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Etrolizumab for maintenance therapy in patients with moderately to severely active ulcerative colitis (LAUREL): a randomised, placebo-controlled, double-blind, phase 3 study

2021; Elsevier BV; Volume: 7; Issue: 1 Linguagem: Inglês

10.1016/s2468-1253(21)00295-8

2468-1253

Séverine Vermeire, Péter L. Lakatos, Timothy E. Ritter, Stephen B. Hanauer, Brian Bressler, Reena Khanna, Kim L. Isaacs, Saumin Shah, Alysha Kadva, Helen E.J. Tyrrell, Young S. Oh, Swati Tole, Akiko Chai, Jennifer Pulley, Christopher Eden, Wenhui Zhang, Brian G. Feagan, Philip Abraham, Mauro Acir Crippa Júnior, Humberto Aguilar, Tasneem Ahmed, I Altorjay, Vibeke Andersen, Ronen Arai, Hays Arnold, Karlee Ausk, Jeffrey Axler, Kamran Ayub, Avinash Balekuduru, Guerino Barbalaco Neto, Isaac Bassan, Brian W. Behm, Pradeep Bekal, Shobna Bhatia, Barnabás Bod, Carlos Eduardo Brandão‐Mello, Julia Brandeburova, Johannes Breedt, Brian Bressler, Ivan V. Chopey, Michael Connor, Richard Corlin, Carlos Alejandro Cortez Hernandez, Arijit De, Alexander de Sá Rolim, Sandra Di Felice Boratto, Tyler Dixon, D. Poli, D Dresner, George Aaron Du Vall, Matthias Ebert, Robert Ehehalt, Atilla Ertan, R Valencia, Jason Etzel, Jan Fallingborg, Brian G. Feagan, Miroslav Fedurco, Enrique Castro, Valéria Ferreira de Almeida e Borges, Mark Finklestein, Andreas Fischer, Mark R. Fleisher, Angel Ricardo Flores Rendon, Ronald Fogel, Osvaldo Franceschi, Curtis Freedland, David Gatof, Kanwar R. Gill, Henning Glerup, Vardaraj Gokak, Eran Goldin, Hector Alejandro Gomez Jaramillo, Nitin Gupta, Z Gurzó, Olga Gyrina, Mohammed Aejaz Habeeb, Stephen Hanauer, Robert Hardi, William R. Harlan, Ammar Hemaidan, Melvin Heyman, Péter Hoffmann, William Holderman, Frank Holtkamp-Endemann, Gyula Horvat, Kim L. Isaacs, Eran Israeli, Sender Jankiel Miszputen, Søren Kejser Jensen, Kenneth P. Johnson, Jennifer Jones, Osvaldo Da Silva Júnior, Barbora Kadleckova, Mukesh Kalla, Zsuzsanna Kallo, N C Karyotakis, Lior H. Katz, Leo Katz, Nirmal Kaur, Reena Khanna, Pavel Kohout, Péter L. Lakatos, Emmanuel Larriva de los Reyes, Robert H. Lee, Bernard Leman, Olena Levchenko, Henry Levine, Lúcia Libanez Bessa Campelo Braga, Edward V. Loftus, Tetiana Lohdanidi, Randy Longman, Josefina Lozano, Christian Maaser, L Mádi-Szabó, Éverson Fernando Malluta, John K. Marshall, Francisca Martinez Silva, Kenneth I. Maynard, Agnieszka Meder, Chetan Mehta, Peter Minárik, Joachim Mueller, Shrikant Mukewar, Béla Nagy, Vasyl Ye. Neiko, Markus F. Neurath, Brian Nichol, J. Novick, Nitin Pai, William M. Pandak, Sarat Panigrahi, Ulrich‐Frank Pape, Raymundo Paraná, Nimisha Parekh, Bhaktasharan Patel, G Pécsi, Sergio Peralta, Martin Pešta, Eva Péterfai, C. Petruzzellis, Robert Petryka, Roberta Pica, Carlos Piniella, V PRATHA, Vlastimil Procházka, Sergey Prokopchuk, L Prystupa, Amarender Singh Puri, Tova Rainis, Bhashyakarla Ramesh Kumar, Odery Ramos, Iaroslava Rishko, Timothy E. Ritter, Bryan Robbins, Elizabeth Rock, Marcelo Rodrigues Borba, Miguel Rodriguez, Jerzy Rozciecha, Azalia Yuriria Ruiz Flores, Grażyna Rydzewska, Rifaat Safadi, Simone Saibeni, Anja Schirbel, Wolff Schmiegel, Robert D. Schnabel, Herbert Schneider, Armando Segui, Jakob Benedict Seidelin, Ursula Seidler, Joseph H. Sellin, Ira Shafran, Saumin Shah, Aasim Sheikh, Alex Sherman, Haim Shirin, Akash Shukla, Firdous Siddiqui, Róbert Sike, Ajit Sood, Andreas Stallmach, Mykola Stanislavchuk, Michael Staun, Daniel S. Stein, Alon Steinberg, Hillary Steinhart, Jonathas Stifft, Rakesh K. Tandon, Vishwanath Tantry, Syed Thiwan, Matthias Treiber, Jan Ulbrych, John F. Valentine, Rajeev Vasudeva, Byron P. Vaughn, Brenda Velasco, Áron Vincze, Miroslava Volfová, Mattitiahu Waterman, Laurence Weiss, Elise Wiesner, A. B. Williams, Thomas Witthoeft, Robert Wohlman, John Wright, Jesús K. Yamamoto‐Furusho, Ziad Younes, Khurshid Yousuf, Yaroslav Zborivskyy, Stefan Zeuzem, Вячеслав Миколайович Ждан,

