Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials,The Lancet

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Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials
The Lancet ( IF 98.4 ) Pub Date : 2022-05-26 , DOI: 10.1016/s0140-6736(22)00467-6
Geert D'Haens 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 , Julian 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 , Marc Ferrante ₂₀

Affiliation

Inflammatory Bowel Disease Centre, Amsterdam University Medical Center, Amsterdam, Netherlands.
Inflammatory Bowel Disease Unit and Gastrointestinal Research, University of Calgary, Calgary, AB, Canada.
AZ Delta, Roeselare, Belgium.
Department of Gastroenterology, Imelda General Hospital, Bonheiden, Belgium.
Icahn School of Medicine at Mt Sinai, New York, NY, USA.
Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University and IRCCS San Raffaele Hospital, Milan, Italy.
Division of Gastroenterology, Department of Medicine, University of Western Ontario, London, ON, Canada; Alimentiv, London, ON, Canada.
Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Tokyo, Japan.
University of Alberta, Edmonton, AB, Canada.
Centre for Immunobiology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
Department of Gastroenterology, Hospital Clinic Barcelona, IDIBAPS, CIBEREHD, Barcelona, Spain.
University of Lorraine, CHRU-Nancy, Department of Gastroenterology, Nancy, France; University of Lorraine, Inserm, NGERE, Nancy, France.
Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai, China; Renji Hospital School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Institute of Digestive Disease, Shanghai, China.
Section of Gastroenterology, Hepatology and Nutrition and Digestive Diseases Center, The University of Chicago Medicine, Chicago, IL, USA.
Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA.
Department of Medicine I, University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany.
AbbVie, North Chicago, IL, USA.
AbbVie Deutschland, Ludwigshafen, Germany.
Department of Gastroenterology and Hepatology, University Hospitals, KU Leuven, Leuven, Belgium.

Background

Risankizumab, an interleukin (IL)-23 p19 inhibitor, was evaluated for safety and efficacy as induction therapy in patients with moderately to severely active Crohn's disease.

Methods

ADVANCE and MOTIVATE were randomised, double-masked, placebo-controlled, phase 3 induction studies. Eligible patients aged 16–80 years with moderately to severely active Crohn's disease, previously showing intolerance or inadequate response to one or more approved biologics or conventional therapy (ADVANCE) or to biologics (MOTIVATE), were randomly assigned to receive a single dose of intravenous risankizumab (600 mg or 1200 mg) or placebo (2:2:1 in ADVANCE, 1:1:1 in MOTIVATE) at weeks 0, 4, and 8. We used interactive response technology for random assignment, with stratification by number of previous failed biologics, corticosteroid use at baseline, and Simple Endoscopic Score for Crohn's disease (SES-CD). All patients and study personnel (excluding pharmacists who prepared intravenous solutions) were masked to treatment allocation throughout the study. Coprimary endpoints were clinical remission (defined by Crohn's disease activity index [CDAI] or patient-reported outcome criteria [average daily stool frequency and abdominal pain score]) and endoscopic response at week 12. The intention-to-treat population (all eligible patients who received at least one dose of study drug in the 12-week induction period) was analysed for efficacy outcomes. Safety was assessed in all patients who received at least one dose of study drug. Both trials were registered on ClinicalTrials.gov, NCT03105128 (ADVANCE) and NCT03104413 (MOTIVATE), and are now complete.

