美泊利单抗或安慰剂用于嗜酸性肉芽肿性多血管炎
Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis.
作者信息
Wechsler Michael E, Akuthota Praveen, Jayne David, Khoury Paneez, Klion Amy, Langford Carol A, Merkel Peter A, Moosig Frank, Specks Ulrich, Cid Maria C, Luqmani Raashid, Brown Judith, Mallett Stephen, Philipson Richard, Yancey Steve W, Steinfeld Jonathan, Weller Peter F, Gleich Gerald J
机构信息
From the Department of Medicine, National Jewish Health, Denver (M.E.W.); the Division of Pulmonary, Critical Care, and Sleep Medicine, University of California San Diego, La Jolla (P.A.); Beth Israel Deaconess Medical Center, Boston (P.A., P.F.W.); the Department of Medicine, University of Cambridge, Cambridge (D.J.), the Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford (R.L.), Research and Development, Immuno-Inflammation Therapy Area Unit (J.B.), and Research and Development, Statistics, Programming, and Data Standards (S.M.), GlaxoSmithKline, Uxbridge, and Trizell, Oxford (R.P.) - all in the United Kingdom; the Human Eosinophil Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (P.K., A.K.); the Center for Vasculitis Care and Research, Cleveland Clinic, Cleveland (C.A.L.); the Division of Rheumatology and the Department of Biostatistics and Clinical Epidemiology, University of Pennsylvania (P.A.M.), and the Respiratory Therapy Area Unit and Flexible Discovery Unit, GlaxoSmithKline (J.S.), Philadelphia; Rheumazentrum, Schleswig-Holstein Mitte, Neumünster, Germany (F.M.); the Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN (U.S.); the Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clinic University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona (M.C.C.); the Respiratory Therapeutic Area, GlaxoSmithKline, Research Triangle Park, NC (S.W.Y.); and the Departments of Dermatology and Medicine, University of Utah School of Medicine, Salt Lake City (G.J.G.).
出版信息
N Engl J Med. 2017 May 18;376(20):1921-1932. doi: 10.1056/NEJMoa1702079.
BACKGROUND
Eosinophilic granulomatosis with polyangiitis is an eosinophilic vasculitis. Mepolizumab, an anti-interleukin-5 monoclonal antibody, reduces blood eosinophil counts and may have value in the treatment of eosinophilic granulomatosis with polyangiitis.
METHODS
In this multicenter, double-blind, parallel-group, phase 3 trial, we randomly assigned participants with relapsing or refractory eosinophilic granulomatosis with polyangiitis who had received treatment for at least 4 weeks and were taking a stable prednisolone or prednisone dose to receive 300 mg of mepolizumab or placebo, administered subcutaneously every 4 weeks, plus standard care, for 52 weeks. The two primary end points were the accrued weeks of remission over a 52-week period, according to categorical quantification, and the proportion of participants in remission at both week 36 and week 48. Secondary end points included the time to first relapse and the average daily glucocorticoid dose (during weeks 48 through 52). The annualized relapse rate and safety were assessed.
RESULTS
A total of 136 participants underwent randomization, with 68 participants assigned to receive mepolizumab and 68 to receive placebo. Mepolizumab treatment led to significantly more accrued weeks of remission than placebo (28% vs. 3% of the participants had ≥24 weeks of accrued remission; odds ratio, 5.91; 95% confidence interval [CI], 2.68 to 13.03; P<0.001) and a higher percentage of participants in remission at both week 36 and week 48 (32% vs. 3%; odds ratio, 16.74; 95% CI, 3.61 to 77.56; P<0.001). Remission did not occur in 47% of the participants in the mepolizumab group versus 81% of those in the placebo group. The annualized relapse rate was 1.14 in the mepolizumab group, as compared with 2.27 in the placebo group (rate ratio, 0.50; 95% CI, 0.36 to 0.70; P<0.001). A total of 44% of the participants in the mepolizumab group, as compared with 7% of those in the placebo group, had an average daily dose of prednisolone or prednisone of 4.0 mg or less per day during weeks 48 through 52 (odds ratio, 0.20; 95% CI, 0.09 to 0.41; P<0.001). The safety profile of mepolizumab was similar to that observed in previous studies.
CONCLUSIONS
In participants with eosinophilic granulomatosis with polyangiitis, mepolizumab resulted in significantly more weeks in remission and a higher proportion of participants in remission than did placebo, thus allowing for reduced glucocorticoid use. Even so, only approximately half the participants treated with mepolizumab had protocol-defined remission. (Funded by GlaxoSmithKline and the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT02020889 .).
背景
嗜酸性肉芽肿性多血管炎是一种嗜酸性粒细胞性血管炎。美泊利单抗是一种抗白细胞介素-5单克隆抗体，可降低血液嗜酸性粒细胞计数，可能对嗜酸性肉芽肿性多血管炎的治疗有价值。
方法
在这项多中心、双盲、平行组3期试验中，我们将复发或难治性嗜酸性肉芽肿性多血管炎患者随机分组，这些患者已接受至少4周治疗且泼尼松龙或泼尼松剂量稳定，分别接受300mg美泊利单抗或安慰剂皮下注射，每4周一次，加标准治疗，共52周。两个主要终点是根据分类量化在52周内累计的缓解周数，以及在第36周和第48周时缓解的参与者比例。次要终点包括首次复发时间和平均每日糖皮质激素剂量（第48周至52周期间）。评估年化复发率和安全性。
结果
共有136名参与者被随机分组，68名接受美泊利单抗，68名接受安慰剂。美泊利单抗治疗导致的累计缓解周数显著多于安慰剂（28%的参与者有≥24周的累计缓解，而安慰剂组为3%；优势比，5.91；95%置信区间[CI]，2.68至13.03；P<0.001），并且在第36周和第48周时缓解的参与者比例更高（32%对3%；优势比，16.74；95%CI，3.61至77.56；P<0.001）。美泊利单抗组47%的参与者未出现缓解，而安慰剂组为81%。美泊利单抗组的年化复发率为1.14，而安慰剂组为2.27（率比，0.50；95%CI，0.36至0.70；P<0.001）。在第48周至52周期间，美泊利单抗组44%的参与者平均每日泼尼松龙或泼尼松剂量为4.0mg或更低，而安慰剂组为7%（优势比，0.20；95%CI，0.09至0.41；P<0.001）。美泊利单抗的安全性与先前研究中观察到的相似。
结论
在嗜酸性肉芽肿性多血管炎患者中，美泊利单抗导致的缓解周数显著多于安慰剂，缓解的参与者比例更高，从而允许减少糖皮质激素的使用。即便如此，接受美泊利单抗治疗的参与者中只有约一半达到方案定义的缓解。（由葛兰素史克公司和美国国立过敏与传染病研究所资助；ClinicalTrials.gov编号，NCT02020889。）
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