Tezepelumab治疗成年和青少年重度难治性哮喘
2021/09/24
摘要
背景：Tezepelumab是一种人源性单克隆抗体，能够阻断胸腺基质淋巴细胞生成素——一种与哮喘发生相关的上皮细胞衍生细胞因子。Tezepelumab对重度、难治性哮喘患者的有效性和安全性有待于进一步评估。
方法：我们开展了一项3期、多中心、双盲、安慰剂对照临床试验。患者（12-80岁）被随机化分配至tezepelumab（120mg）或安慰剂组，皮下注射，1次/4周，持续52周。主要终点是52周内哮喘年发生率。我们也对血液中嗜酸性粒细胞基线计数＜300/ul的患者进行了主要终点评估。本研究的次要终点包括：1s用力呼气量（FEV1）和哮喘控制问卷分数-6（ACQ-6；分值，0分[无损伤]至6分[损伤最重]）、哮喘生活质量问卷（AQLQ；分值，1分[损伤最重]至7分[无损伤]）、哮喘症状日志（ASD；范围，0分[无症状]至4分[可能的最坏症状]）。
结果：整体上，1061名患者接受了随机化分组（529名患者被分配至tezepelumab治疗组，532名患者被分配至安慰剂组）。Tezepelumab治疗组的哮喘年发生率为0.93（95%置信区间CI，0.80至1.07），安慰剂组为2.10（95%CI，1.84至2.39；风险比为0.44；95%CI，0.37至0.53，P＜0.001）。血液中嗜酸性粒细胞基线计数＜300/ul的患者中，接受tezepelumab治疗的患者，哮喘年发生率为1.02（95%CI，0.84至1.23）；接受安慰剂治疗的患者，哮喘年发生率为1.73（95%CI，1.46至2.05；风险比为0.59；95%CI，0.46至0.75；P＜0.001）。在第52周时，Tezepelumab治疗组的患者在以下方面优于安慰剂组：支气管扩张剂使用前FEV1（0.23VS.0.09L；差异为0.13；95%CI，-0.46至-0.20；P＜0.001)、AQLQ（1.49 VS.1.15；差异，0.34；95CI，0.20至0.47；P＜0.001）和ASD（-0.71 vs.-0.59；差异为-0.12；95%CI，-0.19至-0.04；P=0.002）。两治疗组的不良事件发生频率和类别无显著差异。
结论：与安慰剂组患者相比，接受tezepelumab治疗的重度、难治性哮喘患者，病情加重风险较低，肺功能、哮喘控制和健康相关生活质量更好。
Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma
Andrew Menzies-Gow, Jonathan Corren, Arnaud Bourdin, Geoffrey Chupp, Elliot Israel, Michael E Wechsler, Christopher E Brightling, Janet M Griffiths, Åsa Hellqvist, Karin Bowen , Primal Kaur, Gun Almqvist , Sandhia Ponnarambil , Gene Colice
Abstract
Background: Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial-cell-derived cytokine implicated in the pathogenesis of asthma. The efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma require further assessment.
Methods: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Patients (12 to 80 years of age) were randomly assigned to receive tezepelumab (210 mg) or placebo subcutaneously every 4 weeks for 52 weeks. The primary end point was the annualized rate of asthma exacerbations over a period of 52 weeks. This end point was also assessed in patients with baseline blood eosinophil counts of less than 300 cells per microliter. Secondary end points included the forced expiratory volume in 1 second (FEV1) and scores on the Asthma Control Questionnaire-6 (ACQ-6; range, 0 [no impairment] to 6 [maximum impairment]), Asthma Quality of Life Questionnaire (AQLQ; range, 1 [maximum impairment] to 7 [no impairment]), and Asthma Symptom Diary (ASD; range, 0 [no symptoms] to 4 [worst possible symptoms]).
Results: Overall, 1061 patients underwent randomization (529 were assigned to receive tezepelumab and 532 to receive placebo). The annualized rate of asthma exacerbations was 0.93 (95% confidence interval [CI], 0.80 to 1.07) with tezepelumab and 2.10 (95% CI, 1.84 to 2.39) with placebo (rate ratio, 0.44; 95% CI, 0.37 to 0.53; P<0.001). In patients with a blood eosinophil count of less than 300 cells per microliter, the annualized rate was 1.02 (95% CI, 0.84 to 1.23) with tezepelumab and 1.73 (95% CI, 1.46 to 2.05) with placebo (rate ratio, 0.59; 95% CI, 0.46 to 0.75; P<0.001). At week 52, improvements were greater with tezepelumab than with placebo with respect to the prebronchodilator FEV1 (0.23 vs. 0.09 liters; difference, 0.13 liters; 95% CI, 0.08 to 0.18; P<0.001) and scores on the ACQ-6 (-1.55 vs. -1.22; difference, -0.33; 95% CI, -0.46 to -0.20; P<0.001), AQLQ (1.49 vs. 1.15; difference, 0.34; 95% CI, 0.20 to 0.47; P<0.001), and ASD (-0.71 vs. -0.59; difference, -0.12; 95% CI, -0.19 to -0.04; P = 0.002). The frequencies and types of adverse events did not differ meaningfully between the two groups.
Conclusions: Patients with severe, uncontrolled asthma who received tezepelumab had fewer exacerbations and better lung function, asthma control, and health-related quality of life than those who received placebo.
