Efficacy and safety of tezepelumab versus placebo in adults with moderate to very severe chronic obstructive pulmonary disease (COURSE): a randomised, placebo-controlled, phase 2a trial.

We aimed to assess the efficacy and safety of tezepelumab in patients with moderate to very severe COPD despite receiving triple inhaled therapy.

我们的目标是评估在中度至极重度COPD患者中，尽管接受了三联吸入疗法，但使用tezepelumab的疗效和安全性。

Methods

COURSE was a double-blind, randomised, placebo-controlled, phase 2a trial across 90 sites in ten countries in Asia, Europe, and North America.

COURSE 是一项在亚洲、欧洲和北美的90个地点进行的双盲、随机、安慰剂对照的2a期试验。

Eligible participants were aged 40-80 years, had moderate to very severe airflow limitation, were receiving triple inhaled maintenance therapy, and had at least two moderate to severe COPD exacerbations in the 12 months before enrolment.

符合条件的参与者年龄在40至80岁之间，有中度至非常严重的气流受限，正在接受三联吸入维持治疗，并且在入组前的12个月内至少有两次中度至严重的COPD加重。

Patients were randomly assigned (1:1) to receive tezepelumab 420 mg or placebo subcutaneously every 4 weeks for up to 52 weeks.

患者被随机分配（1:1）接受每4周皮下注射420毫克的tezepelumab或安慰剂，最多52周。

Randomisation was stratified by geographical region and by number of exacerbations in the 12 months before enrolment.

随机化按地理区域和入组前12个月的加重次数进行分层。

Participants, investigators, site staff, and the study sponsor were masked to treatment assignment.

参与者、研究者、现场工作人员以及研究赞助商对治疗分配情况均不知情。

The primary endpoint was the annualised rate of moderate or severe COPD exacerbations over 52 weeks.

主要终点是52周内中度或重度慢性阻塞性肺疾病（COPD）加重的年化率。

A prespecified subgroup analysis assessed the primary endpoint in patients grouped by baseline blood eosinophil counts (BECs).

预先设定的亚组分析评估了按基线血嗜酸性粒细胞计数（BECs）分组的患者的初级终点。

Efficacy and safety were assessed in all patients who received at least one dose of study drug.

所有至少接受一次研究药物剂量的患者均进行了疗效和安全性的评估。

This trial is registered with ClinicalTrials.gov, NCT04039113 (completed).

该试验已在ClinicalTrials.gov注册，编号为NCT04039113（已完成）。

Results

Between July 30, 2019, and Oct 4, 2022, 333 patients (mean age 67·2 years [SD 7·0]; 145 [44%] female and 188 [56%] male; 293 [88%] White, 34 [10%] Asian, and four [1%] Black or African American) were randomly assigned and treated with tezepelumab (n=165) or placebo (n=168).

在2019年7月30日至2022年10月4日期间，共有333名患者（平均年龄67.2岁[标准差7.0]；女性145人[44%]，男性188人[56%]；白人293人[88%]，亚洲人34人[10%]，黑人或非裔美国人4人[1%]）被随机分配接受tezepelumab治疗（n=165）或安慰剂（n=168）。

The annualised rate of moderate or severe COPD exacerbations over 52 weeks was 1·75 for tezepelumab versus 2·11 for placebo (rate ratio 0·83 [90% CI 0·64-1·06]; p=0·10 [one-sided]; the primary endpoint was not met).

在52周内，中度或重度COPD急性加重的年化发生率为1.75次，使用tezepelumab治疗，而安慰剂组为2.11次（发生率比为0.83 [90%置信区间0.64-1.06]；p=0.10 [单侧]；主要终点未达到）。

In prespecified subgroup analyses, the annualised rate of moderate or severe COPD exacerbations over 52 weeks was 2·04 with tezepelumab versus 1·71 with placebo (rate ratio 1·19 [95% CI 0·75-1·90]) in patients with a baseline BEC of less than 150 cells per μL, 1·64 versus 2·47 (0·66 [0·42-1·04]) in patients with a baseline BEC of 150 cells per μL to less than 300 cells per μL, and 1·20 versus 2·24 (0·54 [0·25-1·15]) in patients with a baseline BEC of 300 cells per μL or higher.

在预先设定的亚组分析中，对于基线嗜酸性粒细胞计数小于150个/μL的患者，52周内中度或重度COPD急性加重的年化发生率为2.04次，使用tezepelumab治疗，而安慰剂组为1.71次（发生率比为1.19 [95%置信区间0.75-1.90]）；对于基线嗜酸性粒细胞计数在150个/μL至小于300个/μL的患者，发生率为1.64次对比2.47次（发生率比为0.66 [0.42-1.04]）；对于基线嗜酸性粒细胞计数为300个/μL或更高的患者，发生率为1.20次对比2.24次（发生率比为0.54 [0.25-1.15]）。

Adverse events occurred in 133 (81%) of 165 patients in the tezepelumab group and 126 (75%) of 168 patients in the placebo group.

在165名接受tezepelumab治疗的患者中，有133名（81%）出现了不良事件，而在168名接受安慰剂治疗的患者中，有126名（75%）出现了不良事件。

Serious adverse events occurred in 49 (30%) patients in the tezepelumab group and 50 (30%) patients in the placebo group.

在tezepelumab组中有49名（30%）患者出现了严重不良事件，在安慰剂组中有50名（30%）患者出现了严重不良事件。

Five patients died while receiving study treatment: two in the tezepelumab group and three in the placebo group.

在接受研究治疗期间，有五名患者死亡：其中两名在tezepelumab组，三名在安慰剂组。

No deaths were determined to be causally related to study treatment by investigator assessment.

通过研究者评估，没有死亡被确定为与研究治疗有因果关系。

interpretation

A significant reduction was not observed in the annualised rate of moderate or severe COPD exacerbations with tezepelumab versus placebo.

与安慰剂相比，未观察到中度或重度慢性阻塞性肺疾病（COPD）急性加重的年化率有显著降低。

Further studies are required to evaluate the efficacy of tezepelumab in patients with moderate to very severe COPD, particularly in patients with a baseline BEC of 150 cells per μL or higher.

需要进一步的研究来评估中度至极重度慢性阻塞性肺疾病（COPD）患者中，特别是基线嗜酸性粒细胞计数（BEC）为每微升150个细胞或更高的患者中，tezepelumab的疗效。

Tezepelumab was well tolerated, with no safety concerns identified.

Tezepelumab 耐受性良好，未发现任何安全问题。

funding

AstraZeneca and Amgen.

阿斯利康和安进。