Safety and efficacy of tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorder (TANGO): an open-label, multicentre, randomised, phase 2 trial.
Safety and efficacy of tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorder (TANGO): an open-label, multicentre, randomised, phase 2 trial.
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托珠单抗与硫唑嘌呤治疗高度复发性视神经脊髓炎谱系障碍 (TANGO) 的安全性和有效性：一项开放标签、多中心、随机、2 期试验
DOI：
10.1016/s1474-4422(20)30070-3
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发表时间：
2020-05
期刊：
影响因子：
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通讯作者：
TANGO Study Investigators
中科院分区：
文献类型：
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作者：
Zhang C;Zhang M;Qiu W;Ma H;Zhang X;Zhu Z;Yang CS;Jia D;Zhang TX;Yuan M;Feng Y;Yang L;Lu W;Yu C;Bennett JL;Shi FD;TANGO Study Investigators
硫唑嘌呤被用作预防视神经肌萎缩症谱系障碍（NMOSD）复发的一线治疗。在回顾性病例报告中，已报告托珠单抗可降低NMOSD疾病活动度。我们的目的是比较托珠单抗和硫唑嘌呤在高度复发性NMOSD患者中的安全性和有效性。我们在中国的六家医院进行了一项开放标签、多中心、随机、2期试验。我们招募了成年患者（年龄≥18岁）根据2015年国际视神经肌病诊断标准诊断为高度复发性NMOSD，扩展残疾状态量表（EDSS）评分为7.5或更低，并且在前12个月内有至少两次临床复发史，或在前24个月内有三次复发史，在前24个月内至少有一次复发。12个月由一名独立统计员使用计算机生成的随机软件将患者随机（1：1）分配至静脉注射托珠单抗（8 mg/kg，每4周一次）或口服硫唑嘌呤（2-3 mg/kg/天）组，每组4人。中心审查委员会、EDSS评分员、实验室人员和放射科医生对治疗分配设盲，但研究者和患者知道治疗分配。最短计划治疗持续时间为随机化后60周。主要结局是全分析集中至首次复发的时间，包括所有随机分配的接受至少一剂研究药物的患者，以及符合方案人群，包括所有使用硫唑嘌呤或托珠单抗作为单药治疗的患者。对于主要结局的分析，根据伴随自身免疫疾病状态将患者预先指定为两个亚组。在全分析集中评估安全性。本研究已在ClinicalTrials.gov注册，NCT 03350633。在2017年11月1日至2018年8月3日期间，我们入组了118例患者，其中59例随机分配至托珠单抗组，59例随机分配至硫唑嘌呤组。所有118例患者均接受了一剂研究药物，并被纳入全分析集。108名参与者被纳入符合方案分析（托珠单抗组56名，硫唑嘌呤组52名）。在全分析集中，托珠单抗组至首次复发的中位时间长于硫唑嘌呤组（78·9周[IQR 58·3-90·6] vs 56·7 [32·9-81·7]周; p=0·0026）。托珠单抗组59例患者中有8例（14%）和硫唑嘌呤组59例患者中有28例（47%）在研究结束时复发（风险比[HR] 0.236 [95%CI 0.107 - 0.518]; p<0.0001）。在符合方案分析中，研究结束时，托珠单抗组56例患者中有50例（89%）无复发，而硫唑嘌呤组52例患者中有29例（56%）无复发（HR 0.188 [95%CI 0.076 - 0.463]; p<0.0001）;托珠单抗组首次复发的中位时间也长于硫唑嘌呤组（67·2周[IQR 47·9-77·9] vs 38·0 [23·6-64·9]; p<0·0001）。在按伴随自身免疫性疾病分层的全分析集的预先指定亚组分析中，在无伴随自身免疫性疾病的患者中，托珠单抗组34例患者中的3例（9%）和硫唑嘌呤组37例患者中的13例（35%）在研究结束时复发。在伴有自身免疫性疾病的患者中，托珠单抗组复发的患者比例低于硫唑嘌呤组（25例患者中5例[20%] vs 22例患者中15例[68%]; HR 0.192 [95%CI 0.070 - 0.531]; p= 0.0004）。托珠单抗组59例患者中的57例（97%）和硫唑嘌呤组59例患者中的56例（95%）发生不良事件。59例托西珠单抗治疗患者中有36例（61%）和59例硫唑嘌呤治疗患者中有49例（83%）发生治疗相关不良事件。托珠单抗组和硫唑嘌呤组分别有1例（2%）和1例（2%）死亡，但均与治疗无关。与硫唑嘌呤相比，托珠单抗显著降低了随后NMOSD复发的风险。因此，托珠单抗可能是另一种安全有效的治疗方法，以防止NMOSD患者复发。
Azathioprine is used as a first-line treatment to prevent relapses of neuromyelitis optica spectrum disorder (NMOSD). Tocilizumab has been reported to reduce NMOSD disease activity in retrospective case reports. We aimed to compare the safety and efficacy of tocilizumab and azathioprine in patients with highly relapsing NMOSD. We did an open-label, multicentre, randomised, phase 2 trial at six hospitals in China. We recruited adult patients (aged ≥18 years) with highly relapsing NMOSD diagnosed according to 2015 International Panel for Neuromyelitis Optica Diagnosis criteria, who had an Expanded Disability Status Scale (EDSS) score of 7·5 or lower, and had a history of at least two clinical relapses during the previous 12 months or three relapses during the previous 24 months with at least one relapse within the previous 12 months. Patients were randomly assigned (1:1) to intravenous tocilizumab (8 mg/kg every 4 weeks) or oral azathioprine (2–3 