- Fecal Incontinence
|Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials
Lancet. 2022 May 28;399(10340):2015-2030.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 Jr 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
1Inflammatory Bowel Disease Centre, Amsterdam University Medical Center, Amsterdam, Netherlands. Electronic address: firstname.lastname@example.org.
2Inflammatory Bowel Disease Unit and Gastrointestinal Research, University of Calgary, Calgary, AB, Canada.
3AZ Delta, Roeselare, Belgium.
4Department of Gastroenterology, Imelda General Hospital, Bonheiden, Belgium.
5Icahn School of Medicine at Mt Sinai, New York, NY, USA.
6Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University and IRCCS San Raffaele Hospital, Milan, Italy.
7Division of Gastroenterology, Department of Medicine, University of Western Ontario, London, ON, Canada; Alimentiv, London, ON, Canada.
8Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Tokyo, Japan.
9University of Alberta, Edmonton, AB, Canada.
10Centre for Immunobiology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
11Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
12Department of Gastroenterology, Hospital Clinic Barcelona, IDIBAPS, CIBEREHD, Barcelona, Spain.
13University of Lorraine, CHRU-Nancy, Department of Gastroenterology, Nancy, France; University of Lorraine, Inserm, NGERE, Nancy, France.
14Division 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.
15Section of Gastroenterology, Hepatology and Nutrition and Digestive Diseases Center, The University of Chicago Medicine, Chicago, IL, USA.
16Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA.
17Department of Medicine I, University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany.
18AbbVie, North Chicago, IL, USA.
19AbbVie Deutschland, Ludwigshafen, Germany.
20Department 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.