A randomized, placebo-controlled trial evaluating effects of lebrikizumab on airway eosinophilic inflammation and remodelling in uncontrolled asthma (CLAVIER).
A randomized, placebo-controlled trial evaluating effects of lebrikizumab on airway eosinophilic inflammation and remodelling in uncontrolled asthma (CLAVIER).
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DOI：
10.1111/cea.13731
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
CLAVIER Investigators
中科院分区：
文献类型：
--
作者：
Austin CD;Gonzalez Edick M;Ferrando RE;Solon M;Baca M;Mesh K;Bradding P;Gauvreau GM;Sumino K;FitzGerald JM;Israel E;Bjermer L;Bourdin A;Arron JR;Choy DF;Olsson JK;Abreu F;Howard M;Wong K;Cai F;Peng K;Putnam WS;Holweg CTJ;Matthews JG;Kraft M;Woodruff PG;CLAVIER Investigators
抗白细胞介素13（IL-13）单克隆抗体lebrikizumab可改善中重度未控制哮喘患者的肺功能，但其对气道炎症和重塑的影响尚不清楚。CLAVIER旨在评估lebrikizumab对嗜酸性粒细胞炎症和重塑的影响。使用CLAVIER的可用数据报告入组受试者的安全性和疗效结果。我们在lebrikizumab（n = 31）或安慰剂（n = 33）随机双盲治疗12周前后对未控制的哮喘患者进行了支气管镜检查。预先规定的主要终点是气道上皮下嗜酸性粒细胞/mm 2基底膜（细胞/mm 2）的相对变化。预先规定的次要和探索性结局包括IL-13相关生物标志物和气道重塑指标的变化。治疗组间组织嗜酸性粒细胞存在基线失衡和高变异性。lebrikizumab治疗后，经校正的平均上皮下嗜酸性粒细胞/mm 2无明显变化（95% CI，− 82.5%，97.5%）。如前所述，lebrikizumab治疗后FEV 1增加。此外，lebrikizumab治疗后，上皮下胶原厚度降低了21.5%（95% CI，− 32.9%，−10.2%），支气管组织中呼出气一氧化氮、CCL 26和SERPINB 2 mRNA表达也降低。Lebrikizumab耐受性良好，安全性特征与其他lebrikizumab哮喘研究一致。我们没有观察到与lebrikizumab治疗相关的组织嗜酸性粒细胞数量减少。然而，在预先规定的探索性分析中，lebrikizumab治疗与上皮下纤维化程度降低（气道重塑的一个特征）以及肺功能改善和支气管组织中关键药效学生物标志物减少相关。这些结果加强了IL-13在气道病理学中的重要性，并表明IL-13的中和可减少哮喘气道重塑。临床试验注册：NCT 02099656。
The anti‐interleukin 13 (IL‐13) monoclonal antibody lebrikizumab improves lung function in patients with moderate‐to‐severe uncontrolled asthma, but its effects on airway inflammation and remodelling are unknown. CLAVIER was designed to assess lebrikizumab's effect on eosinophilic inflammation and remodelling. To report safety and efficacy results from enrolled participants with available data from CLAVIER. We performed bronchoscopy on patients with uncontrolled asthma before and after 12 weeks of randomized double‐blinded treatment with lebrikizumab (n = 31) or placebo (n = 33). The pre‐specified primary end‐point was relative change in airway subepithelial eosinophils per mm2 of basement membrane (cells/mm2). Pre‐specified secondary and exploratory outcomes included change in IL‐13‐associated biomarkers and measures of airway remodelling. There was a baseline imbalance in tissue eosinophils and high variability between treatment groups. There was no discernible change in adjusted mean subepithelial eosinophils/mm2 in response to lebrikizumab (95% CI, −82.5%, 97.5%). As previously observed, FEV1 increased after lebrikizumab treatment. Moreover, subepithelial collagen thickness decreased 21.5% after lebrikizumab treatment (95% CI, −32.9%, −10.2%), and fractional exhaled nitric oxide, CCL26 and SERPINB2 mRNA expression in bronchial tissues also reduced. Lebrikizumab was well tolerated, with a safety profile consistent with other lebrikizumab asthma studies. We did not observe reduced tissue eosinophil numbers in association with lebrikizumab treatment. However, in pre‐specified exploratory analyses, lebrikizumab treatment was associated with reduced degree of subepithelial fibrosis, a feature of airway remodelling, as well as improved lung function and reduced key pharmacodynamic biomarkers in bronchial tissues. These results reinforce the importance of IL‐13 in airway pathobiology and suggest that neutralization of IL‐13 may reduce asthmatic airway remodelling. Clinical Trial Registration: NCT02099656.
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DOI：
10.1164/rccm.200312-1651oc
发表时间：
2004-09-15
影响因子：
24.7
作者：
Djukanovic, R;Wilson, SJ;Fahy, JV
通讯作者：
Fahy, JV
DOI：
10.1084/jem.194.6.809
发表时间：
2001-09-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lee CG;Homer RJ;Zhu Z;Lanone S;Wang X;Koteliansky V;Shipley JM;Gotwals P;Noble P;Chen Q;Senior RM;Elias JA
通讯作者：
Elias JA
影响因子：
6.1
作者：
de Kluijver, J;Schrumpf, JA;Sterk, PJ
通讯作者：
Sterk, PJ
影响因子：
14.2
作者：
Nyenhuis, Sharmilee M.;Krishnan, Jerry A.;Ackerman, Steven J.
通讯作者：
Ackerman, Steven J.
DOI：
10.1164/ajrccm.155.6.9196087
发表时间：
1997-06-01
影响因子：
24.7
作者：
Olivieri, D;Chetta, A;Foresi, A
通讯作者：
Foresi, A