Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study
Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study
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DOI：
10.1016/s2213-2600(14)70187-0
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发表时间：
2014-11-01
影响因子：
76.2
通讯作者：
van der Merwe, Rene
中科院分区：
文献类型：
--
作者：
Brightling, Christopher E.;Bleecker, Eugene R.;van der Merwe, Rene
背景慢性阻塞性肺疾病(COPD)患者中有10%-20%的患者与嗜酸性呼吸道炎症有关。苯那珠单抗是一种抗白细胞介素5受体的单抗，可以耗尽血液和痰中的嗜酸性粒细胞.我们的目标是确定贝拉珠单抗是否能减少嗜酸性粒细胞增多症和慢性阻塞性肺疾病患者的COPD急性加重。方法我们在2010年11月18日至2013年7月13日期间在英国、波兰、德国、加拿大、美国、丹麦和西班牙的26个地点进行了这项随机、双盲、安慰剂对照的2a期研究。40-85岁的成年人，患有中到重度COPD，至少一次COPD急性加重，前一年内痰嗜酸性粒细胞计数3.0%或更多，随机分配(1：1)通过计算机生成的置换区块随机(区块大小为四)，使用交互式语音或网络反应系统，接受安慰剂或100毫克的苯那珠单抗皮下注射，每4周(3剂)，然后每8周(5剂)，持续48周。研究现场人员沉浸在研究评估中，参与者和数据分析人员被蒙面进行治疗分配。主要终点是56周时COPD急性加重的年化比率，定义为急性加重的数量除以人年随访的总持续时间。次要和探索性终点包括COPD专用圣乔治呼吸问卷(SGRQ-C)、慢性呼吸问卷自填式标准化问卷(CRQ-SAS)、支气管扩张剂前1秒用力呼气量(FEV1)和安全性。我们通过基线血嗜酸性粒细胞计数进行了预先指定的亚群分析。分析按治疗意向和按方案进行。这项试验在ClinicalTrials.gov注册，编号为NCT01227278。我们随机分配101名患者接受安慰剂(n=50)或苯那利单抗(n=51)，其中88名(87%)患者完成了研究。完成研究的6名患者因严重违反方案而被排除在按方案总体之外；因此，按方案总体包括82名患者。与安慰剂相比，Benralizumab并没有降低COPD急性加重的年化比率，其比率分别为0.95(0.68-1.29；n=40)和0.92(0-67-1.25；n=42)。从基线到第56周，服用支气管扩张剂前的平均FEV1变化，安慰剂组为-0.06 L(SD0.24)，苯那利单抗组为0-13 L(0.41)(p=0.014)。在服用苯那珠单抗的患者中，基础血嗜酸性粒细胞浓度为每亩L或更多或L或更多的患者的慢性阻塞性肺疾病、慢性阻塞性肺疾病和FEV1急性加重的改善虽然不显著，但数值上是更大的。两组的紧急治疗不良事件的发生率相似，最常见的事件是呼吸紊乱(服用安慰剂的50名患者中31名[62%]，服用苯那利单抗的51名患者中32名[63%])和感染(28名[56%]对27名[53%])。与安慰剂组相比，苯那珠单抗组患者发生严重的紧急治疗不良事件的发生率更高(14例比9例)，尽管研究者认为这些事件都与苯那珠单抗有关。与安慰剂相比，解释苯那珠单抗并不能降低COPD急性加重的发生率。然而，预先指定的亚组分析结果支持在COPD和嗜酸性粒细胞增多症患者中进一步研究苯那珠单抗。
Background Chronic obstructive pulmonary disease (COPD) is associated with eosinophilic airway inflammation in 10-20% of patients. Benralizumab, an anti-interleukin-5 receptor a monoclonal antibody, depletes blood and sputum eosinophils. We aimed to establish whether benralizumab reduces acute exacerbations of COPD in patients with eosinophilia and COPD.Methods We did this randomised, double-blind, placebo-controlled, phase 2a study between Nov 18,2010, and July 13, 2013, at 26 sites in the UK, Poland, Germany, Canada, the USA, Denmark, and Spain. Adults aged 40-85 years, with moderate-to-severe COPD, at least one acute exacerbation of COPD, and a sputum eosinophil count of 3.0% or more within the previous year, were randomly assigned (1:1) via computer-generated permuted block randomisation (block size of four), with an interactive voice or web-response system, to receive placebo or 100 mg benralizumab subcutaneously, every 4 weeks (three doses), then every 8 weeks (five doses) over 48 weeks. Study site personnel induded in study assessments, participants, and data analysts, were masked to treatment allocation. The primary endpoint was the annualised rate of acute exacerbations of COPD at week 56, defined as the number of acute exacerbations divided by total duration of person-year follow-up. Secondary and exploratory endpoints included COPD-specific Saint George's Respiratory Questionnaire (SGRQ-C), Chronic Respiratory Questionnaire self-administered standardised format (CRQ-SAS), pre-bronchodilator forced expiratory volume in 1 second (FEV1), and safety. We did a prespecified subgroup analysis by baseline blood eosinophil count. Analyses were by intention to treat and per-protocol. This trial is registered with ClinicalTrials.gov, number NCT01227278.Findings We randomly assigned 101 patients to receive placebo (n=50) or benralizumab (n=51), of whom 88 (87%) patients completed the study. Six patients who completed the study were excluded from the per-protocol population because of major protocol violations; the per-protocol population thus induded 82 patients. Benralizumab did not reduce the annualised rate of acute exacerbations of COPD compared with placebo in the per-protocol population, with rates of 0.95 (0.68-1.29; n=40) versus 0.92 (0-67-1.25; n=42). Mean pre-bronchodilator FEV1 change from baseline to week 56 was -0.06 L (SD 0.24) with placebo, and 0-13 L (0.41) with benralizumab (p=0.014). Numerical, albeit non-significant, improvement in acute exacerbations of COPD, SGRQ-C, CRQ-SAS, and FEV1 were greater in benralizumab-treated patients with baseline blood eosinophil concentrations of 200 cells per mu L or more or 300 cells per mu L or more. Incidence of treatment-emergent adverse events was similar between the two groups, with the most common events being respiratory disorders (31 [62%] of 50 patients given placebo vs 32 [63%] of 51 given benralizumab) and infections (28 [56%] vs 27 [53%]). A higher incidence of serious treatment-emergent adverse events were recorded in patients in the benralizumab group than in those in the placebo group (14 vs nine patients), although none of these events were considered by the investigator to be benralizumab related.Interpretation Compared with placebo, benralizumab did not reduce the rate of acute exacerbations of COPD. However, the results of prespecified subgroup analysis support further investigation of benralizumab in patients with COPD and eosinophilia.