title: Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial.
abstract: BACKGROUND
  Systemic sclerosis is a rare disabling autoimmune disease with few treatment options. The efficacy and safety of tocilizumab, an interleukin 6 receptor-α inhibitor, was assessed in the faSScinate phase 2 trial in patients with systemic sclerosis.
  
  
  METHODS
  We did this double-blind, placebo-controlled study at 35 hospitals in Canada, France, Germany, the UK, and the USA. We enrolled adults with progressive systemic sclerosis of 5 or fewer years' duration from first non-Raynaud's sign or symptom. Patients were randomly assigned (1:1) to weekly subcutaneous tocilizumab 162 mg or placebo. The primary endpoint was the difference in mean change from baseline in modified Rodnan skin score at 24 weeks. This study is registered with ClinicalTrials.gov, number NCT01532869.
  
  
  RESULTS
  We enrolled 87 patients: 43 assigned to tocilizumab and 44 assigned to placebo. The least squares mean change in modified Rodnan skin score at 24 weeks was -3·92 in the tocilizumab group and -1·22 in the placebo group (difference -2·70, 95% CI -5·85 to 0·45; p=0·0915). The least squares mean change at 48 weeks was -6·33 in the tocilizumab group and -2·77 in the placebo group (treatment difference -3·55, 95% CI -7·23 to 0·12; p=0·0579). In one of several exploratory analyses, fewer patients in the tocilizumab group than in the placebo group had a decline in percent predicted forced vital capacity at 48 weeks (p=0·0373). However, we detected no significant difference in disability, fatigue, itching, or patient or clinician global disease severity. 42 (98%) of 43 patients in the tocilizumab group versus 40 (91%) of 44 in the placebo group had adverse events. 14 (33%) versus 15 (34%) had serious adverse events. Serious infections were more common in the tocilizumab group (seven [16%] of 43 patients) than in the placebo group (two [5%] of 44). One patient died in relation to tocilizumab treatment.
  
  
  CONCLUSIONS
  Tocilizumab was not associated with a significant reduction in skin thickening. However, the difference was greater in the tocilizumab group than in the placebo group and we found some evidence of less decline in forced vital capacity. The efficacy and safety of tocilizumab should be investigated in a phase 3 trial before definitive conclusions can be made about its risks and benefits.
  
  
  BACKGROUND
  F Hoffmann-La Roche, Genentech.
authors.affiliation: University of Michigan Scleroderma Program, Ann Arbor, MI, USA. Electronic address: khannad@med.umich.edu.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Khanna
authors.affiliation: University College London, London, UK.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Denton
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Angelika
authors.initials: A
authors.lastname: Jahreis
authors.affiliation: University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: van Laar
authors.affiliation: University of Utah, Veterans Affairs Medical Center, Salt Lake City, UT, USA.
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Frech
authors.affiliation: University of Liverpool and Aintree University Hospital, Liverpool, UK.
authors.forename: Marina E
authors.initials: ME
authors.lastname: Anderson
authors.affiliation: Jewish General Hospital, Montreal, QC, Canada.
authors.forename: Murray
authors.initials: M
authors.lastname: Baron
authors.affiliation: Stanford University School of Medicine and Palo Alto VA Health Care System, Palo Alto, CA, USA.
authors.forename: Lorinda
authors.initials: L
authors.lastname: Chung
authors.affiliation: University of Tübingen, Tübingen, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fierlbeck
authors.affiliation: University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Santhanam
authors.initials: S
authors.lastname: Lakshminarayanan
authors.affiliation: Paris Descartes University and Cochin Hospital, Paris, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Allanore
authors.affiliation: Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
authors.forename: Janet E
authors.initials: JE
authors.lastname: Pope
authors.affiliation: Charité University Hospital, German Rheumatism Research Centre, Berlin, Germany.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Riemekasten
authors.affiliation: Georgetown University, Washington, DC, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Steen
authors.affiliation: Justus-Liebig University Giessen, Kerckhoff Clinic, Bad Nauheim, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Müller-Ladner
authors.affiliation: Boston University School of Medicine, Boston, MA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
authors.affiliation: Boston University School of Medicine, Boston, MA, USA.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Stifano
authors.affiliation: Roche Products, Welwyn Garden City, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Spotswood
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Haiyin
authors.initials: H
authors.lastname: Chen-Harris
authors.affiliation: Roche, Basel, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Dziadek
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Morimoto
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Thierry
authors.initials: T
authors.lastname: Sornasse
authors.affiliation: Genentech, South San Francisco, CA, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Siegel
authors.affiliation: University of California, Los Angeles, CA, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Furst
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D002170:Canada; D004311:Double-Blind Method; D005060:Europe; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D015850:Interleukin-6 / Q000502:physiology; D008297:Male; D008875:Middle Aged; D012595:Scleroderma, Systemic / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D016896:Treatment Outcome; D006113:United Kingdom; D014797:Vital Capacity
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D015850:Interleukin-6; C502936:tocilizumab