Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial

Dinesh Khanna*, Celia J.F. Lin, Daniel E. Furst, Jonathan Goldin, Grace Kim, Masataka Kuwana, Yannick Allanore, Marco Matucci-Cerinic, Oliver Distler, Yoshihito Shima, Jacob M. van Laar, Helen Spotswood, Bridget Wagner, Jeffrey Siegel, Angelika Jahreis, Christopher P. Denton, Eleonora Lucero, Bernardo Pons-Estel, Mariano Rivero, Guillermo TateVanessa Smith, Ellen De Langhe, Rasho Rashkov, Anastas Batalov, Ivan Goranov, Rumen Stoilov, James Dunne, Sindhu R. Johnson, Janet E. Pope, Dušanka Martinović Kaliterna, Mette Mogensen, Anne Braae Olesen, Joerg Christoph Henes, Ulf Müller-Ladner, Gabriela Riemekasten, Alla Skapenko, Panayiotis Vlachoyiannopoulos, Emese Kiss, Tünde Minier, Lorenzo Beretta, Elisa Gremese, Gabriele Valentini, Yoshihide Asano, Tatsuya Atsumi, Hironobu Ihn, Tomonori Ishii, Osamu Ishikawa, Hiroki Takahashi, Kazuhiko Takehara, Yoshiya Tanaka, Yoshioki Yamasaki, Loreta Bukauskiene, Irena Butrimiene, Gabriel Medrano Ramirez, Cesar Ramos-Remus, Tatiana Sofia Rodriguez Reyna, Jeska de Vries-Bouwstra, Jacob M. van Laar, Bogdan Batko, Slawomir Jeka, Eugeniusz Kucharz, Maria Majdan, Marzena Olesinska, Zaneta Smolenska, Jose Alves, Maria Santos, Carmen Marina Mihai, Simona Rednic, Ivan Castellvi Barranco, Francisco Javier Lopez Longo, Carmen Simeon Aznar, Patricia Carreira, Ulrich A. Walker, Emma Derrett-Smith, Bridget Griffiths, Neil McKay, Christopher P. Denton, Jacob Aelion, Michael Borofsky, Roy Fleischmann, Joseph Z. Forstot, Daniel E. Furst, Suzanne Kafaja, M. Faisal Khan, Michael D. Kohen, Richard W. Martin, Fabian Mendoza-Ballesteros, Alireza Nami, Shirley Pang, Grissel Rios, Robert Simms, Keith Michael Sullivan, Virginia D. Steen

*Corresponding author for this work
12 Citations (Scopus)


Background: A phase 2 trial of tocilizumab showed preliminary evidence of efficacy in systemic sclerosis. We assessed skin fibrosis and systemic sclerosis-associated interstitial lung disease (SSc-ILD) in a phase 3 trial to investigate the safety and efficacy of tocilizumab, an anti-interleukin-6 receptor antibody, in the treatment of systemic sclerosis. Methods: In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial, participants were recruited from 75 sites in 20 countries across Europe, North America, Latin America, and Japan. Adults with diffuse cutaneous systemic sclerosis for 60 months or less and a modified Rodnan skin score (mRSS) of 10–35 at screening were randomly assigned (1:1) with a voice-web-response system to receive subcutaneous tocilizumab 162 mg or placebo weekly for 48 weeks, stratified by IL-6 levels; participants and investigators were masked to treatment group. The primary endpoint was the difference in change from baseline to week 48 in mRSS. Percentage of predicted forced vital capacity (FVC% predicted) at week 48, time to treatment failure, and patient-reported and physician-reported outcomes were secondary endpoints. This trial is registered with (number NCT02453256) and is closed to accrual. Findings: Between Nov 20, 2015, and Feb 14, 2017, 210 individuals were randomly assigned to receive tocilizumab (n=104) or placebo (n=106). In the intention-to-treat population, least squares mean [LSM] change from baseline to week 48 in mRSS was −6·14 for tocilizumab and −4·41 for placebo (adjusted difference −1·73 [95% CI −3·78 to 0·32]; p=0·10). The shift in distribution of change from baseline in FVC% predicted at week 48 favoured tocilizumab (van Elteren nominal p=0·002 vs placebo), with a difference in LSM of 4·2 (95% CI 2·0–6·4; nominal p=0·0002), as did time to treatment failure (hazard ratio 0·63 [95% CI 0·37–1·06]; nominal p=0·08). Change in LSM from baseline to week 48 in Health Assessment Questionnaire-Disability Index and in patient-global and physician-global visual analogue scale assessments did not differ between tocilizumab and placebo. In the safety set, infections were the most common adverse events (54 [52%] of 104 participants in the tocilizumab group, 53 [50%] of 106 in the placebo group). Serious adverse events were reported in 13 participants treated with tocilizumab and 18 with placebo, primarily infections (three events, eight events) and cardiac events (two events, seven events). Interpretation: The primary skin fibrosis endpoint was not met. Findings for the secondary endpoint of FVC% predicted indicate that tocilizumab might preserve lung function in people with early SSc-ILD and elevated acute-phase reactants. Safety was consistent with the known profile of tocilizumab. Funding: F Hoffmann-La Roche Ltd.

Original languageEnglish
JournalThe Lancet Respiratory Medicine
Issue number10
Pages (from-to)963-974
Number of pages12
Publication statusPublished - 10.2020


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