- Fecal Incontinence
|Etrolizumab as induction and maintenance therapy for ulcerative colitis in patients previously treated with tumour necrosis factor inhibitors (HICKORY): a phase 3, randomised, controlled trial
Lancet Gastroenterol Hepatol. 2022 Feb;7(2):128-140.doi: 10.1016/S2468-1253(21)00298-3. Epub 2021 Nov 17.
Laurent Peyrin-Biroulet 1, Ailsa Hart 2, Peter Bossuyt 3, Millie Long 4, Matthieu Allez 5, Pascal Juillerat 6, Alessandro Armuzzi 7, Edward V Loftus Jr 8, Elham Ostad-Saffari 9, Astrid Scalori 9, Young S Oh 10, Swati Tole 10, Akiko Chai 10, Jennifer Pulley 9, Stuart Lacey 9, William J Sandborn 11, HICKORY Study Group
HICKORY Study Group:
Humberto Aguilar, Tariq Ahmad, Evangelos Akriviadis, Xavier Aldeguer Mante, Matthieu Allez, Istvan Altorjay, Ashwin Ananthakrishnan, Vibeke Andersen, Montserrat Andreu Garcia, Alessandro Armuzzi, Guy Aumais, Irit Avni-Biron, Jeffrey Axler, Kamran Ayub Jr, Filip Baert, Mauro Bafutto, George Bamias, Isaac Bassan, Curtis Baum, Laurent Beaugerie, Brian Behm, Pradeep Bekal, Michael Bennett, Fernando Bermejo San Jose, Charles Bernstein, Dominik Bettenworth, Sudhir Bhaskar, Livia Biancone, Bahri Bilir, Michael Blaeker, Stuart Bloom, Verle Bohman Jr, Francisco Javier Bosques Padilla, Peter Bossuyt, Yoram Bouhnik, Gerd Bouma, Raymond Bourdages, Stephan Brand, Brian Bressler, Markus Brückner, Carsten Buening, Franck Carbonnel, Thomas Caves, Jonathon Chapman, Jae Hee Cheon, Naoki Chiba, Camelia Chioncel, Dimitrios Christodoulou, Martin Clodi, Albert Cohen, Gino Roberto Corazza, Richard Corlin, Rocco Cosintino, Fraser Cummings, Robin Dalal, Silvio Danese, Marc De Maeyer, Carlos Fernando De Magalhães Francesconi, Aminda De Silva, Henry Debinski, Pierre Desreumaux, Olivier Dewit, Geert D'Haens, Sandra Di Felice Boratto, John Nik Ding, Tyler Dixon, Gerald Dryden Jr, George Aaron Du Vall, Matthias Ebert, Ana Echarri Piudo, Robert Ehehalt, Magdy Elkhashab, Craig Ennis, Jason Etzel, Jan Fallingborg, Brian Feagan, Roland Fejes, Daniel Ferraz de Campos Mazo, Valéria Ferreira de Almeida Borges, Andreas Fischer, Alan Fixelle, Mark Fleisher, Sharyle Fowler, Bradley Freilich, Keith Friedenberg, Walter Fries, Csaba Fulop, Mathurin Fumery, Sergio Fuster, Gyula G Kiss, Santiago Garcia Lopez, Sonja Gassner, Kanwar Gill, Cyrielle Gilletta de Saint Joseph, Philip Ginsburg, Paolo Gionchetti, Eran Goldin, Adrian-Eugen Goldis, Hector Alejandro Gomez Jaramillo, Maciej Gonciarz, Glenn Gordon, Daniel Green, Jean-Charles Grimaud, Rogelio Guajardo Rodriguez, Zoltan Gurzo, Alexandra Gutierrez, Tibor Gyökeres, Ki Baik Hahm, Stephen Hanauer, John Hanson, William Harlan Iii, Peter Hasselblatt, Buhussain Hayee, Xavier Hebuterne, Peter Hendy, Melvin Heyman, Peter Higgins, Raouf Hilal, Pieter Hindryckx, Frank Hoentjen, Peter Hoffmann, Frank Holtkamp-Endemann, Gerald Holtmann, Gyula Horvat, Stefanie Howaldt, Samuel Huber, Ikechukwu Ibegbu, Maria Isabel Iborra Colomino, Peter Irving, Kim Isaacs, Kiran Jagarlamudi, Rajesh Jain, Sender Jankiel Miszputen, Jeroen Jansen, Jennifer Jones, Pascal Juillerat, John