Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial
Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial
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DOI：
10.1016/s2213-2600(17)30125-x
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发表时间：
2017-05-01
影响因子：
76.2
通讯作者：
ten Brinke, Anneke
中科院分区：
文献类型：
--
作者：
Chupp, Geoffrey L.;Bradford, Eric S.;ten Brinke, Anneke
背景美泊利单抗是一种抗白细胞介素-5单克隆抗体，已被批准作为重度嗜酸性粒细胞性哮喘患者标准治疗的添加治疗，与安慰剂相比，在先前的研究中已显示可减少急性发作和对口服皮质类固醇的依赖。我们的目的是进一步评估美泊利单抗在严重嗜酸性粒细胞性哮喘患者的影响，通过检查其对健康相关的生活质量（HRQOL）。方法我们做了一个随机，双盲，安慰剂对照，平行组，多中心，3B期试验（MUSCA）在146家医院或研究中心在全球19个国家。合格的参与者为12岁或以上的重度嗜酸性粒细胞性哮喘患者，在筛选前12个月内至少有2次急性发作需要治疗，尽管定期使用高剂量吸入性皮质类固醇加其他控制性药物。排除标准包括当前吸烟者或至少有10包年吸烟史的既往吸烟者。我们按国家随机分配受试者（1：1）接受皮下注射美泊利单抗100 mg或安慰剂，加上标准治疗，每4周一次，持续24周（最后一次剂量在第20周给药）。我们使用交互式语音应答系统和集中式计算机生成的区组大小为6的排列区组设计进行随机化。两种治疗在外观上相同，并以设盲方式给药;患者、研究者、其他研究中心工作人员和整个研究团队（包括评估结局数据的人员）也对分组设盲。主要终点是改良意向治疗（改良ITT）人群中第24周St乔治呼吸问卷（SGRQ）总评分较基线的平均变化（根据其随机分配的治疗进行分析）。在接受至少一剂试验药物的所有患者中评估安全性（根据实际接受的治疗进行分析）。该试验在ClinicalTrials.gov注册，编号NCT 02281318。结果我们在2014年12月11日至2015年11月20日期间招募了患者，研究在2014年12月11日至2016年6月10日期间进行。改良ITT人群包括274例分配至美泊利珠单抗100 mg组的患者和277例分配至安慰剂组的患者。美泊利单抗与安慰剂相比，第24周SGRQ总分较基线显著改善（最小二乘均值[SE]较基线变化为-15.6（1.0）vs -7.9（1.0），治疗差异为-7.7（95%CI-10.5至-4.9; p< 0.0001）。研究期间未发生死亡。273例接受mepolizumab治疗的患者中有192例（70%）和278例接受安慰剂治疗的患者中有207例（74%）报告了至少一次治疗中的不良事件，其中最常见的是头痛（mepolizumab组45例[16%] vs安慰剂组59例[21%]）和鼻咽炎（mepolizumab组31例[11%] vs安慰剂组46例[17%]）。美泊利珠单抗组和安慰剂组分别有15例（5%）和22例（8%）患者发生治疗期间严重不良事件;两组中最常见的是哮喘（3例[1%]给予美泊利单抗，9例[3%]给予安慰剂）。解释美泊利单抗与严重嗜酸性粒细胞性哮喘患者HRQOL的显著改善相关，并且具有与安慰剂相似的安全性特征。这些结果补充并支持使用美泊利珠单抗作为重度嗜酸性粒细胞性哮喘患者标准治疗的有利添加治疗选择。
Background Mepolizumab, an anti-interleukin-5 monoclonal antibody approved as add-on therapy to standard of care for patients with severe eosinophilic asthma, has been shown in previous studies to reduce exacerbations and dependency on oral corticosteroids compared with placebo. We aimed to further assess mepolizumab in patients with severe eosinophilic asthma by examining its effect on health-related quality of life (HRQOL).Methods We did a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial (MUSCA) in 146 hospitals or research centres in 19 countries worldwide. Eligible participants were patients aged 12 years or older with severe eosinophilic asthma and a history of at least two exacerbations requiring treatment in the previous 12 months before screening despite regular use of high-dose inhaled corticosteroids plus other controller medicines. Exclusion criteria included current smokers or former smokers with a history of at least ten pack-years. We randomly assigned participants (1: 1) by country to receive a subcutaneous injection of either mepolizumab 100 mg or placebo, plus standard of care, every 4 weeks for 24 weeks (the final dose was given at week 20). We did the randomisation using an interactive voice response system and a centralised, computer-generated, permuted-block design of block size six. The two treatments were identical in appearance and administered in a masked manner; patients, investigators, other site staff and the entire study team including those assessing outcomes data were also masked to group assignment. The primary endpoint was the mean change from baseline in the St George's Respiratory Questionnaire (SGRQ) total score at week 24 in the modified intention-to-treat (modified ITT) population (analysed according to their randomly assigned treatment). Safety was assessed in all patients who received at least one dose of trial medication (analysed according to the actual treatment received). This trial is registered with ClinicalTrials.gov, number NCT02281318.Findings We recruited patients between Dec 11, 2014, and Nov 20, 2015, and the study was undertaken between Dec 11, 2014, and June 10, 2016. The modified ITT population comprised 274 patients assigned to mepolizumab 100 mg and 277 assigned to placebo. Mepolizumab versus placebo showed significant improvements at week 24 from baseline in SGRQ total score (least squares mean [SE] change from baseline -15.6 (1.0) vs -7.9 (1.0), a treatment difference of -7.7 (95% CI -10.5 to -4.9; p< 0.0001). No deaths occurred during the study. 192 (70%) of 273 patients who received mepolizumab and 207 (74%) of 278 who received placebo reported at least one on-treatment adverse event, the most common of which were headache (in 45 [16%] given mepolizumab vs 59 [21%] given placebo) and nasopharyngitis (in 31 [11%] given mepolizumab vs 46 [17%] given placebo). 15 (5%) and 22 (8%) patients had an on-treatment serious adverse event in the mepolizumab and placebo groups, respectively; the most common was asthma in both groups (in three [1%] given mepolizumab vs nine [3%] given placebo).Interpretation Mepolizumab was associated with significant improvements in HRQOL in patients with severe eosinophilic asthma, and had a safety profile similar to that of placebo. These results add to and support the use of mepolizumab as a favourable add-on treatment option to standard of care in patients with severe eosinophilic asthma.