Findings

Participants were enrolled between May 10, 2017, and Aug 24, 2020 (ADVANCE trial), and Dec 18, 2017 and Sept 9, 2020 (MOTIVATE trial). In ADVANCE, 931 patients were assigned to either risankizumab 600 mg (n=373), risankizumab 1200 mg (n=372), or placebo (n=186). In MOTIVATE, 618 patients were assigned to risankizumab 600 mg (n=206), risankizumab 1200 mg (n=205), or placebo (n=207). The primary analysis population comprised 850 participants in ADVANCE and 569 participants in MOTIVATE. All coprimary endpoints at week 12 were met in both trials with both doses of risankizumab (p values ≤0·0001). In ADVANCE, CDAI clinical remission rate was 45% (adjusted difference 21%, 95% CI 12–29; 152/336) with risankizumab 600 mg and 42% (17%, 8–25; 141/339) with risankizumab 1200 mg versus 25% (43/175) with placebo; stool frequency and abdominal pain score clinical remission rate was 43% (22%, 14–30; 146/336) with risankizumab 600 mg and 41% (19%, 11–27; 139/339) with risankizumab 1200 mg versus 22% (38/175) with placebo; and endoscopic response rate was 40% (28%, 21–35; 135/336) with risankizumab 600 mg and 32% (20%, 14–27; 109/339) with risankizumab 1200 mg versus 12% (21/175) with placebo. In MOTIVATE, CDAI clinical remission rate was 42% (22%, 13–31; 80/191) with risankizumab 600 mg and 40% (21%, 12–29; 77/191) with risankizumab 1200 mg versus 20% (37/187) with placebo; stool frequency and abdominal pain score clinical remission rate was 35% (15%, 6–24; 66/191) with risankizumab 600 mg and 40% (20%, 12–29; 76/191) with risankizumab 1200 mg versus 19% (36/187) with placebo; and endoscopic response rate was 29% (18%, 10–25; 55/191) with risankizumab 600 mg and 34% (23%, 15–31; 65/191) with risankizumab 1200 mg versus 11% (21/187) with placebo. The overall incidence of treatment-emergent adverse events was similar among the treatment groups in both trials. Three deaths occurred during induction (two in the placebo group [ADVANCE] and one in the risankizumab 1200 mg group [MOTIVATE]). The death in the risankizumab-treated patient was deemed unrelated to the study drug.

Interpretation

Risankizumab was effective and well tolerated as induction therapy in patients with moderately to severely active Crohn's disease.

Funding

AbbVie.

中文翻译：

Risankizumab 作为克罗恩病的诱导治疗：3 期 ADVANCE 和 MOTIVATE 诱导试验的结果

背景

Risankizumab 是一种白细胞介素 (IL)-23 p19 抑制剂，作为诱导治疗中度至重度活动性克罗恩病患者的安全性和有效性进行了评估。

方法

ADVANCE 和 MOTIVATE 是随机、双盲、安慰剂对照的 3 期诱导研究。符合条件的 16-80 岁的中度至重度活动性克罗恩病患者，之前对一种或多种批准的生物制剂或常规治疗 (ADVANCE) 或生物制剂 (MOTIVATE) 表现出不耐受或反应不足，被随机分配接受单剂量静脉注射risankizumab（600 mg 或 1200 mg）或安慰剂（ADVANCE 2:2:1，MOTIVATE 1:1:1）在第 0、4 和 8 周。我们使用交互式响应技术进行随机分配，按数量分层以前失败的生物制剂、基线时使用皮质类固醇以及克罗恩病的简单内镜评分 (SES-CD)。在整个研究过程中，所有患者和研究人员（不包括准备静脉注射溶液的药剂师）都被掩盖了治疗分配。共同主要终点是临床缓解（由克罗恩病活动指数 [CDAI] 或患者报告的结果标准 [平均每日大便频率和腹痛评分] 定义）和第 12 周的内镜反应。意向治疗人群（所有符合条件的患者）在 12 周诱导期内接受至少一剂研究药物的患者）进行疗效结果分析。在接受至少一剂研究药物的所有患者中评估安全性。两项试验均已在 ClinicalTrials.gov、NCT03105128 (ADVANCE) 和 NCT03104413 (MOTIVATE) 上注册，现已完成。s 疾病活动指数 [CDAI] 或患者报告的结果标准 [平均每日大便频率和腹痛评分]）和第 12 周的内镜反应。意向治疗人群（所有接受至少一剂研究的合格患者） 12 周诱导期的药物）进行疗效结果分析。在接受至少一剂研究药物的所有患者中评估安全性。两项试验均已在 ClinicalTrials.gov、NCT03105128 (ADVANCE) 和 NCT03104413 (MOTIVATE) 上注册，现已完成。s 疾病活动指数 [CDAI] 或患者报告的结果标准 [平均每日大便频率和腹痛评分]）和第 12 周的内镜反应。意向治疗人群（所有接受至少一剂研究的合格患者） 12 周诱导期的药物）进行疗效结果分析。在接受至少一剂研究药物的所有患者中评估安全性。两项试验均已在 ClinicalTrials.gov、NCT03105128 (ADVANCE) 和 NCT03104413 (MOTIVATE) 上注册，现已完成。在接受至少一剂研究药物的所有患者中评估安全性。两项试验均已在 ClinicalTrials.gov、NCT03105128 (ADVANCE) 和 NCT03104413 (MOTIVATE) 上注册，现已完成。在接受至少一剂研究药物的所有患者中评估安全性。两项试验均已在 ClinicalTrials.gov、NCT03105128 (ADVANCE) 和 NCT03104413 (MOTIVATE) 上注册，现已完成。

