Sandborn William J, Ghosh Subrata, Panes Julian, Schreiber Stefan, D'Haens Geert, Tanida Satoshi, Siffledeen Jesse, Enejosa Jeffrey, Zhou Wen, Othman Ahmed A, Huang Bidan, Higgins Peter D R
University of California San Diego, La Jolla, California.
National Institute for Health Research Biomedical Research Centre Birmingham, University of Birmingham and University Hospitals Birmingham National Health Service Trust, United Kingdom.
Gastroenterology. 2020 Jun;158(8):2139-2149.e14. doi: 10.1053/j.gastro.2020.02.030. Epub 2020 Feb 22.
BACKGROUND & AIMS: We evaluated the efficacy and safety of upadacitinib, an oral selective inhibitor of Janus kinase 1, as induction therapy for ulcerative colitis (UC).
We performed a multicenter, double-blind, phase 2b study of 250 adults with moderately to severely active UC and an inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressive agents, and/or biologic therapies. Patients were randomly assigned to groups that received placebo or induction therapy with upadacitinib (7.5 mg, 15 mg, 30 mg, or 45 mg, extended release), once daily for 8 weeks. The primary endpoint was the proportion of participants who achieve clinical remission according to the adapted Mayo score at week 8. No multiplicity adjustments were applied.
At week 8, 8.5%, 14.3%, 13.5%, and 19.6% of patients receiving 7.5 mg, 15 mg, 30 mg, or 45 mg upadacitinib, respectively, achieved clinical remission compared with none of the patients receiving placebo (P = .052, P = .013, P = .011, and P = .002 compared with placebo, respectively). Endoscopic improvement at week 8, defined as endoscopic subscore of ≤ 1, was achieved in 14.9%, 30.6%, 26.9%, and 35.7% of patients receiving upadacitinib 7.5 mg, 15 mg, 30 mg, or 45 mg, respectively, compared with 2.2% receiving placebo (P = .033, P < .001, P < .001, and P < .001 compared with placebo, respectively). One event of herpes zoster and 1 participant with pulmonary embolism and deep venous thrombosis (diagnosed 26 days after treatment discontinuation) were reported in the group that received upadacitinib 45 mg once daily. Increases in serum lipid levels and creatine phosphokinase with upadacitinib were observed.
In a phase 2b trial, 8 weeks of treatment with upadacitinib was more effective than placebo for inducing remission in patients with moderately to severely active UC. (ClinicalTrials.gov, Number: NCT02819635).
我们评估了口服Janus激酶1选择性抑制剂乌帕替尼作为溃疡性结肠炎（UC）诱导治疗的疗效和安全性。
我们对250例中度至重度活动性UC成年患者进行了一项多中心、双盲、2b期研究，这些患者对皮质类固醇、免疫抑制剂和/或生物疗法反应不足、反应丧失或不耐受。患者被随机分配至接受安慰剂或乌帕替尼（7.5毫克、15毫克、30毫克或45毫克缓释剂）诱导治疗的组，每日一次，共8周。主要终点是在第8周根据改良梅奥评分达到临床缓解的参与者比例。未进行多重性调整。
在第8周时，接受7.5毫克、15毫克、30毫克或45毫克乌帕替尼治疗的患者中，分别有8.5%、14.3%、13.5%和19.6%达到临床缓解，而接受安慰剂治疗的患者无一例达到临床缓解（与安慰剂相比，P分别为0.052、0.013、0.011和0.002）。在接受7.5毫克、15毫克、30毫克或45毫克乌帕替尼治疗的患者中，分别有14.9%、30.6%、26.9%和35.7%在第8周实现内镜改善，定义为内镜子评分≤1，而接受安慰剂治疗的患者为2.2%（与安慰剂相比，P分别为0.033、P<0.001、P<0.001和P<0.001）。在每日一次接受45毫克乌帕替尼治疗的组中，报告了1例带状疱疹事件和1例肺栓塞及深静脉血栓形成参与者（在停药26天后诊断）。观察到乌帕替尼治疗后血脂水平和肌酸磷酸激酶升高。
在一项2b期试验中，对于中度至重度活动性UC患者，8周的乌帕替尼治疗在诱导缓解方面比安慰剂更有效。（ClinicalTrials.gov编号：NCT02819635）