背景：Tezepelumab是一种人源性单克隆抗体，能够阻断胸腺基质淋巴细胞生成素——一种与哮喘发生相关的上皮细胞衍生细胞因子。Tezepelumab对重度、难治性哮喘患者的有效性和安全性有待于进一步评估。
方法：我们开展了一项3期、多中心、双盲、安慰剂对照临床试验。患者（12-80岁）被随机化分配至tezepelumab（120mg）或安慰剂组，皮下注射，1次/4周，持续52周。主要终点是52周内哮喘年发生率。我们也对血液中嗜酸性粒细胞基线计数＜300/ul的患者进行了主要终点评估。本研究的次要终点包括：1s用力呼气量（FEV1）和哮喘控制问卷分数-6（ACQ-6；分值，0分[无损伤]至6分[损伤最重]）、哮喘生活质量问卷（AQLQ；分值，1分[损伤最重]至7分[无损伤]）、哮喘症状日志（ASD；范围，0分[无症状]至4分[可能的最坏症状]）。
结果：整体上，1061名患者接受了随机化分组（529名患者被分配至tezepelumab治疗组，532名患者被分配至安慰剂组）。Tezepelumab治疗组的哮喘年发生率为0.93（95%置信区间CI，0.80至1.07），安慰剂组为2.10（95%CI，1.84至2.39；风险比为0.44；95%CI，0.37至0.53，P＜0.001）。血液中嗜酸性粒细胞基线计数＜300/ul的患者中，接受tezepelumab治疗的患者，哮喘年发生率为1.02（95%CI，0.84至1.23）；接受安慰剂治疗的患者，哮喘年发生率为1.73（95%CI，1.46至2.05；风险比为0.59；95%CI，0.46至0.75；P＜0.001）。在第52周时，Tezepelumab治疗组的患者在以下方面优于安慰剂组：支气管扩张剂使用前FEV1（0.23VS.0.09L；差异为0.13；95%CI，-0.46至-0.20；P＜0.001)、AQLQ（1.49 VS.1.15；差异，0.34；95CI，0.20至0.47；P＜0.001）和ASD（-0.71 vs.-0.59；差异为-0.12；95%CI，-0.19至-0.04；P=0.002）。两治疗组的不良事件发生频率和类别无显著差异。
结论：与安慰剂组患者相比，接受tezepelumab治疗的重度、难治性哮喘患者，病情加重风险较低，肺功能、哮喘控制和健康相关生活质量更好。
(中日友好医院呼吸与危重症医学科 张清 摘译 林江涛 审校)
(N Engl J Med.2021 May 13;384(19):1800-1809.doi: 10.1056/NEJMoa2034975.)
(N Engl J Med.2021 May 13;384(19):1800-1809.doi: 10.1056/NEJMoa2034975.)
Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma
Andrew Menzies-Gow, Jonathan Corren, Arnaud Bourdin, Geoffrey Chupp, Elliot Israel, Michael E Wechsler, Christopher E Brightling, Janet M Griffiths, Åsa Hellqvist, Karin Bowen , Primal Kaur, Gun Almqvist , Sandhia Ponnarambil , Gene Colice
Abstract
Background: Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial-cell-derived cytokine implicated in the pathogenesis of asthma. The efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma require further assessment.
Methods: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Patients (12 to 80 years of age) were randomly assigned to receive tezepelumab (210 mg) or placebo subcutaneously every 4 weeks for 52 weeks. The primary end point was the annualized rate of asthma exacerbations over a period of 52 weeks. This end point was also assessed in patients with baseline blood eosinophil counts of less than 300 cells per microliter. Secondary end points included the forced expiratory volume in 1 second (FEV1) and scores on the Asthma Control Questionnaire-6 (ACQ-6; range, 0 [no impairment] to 6 [maximum impairment]), Asthma Quality of Life Questionnaire (AQLQ; range, 1 [maximum impairment] to 7 [no impairment]), and Asthma Symptom Diary (ASD; range, 0 [no symptoms] to 4 [worst possible symptoms]).
Results: Overall, 1061 patients underwent randomization (529 were assigned to receive tezepelumab and 532 to receive placebo). The annualized rate of asthma exacerbations was 0.93 (95% confidence interval [CI], 0.80 to 1.07) with tezepelumab and 2.10 (95% CI, 1.84 to 2.39) with placebo (rate ratio, 0.44; 95% CI, 0.37 to 0.53; P<0.001). In patients with a blood eosinophil count of less than 300 cells per microliter, the annualized rate was 1.02 (95% CI, 0.84 to 1.23) with tezepelumab and 1.73 (95% CI, 1.46 to 2.05) with placebo (rate ratio, 0.59; 95% CI, 0.46 to 0.75; P<0.001). At week 52, improvements were greater with tezepelumab than with placebo with respect to the prebronchodilator FEV1 (0.23 vs. 0.09 liters; difference, 0.13 liters; 95% CI, 0.08 to 0.18; P<0.001) and scores on the ACQ-6 (-1.55 vs. -1.22; difference, -0.33; 95% CI, -0.46 to -0.20; P<0.001), AQLQ (1.49 vs. 1.15; difference, 0.34; 95% CI, 0.20 to 0.47; P<0.001), and ASD (-0.71 vs. -0.59; difference, -0.12; 95% CI, -0.19 to -0.04; P = 0.002). The frequencies and types of adverse events did not differ meaningfully between the two groups.
Conclusions: Patients with severe, uncontrolled asthma who received tezepelumab had fewer exacerbations and better lung function, asthma control, and health-related quality of life than those who received placebo.
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哮喘急性发作的成人或儿童使用肾上腺素与选择性β-2激动剂的比较：一项系统回顾和荟萃分析
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