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Etrolizumab versus infliximab for the treatment of moderately to severely active ulcerative colitis (GARDENIA): a randomised, double-blind, double-dummy, phase 3 study

2021; Elsevier BV; Volume: 7; Issue: 2 Linguagem: Inglês

10.1016/s2468-1253(21)00294-6

2468-1253

Silvio Danese, Jean‐Frédéric Colombel, Milan Lukáš, Javier P. Gisbert, Geert R. D’Haens, Bu Hayee, Remo Panaccione, Hyun‐Soo Kim, Walter Reinisch, Helen E.J. Tyrrell, Young S. Oh, Swati Tole, Akiko Chai, Kirsten Chamberlain-James, Meina Tang, Stefan Schreiber, Nazimuddin Aboo, Tariq Ali Ahmad, Xavier Aldeguer Manté, Matthieu Allez, Sven Almér, Romain Altwegg, Montserrat Andreu García, Ramesh Arasaradnam, Sandro Ardizzone, Alessandro Armuzzi, Ian Arnott, Guy Aumais, Irit Avni‐Biron, Peter Barrow, Ian Beales, Fernando Bermejo San José, Abraham F. Bezuidenhout, Livia Biancone, Michael Blaeker, Stuart Bloom, Bernd Bokemeyer, Fabrizio Bossa, Peter Bossuyt, Guillaume Bouguen, Yoram Bouhnik, Gerd Bouma, Raymond Bourdages, Arnaud Bourreille, Christian Boustière, Tomáš Brabec, Stephan Brand, Carsten Buening, Anthony Buisson, Guillaume Cadiot, Xavier Calvet, Franck Carbonnel, Daniel Carpio, Jae Hee Cheon, Naoki Chiba, Camelia Chioncel, Nicoleta-Claudia Cimpoeru, Martin Clodi, Gino Roberto Corazza, R. Cosintino, José Cotter, Thomas Creed, Fraser Cummings, Silvio Danese, Gian Luigi De’ Angelis, Marc De Maeyer, Milind Y. Desai, Étienne Désilets, Pierre Desreumaux, Olivier Dewit, Geert R. D’Haens, Johanna Dinter, Ecaterina Daniela Dobru, Tomáš Douda, Dan L. Dumitraşcu, Matthias Ebert, Ana Echarri, Magdy Elkhashab, Chang Soo Eun, Brian G. Feagan, R Fejes, Catarina Fidalgo, Sigal Fishman, Bernard Flourié, Sharyle Fowler, Walter Fries, Csaba Fülöp, Mathurin Fuméry, G Kiss, Sonja Gassner, Daniel R. Gaya, Bastianello Germanà, Liliana Gheorghe, Cyrielle Gilletta, Paolo Gionchetti, Adrian-Eugen Goldis, Raquel Gonçalves, Jean–Charles Grimaud, T Gyökeres, Hervé Hagège, Andrei Haidar, Heinz Hartmann, Peter Hasselblatt, Bu Hayee, Xavier Hébuterne, Per M. Hellström, P. Hindryckx, Helena Hlavova, Frank Hoentjen, Stefanie Howaldt, Luděk Hrdlička, Kyu Chan Huh, Maria Isabel Iborra Colomino, Florentina Ioniţă‐Radu, Peter M. Irving, Jørgen Jahnsen, Byung-Ik Jang, Jeroen P. Jansen, Seong Woo Jeon, Rodrigo Jover Martínez, Pascal Juillerat, Per Karlén, Arthur Kaser, Radan Keil, Deepak Kejariwal, Dan Keret, Reena Khanna, Dong‐Woo Kim, Duk Hwan Kim, Hyo Jong Kim, Hyun‐Soo Kim, Joo Sung Kim, Kueongok Kim, Kyung-Jo Kim, Sung Kook Kim, Young‐Ho Kim, Jochen Klaus, Anna Kohn, Vladimír Kojecký, Ja Seol Koo, Robert Kozak, Milan Kremer, Tünde Kristóf, Frederik Cornelius Kruger, David Laharie, Adi Lahat-Zok, E. Landa, Jong Hun Lee, Kang‐Moon Lee, Kook Lae Lee, Yoojin Lee, Frank Lenze, Wee Chian Lim, Jimmy K. Limdi, James O. Lindsay, Pilar López Serrano, Édouard Louis, Stefan Lueth, Milan Lukáš, Giovanni Maconi, Fazia Mana, Steven Mann, John Mansfield, Santino Marchi, Marco Marino, John K. Marshall, María Dolores Martín‐Arranz, Bogdan Mateescu, John McLaughlin, Simon D. McLaughlin, Ehud Melzer, Jessica Mertens, Paul Mitruț, Tamás Molnár, Vinciane Muls, Pushpakaran Munuswamy, Charles Murray, Timna Naftali, Visvakuren Naidoo, Yusuf Nanabhay, Lucian Negreanu, Augustin Nguyen, Thomas Ochsenkuehn, Ambrogio Orlando, Remo Panaccione, Julián Panés Díaz, Maya Paritsky, Dong Il Park, Jihye Park, Luca Pastorelli, Markus Peck‐Radosavljevic, Farhad Peerani, Javier P. Gisbert, Laurent Peyrin‐Biroulet, Laurence Picon, Marieke Pierik, Terry Ponich, Francisco Portela, Maartens Jeroen Prins, I Rácz, Khan Fareed Rahman, Jean‐Marie Reimund, Max Reinshagen, Xavier Roblin, Rodolfo Rocca, Francesca Rogai, Gerhard Rogler, Á Salamon, Ennaliza Salazar, Zoltán Salló, Sunil Samuel, Miquel de los Santos Sans Cuffi, Edoardo Savarino, Vincenzo Savarino, Guillaume Savoye, Stefan Schreiber, Andrada Seicean, Christian P. Selinger, David Martins Serra, Hang Hock Shim, Sung Jae Shin, Britta Siegmund, Jesse Siffledeen, Wayne M Simmonds, Jan Šmíd, Jose D. Sollano, Geun Am Song, Alexander Speight, Ioan Sporea, Dirk Staessen, George Stancu, Alan Steel, David Stepek, Victor Stoica, Andreas Sturm, Gyorgy Szekely, Teck Kiang Tan, Carlos Taxonera, John Thomson, Michal Tichý, Gábor Tamás Tóth, Zsolt Tulassay, Marcello Vangeli, Márta Varga, Ana Paula Vieira, Stéphanie Viennot, Erica Villa, Petr Vítek, Harald Vogelsang, P Vyhnálek, Peter J. Wahab, Jens Walldorf, Byong Duk Ye, Christopher Ziady,

Celiac Disease Research and Management

Background Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis. Methods We conducted a randomised, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centres worldwide. We included adults (age 18–80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6–12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary endpoint was the proportion of patients who had both clinical response at week 10 (MCS ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1); efficacy was analysed using a modified intention-to-treat population (all randomised patients who received at least one dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT02136069, and is now closed to recruitment. Findings Between Dec 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n=199) or infliximab (n=198). 95 (48%) patients in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 (18·6%) of 199 patients in the etrolizumab group and 39 (19·7%) of 198 in the infliximab group met the primary endpoint (adjusted treatment difference –0·9% [95% CI –8·7 to 6·8]; p=0·81). The number of patients reporting one or more adverse events was similar between treatment groups (154 [77%] of 199 in the etrolizumab group and 151 [76%] of 198 in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 [28%] patients in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was one death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment. Interpretation To our knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary endpoint, etrolizumab performed similarly to infliximab from a clinical viewpoint. Funding F Hoffmann-La Roche.