Karagiannis, Nicholas Karyotakis, Arthur Kaser, Lior Katz, Seymour Katz, Leo Katz, Nirmal Kaur, Edita Kazenaite, Reena Khanna, Sunil Khurana, Joo Sung Kim, Young-Ho Kim, Sung Kook Kim, Dongwoo Kim, Jochen Klaus, Dariusz Kleczkowski, Pavel Kohout, Bartosz Korczowski, Georgios Kouklakis, Ioannis Koutroubakis, Richard Krause, Tunde Kristof, Ian Kronborg, Annette Krummenerl, Limas Kupcinskas, Jorge Laborda Molteni, David Laharie, Adi Lahat-Zok, Jonghun Lee, Kang-Moon Lee, Rupert Leong, Henry Levine, Jimmy Limdi, James Lindsay, Nilesh Lodhia, Edward Loftus, Randy Longman, Pilar Lopez Serrano, Edouard Louis, Maria Helena Louzada Pereira, John Lowe, Stefan Lueth, Milan Lukas, Giovanni Maconi, Finlay Macrae, Laszlo Madi-Szabo, Uma Mahadevan-Velayos, Everson Fernando Malluta, Fazia Mana, Peter Mannon, Gerasimos Mantzaris, Ignacio Marin Jimenez, Maria Dolores Martin Arranz, Radu-Bogdan Mateescu, Felipe Mazzoleni, Agnieszka Meder, Ehud Melzer, Jessica Mertens, Konstantinos Mimidis, Brent Mitchell, Tamas Molnar, Gregory Moore, Luis Alonso Morales Garza, Reme Mountifield, Vinciane Muls, Charles Murray, Bela Nagy, Markus Neurath, Augustin Nguyen, Remo Panaccione, William Pandak, Julian Panes Diaz, Jihye Park, Luca Pastorelli, Bhaktasharan Patel, Markus Peck-Radosavljevic, Gyula Pecsi, Farhad Peerani, Javier Perez Gisbert, Martin Pesta, Robert Petryka, Laurent Peyrin-Biroulet, Raymond Phillips, Marieke Pierik, Vijayalakshmi Pratha, Vlastimil Prochazka, Istvan Racz, Graham Radford-Smith, Daniel Ramos Castañeda, Odery Ramos Júnior, Jaroslaw Regula, Jean-Marie Reimund, Bryan Robbins, Xavier Roblin, Francesca Rogai, Gerhard Rogler, Jerzy Rozciecha, David Rubin, Azalia Yuriria Ruiz Flores, Maciej Rupinski, Grazyna Rydzewska, Sumona Saha, Simone Saibeni, Agnes Salamon, Zoltan Sallo, Bruce Salzberg, Douglas Samuel, Sunil Samuel, William Sandborn, Edoardo Vincenzo Savarino, Anja Schirbel, Robert Schnabel, Stefan Schreiber, John Scott, Shahriar Sedghi, Frank Seibold, Jakob Seidelin, Ursula Seidler, Ahmad Shaban, Ira Shafran, Aasim Sheikh, Alex Sherman, Haim Shirin, Patryk Smolinski, Geun Am Song, Konstantinos Soufleris, Alexander Speight, Dirk Staessen, Andreas Stallmach, Michael Staun, Daniel Stein, Hillary Steinhart, Jonathas Stifft, David Stokesberry, Andreas Sturm, Keith Sultan, Gyorgy Szekely, Kuldeep Tagore, Hugo Tanno, Lena Thin, Syed Thiwan, Carlton Thomas, Michal Tichy, Gabor Tamas Toth, Zsolt Tulassay, Jan Ulbrych, John Valentine, Marta Varga, Eduardo Vasconcellos, Byron Vaughn, Brenda Velasco, Francisco Velazquez, Severine Vermeire, Erica Villa, Aron Vincze, Harald Vogelsang, Miroslava Volfova, Lucine Vuitton, Petr Vyhnalek, Peter Wahab, Jens Walldorf, Mattitiahu Waterman, John Weber, L Michael Weiss, Anna Wiechowska-Kozlowska, Elise Wiesner, Thomas Witthoeft, Robert Wohlman, Barbara Wozniak-Stolarska, Bruce Yacyshyn, Byong-Duk Ye, Ziad Younes, Lígia Yukie Sassaki, Cyrla Zaltman, Stefan Zeuzem
1Université Centre Hospitalier Régional et Universitaire de Nancy, Vandoeuvre-lès-Nancy, France.
2St Mark's Academic Institute, London, UK.
