University of Michigan, Ann Arbor, MI, USA.
Genentech, South San Francisco, CA, USA.
Lancet Respir Med. 2020 Oct;8(10):963-974. doi: 10.1016/S2213-2600(20)30318-0. Epub 2020 Aug 28.
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.
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.
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).
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.
F Hoffmann-La Roche Ltd.
托珠单抗的 2 期临床试验初步证明了其在系统性硬化症中的疗效。我们在 3 期临床试验中评估了皮肤纤维化和系统性硬化症相关间质性肺病（SSc-ILD），以研究抗白细胞介素-6 受体抗体托珠单抗治疗系统性硬化症的安全性和疗效。
在这项多中心、随机、双盲、安慰剂对照的 3 期临床试验中，参与者从欧洲、北美、拉丁美洲和日本的 75 个地点招募。筛选时有 60 个月或以下弥漫性皮肤系统性硬化症和改良罗登皮肤评分（mRSS）为 10-35 的成年人，随机（1:1）通过语音网络应答系统接受每周皮下注射托珠单抗 162mg 或安慰剂治疗 48 周，按白细胞介素-6 水平分层；参与者和研究人员对治疗组均不知情。主要终点是从基线到第 48 周 mRSS 的变化差异。第 48 周预测用力肺活量百分比（FVC%pred）、治疗失败时间以及患者报告和医生报告的结果是次要终点。这项试验在 ClinicalTrials.gov （编号 NCT02453256）注册，现已关闭入组。
在 2015 年 11 月 20 日至 2017 年 2 月 14 日期间，210 名参与者被随机分配接受托珠单抗（n=104）或安慰剂（n=106）治疗。在意向治疗人群中，从基线到第 48 周时 mRSS 的最小二乘均数（LSM）变化，托珠单抗组为-6.14，安慰剂组为-4.41（调整差异-1.73 [95%CI-3.78 至 0.32]；p=0.10）。第 48 周时 FVC%pred 变化的分布变化有利于托珠单抗（van Elteren 名义 p=0.002 与安慰剂相比），LSM 差异为 4.2（95%CI 2.0-6.4；名义 p=0.0002），治疗失败时间也如此（风险比 0.63 [95%CI 0.37-1.06]；名义 p=0.08）。从基线到第 48 周时，健康评估问卷残疾指数和患者整体及医生整体视觉模拟量表的 LSM 变化在托珠单抗组和安慰剂组之间没有差异。在安全性组中，感染是最常见的不良事件（托珠单抗组 54 名[52%]参与者，安慰剂组 53 名[50%]参与者）。托珠单抗治疗的 13 名参与者和安慰剂组的 18 名参与者报告了严重不良事件，主要是感染（3 例，8 例）和心脏事件（2 例，7 例）。
主要皮肤纤维化终点未达到。次要终点 FVC%pred 的结果表明，托珠单抗可能在早期 SSc-ILD 和急性反应蛋白升高的患者中保留肺功能。安全性与托珠单抗的已知特征一致。
F. Hoffmann-La Roche Ltd.
