Background

The global prevalence of ulcerative colitis is increasing, and induction and maintenance of remission is a crucial therapeutic goal. We assessed the efficacy and safety of filgotinib, a once-daily, oral Janus kinase 1 preferential inhibitor, for treatment of ulcerative colitis.

Methods

This phase 2b/3, double-blind, randomised, placebo-controlled trial including two induction studies and one maintenance study was done in 341 study centres in 40 countries. Eligible patients were aged 18–75 years with moderately to severely active ulcerative colitis for at least 6 months before enrolment (induction study A: inadequate clinical response, loss of response to or intolerance to corticosteroids or immunosuppressants, naive to tumour necrosis factor [TNF] antagonists and vedolizumab [biologic-naive]; induction study B: inadequate clinical response, loss of response to or intolerance to any TNF antagonist or vedolizumab, no TNF antagonist or vedolizumab use within 8 weeks before screening [biologic-experienced]). Patients were randomly assigned 2:2:1 to receive oral filgotinib 200 mg, filgotinib 100 mg, or placebo once per day for 11 weeks. Patients who had either clinical remission or a Mayo Clinic Score response at week 10 in either induction study entered the maintenance study. Patients who received induction filgotinib were rerandomised 2:1 to continue their induction filgotinib regimen or to placebo. Patients who received induction placebo continued receiving placebo. The primary endpoint was clinical remission by Mayo endoscopic, rectal bleeding, and stool frequency subscores at weeks 10 and 58. For the induction studies, efficacy was assessed in all randomised patients who received at least one dose of study drug or placebo within that study. For the maintenance study, efficacy was assessed in all patients randomised to any filgotinib treatment group in the induction studies who received at least one dose of study drug or placebo in the maintenance study. Patients who received placebo throughout the induction and maintenance study were not included in the full analysis set for the maintenance study. Safety was assessed in all patients who received at least one dose of the study drug or placebo within each study. This trial is registered with ClinicalTrials.gov, NCT02914522.

Findings

Between Nov 14, 2016, and March 31, 2020, we screened 2040 patients for eligibility. 659 patients enrolled in induction study A were randomly assigned to receive filgotinib 100 mg (n=277), filgotinib 200 mg (n=245), or placebo (n=137). 689 patients enrolled into induction study B were randomly assigned to receive filgotinib 100 mg (n=285), filgotinib 200 mg (n=262), or placebo (n=142). 34 patients in induction study A and 54 patients in induction study B discontinued the study drug before week 10. After efficacy assessment at week 10, 664 patients entered the maintenance study (391 from induction study A, 273 from induction study B). 93 patients continued to receive placebo. 270 patients who had received filgotinib 100 mg in the induction study were randomly assigned to receive filgotinib 100 mg (n=179) or placebo (n=91). 301 patients who had received filgotinib 200 mg in the induction study were randomly assigned to receive filgotinib 200 mg (n=202) or placebo (n=99). 263 patients discontinued treatment in the maintenance study. At week 10, a greater proportion of patients given filgotinib 200 mg had clinical remission than those given placebo (induction study A 26·1% vs 15·3%, difference 10·8%; 95% CI 2·1–19·5, p=0·0157; induction study B 11·5% vs 4·2%, 7·2%; 1·6–12·8, p=0·0103). At week 58, 37·2% of patients given filgotinib 200 mg had clinical remission versus 11·2% in the respective placebo group (difference 26·0%, 95% CI 16·0–35·9; p<0·0001). Clinical remission was not significantly different between filgotinib 100 mg and placebo at week 10, but was significant by week 58 (23·8% vs 13·5%, 10·4%; 0·0–20·7, p=0·0420). The incidence of serious adverse events and adverse events of interest was similar between treatment groups. In the induction studies, serious adverse events occurred in 28 (5·0%) of 562 patients given filgotinib 100 mg, 22 (4·3%) of 507 patients given filgotinib 200 mg, and 13 (4·7%) of 279 patients given placebo. In the maintenance study, serious adverse events were reported in eight (4·5%) of 179 patients given filgotinib 100 mg, seven (7·7%) of 91 patients in the respective placebo group, nine (4·5%) of 202 patients in the filgotinib 200 mg group, and no patients in the respective placebo group. No deaths were reported during either induction study. Two patients died during the maintenance study; neither was related to treatment.

Interpretation

Filgotinib 200 mg was well tolerated, and efficacious in inducing and maintaining clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis.

Funding

Gilead Sciences.

