TY - JOUR
T1 - Etrolizumab as induction and maintenance therapy for ulcerative colitis in patients previously treated with tumour necrosis factor inhibitors (HICKORY)
T2 - A phase 3, randomised, controlled trial
AU - Peyrin-Biroulet, Laurent
AU - Hart, Ailsa
AU - Bossuyt, Peter
AU - Long, Millie
AU - Allez, Matthieu
AU - Juillerat, Pascal
AU - Armuzzi, Alessandro
AU - Loftus Jr, Edward V
AU - Ostad-Saffari, Elham
AU - Scalori, Astrid
AU - Oh, Young S.
AU - Tole, Swati
AU - Chai, Akiko
AU - Pulley, Jennifer
AU - Lacey, Stuart
AU - Sandborn, William J.
AU - HICKORY Study Group
AU - Aguilar, Humberto
AU - Ahmad, Tariq
AU - Akriviadis, Evangelos
AU - Aldeguer Mante, Xavier
AU - Altorjay, Istvan
AU - Ananthakrishnan, Ashwin
AU - Andersen, Vibeke
AU - Andreu Garcia, Montserrat
AU - Aumais, Guy
AU - Avni-Biron, Irit
AU - Axler, Jeffrey
AU - Kamran Ayub, Kamran
AU - Baert, Filip
AU - Bafutto, Mauro
AU - Bamias, George
AU - Bassan, Isaac
AU - Baum, Curtis
AU - Beaugerie, Laurent
AU - Behm, Brian
AU - Bekal, Pradeep
AU - Bennett, Michael
AU - Bermejo San Jose, Fernando
AU - Bernstein, Charles
AU - Bettenworth, Dominik
AU - Bhaskar, Sudhir
AU - Biancone, Livia
AU - Bilir, Bahri
AU - Blaeker, Michael
AU - Bloom, Stuart
AU - Bohman, Verle
AU - Bosques Padilla, Francisco Javier
AU - Bouhnik, Yoram
AU - Bouma, Gerd
AU - Bourdages, Raymond
AU - Brand, Stephan
AU - Bressler, Brian
AU - Brückner, Markus
AU - Buening, Carsten
AU - Carbonnel, Franck
AU - Caves, Thomas
AU - Chapman, Jonathon
AU - Cheon, Jae Hee
AU - Chiba, Naoki
AU - Chioncel, Camelia
AU - Christodoulou, Dimitrios
AU - Clodi, Martin
AU - Cohen, Albert
AU - Corazza, Gino Roberto
AU - Corlin, Richard
AU - Cosintino, Rocco
AU - Cummings, Fraser
AU - Dalal, Robin
AU - Danese, Silvio
AU - De Maeyer, Marc
AU - Fernando De Magalhães Francesconi, Carlos
AU - De Silva, Aminda
AU - Debinski, Henry
AU - Desreumaux, Pierre
AU - Dewit, Olivier
AU - D'Haens, Geert
AU - Di Felice Boratto, Sandra
AU - Ding, John Nik
AU - Dixon, Tyler
AU - Dryden, Gerald
AU - Du Vall, George Aaron
AU - Ebert, Matthias
AU - Echarri Piudo, Ana
AU - Ehehalt, Robert
AU - Elkhashab, Magdy
AU - Ennis, Craig
AU - Etzel, Jason
AU - Fallingborg, Jan
AU - Feagan, Brian
AU - Fejes, Roland
AU - Ferraz de Campos Mazo, Daniel
AU - Ferreira de Almeida Borges, Valéria
AU - Fischer, Andreas
AU - Fixelle, Alan
AU - Fleisher, Mark
AU - Fowler, Sharyle
AU - Freilich, Bradley
AU - Friedenberg, Keith
AU - Fries, Walter
AU - Fulop, Csaba
AU - Fumery, Mathurin
AU - Fuster, Sergio
AU - Kiss, Gyula G.
AU - Garcia Lopez, Santiago
AU - Gassner, Sonja
AU - Gill, Kanwar
AU - Gilletta de Saint Joseph, Cyrielle
AU - Ginsburg, Philip
AU - Gionchetti, Paolo
AU - Goldin, Eran
AU - Goldis, Adrian-Eugen
AU - Gomez Jaramillo, Hector Alejandro
AU - Gonciarz, Maciej
AU - Gordon, Glenn
AU - Green, Daniel
AU - Grimaud, Jean-Charles
AU - Guajardo Rodriguez, Rogelio
AU - Gurzo, Zoltan
AU - Gutierrez, Alexandra
AU - Gyökeres, Tibor
AU - Hahm, Ki Baik
AU - Hanauer, Stephen
AU - Hanson, John
AU - Harlan, William
AU - Hasselblatt, Peter
AU - Hayee, Buhussain
AU - Hebuterne, Xavier
AU - Hendy, Peter
AU - Heyman, Melvin
AU - Higgins, Peter
AU - Hilal, Raouf
AU - Hindryckx, Pieter
AU - Hoentjen, Frank
AU - Hoffmann, Peter
AU - Holtkamp-Endemann, Frank
AU - Holtmann, Gerald
AU - Horvat, