乌司奴单抗诱导和维持溃疡性结肠炎的治疗。
Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis.
机构信息
From the Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (B.E.S.); the Division of Gastroenterology, University of California, San Diego, La Jolla (W.J.S.), and the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles (S.T.) - both in California; the Departments of Medicine and Community Health Sciences, University of Calgary, Calgary, AB, Canada (R.P.); Janssen Research and Development, Spring House, PA (C.D.O., H.Z., J.J., O.J.A., K.L., P.S., C.M.); the Gastroenterology Department and INSERM 1256, Nutrition, Genetics, and Environmental Risk Exposure, Nancy University Hospital, Université de Lorraine, Nancy, France (L.P.-B.); the Division of Gastroenterology and Hepatology, University Hospitals Leuven and Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium (G.V.A.); the IBD Center, Department of Gastroenterology, Humanitas Research Hospital and Humanitas University, Milan (S.D.); the Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami (M.T.A.); and the Division of Gastroenterology, Third Department of Internal Medicine, Kyorin University School of Medicine, Tokyo (T.H.).
出版信息
N Engl J Med. 2019 Sep 26;381(13):1201-1214. doi: 10.1056/NEJMoa1900750.
BACKGROUND
The efficacy of ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23, as induction and maintenance therapy in patients with ulcerative colitis is unknown.
METHODS
We evaluated ustekinumab as 8-week induction therapy and 44-week maintenance therapy in patients with moderate-to-severe ulcerative colitis. A total of 961 patients were randomly assigned to receive an intravenous induction dose of ustekinumab (either 130 mg [320 patients] or a weight-range-based dose that approximated 6 mg per kilogram of body weight [322]) or placebo (319). Patients who had a response to induction therapy 8 weeks after administration of intravenous ustekinumab were randomly assigned again to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 12 weeks [172 patients] or every 8 weeks [176]) or placebo (175). The primary end point in the induction trial (week 8) and the maintenance trial (week 44) was clinical remission (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore >1 [range, 0 to 3] on any of the four Mayo scale components).
RESULTS
The percentage of patients who had clinical remission at week 8 among patients who received intravenous ustekinumab at a dose of 130 mg (15.6%) or 6 mg per kilogram (15.5%) was significantly higher than that among patients who received placebo (5.3%) (P<0.001 for both comparisons). Among patients who had a response to induction therapy with ustekinumab and underwent a second randomization, the percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%) (P = 0.002 and P<0.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo. Through 52 weeks of exposure, there were two deaths (one each from acute respiratory distress syndrome and hemorrhage from esophageal varices) and seven cases of cancer (one each of prostate, colon, renal papillary, and rectal cancer and three nonmelanoma skin cancers) among 825 patients who received ustekinumab and no deaths and one case of cancer (testicular cancer) among 319 patients who received placebo.
CONCLUSIONS
Ustekinumab was more effective than placebo for inducing and maintaining remission in patients with moderate-to-severe ulcerative colitis. (Funded by Janssen Research and Development; UNIFI ClinicalTrials.gov number, NCT02407236.).
背景
乌司奴单抗是白细胞介素-12 和白细胞介素-23 的 p40 亚单位拮抗剂，作为中重度溃疡性结肠炎患者的诱导和维持治疗的疗效尚不清楚。
方法
我们评估了乌司奴单抗作为中重度溃疡性结肠炎患者的 8 周诱导治疗和 44 周维持治疗。共有 961 名患者被随机分配接受静脉注射诱导剂量的乌司奴单抗（130mg[320 名患者]或基于体重范围的剂量，约为每公斤体重 6mg[322 名患者]）或安慰剂（319 名患者）。在接受静脉注射乌司奴单抗 8 周后对诱导治疗有反应的患者再次随机接受乌司奴单抗 90mg 皮下维持注射（每 12 周[172 名患者]或每 8 周[176 名患者]）或安慰剂（175 名患者）。诱导试验（第 8 周）和维持试验（第 44 周）的主要终点是临床缓解（定义为 Mayo 量表总分≤2[范围为 0 至 12，得分越高表示疾病越严重]，且任何四个 Mayo 量表组成部分的任何一个亚量表得分>1[范围为 0 至 3]）。
结果
接受 130mg 静脉乌司奴单抗（15.6%）或每公斤体重 6mg（15.5%）治疗的患者在第 8 周达到临床缓解的比例明显高于接受安慰剂治疗的患者（5.3%）（两者比较 P<0.001）。在对乌司奴单抗诱导治疗有反应并进行第二次随机分组的患者中，接受乌司奴单抗 90mg 每 12 周或每 8 周皮下注射的患者在第 44 周达到临床缓解的比例明显高于接受安慰剂的患者（38.4%和 43.8%）（P=0.002 和 P<0.001）。乌司奴单抗的严重不良事件发生率与安慰剂相似。在 52 周的暴露期间，接受乌司奴单抗治疗的 825 名患者中有两例死亡（分别为急性呼吸窘迫综合征和食管静脉曲张出血）和七例癌症（前列腺癌、结肠癌、肾乳头状癌和直肠癌各一例，三例非黑色素瘤皮肤癌），而接受安慰剂治疗的 319 名患者中无死亡和一例癌症（睾丸癌）。
结论
乌司奴单抗在诱导和维持中重度溃疡性结肠炎患者缓解方面优于安慰剂。（由杨森研发资助；UNIFI 临床试验注册编号，NCT02407236。）
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