中文翻译：

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Filgotinib 作为溃疡性结肠炎的诱导和维持治疗（选择）：2b/3 期双盲、随机、安慰剂对照试验

背景

溃疡性结肠炎的全球患病率正在增加，诱导和维持缓解是一个关键的治疗目标。我们评估了 filgotinib（一种每日一次的口服 Janus 激酶 1 优先抑制剂）治疗溃疡性结肠炎的疗效和安全性。

方法

这项 2b/3 期双盲、随机、安慰剂对照试验包括两项诱导研究和一项维持研究，在 40 个国家的 341 个研究中心进行。符合条件的患者年龄在 18-75 岁，在入组前至少 6 个月患有中度至重度活动性溃疡性结肠炎（诱导研究 A：临床反应不足、对皮质类固醇或免疫抑制剂的反应丧失或不耐受、未使用肿瘤坏死因子 [TNF]拮抗剂和 vedolizumab [生物试验]；诱导研究 B：临床反应不足，对任何 TNF 拮抗剂或 vedolizumab 的反应丧失或不耐受，筛选前 8 周内未使用 TNF 拮抗剂或 vedolizumab [生物试验]）。患者被随机分配 2:2:1 接受口服 filgotinib 200 mg、filgotinib 100 mg、或安慰剂每天一次，持续 11 周。在任一诱导研究中在第 10 周有临床缓解或 Mayo Clinic 评分反应的患者进入维持研究。接受诱导 filgotinib 的患者以 2:1 的比例重新随机分配以继续其诱导 filgotinib 方案或安慰剂。接受诱导安慰剂的患者继续接受安慰剂。主要终点是在第 10 周和第 58 周通过 Mayo 内窥镜检查、直肠出血和大便频率子评分进行临床缓解。对于诱导研究，在该研究中接受至少一剂研究药物或安慰剂的所有随机患者中评估疗效。对于维护研究，在诱导研究中随机分配到任何丝氨酸治疗组的所有患者中评估疗效，这些患者在维持研究中接受了至少一剂研究药物或安慰剂。在整个诱导和维持研究中接受安慰剂的患者不包括在维持研究的完整分析集中。在每项研究中接受至少一剂研究药物或安慰剂的所有患者中评估安全性。该试验已在 ClinicalTrials.gov 注册，NCT02914522。

发现

在 2016 年 11 月 14 日至 2020 年 3 月 31 日期间，我们筛选了 2040 名患者的资格。参与诱导研究 A 的 659 名患者被随机分配接受 100 mg (n=277) filgotinib、200 mg (n=245) 或安慰剂 (n=137)。参加诱导研究 B 的 689 名患者被随机分配接受 100 mg (n=285)、200 mg (n=262) 或安慰剂 (n=142) 的 filgotinib。诱导研究 A 中的 34 名患者和诱导研究 B 中的 54 名患者在第 10 周前停用了研究药物。在第 10 周进行疗效评估后，664 名患者进入维持研究（诱导研究 A 中的 391 名患者，诱导研究 B 中的 273 名患者）。93 名患者继续接受安慰剂。在诱导研究中接受 100 mg filgotinib 的 270 名患者被随机分配接受 100 mg filgotinib (n=179) 或安慰剂 (n=91)。在诱导研究中接受 200 mg filgotinib 的 301 名患者被随机分配接受 200 mg filgotinib (n=202) 或安慰剂 (n=99)。263 名患者在维持研究中停止治疗。在第 10 周，给予 filgotinib 200 mg 的患者临床缓解的比例高于给予安慰剂的患者（诱导研究 A 26·1%vs 15·3%，相差10·8%；95% CI 2·1–19·5，p=0·0157；诱导研究 B 11·5% vs 4·2%, 7·2%；1·6–12·8，p=0·0103)。在第 58 周，37·2% 给予 filgotinib 200 mg 的患者临床缓解，而相应安慰剂组为 11·2%（差异 26·0%，95% CI 16·0–35·9；p<0·0001 ）。filgotinib 100 mg 和安慰剂在第 10 周时临床缓解无显着差异，但在第 58 周时显着（23·8% vs13·5%、10·4%；0·0-20·7，p=0·0420)。治疗组之间严重不良事件和相关不良事件的发生率相似。在诱导研究中，接受 100 mg filgotinib 的 562 名患者中有 28 名（5·0%）发生严重不良事件，接受 200 mg filgotinib 的 507 名患者中有 22 名（4·3%）发生严重不良事件，279 名患者中有 13 名（4·7%）发生了严重不良事件给予安慰剂的患者。在维持研究中，179 名接受 100 mg filgotinib 的患者中有 8 名（4·5%）报告了严重不良事件，安慰剂组 91 名患者中有 7 名（7·7%），9 名（4·5%） filgotinib 200 mg 组中有 202 名患者，而相应的安慰剂组中没有患者。两项诱导研究期间均未报告死亡。两名患者在维持研究期间死亡；两者都与治疗无关。

解释

Filgotinib 200 mg 耐受性良好，与安慰剂相比，在中度至重度活动性溃疡性结肠炎患者中可有效诱导和维持临床缓解。

资金

吉利德科学。