William J Sandborn1, Brian G Feagan2, Edward V Loftus3, Laurent Peyrin-Biroulet4, Gert Van Assche5, Geert D'Haens6, Stefan Schreiber7, Jean-Frederic Colombel8, James D Lewis9, Subrata Ghosh10, Alessandro Armuzzi11, Ellen Scherl12, Hans Herfarth13, Lauren Vitale14, Mohamed-Eslam F Mohamed14, Ahmed A Othman14, Qian Zhou14, Bidan Huang14, Roopal B Thakkar14, Aileen L Pangan14, Ana P Lacerda14, Julian Panes15. 1. Division of Gastroenterology, University of California San Diego, La Jolla, California. 2. Western University, Robarts Clinical Trials, St Joseph's Health Care, London, Ontario, Canada. 3. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. 4. Department of Gastroenterology and Inserm U1256 Nutrition-Génétique et Exposition aux Risques Environnementaux, niversity of Lorraine, Nancy, France. 5. Department of Gastroenterology and Hepatology, University of Leuven, Leuven, Belgium. 6. Department of Gastroenterology, Amsterdam University Medical Center campus Academic Medical Center, Amsterdam, The Netherlands. 7. Department of Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany. 8. Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York. 9. Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 10. University of Birmingham, National Institute for Health Research Biomedical Research Centre, Birmingham, United Kingdom. 11. Presidio Columbus, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico Università Cattolica del Sacro Cuore, Rome, Italy. 12. Weill Department of Medicine, New York Presbyterian Hospital Weill Cornell Medicine, New York, New York. 13. Department of Medicine, University of North Carolina, Chapel Hill, North Carolina. 14. AbbVie Inc., North Chicago, Illinois. 15. Inflammatory Bowel Diseases Unit, Hospital Clínic Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain. Electronic address: JPANES@clinic.cat.
Abstract
BACKGROUND & AIMS: We evaluated the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, in a randomized trial of patients with Crohn's disease (CD). METHODS: We performed a double-blind, phase 2 trial in adults with moderate to severe CD and inadequate response or intolerance to immunosuppressants or tumor necrosis factor antagonists. Patients were randomly assigned (1:1:1:1:1:1) to groups given placebo; or 3 mg, 6 mg, 12 mg, or 24 mg upadacitinib twice daily; or 24 mg upadacitinib once daily and were evaluated by ileocolonoscopy at weeks 12 or 16 of the induction period. Patients who completed week 16 were re-randomized to a 36-week period of maintenance therapy with upadacitinib. The primary endpoints were clinical remission at week 16 and endoscopic remission at week 12 or 16 using the multiple comparison procedure and modeling and the Cochran-Mantel-Haenszel test, with a 2-sided level of 10%. RESULTS: Among the 220 patients in the study, clinical remission was achieved by 13% of patients receiving 3 mg upadacitinib, 27% of patients receiving 6 mg upadacitinib (P < .1 vs placebo), 11% of patients receiving 12 mg upadacitinib, and 22% of patients receiving 24 mg upadacitinib twice daily, and by 14% of patients receiving 24 mg upadacitinib once daily, vs 11% of patients receiving placebo. Endoscopic remission was achieved by 10% (P < .1 vs placebo), 8%, 8% (P < .1 vs placebo), 22% (P < .01 vs placebo), and 14% (P < .05 vs placebo) of patients receiving upadacitinib, respectively, vs none of the patients receiving placebo. Endoscopic but not clinical remission increased with dose during the induction period. Efficacy was maintained for most endpoints through week 52. During the induction period, patients in the upadacitinib groups had higher incidences of infections and serious infections vs placebo. Patients in the twice-daily 12 mg and 24 mg upadacitinib groups had significant increases in total, high-density lipoprotein, and low-density lipoprotein cholesterol levels compared with patients in the placebo group. CONCLUSIONS: In a phase 2 trial of patients with CD, upadacitinib induced endoscopic remission in a significant proportion of patients compared with placebo. Upadacitinib's benefit/risk profile supports further development for treatment of CD. (Clinicaltrials.gov, Number: NCT02365649).
RCT Entities:
BACKGROUND & AIMS: We evaluated the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, in a randomized trial of patients with Crohn's disease (CD). METHODS: We performed a double-blind, phase 2 trial in adults with moderate to severe CD and inadequate response or intolerance to immunosuppressants or tumornecrosis factor antagonists. Patients were randomly assigned (1:1:1:1:1:1) to groups given placebo; or 3 mg, 6 mg, 12 mg, or 24 mg upadacitinib twice daily; or 24 mg upadacitinib once daily and were evaluated by ileocolonoscopy at weeks 12 or 16 of the induction period. Patients who completed week 16 were re-randomized to a 36-week period of maintenance therapy with upadacitinib. The primary endpoints were clinical remission at week 16 and endoscopic remission at week 12 or 16 using the multiple comparison procedure and modeling and the Cochran-Mantel-Haenszel test, with a 2-sided level of 10%. RESULTS: Among the 220 patients in the study, clinical remission was achieved by 13% of patients receiving 3 mg upadacitinib, 27% of patients receiving 6 mg upadacitinib (P < .1 vs placebo), 11% of patients receiving 12 mg upadacitinib, and 22% of patients receiving 24 mg upadacitinib twice daily, and by 14% of patients receiving 24 mg upadacitinib once daily, vs 11% of patients receiving placebo. Endoscopic remission was achieved by 10% (P < .1 vs placebo), 8%, 8% (P < .1 vs placebo), 22% (P < .01 vs placebo), and 14% (P < .05 vs placebo) of patients receiving upadacitinib, respectively, vs none of the patients receiving placebo. Endoscopic but not clinical remission increased with dose during the induction period. Efficacy was maintained for most endpoints through week 52. During the induction period, patients in the upadacitinib groups had higher incidences of infections and serious infections vs placebo. Patients in the twice-daily 12 mg and 24 mg upadacitinib groups had significant increases in total, high-density lipoprotein, and low-density lipoprotein cholesterol levels compared with patients in the placebo group. CONCLUSIONS: In a phase 2 trial of patients with CD, upadacitinib induced endoscopic remission in a significant proportion of patients compared with placebo. Upadacitinib's benefit/risk profile supports further development for treatment of CD. (Clinicaltrials.gov, Number: NCT02365649).
Authors: Aditi Kumar; Alexander Cole; Jonathan Segal; Philip Smith; Jimmy K Limdi Journal: Therap Adv Gastroenterol Date: 2022-02-17 Impact factor: 4.409
Authors: Maria D Giraldez; David Carneros; Christoph Garbers; Stefan Rose-John; Matilde Bustos Journal: Nat Rev Gastroenterol Hepatol Date: 2021-07-01 Impact factor: 46.802