From the Icahn School of Medicine at Mount Sinai, New York (B.E.S., J.-F.C.); Nancy University Hospital, Nancy, France (L.P.-B.); Mayo Clinic College of Medicine, Rochester, MN (E.V.L.); Humanitas University, Milan (S.D.); Ankara University School of Medicine, Ankara, Turkey (M.T.); Lithuanian University of Health Sciences, Kaunas, Lithuania (L.J.); Takeda Development Centre Europe, London (B.A.); Takeda Development Center Americas, Cambridge, MA (J.C., R.R., R.A.L., J.D.B.); and the University Hospital Schleswig-Holstein, Kiel, Germany (S.S.).
N Engl J Med. 2019 Sep 26;381(13):1215-1226. doi: 10.1056/NEJMoa1905725.
Biologic therapies are widely used in patients with ulcerative colitis. Head-to-head trials of these therapies in patients with inflammatory bowel disease are lacking.
In a phase 3b, double-blind, double-dummy, randomized trial conducted at 245 centers in 34 countries, we compared vedolizumab with adalimumab in adults with moderately to severely active ulcerative colitis to determine whether vedolizumab was superior. Previous exposure to a tumor necrosis factor inhibitor other than adalimumab was allowed in up to 25% of patients. The patients were assigned to receive infusions of 300 mg of vedolizumab on day 1 and at weeks 2, 6, 14, 22, 30, 38, and 46 (plus injections of placebo) or subcutaneous injections of 40 mg of adalimumab, with a total dose of 160 mg at week 1, 80 mg at week 2, and 40 mg every 2 weeks thereafter until week 50 (plus infusions of placebo). Dose escalation was not permitted in either group. The primary outcome was clinical remission at week 52 (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). To control for type I error, efficacy outcomes were analyzed with a hierarchical testing procedure, with the variables in the following order: clinical remission, endoscopic improvement (subscore of 0 to 1 on the Mayo endoscopic component), and corticosteroid-free remission at week 52.
A total of 769 patients underwent randomization and received at least one dose of vedolizumab (383 patients) or adalimumab (386 patients). At week 52, clinical remission was observed in a higher percentage of patients in the vedolizumab group than in the adalimumab group (31.3% vs. 22.5%; difference, 8.8 percentage points; 95% confidence interval [CI], 2.5 to 15.0; P = 0.006), as was endoscopic improvement (39.7% vs. 27.7%; difference, 11.9 percentage points; 95% CI, 5.3 to 18.5; P<0.001). Corticosteroid-free clinical remission occurred in 12.6% of the patients in the vedolizumab group and in 21.8% in the adalimumab group (difference, -9.3 percentage points; 95% CI, -18.9 to 0.4). Exposure-adjusted incidence rates of infection were 23.4 and 34.6 events per 100 patient-years with vedolizumab and adalimumab, respectively, and the corresponding rates for serious infection were 1.6 and 2.2 events per 100 patient-years.
In this trial involving patients with moderately to severely active ulcerative colitis, vedolizumab was superior to adalimumab with respect to achievement of clinical remission and endoscopic improvement, but not corticosteroid-free clinical remission. (Funded by Takeda; VARSITY ClinicalTrials.gov number, NCT02497469; EudraCT number, 2015-000939-33.).
生物疗法在溃疡性结肠炎患者中广泛应用。但在炎症性肠病患者中，这些疗法的头对头试验尚缺乏。
在一项 3b 期、双盲、双模拟、随机试验中，我们在 34 个国家的 245 个中心比较了维得利珠单抗与阿达木单抗在中度至重度活动性溃疡性结肠炎成人患者中的疗效，以确定维得利珠单抗是否更优。此前允许多达 25%的患者使用除阿达木单抗以外的肿瘤坏死因子抑制剂。患者被分配接受维得利珠单抗 300mg 剂量的第 1 天和第 2、6、14、22、30、38 和 46 天（同时给予安慰剂注射），或阿达木单抗 40mg 剂量的皮下注射，第 1 周 160mg，第 2 周 80mg，此后每 2 周 40mg，直至第 50 周（同时给予安慰剂输注）。两组均不允许剂量递增。主要终点是第 52 周的临床缓解（定义为 Mayo 评分≤2[范围 0 至 12，分数越高表示疾病越严重]，且四个 Mayo 评分组成部分中任何一个的亚评分均不超过 1[范围 0 至 3]）。为了控制 I 型错误，采用分层检验程序分析疗效结局，变量按以下顺序排列：临床缓解、内镜改善（Mayo 内镜评分 0 至 1）和第 52 周无皮质类固醇缓解。
共有 769 名患者接受了随机分组，并接受了至少一剂维得利珠单抗（383 名患者）或阿达木单抗（386 名患者）。第 52 周时，维得利珠单抗组的患者临床缓解率高于阿达木单抗组（31.3%比 22.5%；差值为 8.8 个百分点；95%置信区间[CI]为 2.5 至 15.0；P=0.006），内镜改善率也高于阿达木单抗组（39.7%比 27.7%；差值为 11.9 个百分点；95%CI 为 5.3 至 18.5；P<0.001）。维得利珠单抗组中有 12.6%的患者达到无皮质类固醇的临床缓解，阿达木单抗组中有 21.8%的患者达到无皮质类固醇的临床缓解（差值为-9.3 个百分点；95%CI 为-18.9 至 0.4）。维得利珠单抗和阿达木单抗的感染发生率分别为每 100 患者-年 23.4 和 34.6 例，相应的严重感染发生率分别为每 100 患者-年 1.6 和 2.2 例。
在这项涉及中度至重度活动性溃疡性结肠炎患者的试验中，与阿达木单抗相比，维得利珠单抗在实现临床缓解和内镜改善方面更优，但在无皮质类固醇的临床缓解方面无差异。（由武田公司资助；VARSITY 临床试验.gov 编号，NCT02497469；EudraCT 编号，2015-000939-33。）