3Imelda GI Clinical Research Centre, Imelda General Hospital, Bonheiden, Belgium.
4Division of Gastroenterology and Hepatology, School of Medicine, The University of North Carolina, Chapel Hill, NC, USA.
5Department of Gastroenterology Hôpital Saint-Louis, AP-HP, INSERM U1160, University Denis Diderot, Paris, France.
6Inselspital, Gastroenterology, Clinic for Visceral Surgery and Medicine, University Hospital of Bern, Bern, Switzerland.
7Fondazione Policlinico Universitario Agostino Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico, Università Cattolica, Dipartimento di Scienze Mediche e Chirurgiche, Policlinico Agostino Gemelli, Rome, Italy.
8Gastroenterology and Hepatology, Mayo Clinic School of Medicine, Rochester, MN, USA.
9Roche Products Limited, Welwyn Garden City, UK.
10Genentech, South San Francisco, CA, USA.
11University of California San Diego, La Jolla, CA, USA. Electronic address: firstname.lastname@example.org.
Background: Etrolizumab is a gut-targeted, anti-β7 integrin, monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab in patients with moderately to severely active ulcerative colitis who had been previously treated with anti-tumour necrosis factor (TNF) agents.
Methods: HICKORY was a multicentre, phase 3, double-blind, placebo-controlled study in adult (18-80 years) patients 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) previously treated with TNF inhibitors. Patients were recruited from 184 treatment centres across 24 countries in North America, South America, Europe, Asia, Oceania, and the Middle East. Patients needed to have 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. In cohort 1, patients received open-label etrolizumab 105 mg every 4 weeks for a 14-week induction period. In cohort 2, patients were randomly assigned (4:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks for the 14-week induction phase. Patients in either cohort achieving clinical response to etrolizumab induction were eligible for the maintenance phase, in which they were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks through to week 66. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants (induction randomisation only), baseline disease activity, week 14 MCS remission status (maintenance randomisation only), and induction cohort (maintenance randomisation only). All patients and study site personnel were masked to treatment assignment. Primary endpoints were remission (Mayo Clinic total score [MCS] ≤2, with individual subscores of ≤1 and a rectal bleeding subscore of 0) at week 14, and remission at week 66 among patients with a clinical response (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) at week 14. Efficacy was analysed using a modified intent-to-treat population. Safety analyses included all patients who received at least one dose of study drug during the induction phase. This study is registered at ClinicalTrials.gov, NCT02100696.
Findings: HICKORY was conducted from May 21, 2014, to April 16, 2020, during which time 1081 patients were screened, and 609 deemed eligible for inclusion. 130 patients were included in cohort 1. In cohort 2,479 patients were randomly assigned to the induction phase (etrolizumab n=384, placebo n=95). 232 patients were randomly assigned to the maintenance phase (etrolizumab to etrolizumab n=117, etrolizumab to placebo n=115). At week 14, 71 (18·5%) of 384 patients in the etrolizumab group and six (6·3%) of 95 patients in the placebo group achieved the primary induction endpoint of remission (p=0·0033). No significant difference between etrolizumab and placebo was observed for the primary maintenance endpoint of remission at week 66 among patients with a clinical response at week 14 (27 [24·1%] of 112 vs 23 [20·2%] of 114; p=0·50). Four patients in the etrolizumab group reported treatment-related adverse events leading to treatment discontinuation. The proportion of patients reporting at least adverse event was similar between treatment groups for induction (etrolizumab 253 [66%] of 384; placebo 63 [66%] of 95) and maintenance (etrolizumab to etrolizumab 98 [88%] of 112; etrolizumab to placebo 97 [85%] of 114). The most common adverse event in both groups was ulcerative colitis flare. Most adverse events were mild or moderate. During induction, the most common serious adverse event was ulcerative colitis flare (etrolizumab ten [3%] of 384; placebo: two [2%] of 95). During maintenance, the most common serious adverse event in the etrolizumab to etrolizumab group was appendicitis (two [2%] of 112) and the most common serious adverse events in the etrolizumab to placebo group were ulcerative colitis flare (two [2%] of 114) and anaemia (two [2%] of 114).
Interpretation: HICKORY demonstrated that a significantly higher proportion of patients with moderately to severely active ulcerative colitis who had been previously treated with anti-TNF agent were able to achieve remission at week 14 when treated with etrolizumab compared with placebo; however, there was no significant difference between groups in remission at week 66 among patients with a clinical response at week 14.
Funding: F Hoffmann-La Roche.