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Risankizumab as maintenance therapy for moderately to severely active Crohn's disease: results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial
The Lancet ( IF 168.9 ) Pub Date : 2022-05-26 , DOI: 10.1016/s0140-6736(22)00466-4
Marc Ferrante 1 , Remo Panaccione 2 , Filip Baert 3 , Peter Bossuyt 4 , Jean-Frederic Colombel 5 , Silvio Danese 6 , Marla Dubinsky 5 , Brian G Feagan 7 , Tadakazu Hisamatsu 8 , Allen Lim 9 , James O Lindsay 10 , Edward V Loftus 11 , Julián Panés 12 , Laurent Peyrin-Biroulet 13 , Zhihua Ran 14 , David T Rubin 15 , William J Sandborn 16 , Stefan Schreiber 17 , Ezequiel Neimark 18 , Alexandra Song 18 , Kristina Kligys 18 , Yinuo Pang 18 , Valerie Pivorunas 18 , Sofie Berg 18 , W Rachel Duan 18 , Bidan Huang 18 , Jasmina Kalabic 19 , Xiaomei Liao 18 , Anne Robinson 18 , Kori Wallace 18 , Geert D'Haens 20
Affiliation  

Background

There is a great unmet need for new therapeutics with novel mechanisms of action for patients with Crohn's disease. The ADVANCE and MOTIVATE studies showed that intravenous risankizumab, a selective p19 anti-interleukin (IL)-23 antibody, was efficacious and well tolerated as induction therapy. Here, we report the efficacy and safety of subcutaneous risankizumab as maintenance therapy.

Methods

FORTIFY is a phase 3, multicentre, randomised, double-blind, placebo-controlled, maintenance withdrawal study across 273 clinical centres in 44 countries across North and South America, Europe, Oceania, Africa, and the Asia-Pacific region that enrolled participants with clinical response to risankizumab in the ADVANCE or MOTIVATE induction studies. Patients in ADVANCE or MOTIVATE were aged 16–80 years with moderately to severely active Crohn's disease. Patients in the FORTIFY substudy 1 were randomly assigned again (1:1:1) to receive either subcutaneous risankizumab 180 mg, subcutaneous risankizumab 360 mg, or withdrawal from risankizumab to receive subcutaneous placebo (herein referred to as withdrawal [subcutaneous placebo]). Treatment was given every 8 weeks. Patients were stratified by induction dose, post-induction endoscopic response, and clinical remission status. Patients, investigators, and study personnel were masked to treatment assignments. Week 52 co-primary endpoints were clinical remission (Crohn's disease activity index [CDAI] in the US protocol, or stool frequency and abdominal pain score in the non-US protocol) and endoscopic response in patients who received at least one dose of study drug during the 52-week maintenance period. Safety was assessed in patients receiving at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03105102.

Findings

712 patients were initially assessed and, between April 9, 2018, and April 24, 2020, 542 patients were randomly assigned to either the risankizumab 180 mg group (n=179), the risankizumab 360 mg group (n=179), or the placebo group (n=184). Greater clinical remission and endoscopic response rates were reached with 360 mg risankizumab versus placebo (CDAI clinical remission was reached in 74 (52%) of 141 patients vs 67 (41%) of 164 patients, adjusted difference 15% [95% CI 5–24]; stool frequency and abdominal pain score clinical remission was reached in 73 (52%) of 141 vs 65 (40%) of 164, adjusted difference 15% [5–25]; endoscopic response 66 (47%) of 141 patients vs 36 (22%) of 164 patients, adjusted difference 28% [19–37]). Higher rates of CDAI clinical remission and endoscopic response (but not stool frequency and abdominal pain score clinical remission [p=0·124]) were also reached with risankizumab 180 mg versus withdrawal (subcutaneous placebo; CDAI clinical remission reached in 87 [55%] of 157 patients, adjusted difference 15% [95% CI 5–24]; endoscopic response 74 [47%] of 157, adjusted difference 26% [17–35]). Results for more stringent endoscopic and composite endpoints and inflammatory biomarkers were consistent with a dose–response relationship. Maintenance treatment was well tolerated. Adverse event rates were similar among groups, and the most frequently reported adverse events in all treatment groups were worsening Crohn's disease, arthralgia, and headache.

