使用贝那利珠单抗（PONENTE）治疗成人重度嗜酸性哮喘的患者，通过个体化减少算法减少口服皮质类固醇：一项多中心、开放标
2021/11/24
使用贝那利珠单抗（PONENTE）治疗成人重度嗜酸性哮喘的患者，通过个体化减少算法减少口服皮质类固醇：一项多中心、开放标签、单臂研究
摘要
背景：重症哮喘患者开始生物制剂治疗后如何减少口服皮质类固醇尚未达成共识。PONENTE试验评估了贝那利珠单抗起始后快速，个体化类固醇减少算法（包括肾上腺功能不全监测）的有效性和安全性。
方法：这项多中心，开放标签，单臂研究在17个国家的138个临床哮喘治疗中心完成。我们招募了成年患者（年龄≥18岁）患有重症嗜酸性粒细胞性哮喘（血嗜酸性粒细胞计数≥150个细胞/μL或前一年≥300个细胞/μL），需要在入组前至少3个月维持口服皮质类固醇。患者每4周接受一次贝那利珠单抗30mg（皮下注射），共三剂，然后每8周一次。口服皮质类固醇减少阶段从第4周开始，根据起始剂量，哮喘控制和肾上腺功能状态，每日口服皮质类固醇剂量每1-4周减少1-5mg。一旦患者每日口服皮质类固醇剂量为5mg/天，持续4周，则通过清晨血清皮质醇测量评估肾上腺功能，然后在需要时刺激促肾上腺皮质激素。在第一次测试时，对有肾上腺功能不全证据的患者重复进行皮质醇测量。在整个诱导和口服皮质类固醇减少阶段，每周用哮喘控制问卷-6（ACQ-6）评估哮喘控制。主要终点是患者每天停用口服皮质类固醇（持续至少4周）的百分比，以及如果没有进一步减少的原因是肾上腺功能不全，则至少4周内达到停用或每日使用5 mg或以下的泼尼松龙或泼尼松龙剂量的百分比。安全性和有效性分析包括所有接受至少一剂贝那利珠单抗并且是描述性的患者。我们在口服皮质类固醇减少阶段结束后得出研究结果；维持阶段研究尚在进行中。该试验在ClinicalTrials.gov注册，NCT03557307。
结果：在2018年4月1日至2020年9月5日期间，705名患者被评估为合格，598名被招募，并且全部接受至少一剂贝那利珠单抗。总体而言，598例患者中有376例（62.88%，95%CI 58.86-66.76）停用了口服皮质类固醇激素，598例中有490例（81.94%，78.62-84.94）停用或达到了若停止减量的原因是肾上腺功能不全，则剂量为5mg或更少。亚组分析显示剂量减少与基线嗜酸性粒细胞计数，基线口服皮质类固醇剂量或口服皮质类固醇治疗持续时间无关。首次评估时533例患者中有321例（60%）检测到肾上腺功能不全，2-3个月后533例患者中有205例（38%）检测到肾上腺功能不全。安全概况与以前的经验一致。大多数患者（598例中有448例[75%]）在口服皮质类固醇激素减量阶段没有哮喘恶化，年恶化率为0.63。在598名患者中，38名（6%）共发生46次恶化，导致急诊科或紧急护理就诊或住院。
解释：尽管肾上腺功能不全患病率很高，但大多数用贝那利珠单抗治疗的嗜酸性粒细胞性哮喘患者使用个性化的剂量减少算法实现了停用口服皮质类固醇的或最大可能的减少。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(Lancet Respir Med. 2021 Oct 22:S2213-2600(21)00464-1. doi: 10.1016/S2213-2600(21)00464-1.)
Oral corticosteroid elimination via a personalised reduction algorithm in adults with severe, eosinophilic asthma treated with benralizumab (PONENTE): a multicentre, open-label, single-arm study
Andrew Menzies-Gow, Mark Gurnell, Liam G Heaney, Jonathan Corren, Elisabeth H Bel, Jorge Maspero, Timothy Harrison, David J Jackson, David Price, Njira Lugogo, James Kreindler, Annie Burden, Alex de Giorgio-Miller, Kelly Padilla, Ubaldo J Martin, Esther Garcia Gil
Abstract
Background: No consensus exists on how to reduce oral corticosteroids after the initiation of biologics in severe asthma. The PONENTE trial evaluated the effectiveness and safety of a rapid, individualised steroid-reduction algorithm, including adrenal insufficiency monitoring, after benralizumab initiation.
Methods: This multicentre, open-label, single-arm study was done at 138 clinical asthma treatment centres across 17 countries. We enrolled adult patients (age ≥18 years) with severe, eosinophilic asthma (blood eosinophil count ≥150 cells per μL at enrolment or ≥300 cells per μL in the previous year) requiring maintenance oral corticosteroids for at least 3 months preceding enrolment. Patients received benralizumab 30 mg (subcutaneous injection) every 4 weeks for three doses, then every 8 weeks thereafter. The oral corticosteroid reduction phase began at week 4 with daily oral corticosteroid dosages reduced by 1-5 mg every 1-4 weeks depending on the starting dosage, asthma control, and adrenal function status. Adrenal function was assessed with an early morning serum cortisol measurement, followed by adrenocorticotropic hormone stimulation when required, once patients achieved a daily oral corticosteroid dosage of 5 mg/day for 4 weeks. Repeat cortisol measurements were taken for patients with evidence of adrenal insufficiency at first testing. Asthma control was assessed with the Asthma Control Questionnaire-6 (ACQ-6) weekly throughout the induction and oral corticosteroid reduction phases. The primary endpoints were the percentage of patients eliminating daily oral corticosteroids, sustained for at least 4 weeks, and the percentage achieving elimination or a daily prednisone or prednisolone dosage of 5 mg or less, for at least 4 weeks, if the reason for no further reduction was adrenal insufficiency. Safety and efficacy analyses included all patients who received at least one dose of benralizumab and were descriptive. We present results after the oral corticosteroid reduction phase; a maintenance phase is ongoing. The trial is registered with ClinicalTrials.gov, NCT03557307.
Findings: Between April 1, 2018, and Sept 5, 2020, of 705 patients assessed for eligibility, 598 were recruited and all received at least one dose of benralizumab. Overall, 376 (62·88%, 95% CI 58·86-66·76) of 598 patients eliminated oral corticosteroids and 490 (81·94%, 78·62-84·94) of 598 eliminated use or achieved a dosage of 5 mg or less if the reason for stopping the reduction was adrenal insufficiency. Subgroup analysis showed that dosage reductions were achieved irrespective of baseline eosinophil count, baseline oral corticosteroid dosage, or oral corticosteroid treatment duration. Adrenal insufficiency was detected in 321 (60%) of 533 patients at first assessment and in 205 (38%) of 533 patients 2-3 months later. The safety profile was consistent with previous experience. Most patients (448 [75%] of 598) had no asthma exacerbations during the oral corticosteroid reduction phase with an annualised exacerbation rate of 0·63. Of 598 patients, 38 (6%) experienced a total of 46 exacerbations resulting in emergency department or urgent care visits or hospitalisations.
Interpretation: Despite a high prevalence of adrenal insufficiency, most patients with eosinophilic asthma treated with benralizumab achieved elimination of oral corticosteroids or maximal possible reduction using a personalised dosage-reduction algorithm.
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