贝纳利珠单抗（ABRA）治疗哮喘和COPD的嗜酸性粒细胞加重：一项双盲、双模拟、有效安慰剂对照随机试验
2025/01/26
摘要
背景：哮喘和慢性阻塞性肺疾病（COPD）的恶化是重要事件，并与危重疾病相关。嗜酸性粒细胞炎症是一种可治疗的特征，常见于哮喘和慢性阻塞性肺病的急性加重期。
目的：我们假设，对于嗜酸性粒细胞恶化的患者，与泼尼松龙（治疗标准）相比，单次注射贝那利单抗（一种针对白细胞介素-5受体-α的人源化单克隆抗体）或与泼尼松龙联合使用将改善临床结果。
方法：用贝那利珠单抗试验（ABRA）治疗的急性加重是一项多中心，2期，双盲，双模拟，主动安慰剂对照的随机试验，在英国牛津大学医院NHS基金会信托基金会和盖伊和圣托马斯NHS基金会信托基金会完成。患者是从这两家医院的急诊诊所和急诊科招募的。在哮喘或COPD急性加重时，血液嗜酸性粒细胞计数等于或超过300个细胞/μL的成年人以1:1:1的比例随机分配，接受泼尼松龙30 mg每日一次的急性治疗5天和100 mg贝那利珠单抗皮下注射一次（BENRA加PRED组）；安慰剂片每日一次，持续5天，100 mg贝那利珠单抗皮下注射一次（BENRA组）；或泼尼松龙30 mg，每日一次，持续5天，安慰剂皮下注射一次（泼尼松龙组）。随机化是通过中央交互式计算机随机化服务进行的。所有参与数据收集的患者和研究人员都被盲，以研究血液结果和治疗分配。与单独使用泼尼松龙组相比，合并贝那利珠单抗组在90天内治疗失败的比例和第28天的总视觉模拟评分（VAS）症状，并在意向治疗人群中进行分析。该试验已在Clinicaltrials.govNCT04098718上注册。
结果：在2021年5月13日至2024年2月5日期间，筛选了287名患者纳入研究。129名患者因未恶化或不符合嗜酸性粒细胞排除标准而被排除在外。158名患者被随机分配到哮喘或COPD急性嗜酸性粒细胞加重期，其中86名（54%）患者为女性，72名（46%）为男性，平均年龄57岁（范围18-84岁）。53名患者被随机分配到PRED组，53名被随机分配到BENRA组，52名被分配到BENRA加PRED治疗组。在90天时，PRED组53例中有39例（74%）发生治疗失败，合并BENRA组105例中有47例（45%）（OR 0.26[95%CI 0.13-0.56]；p=0.0005）。28天的总VAS平均差异为49 mm（95%CI 14-84；p=0.0065），有利于合并的BENRA组。没有致命的不良事件，贝那利珠单抗耐受性良好。值得注意的是，高血糖和鼻窦炎或鼻窦感染不良事件仅与泼尼松龙研究药物有关。
结论：贝那利珠单抗可用于治疗急性嗜酸性粒细胞恶化，并且比目前单独使用泼尼松龙的标准治疗效果更好。这些结果为治疗哮喘和COPD急性加重的嗜酸性粒细胞内型提供了一种新方法。
Treating eosinophilic exacerbations of asthma and COPD with benralizumab (ABRA): a double-blind, double-dummy, active placebo-controlled randomised trial.
Sanjay, Ramakrishnan; Richard E K, Russell;
Abstrast
Background: Exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are important events and are associated with critical illness. Eosinophilic inflammation is a treatable trait commonly found during acute exacerbations of asthma and COPD.
Objective: We hypothesised that for patients with eosinophilic exacerbations, a single injection of benralizumab, a humanised monoclonal antibody against interleukin-5 receptor-α, alone or in combination with prednisolone, will improve clinical outcomes compared with prednisolone, the standard of care.
