贝那利珠单抗治疗高剂量吸入皮质类固醇激素和长效β2受体激动剂（SIROCCO）的重度哮喘患者的疗效和安全性：一项随机，多
2017/12/20
贝那利珠单抗治疗高剂量吸入皮质类固醇激素和长效β2受体激动剂（SIROCCO）的重度哮喘患者的疗效和安全性：一项随机，多中心，安慰剂对照的3期临床试验
摘要
背景：嗜酸性粒细胞增多与哮喘严重程度恶化及肺功能下降有关，同时伴随恶化发生频率增加。 我们评估了贝那利珠单抗（一种抗白细胞介素-5受体α的单克隆抗体）的安全性和有效性，该抗体通过抗体依赖性细胞介导的细胞毒性消耗嗜酸性粒细胞，用于患有嗜酸性粒细胞增多症的严重的，不受控制的哮喘的患者。
方法：我们在17个国家的374个地点进行了一项随机，双盲，平行，安慰剂对照的3期研究。我们招募了患者（年龄12-75岁），以基于内科医生为基础的哮喘诊断至少1年，并且在过去的一年里高剂量使用吸入糖皮质激素和长效β2受体激动剂（ICS加LABA）的同时至少两次恶化。通过交互式基于网络的语音应答系统将患者随机分配（1：1：1）到每4周30mg贝那珠单抗（Q4W）或每8周（Q8W;每4周的前三个剂量）或安慰剂每4周一次给予48周作为他们的标准治疗的补充。根据血液嗜酸性粒细胞计数至少300个细胞/μL和小于300个细胞/μL，将患者分层为2：1。所有参与患者治疗或临床评估的患者和研究者都不知情治疗分配。对于血嗜酸性粒细胞计数至少为300个细胞/μL的患者来说主要终点为安慰剂组每年恶化率，主要次要终点是支气管扩张剂前1秒用力呼气容积（FEV1）和48周总哮喘症状评分。有效性分析是通过打算治疗的意图（基于完整的分析集）;安全性分析是通过收到研究药物的患者。
发现：2013年9月19日至2015年3月16日，共有2681名患者入选，其中1205名符合研究标准，随机分配：407名安慰剂，400名贝那珠单抗 30 mg Q4W，398名贝那珠 30 mg Q8W。安慰剂组中的267名患者，贝那利珠单抗30mg Q4W组中的275名并且贝那利珠单抗30mg Q8W组中的267名患者具有至少300个细胞/μL的血液嗜酸性粒细胞计数，而且要被包括在主要分析群体中。与安慰剂相比，贝那利珠单抗降低了年哮喘恶化率在给予Q4W（比率0·55，95％CI 0·42-0·71; p <0·0001）或Q8W（0·49·0· 37-0·64; p <0.0001）的48周期间。与安慰剂组相比，贝那利珠单抗给药方案显着改善了患者使用支气管扩张剂前FEV1的变化（相对于基线的最小二乘均值变化：Q4W组0·106 L，95％CI 0·016-0·196; Q8W组0·159 L， 0·068-0·249）。与安慰剂相比，Q8W方案改善了哮喘症状（最小二乘均数差为-0.25，95％CI -0.45至-0.06），而不是Q4W方案（-0.08，-0 ·27至0·12）。最常见的不良事件是哮喘恶化（797名贝那利珠单抗治疗的患者中有105名（13％）与407名安慰剂治疗患者中的78名（19％））和鼻咽炎（93名[12％]比47名[12％]）。
解释：这些结果证实了贝那利珠单抗对严重哮喘和嗜酸性粒细胞升高的患者疗效和安全性，这些患者不受高剂量ICS加LABA的控制，并且为贝那利珠单抗作为在这类患者群体中治疗该疾病的附加措施提供支持。
（中日友好医院 呼吸与危重症医学科 张鑫 摘译 林江涛 审校）
（Lancet 2016; 388: 2115–27）
（Lancet 2016; 388: 2115–27）
Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO):a randomised, multicentre,placebo-controlled phase 3 trial
Eugene R Bleecker, J Mark FitzGerald, Pascal Chanez, Alberto Papi, Steven F Weinstein, Peter Barker, Stephanie Sproule, Geoffrey Gilmartin, Magnus Aurivillius, Viktoria Werkström, Mitchell Goldman, on behalf of the SIROCCO study investigators*
Summary
Background：Eosinophilia is associated with worsening asthma severity and decreased lung function, with increased exacerbation frequency. We assessed the safety and efficacy of benralizumab, a monoclonal antibody against interleukin-5 receptor α that depletes eosinophils by antibody-dependent cell-mediated cytotoxicity, for patients with severe, uncontrolled asthma with eosinophilia.
Methods：We did a randomised, double-blind, parallel-group, placebo-controlled phase 3 study at 374 sites in 17 countries. We recruited patients (aged 12–75 years) with a physician-based diagnosis of asthma for at least 1 year and at least two exacerbations while on high-dosage inhaled corticosteroids and long-acting β2-agonists (ICS plus LABA) in the previous year. Patients were randomly assigned (1:1:1) by an interactive web-based voice response system to benralizumab 30 mg either every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses every 4 weeks) or placebo Q4W for 48 weeks as add on to their standard treatment. Patients were stratified 2:1 according to blood eosinophil counts of at least 300 cells per μL and less than 300 cells per μL. All patients and investigators involved in patient treatment or clinical assessment were masked to treatment allocation. The primary endpoint was annual exacerbation rate ratio versus placebo, and key secondary endpoints were prebronchodilator forced expiratory volume in 1 s (FEV1) and total asthma symptom score at week 48, for patients with blood eosinophil counts of at least 300 cells per μL. Efficacy analyses were by intention to treat (based on the full analysis set); safety analyses included patients according to study drug received.
Findings：Between Sept 19, 2013, and March 16, 2015, 2681 patients were enrolled, 1205 of whom met the study criteria and were randomly assigned: 407 to placebo, 400 to benralizumab 30 mg Q4W, and 398 to benralizumab 30 mg Q8W. 267 patients in the placebo group, 275 in the benralizumab 30 mg Q4W group, and 267 in the benralizumab 30 mg Q8W group had blood eosinophil counts at least 300 cells per μL and were included in the primary analysis population. Compared with placebo, benralizumab reduced the annual asthma exacerbation rate over 48 weeks when given Q4W (rate ratio 0·55, 95% CI 0·42–0·71; p<0·0001) or Q8W (0·49, 0·37–0·64; p<0·0001). Both benralizumab dosing regimens significantly improved prebronchodilator FEV1 in patients at week 48 compared with placebo (least-squares mean change from baseline: Q4W group 0·106 L, 95% CI 0·016–0·196; Q8W group 0·159 L, 0·068–0·249). Compared with placebo, asthma symptoms were improved by the Q8W regimen (least-squares mean difference –0·25, 95% CI –0·45 to –0·06), but not the Q4W regimen (–0·08, –0·27 to 0·12). The most common adverse events were worsening asthma (105 [13%] of 797 benralizumab-treated patients vs 78 [19%] of 407 placebo-treated patients) and nasopharyngitis (93 [12%] vs 47 [12%]).
Interpretation：These results confirm the efficacy and safety of benralizumab for patients with severe asthma and elevated eosinophils, which are uncontrolled by high-dosage ICS plus LABA, and provide support for benralizumab to be an additional option to treat this disease in this patient population.
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重症哮喘患者支气管热成形术后的远期疗效:两个前瞻性多中心研究的3年随访结果比较
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