CASCADE:一项2期随机、双盲、安慰剂对照、平行组试验，评估tezepelumab对未控制哮喘患者气道炎症的影响
2020/11/17
摘要
背景:患有严重，不受控制的哮喘的患者，尤其是那些非嗜酸性表型的哮喘患者，迫切需要能够对广泛的炎症途径起作用的新疗法。Tezepelumab是一种人类单克隆抗体，可阻断胸腺基质淋巴细胞生成素（一种上皮细胞因子）的活性。在PATHWAY2b期研究（NCT02054130）中，无论基线嗜酸性粒细胞炎性水平如何，tezepelumab均可将严重，不受控制的哮喘患者的病情恶化幅度降低多达71％。本文报告了CASCADE 2期研究的设计和目标。
方法：CASCADE是一项正在进行的探索性，2期随机，双盲，安慰剂对照，平行组研究，旨在评估持续28周患有不受控制的中度至重度哮喘18周至75岁成人每4周皮下注射210mg tezepelumab的抗炎作用。主要终点是支气管镜活检中气道粘膜下炎性细胞（嗜酸性粒细胞，中性粒细胞，T细胞和肥大细胞）从基线到第28周的变化。包含三基因均值技术的上皮分子表型将用于评估参与者的2型（T2）状态，以评估tezepelumab在整个T2激活过程中的抗炎作用。其他探索性分析包括评估tezepelumab对气道重塑的影响，包括网状基底膜增厚和气道上皮完整性。在COVID-19大流行开始时，对该协议进行了修改，以解决现场访问受到限制的可能性。该修正案允许：由医疗保健专业人员在家中服用研究药物，将治疗期延长长达6个月，以便患者能够进行现场随访以接受治疗结束后的支气管镜检查，并通过虚拟随访或电话随访进行后续访问。
讨论：CASCADE的目的是通过评估tezepelumab对中度至重度，不受控制的哮喘患者的气道炎性细胞和重塑的作用来确定tezepelumab改善临床哮喘预后的机制。这项研究的一个重要方面是评估tezepelumab在嗜酸性粒细胞和T2炎症水平不同的患者中的抗炎作用。
CASCADE: a phase 2, randomized, double blind, placebo-controlled, parallel-group trial to evaluate the effect of tezepelumab on airway inflammation in patients with uncontrolled asthma
Claire Emson, Sarah Diver , Latifa Chachi , et al.
Abstract
BACKGROUND:Patients with severe, uncontrolled asthma, particularly those with a non-eosinophilic phenotype, have a great unmet need for new treatments that act on a broad range of inflammatory pathways in the airway. Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, an epithelial cytokine. In the PATHWAY phase 2b study (NCT02054130), tezepelumab reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma, irrespective of baseline eosinophilic inflammatory status. This article reports the design and objectives of the phase 2 CASCADE study.
METHODS:CASCADE is an ongoing exploratory, phase 2, randomized, double-blind, placebo-controlled, parallel-group study aiming to assess the anti-inflammatory effects of tezepelumab 210 mg administered subcutaneously every 4 weeks for 28 weeks in adults aged 18–75 years with uncontrolled, moderate-to-severe asthma. The primary endpoint is the change from baseline to week 28 in airway submucosal inflammatory cells (eosinophils, neutrophils, T cells and mast cells) from bronchoscopic biopsies. Epithelial molecular phenotyping, comprising the three-gene-mean technique, will be used to assess participants’ type 2 (T2) status to enable evaluation of the anti-inflammatory effect of tezepelumab across the continuum of T2 activation. Other exploratory analyses include assessments of the impact of tezepelumab on airway remodelling, including reticular basement membrane thickening and airway epithelial integrity. At the onset of the COVID-19 pandemic, the protocol was amended to address the possibility that site visits would be limited. The amendment allowed for: at-home dosing of study drug by a healthcare professional, extension of the treatment period by up to 6 months so patients are able to attend an onsite visit to undergo the end-of-treatment bronchoscopy, and replacement of final follow-up visits with a virtual or telephone visit.
DISCUSSION: CASCADE aims to determine the mechanisms by which tezepelumab improves clinical asthma outcomes by evaluating the effect of tezepelumab on airway inflammatory cells and remodelling in patients with moderate-to-severe, uncontrolled asthma. An important aspect of this study is the evaluation of the anti-inflammatory effect of tezepelumab across patients with differing levels of eosinophilic and T2 inflammation.
