BACKGROUND Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) generally have a high symptom burden and poor health-related quality of life, often requiring recurring systemic corticosteroid use and repeated sinus surgery. Dupilumab is a fully human monoclonal antibody that inhibits signalling of interleukin (IL)-4 and IL-13, key drivers of type 2 inflammation, and has been approved for use in atopic dermatitis and asthma. In these two studies, we aimed to assess efficacy and safety of dupilumab in patients with CRSwNP despite previous treatment with systemic corticosteroids, surgery, or both. METHODS LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52 were two multinational, multicentre, randomised, double-blind, placebo-controlled, parallel-group studies assessing dupilumab added to standard of care in adults with severe CRSwNP. SINUS-24 was done in 67 centres in 13 countries, and SINUS-52 was done in 117 centres in 14 countries. Eligible patients were 18 years or older with bilateral CRSwNP and symptoms despite intranasal corticosteroid use, receiving systemic corticosteroids in the preceding 2 years, or having had sinonasal surgery. Patients in SINUS-24 were randomly assigned (1:1) to subcutaneous dupilumab 300 mg or placebo every 2 weeks for 24 weeks. Patients in SINUS-52 were randomly assigned (1:1:1) to dupilumab 300 mg every 2 weeks for 52 weeks, dupilumab every 2 weeks for 24 weeks and then every 4 weeks for the remaining 28 weeks, or placebo every 2 weeks for 52 weeks. All patients were randomly assigned centrally with a permuted block randomisation schedule. Randomisation was stratified by asthma or non-steroidal anti-inflammatory drug-exacerbated respiratory disease status at screening, previous surgery at screening, and country. Patients with or without comorbid asthma were included. Coprimary endpoints were changes from baseline to week 24 in nasal polyp score (NPS), nasal congestion or obstruction, and sinus Lund-Mackay CT scores (a coprimary endpoint in Japan), done in an intention-to-treat population. Safety was assessed in a pooled population of both dupilumab groups in SINUS-52 up to week 24 and the dupilumab group in SINUS-24 and the placebo groups in both studies until week 24. The trials are complete and registered at ClinicalTrials.gov, NCT02912468 and NCT02898454. FINDINGS Between Dec 5, 2016, and Aug 3, 2017, 276 patients were enrolled in SINUS-24, with 143 in the dupilumab group and 133 in the placebo group receiving at least one study drug dose. Between Nov 28, 2016, and Aug 28, 2017, 448 patients were enrolled in SINUS-52, with 150 receiving at least one dose of dupilumab every 2 weeks, 145 receiving at least one dose of dupilumab every 2 weeks for 24 weeks and every 4 weeks until week 52, and 153 receiving at least one dose of placebo. Dupilumab significantly improved the coprimary endpoints in both studies. At 24 weeks, least squares mean difference in NPS of dupilumab treatment versus placebo was -2·06 (95% CI -2·43 to -1·69; p<0·0001) in SINUS-24 and -1·80 (-2·10 to -1·51; p<0·0001) in SINUS-52; difference in nasal congestion or obstruction score was -0·89 (-1·07 to -0·71; p<0·0001) in SINUS-24 and -0·87 (-1·03 to -0·71; p<0·0001) in SINUS-52; and difference in Lund-Mackay CT scores was -7·44 (-8·35 to -6·53; p<0·0001) in SINUS-24 and -5·13 (-5·80 to -4·46; p<0·0001) in SINUS-52. The most common adverse events (nasopharyngitis, worsening of nasal polyps and asthma, headache, epistaxis, and injection-site erythema) were more frequent with placebo. INTERPRETATION In adult patients with severe CRSwNP, dupilumab reduced polyp size, sinus opacification, and severity of symptoms and was well tolerated. These results support the benefits of adding dupilumab to daily standard of care for patients with severe CRSwNP who otherwise have few therapeutic options. FUNDING Sanofi and Regeneron Pharmaceuticals.

