皮下注射 C1 抑制剂预防遗传性血管性水肿发作。
Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor.
机构信息
From Barts Health NHS Trust (H.L.) and St. John's Institute of Dermatology, Guy's Hospital (C.G.), London, and the Clinical Investigation and Research Unit, Royal Sussex County Hospital, Brighton (M.T.) - all in the United Kingdom; Ospedale Luigi Sacco-U.O. Medicina Generale, Milan (M.C.), and the Department of Internal Medicine, University of Catania, Catania (S.N.) - both in Italy; Department of Medicine and Pediatrics, Penn State Hershey Allergy, Asthma, and Immunology, Hershey (T. Craig), and CSL Behring, King of Prussia (D.B.-K., J.E., D.P.) - both in Pennsylvania; the Department of Dermatology, Johannes Gutenberg University Mainz, Mainz (K.B.), and CSL Behring, Marburg (H. Feuersenger, J.-P.L., T.M., I.P.) - both in Germany; Baker Allergy, Asthma and Dermatology Research Center, Portland, OR (J. Baker); Institute for Asthma and Allergy, Chevy Chase, MD (H.H.L.); Allergy and Immunology Unit, Chaim Sheba Medical Center, Tel Hashomer (A.R.), and Allergy and Immunology Unit, Tel Aviv Sourasky Medical Center, Tel Aviv (S.K.) - both in Israel; Clinical Research Center of Alabama, Birmingham (J. Bonner, J.A.); Department of Internal Medicine, Allergy Section Cincinnati, University of Cincinnati College of Medicine, Cincinnati (J.A.B.), and Toledo Institute of Clinical Research, Toledo (S.M.R.) - both in Ohio; Allergy Asthma Research Associates Research Center, Dallas (W.R.L.); Hungarian Angioedema Center, Third Department of Internal Medicine, Semmelweis University, Budapest (H. Farkas); the Department of Medicine, Immunology, and Allergy, Campbelltown Hospital, Campbelltown, NSW, Australia (C.H.K.); the Department of Clinical Immunology and Allergy, St. Michael's Hospital, Toronto (G.L.S.), Centre de Recherche Appliqué en Allergie de Québec, Quebec, QC (J.H.), McMaster University, Hamilton, ON (P.K.K.), Ottawa Allergy Research and University of Ottawa Medical School, Ottawa (W.Y.), and University of Alberta Hospital, Edmonton (B.R.) - all in Canada; Allergy and Asthma Clinical Research, Walnut Creek (J.J.), University of California, San Diego School of Medicine, La Jolla (M.R., B.L.Z.), and 705 W. La Veta Ave., Suite 101, Orange (D.S.L.) - all in California; Medical Research of Arizona, Scottsdale (M.E.M.); Hospital General Universitario Gregorio Marañón and Biomedical Research Network on Rare Diseases-U761, Institute for Health Research, Gregorio Marañón (M.L.B.), and the Allergy Department, Hospital La Paz Institute for Health Research, Biomedical Research Network on Rare Diseases (T. Caballero), Madrid, the Allergy Department, IIS Hospital Universitario La Fe, Valencia (M.D.H.), and Hospital Universitario Vall d'Hebron, Barcelona (M.G.) - all in Spain; Asthma and Allergy Association, Colorado Springs, CO (R.N.); Department of Internal Medicine, Virginia Commonwealth University, Richmond (L.B.S.); Spitalul Clinic Municipal, Cluj-Napoca, Romania (I.C.); Vital Prospects Clinical Research Institute, Tulsa, OK (I.H.); Institute of Clinical Immunology and Allergology, University Hospital, Hradec Kralove, Czech Republic (P.K.); Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston (A.B.); and Marycliff Allergy Specialists, Spokane, WA (R.G.G.).
出版信息
N Engl J Med. 2017 Mar 23;376(12):1131-1140. doi: 10.1056/NEJMoa1613627.
BACKGROUND
Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks.
METHODS
We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used.
RESULTS
Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo.
CONCLUSIONS
In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456 .).
背景
遗传性血管性水肿是一种致残性疾病，可能致命，由 C1 抑制剂蛋白缺乏（I 型）或功能障碍（II 型）引起。在一项 2 期试验中，使用 CSL830（一种适合皮下注射的纳米过滤 C1 抑制剂制剂）可产生预期能有效预防发作的功能性 C1 抑制剂活性水平。
方法
我们开展了一项国际性、前瞻性、多中心、随机、双盲、安慰剂对照、剂量范围、3 期临床试验，评估了用于 I 型或 II 型遗传性血管性水肿患者的自我管理皮下 CSL830 的疗效和安全性，这些患者在筛选前 3 个月内连续 2 个月内经历过 4 次或更多次发作。我们采用交叉设计将患者随机分为 4 种治疗序列中的一种，每种序列均包括两个 16 周的治疗期：每公斤体重接受 40IU 或 60IU 的 CSL830，每周 2 次，随后给予安慰剂，或反之。主要疗效终点是血管性水肿发作的次数。次要疗效终点是有反应（与安慰剂相比，CSL830 治疗使发作次数减少≥50%）的患者比例和使用急救药物的次数。
结果
在 90 名接受随机分组的患者中，有 79 名完成了试验。与安慰剂相比，两种剂量的 CSL830 均降低了遗传性血管性水肿的发作率（与 40IU 相比，每月发作次数减少 2.42 次；95%置信区间 [CI]，-3.38 至-1.46；与 60IU 相比，每月发作次数减少 3.51 次；95%CI，-4.21 至-2.81；两者均 P<0.001）。40IU 组的反应率为 76%（95%CI，62 至 87），60IU 组为 90%（95%CI，77 至 96）。与安慰剂组每月需要急救药物 5.55 次相比，40IU 组每月需要急救药物 1.13 次，60IU 组每月需要急救药物 0.32 次。接受 CSL830 和接受安慰剂的患者发生的不良事件（多数为轻微和短暂的局部反应）比例相似。
结论
每周两次预防性使用皮下 C1 抑制剂可显著降低遗传性血管性水肿急性发作的频率。（由 CSL 贝林公司资助；COMPACT EudraCT 编号：2013-000916-10；ClinicalTrials.gov 编号：NCT01912456）。
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