Methods: The Acute exacerbations treated with BenRAlizumab trial (ABRA) was a multicentre, phase 2, double-blind, double-dummy, active placebo-controlled randomised trial completed in the UK at Oxford University Hospitals NHS Foundation Trust and Guy's and St Thomas' NHS Foundation Trust. Patients were recruited from urgent care clinics and emergency departments of these two hospitals. At the time of an acute exacerbation of asthma or COPD, adults with blood eosinophil counts of equal to or more than 300 cells per μL were randomly assigned in a 1:1:1 ratio to receive acute treatment with: prednisolone 30 mg once daily for 5 days and 100 mg benralizumab subcutaneous injection once (BENRA plus PRED group); placebo tablets once daily for 5 days and 100 mg benralizumab subcutaneous injection once (BENRA group); or prednisolone 30 mg once daily for 5 days and placebo subcutaneous injection once (PRED group). Randomisation was performed with a centralised interactive computer randomisation service. All patients and study research staff involved in data collection were masked to study blood results and treatment allocation. The co-primary outcomes were proportion of treatment failures over 90 days and total visual analogue scale (VAS) symptoms at day 28 in the pooled benralizumab groups compared with the prednisolone alone group and analysed in the intention-to-treat population. The trial was registered on Clinicaltrials.govNCT04098718.
Results: Between May 13, 2021, and Feb 5, 2024, 287 patients were screened for study inclusion. 129 were excluded due to not having an exacerbation captured or not meeting the eosinophil exclusion criteria. 158 patients were randomly assigned at acute eosinophilic exacerbation of asthma or COPD where 86 (54%) patients were female and 72 (46%) were male with a mean age of 57 years (range, 18-84). 53 patients were randomly assigned to the PRED group, 53 were randomly assigned to the BENRA group, and 52 were assigned to the BENRA plus PRED treatment group. At 90 days, treatment failures occurred in 39 (74%) of 53 in the PRED group, and 47 (45%) of 105 in the pooled-BENRA group (OR 0·26 [95% CI 0·13-0·56]; p=0·0005). The 28-day total VAS mean difference was 49 mm (95% CI 14-84; p=0·0065), favouring the pooled-BENRA group. There were no fatal adverse events and benralizumab was well tolerated. Notably, hyperglycaemia and sinusitis or sinus infection adverse events were related to the prednisolone study drug only.
Conclusions：Benralizumab can be used as a treatment of acute eosinophilic exacerbations and achieves better outcomes than the current standard of care with prednisolone alone. These results offer a new way of treating eosinophilic endotypes of asthma and COPD exacerbations.
背景：哮喘和慢性阻塞性肺疾病（COPD）的恶化是重要事件，并与危重疾病相关。嗜酸性粒细胞炎症是一种可治疗的特征，常见于哮喘和慢性阻塞性肺病的急性加重期。
目的：我们假设，对于嗜酸性粒细胞恶化的患者，与泼尼松龙（治疗标准）相比，单次注射贝那利单抗（一种针对白细胞介素-5受体-α的人源化单克隆抗体）或与泼尼松龙联合使用将改善临床结果。
方法：用贝那利珠单抗试验（ABRA）治疗的急性加重是一项多中心，2期，双盲，双模拟，主动安慰剂对照的随机试验，在英国牛津大学医院NHS基金会信托基金会和盖伊和圣托马斯NHS基金会信托基金会完成。患者是从这两家医院的急诊诊所和急诊科招募的。在哮喘或COPD急性加重时，血液嗜酸性粒细胞计数等于或超过300个细胞/μL的成年人以1:1:1的比例随机分配，接受泼尼松龙30 mg每日一次的急性治疗5天和100 mg贝那利珠单抗皮下注射一次（BENRA加PRED组）；安慰剂片每日一次，持续5天，100 mg贝那利珠单抗皮下注射一次（BENRA组）；或泼尼松龙30 mg，每日一次，持续5天，安慰剂皮下注射一次（泼尼松龙组）。随机化是通过中央交互式计算机随机化服务进行的。所有参与数据收集的患者和研究人员都被盲，以研究血液结果和治疗分配。与单独使用泼尼松龙组相比，合并贝那利珠单抗组在90天内治疗失败的比例和第28天的总视觉模拟评分（VAS）症状，并在意向治疗人群中进行分析。该试验已在Clinicaltrials.govNCT04098718上注册。
结果：在2021年5月13日至2024年2月5日期间，筛选了287名患者纳入研究。129名患者因未恶化或不符合嗜酸性粒细胞排除标准而被排除在外。158名患者被随机分配到哮喘或COPD急性嗜酸性粒细胞加重期，其中86名（54%）患者为女性，72名（46%）为男性，平均年龄57岁（范围18-84岁）。53名患者被随机分配到PRED组，53名被随机分配到BENRA组，52名被分配到BENRA加PRED治疗组。在90天时，PRED组53例中有39例（74%）发生治疗失败，合并BENRA组105例中有47例（45%）（OR 0.26[95%CI 0.13-0.56]；p=0.0005）。28天的总VAS平均差异为49 mm（95%CI 14-84；p=0.0065），有利于合并的BENRA组。没有致命的不良事件，贝那利珠单抗耐受性良好。值得注意的是，高血糖和鼻窦炎或鼻窦感染不良事件仅与泼尼松龙研究药物有关。
结论：贝那利珠单抗可用于治疗急性嗜酸性粒细胞恶化，并且比目前单独使用泼尼松龙的标准治疗效果更好。这些结果为治疗哮喘和COPD急性加重的嗜酸性粒细胞内型提供了一种新方法。
(中日友好医院呼吸与危重症医学科 万静萱 摘译 林江涛 审校)
(Lancet Respir Med 2024 Nov 27;0(0)；DOI: 10.1016/S2213-2600(24)00299-6；IF：25.094.)
