BACKGROUND Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. METHODS We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II-IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. FINDINGS Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference -11·7, 95% CI -24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. INTERPRETATION The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. FUNDING Alexion Pharmaceuticals.

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依库珠单抗在抗乙酰胆碱受体抗体阳性难治性全身性重症肌无力 (REGAIN) 中的安全性和有效性：3 期、随机、双盲、安慰剂对照、多中心研究

背景补体可能在难治性全身性重症肌无力中起作用，但没有批准的疗法专门针对该系统。2 期研究的结果表明，依库珠单抗（一种终末补体抑制剂）对抗乙酰胆碱受体抗体阳性的难治性全身性重症肌无力患者产生了具有临床意义的改善。我们在 3 期试验中进一步评估了依库珠单抗在该患者人群中的疗效和安全性。方法 我们在北美、拉丁美洲、欧洲和亚洲 17 个国家的 76 家医院和专科诊所进行了一项随机、双盲、安慰剂对照、多中心 3 期研究 (REGAIN)。符合条件的患者年龄至少为 18 岁，重症肌无力 - 日常生活活动 (MG-ADL) 评分为 6 或更高，美国重症肌无力基金会 (MGFA) II-IV 类疾病，接种脑膜炎奈瑟菌疫苗，之前接受过至少两种免疫抑制疗法或一种免疫抑制疗法和慢性静脉注射免疫球蛋白或血浆置换治疗 12 个月，但症状未得到控制。排除有胸腺瘤或胸腺肿瘤病史、筛选前 12 个月内接受过胸腺切除术、或随机分组前 4 周内使用静脉内免疫球蛋白或血浆置换、或筛选前 6 个月内使用利妥昔单抗的患者。我们将参与者 (1:1) 随机分配至静脉注射依库珠单抗或静脉注射匹配安慰剂 26 周。在第 1 天和第 1、2 和 3 周，依库珠单抗的剂量为 900 mg；第 4 周 1200 毫克；并且此后每两周给予 1200 mg 作为维持剂量。随机化是通过交互式语音或网络响应系统集中完成的，患者根据 MGFA 疾病分类分为四组之一。在可能的情况下，患者继续接受现有的重症肌无力疗法，并根据研究医师的判断允许使用救援药物。患者、研究人员、工作人员和结果评估员对治疗分配不知情。主要疗效终点是由最差等级 ANCOVA 测量的 MG-ADL 总分从基线到第 26 周的变化。疗效人群集定义为随机分配到接受至少一剂研究药物、具有有效基线 MG-ADL 评估和至少一项基线后 MG-ADL 评估的治疗组的所有患者。安全性分析包括所有随机分配的接受依库珠单抗或安慰剂治疗的患者。该试验已在 ClinicalTrials.gov 注册，编号 NCT01997229。结果 在 2014 年 4 月 30 日至 2016 年 2 月 19 日期间，我们随机分配并治疗了 125 名患者，其中 62 名使用依库珠单抗，63 名使用安慰剂。主要分析显示依库珠单抗和安慰剂之间没有显着差异（最小二乘平均等级 56·6 [SEM 4·5] vs 68·3 [4·5]；基于等级的治疗差异 -11·7，95% CI - 24·3 到 0·96；p=0·0698)。研究期间没有发生死亡或脑膜炎球菌感染病例。两组中最常见的不良事件是头痛和上呼吸道感染（依库珠单抗组的两个事件均为 10 [16%]，安慰剂组均为 12 [19%]）。依库珠单抗组 6 名 (10%) 患者和安慰剂组 15 名 (24%) 患者报告了重症肌无力恶化。依库珠单抗组 6 名 (10%) 患者和安慰剂组 12 名 (19%) 患者需要抢救治疗。解释 根据最差等级分析衡量，依库珠单抗和安慰剂之间的 MG-ADL 评分变化无统计学意义。依库珠单抗耐受性良好。使用最差分析方法被证明是本研究的一个重要限制，因为次要和敏感性分析结果与主要终点结果不一致；需要进一步研究补体的作用。资助 Alexion Pharmaceuticals。解释 根据最差等级分析衡量，依库珠单抗和安慰剂之间的 MG-ADL 评分变化无统计学意义。依库珠单抗耐受性良好。使用最差分析方法被证明是本研究的一个重要限制，因为次要和敏感性分析结果与主要终点结果不一致；需要进一步研究补体的作用。资助 Alexion Pharmaceuticals。解释 根据最差等级分析衡量，依库珠单抗和安慰剂之间的 MG-ADL 评分变化无统计学意义。依库珠单抗耐受性良好。使用最差分析方法被证明是本研究的一个重要限制，因为次要和敏感性分析结果与主要终点结果不一致；需要进一步研究补体的作用。资助 Alexion Pharmaceuticals。需要进一步研究补体的作用。资助 Alexion Pharmaceuticals。需要进一步研究补体的作用。资助 Alexion Pharmaceuticals。