Interpretation

Subcutaneous risankizumab is a safe and efficacious treatment for maintenance of remission in patients with moderately to severely active Crohn's disease and offers a new therapeutic option for a broad range of patients by meeting endpoints that might change the future course of disease.

Funding

AbbVie.



中文翻译:

Risankizumab 作为中度至重度活动性克罗恩病的维持治疗:来自多中心、随机、双盲、安慰剂对照、退出 3 期 FORTIFY 维持试验的结果

背景

对于克罗恩病患者,对具有新作用机制的新疗法存在巨大的未满足需求。ADVANCE 和 MOTIVATE 研究表明,静脉注射 risankizumab 是一种选择性 p19 抗白细胞介素 (IL)-23 抗体,作为诱导治疗有效且耐受性良好。在这里,我们报告了皮下 risankizumab 作为维持治疗的疗效和安全性。

方法

FORTIFY 是一项 3 期、多中心、随机、双盲、安慰剂对照、维持性停药研究,涉及北美和南美、欧洲、大洋洲、非洲和亚太地区 44 个国家的 273 个临床中心在 ADVANCE 或 MOTIVATE 诱导研究中对 risankizumab 的临床反应。ADVANCE 或 MOTIVATE 的患者年龄在 16-80 岁之间,患有中度至重度活动性克罗恩病。FORTIFY 子研究 1 中的患者再次被随机分配 (1:1:1) 接受皮下注射 risankizumab 180 mg、皮下注射 risankizumab 360 mg,或退出 risankizumab 接受皮下注射安慰剂(本文称为退出 [皮下安慰剂])。每8周进行一次治疗。患者按诱导剂量、诱导后内镜反应、和临床缓解状态。患者、研究人员和研究人员对治疗分配不知情。第 52 周的共同主要终点是临床缓解(美国方案中的克罗恩病活动指数 [CDAI],或非美国方案中的大便频率和腹痛评分)和接受至少一剂研究药物的患者的内镜反应在 52 周的维护期内。在接受至少一剂研究药物的患者中评估安全性。该研究已在 ClinicalTrials.gov 注册,NCT03105102。或非美国方案中的大便频率和腹痛评分)和在 52 周维持期内接受至少一剂研究药物的患者的内窥镜反应。在接受至少一剂研究药物的患者中评估安全性。该研究已在 ClinicalTrials.gov 注册,NCT03105102。或非美国方案中的大便频率和腹痛评分)和在 52 周维持期内接受至少一剂研究药物的患者的内窥镜反应。在接受至少一剂研究药物的患者中评估安全性。该研究已在 ClinicalTrials.gov 注册,NCT03105102。

发现

最初评估了 712 名患者,在 2018 年 4 月 9 日至 2020 年 4 月 24 日期间,542 名患者被随机分配到 risankizumab 180 mg 组 (n=179)、risankizumab 360 mg 组 (n=179) 或安慰剂组(n = 184)。与安慰剂相比,360 mg risankizumab 的临床缓解率和内镜缓解率更高(141 名患者中有 74 名(52%)达到了 CDAI 临床缓解,164 名患者中有 67 名(41%)达到了 CDAI 临床缓解,调整后差异为 15% [95% CI 5– 24];141人中有 73 人(52%)达到了大便频率和腹痛评分临床缓解,164 人中有 65 人(40%)达到了临床缓解,调整后差异为 15%[5-25];141 名患者中的 66 人(47%)内镜反应对比164 名患者中的 36 名(22%),调整后的差异为 28% [19-37])。与停用 risankizumab 180 mg 相比(皮下安慰剂;CDAI 临床缓解率在 87 [55%] ] 157 名患者,调整后差异 15% [95% CI 5-24];157 名内镜反应 74 [47%],调整后差异 26% [17-35])。更严格的内窥镜和复合终点以及炎症生物标志物的结果与剂量反应关系一致。维持治疗耐受性良好。各组的不良事件发生率相似,所有治疗组中最常报告的不良事件是克罗恩病恶化、关节痛和头痛。

解释

皮下 risankizumab 是一种安全有效的治疗方法,用于维持中度至重度活动性克罗恩病患者的缓解,并通过满足可能改变未来疾病进程的终点为广泛的患者提供新的治疗选择。

资金

艾伯维。

更新日期:2022-05-27
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