重症嗜酸性粒细胞性哮喘患者贝那利珠单抗治疗中每日维持吸入糖皮质激素减量研究：一项随机多中心开放标签4期临床试验
2023/12/20
摘要
背景：尽管部分重症嗜酸性粒细胞性哮喘患者对高剂量吸入性糖皮质激素（ICS）反应不佳，但逐阶梯强化吸入性糖皮质激素是重症嗜酸性粒细胞性哮喘的常规治疗方法。建议对生物制剂有反应的患者减少ICS剂量，但鲜少有证据支持其安全性。方法：SHAMAL是一项在4个国家22个研究地点进行的4期随机开放标签主动对照研究。纳入标准为患有重症嗜酸性粒细胞性哮喘的成年人（年龄≥18岁），哮喘控制问卷五项评分低于1.5，并且在筛查前至少连续接受了三剂贝那利珠单抗。将受试患者按3:1随机分为2组，即ICS从高剂量逐渐减至中剂量、低剂量或按需剂量（减量组）和维持原量（对照组），分别吸入ICS-福莫特罗治疗32周，随后维持16周。主要终点为到第32周ICS-福莫特罗减量患者的比例。主要结局在减量组中评估，而安全性分析包括所有随机分配的接受研究治疗的患者。本研究注册于ClinicalTrials.gov，NCT04159519。
结果：在2019年11月12日至2023年2月16日期间，本研究共筛选纳入了208名患者。将168例（81%）患者随机分为减量组（n=125[74%]）和对照组（n=43[26%]）。总的来说，110名（92%）患者减少了ICS-福莫特罗的剂量：18名（15%）降至中剂量，20名（17%）降至低剂量，72名（61%）降至按需剂量。113名（96%）患者维持减量后剂量至第48周，减量组中114名（91%）患者在减量期间未出现急性发作。各组间不良事件发生率相似：减量组中91名（73%）患者出现不良事件，而对照组中35名（83%）患者出现不良事件。本研究中共有17名患者出现严重不良事件：减量组12名（10%），对照组5名（12%）。研究期间未发生死亡事件。
结论：上述发现表明，在哮喘维持控制期间，应用贝那利珠单抗的患者可显著减少ICS用量。
(中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校)
(Lancet. 2023 Dec 7:S0140-6736(23)02284-5. doi: 10.1016/S0140-6736(23)02284-5.)
(Lancet. 2023 Dec 7:S0140-6736(23)02284-5. doi: 10.1016/S0140-6736(23)02284-5.)
Reduction of daily maintenance inhaled corticosteroids in patients with severe eosinophilic asthma treated with benralizumab (SHAMAL): a randomised, multicentre, open-label, phase 4 study.
Jackson DJ, Heaney LG, Humbert M, Kent BD, Shavit A, Hiljemark L, Olinger L, Cohen D, Menzies-Gow A, Korn S; SHAMAL Investigators.
Abstract
BACKGROUND: Stepwise intensification of inhaled corticosteroids (ICS) is routine for severe eosinophilic asthma, despite some poor responses to high-dose ICS. Dose reductions are recommended in patients responding to biologics, but little supporting safety evidence exists.
METHODS: SHAMAL was a phase 4, randomised, open-label, active-controlled study done at 22 study sites in four countries. Eligible participants were adults (aged ≥18 years) with severe eosinophilic asthma and a five-item Asthma Control Questionnaire score below 1·5 and who received at least three consecutive doses of benralizumab before screening. We randomly assigned patients (3:1) to taper their high-dose ICS to a medium-dose, low-dose, and as-needed dose (reduction group) or continue (reference group) their ICS-formoterol therapy for 32 weeks, followed by a 16-week maintenance period. The primary endpoint was the proportion of patients reducing their ICS-formoterol dose by week 32. The primary outcome was assessed in the reduction group, and safety analyses included all randomly assigned patients receiving study treatment. This study is registered at ClinicalTrials.gov, NCT04159519.
RESULTS: Between Nov 12, 2019, and Feb 16, 2023, we screened and enrolled in the run-in period 208 patients. We randomly assigned 168 (81%) to the reduction (n=125 [74%]) and reference arms (n=43 [26%]). Overall, 110 (92%) patients reduced their ICS-formoterol dose: 18 (15%) to medium-dose, 20 (17%) to low-dose, and 72 (61%) to as-needed only. In 113 (96%) patients, reductions were maintained to week 48; 114 (91%) of patients in the reduction group had zero exacerbations during tapering. Rates of adverse events were similar between groups. 91 (73%) patients had adverse events in the reduction group and 35 (83%) in the reference group. 17 patients had serious adverse events in the study: 12 (10%) in the reduction group and five (12%) in the reference group. No deaths occurred during the study.
CONCLUSION: These findings show that patients controlled on benralizumab can have meaningful reductions in ICS therapy while maintaining asthma control.
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