发现

参与者于 2017 年 5 月 10 日至 2020 年 8 月 24 日（ADVANCE 试验）以及 2017 年 12 月 18 日至 2020 年 9 月 9 日（MOTIVATE 试验）期间入组。在 ADVANCE 中，931 名患者被分配到 risankizumab 600 mg (n=373)、risankizumab 1200 mg (n=372) 或安慰剂组 (n=186)。在 MOTIVATE 中，618 名患者被分配到 risankizumab 600 mg (n=206)、risankizumab 1200 mg (n=205) 或安慰剂 (n=207)。主要分析人群包括 ADVANCE 的 850 名参与者和 MOTIVATE 的 569 名参与者。在两个试验中，两种剂量的 risankizumab 均达到了第 12 周的所有共同主要终点（p 值 ≤0·0001）。在 ADVANCE 中，risankizumab 600 mg 和 risankizumab 1200 mg 的 CDAI 临床缓解率为 45%（调整差异 21%，95% CI 12-29；152/336）和 42%（17%，8-25；141/339）安慰剂组为 25% (43/175)；大便频率和腹痛评分临床缓解率为 43% (22%, 14-30; 146/336) 与 risankizumab 600 mg 和 41% (19%, 11-27; 139/339) 与 risankizumab 1200 mg 相比 22% (38/175) 与安慰剂；risankizumab 600 mg 和 risankizumab 1200 mg 的内镜缓解率为 40% (28%, 21-35; 135/336) 和 32% (20%, 14-27; 109/339) vs 12% (21/175)与安慰剂。在 MOTIVATE 中，使用 risankizumab 600 mg 的 CDAI 临床缓解率为 42%（22%，13-31；80/191），使用 risankizumab 1200 mg 的 CDAI 临床缓解率为 40%（21%，12-29；77/191）与 20%（37 /187) 与安慰剂；大便频率和腹痛评分临床缓解率为 35% (15%, 6-24; 66/191) 与 risankizumab 600 mg 和 40% (20%, 12-29; 76/191) 与 risankizumab 1200 mg 相比 19% (36/187) 与安慰剂；内镜反应率为 29% (18%, 10-25; 55/191) 与 risankizumab 600 mg 和 34% (23%, 15–31; 65/191) 与 risankizumab 1200 mg 相比 11% (21/187) 与安慰剂。在两项试验中，治疗组中治疗出现的不良事件的总体发生率相似。诱导期间发生 3 例死亡（安慰剂组 2 例 [ADVANCE] 和 risankizumab 1200 mg 组 [MOTIVATE] 1 例）。接受 risankizumab 治疗的患者的死亡被认为与研究药物无关。