TY - JOUR

T1 - Tocilizumab in systemic sclerosis

T2 - a randomised, double-blind, placebo-controlled, phase 3 trial

AU - Khanna, Dinesh

AU - Lin, Celia J.F.

AU - Furst, Daniel E.

AU - Goldin, Jonathan

AU - Kim, Grace

AU - Kuwana, Masataka

AU - Allanore, Yannick

AU - Matucci-Cerinic, Marco

AU - Distler, Oliver

AU - Shima, Yoshihito

AU - van Laar, Jacob M.

AU - Spotswood, Helen

AU - Wagner, Bridget

AU - Siegel, Jeffrey

AU - Jahreis, Angelika

AU - Denton, Christopher P.

AU - Lucero, Eleonora

AU - Pons-Estel, Bernardo

AU - Rivero, Mariano

AU - Tate, Guillermo

AU - Smith, Vanessa

AU - De Langhe, Ellen

AU - Rashkov, Rasho

AU - Batalov, Anastas

AU - Goranov, Ivan

AU - Stoilov, Rumen

AU - Dunne, James

AU - Johnson, Sindhu R.

AU - Pope, Janet E.

AU - Martinović Kaliterna, Dušanka

AU - Mogensen, Mette

AU - Olesen, Anne Braae

AU - Henes, Joerg Christoph

AU - Müller-Ladner, Ulf

AU - Riemekasten, Gabriela

AU - Skapenko, Alla

AU - Vlachoyiannopoulos, Panayiotis

AU - Kiss, Emese

AU - Minier, Tünde

AU - Beretta, Lorenzo

AU - Gremese, Elisa

AU - Valentini, Gabriele

AU - Asano, Yoshihide

AU - Atsumi, Tatsuya

AU - Ihn, Hironobu

AU - Ishii, Tomonori

AU - Ishikawa, Osamu

AU - Takahashi, Hiroki

AU - Takehara, Kazuhiko

AU - Tanaka, Yoshiya

AU - Yamasaki, Yoshioki

AU - Bukauskiene, Loreta

AU - Butrimiene, Irena

AU - Medrano Ramirez, Gabriel

AU - Ramos-Remus, Cesar

AU - Sofia Rodriguez Reyna, Tatiana

AU - de Vries-Bouwstra, Jeska

AU - van Laar, Jacob M.

AU - Batko, Bogdan

AU - Jeka, Slawomir

AU - Kucharz, Eugeniusz

AU - Majdan, Maria

AU - Olesinska, Marzena

AU - Smolenska, Zaneta

AU - Alves, Jose

AU - Santos, Maria

AU - Mihai, Carmen Marina

AU - Rednic, Simona

AU - Castellvi Barranco, Ivan

AU - Lopez Longo, Francisco Javier

AU - Simeon Aznar, Carmen

AU - Carreira, Patricia

AU - Walker, Ulrich A.

AU - Derrett-Smith, Emma

AU - Griffiths, Bridget

AU - McKay, Neil

AU - Denton, Christopher P.

AU - Aelion, Jacob

AU - Borofsky, Michael

AU - Fleischmann, Roy

AU - Forstot, Joseph Z.

AU - Furst, Daniel E.

AU - Kafaja, Suzanne

AU - Khan, M. Faisal

AU - Kohen, Michael D.

AU - Martin, Richard W.

AU - Mendoza-Ballesteros, Fabian

AU - Nami, Alireza

AU - Pang, Shirley

AU - Rios, Grissel

AU - Simms, Robert

AU - Sullivan, Keith Michael

AU - Steen, Virginia D.

PY - 2020

Y1 - 2020

N2 - 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 ClinicalTrials.gov (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.

AB - 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 ClinicalTrials.gov (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.

U2 - 10.1016/S2213-2600(20)30318-0

DO - 10.1016/S2213-2600(20)30318-0

M3 - Journal article

C2 - 32866440

AN - SCOPUS:85090589707

VL - 8

SP - 963

EP - 974

JO - The Lancet Respiratory Medicine

JF - The Lancet Respiratory Medicine

SN - 2213-2600

IS - 10

ER -