(Lancet Respir Med 2024 Nov 27;0(0)；DOI: 10.1016/S2213-2600(24)00299-6；IF：25.094.)
Treating eosinophilic exacerbations of asthma and COPD with benralizumab (ABRA): a double-blind, double-dummy, active placebo-controlled randomised trial.
Sanjay, Ramakrishnan; Richard E K, Russell;
Abstrast
Background: Exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are important events and are associated with critical illness. Eosinophilic inflammation is a treatable trait commonly found during acute exacerbations of asthma and COPD.
Objective: We hypothesised that for patients with eosinophilic exacerbations, a single injection of benralizumab, a humanised monoclonal antibody against interleukin-5 receptor-α, alone or in combination with prednisolone, will improve clinical outcomes compared with prednisolone, the standard of care.
Methods: The Acute exacerbations treated with BenRAlizumab trial (ABRA) was a multicentre, phase 2, double-blind, double-dummy, active placebo-controlled randomised trial completed in the UK at Oxford University Hospitals NHS Foundation Trust and Guy's and St Thomas' NHS Foundation Trust. Patients were recruited from urgent care clinics and emergency departments of these two hospitals. At the time of an acute exacerbation of asthma or COPD, adults with blood eosinophil counts of equal to or more than 300 cells per μL were randomly assigned in a 1:1:1 ratio to receive acute treatment with: prednisolone 30 mg once daily for 5 days and 100 mg benralizumab subcutaneous injection once (BENRA plus PRED group); placebo tablets once daily for 5 days and 100 mg benralizumab subcutaneous injection once (BENRA group); or prednisolone 30 mg once daily for 5 days and placebo subcutaneous injection once (PRED group). Randomisation was performed with a centralised interactive computer randomisation service. All patients and study research staff involved in data collection were masked to study blood results and treatment allocation. The co-primary outcomes were proportion of treatment failures over 90 days and total visual analogue scale (VAS) symptoms at day 28 in the pooled benralizumab groups compared with the prednisolone alone group and analysed in the intention-to-treat population. The trial was registered on Clinicaltrials.govNCT04098718.
Results: Between May 13, 2021, and Feb 5, 2024, 287 patients were screened for study inclusion. 129 were excluded due to not having an exacerbation captured or not meeting the eosinophil exclusion criteria. 158 patients were randomly assigned at acute eosinophilic exacerbation of asthma or COPD where 86 (54%) patients were female and 72 (46%) were male with a mean age of 57 years (range, 18-84). 53 patients were randomly assigned to the PRED group, 53 were randomly assigned to the BENRA group, and 52 were assigned to the BENRA plus PRED treatment group. At 90 days, treatment failures occurred in 39 (74%) of 53 in the PRED group, and 47 (45%) of 105 in the pooled-BENRA group (OR 0·26 [95% CI 0·13-0·56]; p=0·0005). The 28-day total VAS mean difference was 49 mm (95% CI 14-84; p=0·0065), favouring the pooled-BENRA group. There were no fatal adverse events and benralizumab was well tolerated. Notably, hyperglycaemia and sinusitis or sinus infection adverse events were related to the prednisolone study drug only.
Conclusions：Benralizumab can be used as a treatment of acute eosinophilic exacerbations and achieves better outcomes than the current standard of care with prednisolone alone. These results offer a new way of treating eosinophilic endotypes of asthma and COPD exacerbations.
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贝那利珠单抗在东京哮喘研究（TOAST）中的有效性：一项现实世界的前瞻性介入试验
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