加拿大韦仕敦大学Brian G Feagan团队研究了非戈替尼作为溃疡性结肠炎的诱导和维持治疗的效果。2021年6月3日，《柳叶刀》杂志发表了该成果。
溃疡性结肠炎的全球患病率正在增加，诱导和维持病情缓解是一个关键的治疗目标。研究组评估了每日一次口服Janus激酶1优先抑制剂非戈替尼治疗溃疡性结肠炎的疗效和安全性。
研究组在40个国家的341个研究中心进行了一项临床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。招募年龄为18-75岁，至少在入组前6个月患有中度至重度活动性溃疡性结肠炎的患者。将其按2：2：1随机分组，分别口服非戈替尼200 mg、非戈替尼100 mg或安慰剂治疗，每天一次，共11周。
在诱导研究的第10周出现临床缓解或梅奥临床评分缓解的患者进入维持研究。接受非戈替尼诱导治疗的患者按2：1重新随机分组，继续接受非戈替尼诱导治疗或安慰剂治疗。接受诱导安慰剂的患者继续接受安慰剂治疗。主要终点是在第10周和第58周通过梅奥内窥镜检查、直肠出血和大便次数的临床缓解。
2016年11月14日至2020年3月31日，研究组对2040名患者进行了资格筛查。纳入诱导研究A的659名患者中，277例接受非戈替尼100 mg，245例接受非戈替尼200 mg，137例接受安慰剂治疗。纳入诱导研究B的689名患者中，285例接受非戈替尼100 mg，262例接受非戈替尼200 mg，142例接受安慰剂治疗。
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周前停药。在第10周进行疗效评估后，664名患者进入维持研究（391名来自诱导研究A，273名来自诱导研究B）。93名患者继续接受安慰剂治疗。
在诱导研究中，270名接受了100 mg非戈替尼治疗的患者被随机分组，其中179例接受100 mg非戈替尼治疗，91例接受安慰剂治疗。301名在诱导研究中接受了200 mg非戈替尼治疗的患者被随机分组，其中202例接受200 mg非戈替尼治疗，99例接受安慰剂治疗。263名患者在维持性研究中停止了治疗。
在第10周，服用200 mg非戈替尼的患者临床病情缓解的比例显著高于服用安慰剂的患者。在第58周，服用200 mg非戈替尼的患者中有37.2%临床病情缓解，显著高于安慰剂组的11.2%。
在第10周时，100 mg非戈替尼组与安慰剂组的临床缓解率无显著性差异，但在第58周时差异显著，分别为23.8%与13.5%。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，562名服用100 mg非戈替尼的患者中有28名（5.0%）发生严重不良事件，507名服用200 mg非戈替尼的患者中有22名（4.3%），279名服用安慰剂的患者中有13名（4.7%）。
在维持研究中，179名服用100 mg非戈替尼的患者中有8名（4.5%）出现严重不良事件，91名服用安慰剂的患者中有7名（7.7%）；202名服用200 mg非戈替尼的患者中有9名（4.5%），安慰剂组中则没有。两项诱导研究均未报告死亡病例。两名患者在维持研究期间死亡；均与治疗无关。
研究结果表明，对于中重度活动性溃疡性结肠炎患者，与安慰剂相比，200 mg非戈替尼治疗耐受性良好，在诱导和维持临床缓解方面均有效。
附：英文原文
Title: Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial
Author: Brian G Feagan, Silvio Danese, Edward V Loftus, Séverine Vermeire, Stefan Schreiber, Timothy Ritter, Ronald Fogel, Rajiv Mehta, Sandeep Nijhawan, Radosaw Kempiński, Rafa Filip, Ihor Hospodarskyy, Ursula Seidler, Frank Seibold, Ian L P Beales, Hyo Jong Kim, John McNally, Chohee Yun, Sally Zhao, Xiaopeng Liu, Chia-Hsiang Hsueh, Chantal Tasset, Robin Besuyen, Mamoru Watanabe, William J Sandborn, Gerhard Rogler, Toshifumi Hibi, Laurent Peyrin-Biroulet
Issue&Volume: 2021-06-03
Abstract:
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.
DOI: 10.1016/S0140-6736(21)00666-8
Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00666-8/fulltext
LANCET：《柳叶刀》，创刊于1823年。隶属于爱思唯尔出版社，最新IF：202.731
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