Department of Otolaryngology, Eastern Virginia Medical School, Norfolk, VA, USA.
Department of Oto-Rhino-Laryngology, Upper Airways Research Laboratory, Ghent University Hospital, Ghent University, Ghent, Belgium; Division of ENT Diseases, CLINTEC, Karolinska Institutet, University of Stockholm, Stockholm, Sweden.
Lancet Respir Med. 2021 Oct;9(10):1141-1153. doi: 10.1016/S2213-2600(21)00097-7. Epub 2021 Apr 16.
Chronic rhinosinusitis with nasal polyps affects approximately 2-4% of the general population, and long-term use of systemic corticosteroids is associated with adverse effects. The aim of this study was to assess the efficacy and safety of mepolizumab in adults with recurrent, refractory severe bilateral chronic rhinosinusitis with nasal polyps.
SYNAPSE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done at 93 centres, mainly hospitals, in 11 countries. Eligible patients were aged 18 years or older with recurrent, refractory, severe, bilateral nasal polyp symptoms (nasal obstruction symptom visual analogue scale [VAS] score of >5), were eligible for repeat nasal surgery (overall symptoms VAS score >7 and endoscopic nasal polyps score of ≥5, with a minimum score of 2 in each nasal cavity) despite standard of care treatment, and had to have at least one nasal surgery in the past 10 years. Patients were randomly assigned (1:1), using permuted block design, to receive either 100 mg mepolizumab subcutaneously or placebo once every 4 weeks, in addition to standard of care (mometasone furoate intranasal spray for at least 8 weeks before screening and during the study, saline nasal irrigations, systemic corticosteroids or antibiotics, or both), as required, for 52 weeks. Site staff, the central study team, and patients were masked to study treatment and absolute blood eosinophil counts. The coprimary endpoints were change from baseline in total endoscopic nasal polyp score at week 52 and in mean nasal obstruction VAS score during weeks 49-52, assessed in the intention-to-treat population (ITT). This study is registered with ClinicalTrials.gov, NCT03085797.
From May 25, 2017, to Dec 12, 2018, 854 patients were screened for eligibility. 414 patients were randomly assigned with 407 included in the ITT population; 206 received mepolizumab and 201 received placebo. Total endoscopic nasal polyp score significantly improved at week 52 from baseline with mepolizumab versus placebo (adjusted difference in medians -0·73, 95% CI -1·11 to -0·34; p<0·0001) and nasal obstruction VAS score during weeks 49-52 also significantly improved (-3·14, -4·09 to -2·18; p<0·0001). Adverse events considered related to study treatment were reported in 30 (15%) of 206 patients receiving mepolizumab and 19 (9%) of 201 receiving placebo. On-treatment serious adverse events occurred in 12 (6%) patients receiving mepolizumab and 13 (6%) receiving placebo; none were considered related to treatment in those receiving mepolizumab. One death was reported in the placebo group (myocardial infarction; death occurred 99 days after the last dose) and was considered unrelated to the treatment.
Mepolizumab treatment improved nasal polyp size and nasal obstruction compared with placebo, with no new safety indications, in patients with recurrent, refractory severe chronic rhinosinusitis with nasal polyps. These findings suggest that mepolizumab provides an effective add-on treatment option to standard of care in this population.
GlaxoSmithKline.
慢性鼻-鼻窦炎伴鼻息肉影响约 2-4%的普通人群，长期使用全身皮质类固醇会产生不良反应。本研究旨在评估美泊利珠单抗在复发性、难治性双侧慢性鼻-鼻窦炎伴鼻息肉的成年患者中的疗效和安全性。
SYNAPSE 是一项随机、双盲、安慰剂对照、平行组、III 期试验，在 11 个国家的 93 个中心（主要是医院）进行。符合条件的患者年龄在 18 岁或以上，有复发性、难治性、严重、双侧鼻息肉症状（鼻腔阻塞症状视觉模拟量表 [VAS] 评分>5），符合标准护理治疗的再次鼻手术标准（总体症状 VAS 评分>7 和内镜下鼻息肉评分≥5，每个鼻腔至少有 2 分），并且在过去 10 年内至少有一次鼻手术。患者以 1:1 的比例随机（采用置换块设计）接受皮下注射 100mg 美泊利珠单抗或安慰剂，每周一次，此外还接受标准护理（在筛选前和研究期间至少使用 8 周糠酸莫米松鼻喷雾剂、盐水鼻腔冲洗、全身皮质类固醇或抗生素，或两者联合使用），持续 52 周。研究人员、中央研究团队和患者对研究治疗和绝对血嗜酸性粒细胞计数均不知情。主要终点是在第 52 周时总内镜下鼻息肉评分与基线相比的变化，以及在第 49-52 周期间平均鼻腔阻塞 VAS 评分，在意向治疗人群（ITT）中评估。这项研究在 ClinicalTrials.gov 上注册，编号为 NCT03085797。
从 2017 年 5 月 25 日至 2018 年 12 月 12 日，共有 854 名患者接受了资格筛选。414 名患者随机分配，407 名患者纳入 ITT 人群；206 名患者接受美泊利珠单抗治疗，201 名患者接受安慰剂治疗。与安慰剂相比，美泊利珠单抗在第 52 周时总内镜下鼻息肉评分显著改善（中位数差值 -0.73，95%CI-1.11 至 -0.34；p<0.0001），第 49-52 周期间的鼻腔阻塞 VAS 评分也显著改善（-3.14，-4.09 至 -2.18；p<0.0001）。接受美泊利珠单抗治疗的 206 名患者中有 30 名（15%）和接受安慰剂治疗的 201 名患者中有 19 名（9%）报告了认为与研究治疗相关的不良事件。接受美泊利珠单抗治疗的 12 名（6%）患者和接受安慰剂治疗的 13 名（6%）患者发生了治疗期间的严重不良事件；没有一人被认为与治疗有关。安慰剂组报告了一例死亡（心肌梗死；死亡发生在最后一次给药后 99 天），与治疗无关。
在复发性、难治性严重慢性鼻-鼻窦炎伴鼻息肉患者中，与安慰剂相比，美泊利珠单抗治疗可改善鼻息肉大小和鼻腔阻塞，且无新的安全性提示。这些发现表明，美泊利珠单抗为该人群的标准护理提供了一种有效的附加治疗选择。
葛兰素史克公司。
