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. 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.gov NCT04098718.

Findings

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.

Interpretation

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.

Funding

AstraZeneca.

中文翻译：

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用贝那利珠单抗 （ABRA） 治疗哮喘和 COPD 的嗜酸性粒细胞性加重：一项双盲、双模拟、活性安慰剂对照随机试验

 背景

哮喘和慢性阻塞性肺疾病 （COPD） 的恶化是重要事件，与危重疾病有关。嗜酸性粒细胞性炎症是哮喘和 COPD 急性加重期间常见的可治疗特征。我们假设对于嗜酸性粒细胞增重的患者，与标准护理泼尼松龙相比，单次注射贝那利珠单抗（一种针对白细胞介素 5 受体α的人源化单克隆抗体）将改善临床结局。

 方法

用 BenRAlizumab 治疗急性加重试验 （ABRA） 是一项多中心、2 期、双盲、双模拟、活性安慰剂对照随机试验，在英国牛津大学医院 NHS 基金会信托基金和盖伊和圣托马斯 NHS 基金会信托基金完成。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，血嗜酸性粒细胞计数等于或超过 300 个细胞/μL 的成人以 1：1：1 的比例随机分配接受急性治疗：泼尼松龙 30 mg，每天一次，持续 5 天和 100 mg 贝那利珠单抗皮下注射一次（BENRA 加 PRED 组）;安慰剂片剂每天一次，持续 5 天和 100 mg 贝那利珠单抗皮下注射一次（BENRA 组）;或泼尼松龙 30 mg 每天一次，持续 5 天和安慰剂皮下注射一次（PRED 组）。随机化使用集中式交互式计算机随机化服务进行。所有参与数据收集的患者和研究研究人员都戴着盲法，以研究血液结果和治疗分配。共同主要结局是与泼尼松龙单独使用组相比，合并贝那利珠单抗组 90 天内治疗失败的比例和第 28 天的总视觉模拟量表 （VAS） 症状，并在意向治疗人群中进行了分析。该试验于 Clinicaltrials.govNCT04098718 注册。

 发现

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 例因未捕获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 的急性嗜酸性粒细胞性加重组，其中 86 名 （54%） 患者为女性，72 名 （46%） 为男性，平均年龄为 57 岁 （范围，18-84 岁）。53 例患者被随机分配到 PRED 组，53 例被随机分配到 BENRA 组，52 例被分配到 BENRA 联合 PRED 治疗组。90 天时，PRED 组 53 例中有 39 例 （74%） 发生治疗失败，混合 BENRA 组 105 例中有 47 例 （45%） 发生治疗失败 （OR 0·26 [95% CI 0·13–0·56];p=0·0005）。28 天总 VAS 平均差为 49 mm（95% CI 14-84;p=0·0065），有利于混合 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。

 解释

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护理标准获得更好的结果。这些结果为治疗哮喘嗜酸性粒细胞内型和 COPD 恶化提供了一种新方法。

 资金

 阿斯利康。