mg/kg per day) by an independent statistician using computer-generated randomisation software with permuted blocks of four. The central review committee, EDSS raters, laboratory personnel, and radiologists were masked to the treatment assignment, but investigators and patients were aware of treatment allocation. The minimum planned duration of treatment was 60 weeks following randomisation. The primary outcome was time to first relapse in the full analysis set, which included all randomly assigned patients who received at least one dose of study drug, and the per-protocol population, which included all patients who used azathioprine or tocilizumab as monotherapy. For the analyses of the primary outcome, the patients were prespecified into two subgroups according to concomitant auto immune disease status. Safety was assessed in the full analysis set. This study is registered with ClinicalTrials.gov, NCT03350633. Between Nov 1, 2017, and Aug 3, 2018, we enrolled 118 patients, of whom 59 were randomly assigned to tocilizumab and 59 were randomly assigned to azathioprine. All 118 patients received one dose of study drug and were included in the full analysis set. 108 participants were included in the per-protocol analysis (56 in the tocilizumab group and 52 in the azathioprine group). In the full analysis set, median time to the first relapse was longer in the tocilizumab group than the azathioprine group (78·9 weeks [IQR 58·3–90·6] vs 56·7 [32·9–81·7] weeks; p=0·0026). Eight (14%) of 59 patients in the tocilizumab group and 28 (47%) of 59 patients in the azathioprine group had a relapse at the end of the study (hazard ratio [HR] 0·236 [95% CI 0·107–0·518]; p<0·0001). In the per-protocol analysis, 50 (89%) of 56 patients in the tocilizumab group were relapse-free compared with 29 (56%) of 52 patients in the azathioprine group at the end of the study (HR 0·188 [95% CI 0·076–0·463]; p<0·0001); the median time to first relapse was also longer in the tocilizumab group than the azathioprine group (67·2 weeks [IQR 47·9–77·9] vs 38·0 [23·6–64·9]; p<0·0001). In the prespecified subgroup analysis of the full analysis set stratified by concomitant autoimmune diseases, among patients without concomitant autoimmune diseases, three (9%) of 34 patients in the tocilizumab group and 13 (35%) of 37 patients in the azathioprine group had relapsed by the end of the study. Among patients with concomitant autoimmune diseases, a lower proportion of patients in the tocilizumab group had a relapse than in the azathioprine group (five [20%] of 25 patients vs 15 [68%] of 22 patients; HR 0·192 [95% CI 0·070–0·531]; p=0·0004). 57 (97%) of 59 patients in the tocilizumab group and 56 (95%) of 59 patients in the azathioprine group had adverse events. Treatment-associated adverse events occurred in 36 (61%) of 59 tocilizumab-treated patients and 49 (83%) of 59 azathioprine-treated patients. One death (2%) occurred in the tocilizumab group and one (2%) in the azathioprine group, but neither of the deaths were treatment-related. Tocilizumab significantly reduced the risk of a subsequent NMOSD relapse compared with azathioprine. Tocilizumab might therefore be another safe and effective treatment to prevent relapses in patients with NMOSD.