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dupilumab在重度慢性鼻鼻窦炎伴鼻息肉患者中的疗效和安全性（LIBERTY NP SINUS-24和LIBERTY NP SINUS-52）：两项多中心，随机，双盲，安慰剂对照，平行组3期试验的结果。

背景技术患有鼻息肉（CRSwNP）的慢性鼻鼻窦炎患者通常有较高的症状负担和与健康相关的不良生活质量，经常需要反复使用全身性皮质类固醇激素和反复进行鼻窦手术。Dupilumab是一种完全人类单克隆抗体，可抑制2型炎症的关键驱动因子白介素（IL）-4和IL-13的信号传导，已被批准用于特应性皮炎和哮喘。在这两项研究中，我们旨在评估dupilumab在CRSwNP患者中的有效性和安全性，尽管先前曾接受全身性皮质类固醇治疗，手术或两者兼而有之。方法LIBERTY NP SINUS-24和LIBERTY NP SINUS-52是两项多国，多中心，随机，双盲，安慰剂对照，平行组研究，评估了在重度CRSwNP成人中加用dupilumab的护理标准。SINUS-24在13个国家的67个中心完成，SINUS-52在14个国家的117个中心完成。符合条件的患者年龄在18岁或以上，尽管鼻内使用了皮质类固醇，但在过去的两年中接受了全身性皮质类固醇治疗，或者接受了鼻窦手术，但均出现了双侧CRSwNP并出现症状。SINUS-24中的患者每2周被随机分配（1：1）皮下注射dupilumab 300 mg或安慰剂，持续24周。SINUS-52患者每2周随机（1：1：1）分配dupilumab 300 mg，持续52周，dupilumab每2周，持续24周，然后每4周持续28周，或每2周给予安慰剂52周。所有患者均按排列的分组随机分配方案随机分配到中心。筛查时，哮喘，非甾体类抗炎药加重呼吸道疾病的状态，筛查前的手术和国家对患者进行随机分组。包括或不合并哮喘的患者。主要终点是在意向性治疗人群中从基线到第24周时鼻息肉评分（NPS），鼻充血或阻塞以及鼻窦Lund-Mackay CT得分（在日本是主要终点）的变化。直到第24周为止，在SINUS-52的dupilumab组和SINUS-24的dupilumab组以及安慰剂组的两个人群中直至24周的安全性均已评估。试验已经完成并在ClinicalTrials.gov上注册，NCT02912468和NCT02898454。结果在2016年12月5日至2017年8月3日之间，SINUS-24纳入了276例患者，dupilumab组中的143位患者和安慰剂组中的133位患者接受了至少一种研究药物剂量。在2016年11月28日至2017年8月28日之间，SINUS-52入组448例患者，其中150例每2周接受至少一剂dupilumab，145例每2周接受至少一剂dupilumab，持续24周，且每2周一次直到第52周为止的4周，以及153接受至少一剂安慰剂。在这两项研究中，Dupilumab均显着改善了共主要终点。在第24周时，在SINUS-24和-1·80中，dupilumab治疗组与安慰剂组的NPS的最小均方差均值为-2·06（95％CI -2·43至-1·69； p <0·0001）。在SINUS-52中为-2·10至-1·51; p <0·0001）; SINUS-24鼻塞或阻塞分数的差异为-0·89（-1·07至-0·71; p <0·0001）和-0·87（-1·03至-0·71; p <0·0001）在SINUS-52中；在SINUS-24中，Lund-Mackay CT评分的差异为-7·44（-8·35至-6·53； p <0·0001）和-5·13（-5·80至-4·46； -5）（13）。 p <0·0001）在SINUS-52中。安慰剂最常见的不良事件（鼻咽炎，鼻息肉和哮喘恶化，头痛，鼻出血和注射部位红斑）更为常见。解释在患有严重CRSwNP的成年患者中，dupilumab减少了息肉大小，鼻窦混浊和症状的严重程度，并且耐受性良好。这些结果支持在严重的CRSwNP患者中将dupilumab添加到日常护理标准中的益处，这些患者否则几乎没有治疗选择。资助赛诺菲和再生元制药。安慰剂会使鼻息肉恶化和哮喘，头痛，鼻epi和注射部位红斑恶化。解释在患有严重CRSwNP的成年患者中，dupilumab减少了息肉大小，鼻窦混浊和症状的严重程度，并且耐受性良好。这些结果支持在严重的CRSwNP患者中将dupilumab添加到日常护理标准中的益处，这些患者否则几乎没有治疗选择。资助赛诺菲和再生元制药。安慰剂使鼻息肉恶化和哮喘，头痛，鼻epi和注射部位红斑更加频繁。解释在患有严重CRSwNP的成年患者中，dupilumab减少了息肉大小，鼻窦混浊和症状的严重程度，并且耐受性良好。这些结果支持在严重的CRSwNP患者中将dupilumab添加到日常护理标准中的益处，这些患者否则几乎没有治疗选择。资助赛诺菲和再生元制药。这些结果支持在严重的CRSwNP患者中将dupilumab添加到日常护理标准中的益处，这些患者否则几乎没有治疗选择。资助赛诺菲和再生元制药。这些结果支持在严重的CRSwNP患者中将dupilumab添加到日常护理标准中的益处，这些患者否则几乎没有治疗选择。资助赛诺菲和再生元制药。