背景:患有严重，不受控制的哮喘的患者，尤其是那些非嗜酸性表型的哮喘患者，迫切需要能够对广泛的炎症途径起作用的新疗法。Tezepelumab是一种人类单克隆抗体，可阻断胸腺基质淋巴细胞生成素（一种上皮细胞因子）的活性。在PATHWAY2b期研究（NCT02054130）中，无论基线嗜酸性粒细胞炎性水平如何，tezepelumab均可将严重，不受控制的哮喘患者的病情恶化幅度降低多达71％。本文报告了CASCADE 2期研究的设计和目标。
方法：CASCADE是一项正在进行的探索性，2期随机，双盲，安慰剂对照，平行组研究，旨在评估持续28周患有不受控制的中度至重度哮喘18周至75岁成人每4周皮下注射210mg tezepelumab的抗炎作用。主要终点是支气管镜活检中气道粘膜下炎性细胞（嗜酸性粒细胞，中性粒细胞，T细胞和肥大细胞）从基线到第28周的变化。包含三基因均值技术的上皮分子表型将用于评估参与者的2型（T2）状态，以评估tezepelumab在整个T2激活过程中的抗炎作用。其他探索性分析包括评估tezepelumab对气道重塑的影响，包括网状基底膜增厚和气道上皮完整性。在COVID-19大流行开始时，对该协议进行了修改，以解决现场访问受到限制的可能性。该修正案允许：由医疗保健专业人员在家中服用研究药物，将治疗期延长长达6个月，以便患者能够进行现场随访以接受治疗结束后的支气管镜检查，并通过虚拟随访或电话随访进行后续访问。
讨论：CASCADE的目的是通过评估tezepelumab对中度至重度，不受控制的哮喘患者的气道炎性细胞和重塑的作用来确定tezepelumab改善临床哮喘预后的机制。这项研究的一个重要方面是评估tezepelumab在嗜酸性粒细胞和T2炎症水平不同的患者中的抗炎作用。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（Respir Res, 2020, 21(1): 265.）
（Respir Res, 2020, 21(1): 265.）
CASCADE: a phase 2, randomized, double blind, placebo-controlled, parallel-group trial to evaluate the effect of tezepelumab on airway inflammation in patients with uncontrolled asthma
Claire Emson, Sarah Diver , Latifa Chachi , et al.
Abstract
BACKGROUND:Patients with severe, uncontrolled asthma, particularly those with a non-eosinophilic phenotype, have a great unmet need for new treatments that act on a broad range of inflammatory pathways in the airway. Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, an epithelial cytokine. In the PATHWAY phase 2b study (NCT02054130), tezepelumab reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma, irrespective of baseline eosinophilic inflammatory status. This article reports the design and objectives of the phase 2 CASCADE study.
METHODS:CASCADE is an ongoing exploratory, phase 2, randomized, double-blind, placebo-controlled, parallel-group study aiming to assess the anti-inflammatory effects of tezepelumab 210 mg administered subcutaneously every 4 weeks for 28 weeks in adults aged 18–75 years with uncontrolled, moderate-to-severe asthma. The primary endpoint is the change from baseline to week 28 in airway submucosal inflammatory cells (eosinophils, neutrophils, T cells and mast cells) from bronchoscopic biopsies. Epithelial molecular phenotyping, comprising the three-gene-mean technique, will be used to assess participants’ type 2 (T2) status to enable evaluation of the anti-inflammatory effect of tezepelumab across the continuum of T2 activation. Other exploratory analyses include assessments of the impact of tezepelumab on airway remodelling, including reticular basement membrane thickening and airway epithelial integrity. At the onset of the COVID-19 pandemic, the protocol was amended to address the possibility that site visits would be limited. The amendment allowed for: at-home dosing of study drug by a healthcare professional, extension of the treatment period by up to 6 months so patients are able to attend an onsite visit to undergo the end-of-treatment bronchoscopy, and replacement of final follow-up visits with a virtual or telephone visit.
DISCUSSION: CASCADE aims to determine the mechanisms by which tezepelumab improves clinical asthma outcomes by evaluating the effect of tezepelumab on airway inflammatory cells and remodelling in patients with moderate-to-severe, uncontrolled asthma. An important aspect of this study is the evaluation of the anti-inflammatory effect of tezepelumab across patients with differing levels of eosinophilic and T2 inflammation.
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小气道功能障碍作为严重嗜酸性粒细胞性哮喘生物治疗临床反应的预测指标和标志物：一项纵向观察性研究
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