:Mycophenolic Acid