Helicobacter pylori-related gastroenterology studies

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 evaluate the efficacy and safety of etrolizumab for maintenance of remission in patients with moderately to severely active ulcerative colitis. Methods We conducted a randomised, placebo-controlled, double-blind, phase 3 study (LAUREL) across 111 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. During open-label induction, participants received subcutaneous etrolizumab 105 mg once every 4 weeks. Participants who had clinical response at week 10 (MCS with ≥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) proceeded into the double-blind maintenance phase and were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or matched placebo until week 62. Randomisation was stratified by baseline concomitant treatment with corticosteroids, treatment with immunosuppressants, baseline disease activity, and week 10 remission status. All participants and study site personnel were masked to treatment assignment. The primary endpoint was remission at week 62 (MCS ≤2, with individual subscores ≤1, and rectal bleeding subscore of 0) among patients with a clinical response at week 10, measured in the modified intention-to-treat population (all randomised patients who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, NCT02165215, and is now closed to recruitment. Findings Between Aug 12, 2014, and June 4, 2020, 658 patients were screened for eligibility and 359 were enrolled into the induction phase. 214 (60%) patients had a clinical response at week 10 and were randomly assigned to receive etrolizumab (n=108) or placebo (n=106) in the maintenance phase. 80 (74%) patients in the etrolizumab group and 42 (40%) in the placebo group completed the study through week 62. Four patients in the placebo group did not receive study treatment and were excluded from the analyses. At week 62, 32 (29·6%) of 108 patients in the etrolizumab group and 21 (20·6%) of 102 in the placebo group were in remission (adjusted treatment difference 7·7% [95% CI –4·2 to 19·2]; p=0·19). A greater proportion of patients reported one or more adverse events in the placebo group (82 [80%] of 102) than in the etrolizumab group (70 [65%] of 108); the most common adverse event in both groups was ulcerative colitis (16 [15%] patients in the etrolizumab group and 37 [36%] in the placebo group). Ten (9%) patients in the etrolizumab group and eight (8%) in the placebo group reported one or more serious adverse events. No deaths were reported in either treatment group. Interpretation No significant differences were observed between maintenance etrolizumab and placebo in the primary endpoint of remission at week 62 among patients who had a clinical response at week 10. Etrolizumab was well tolerated in this population and no new safety signals were identified. Funding F Hoffmann-La Roche.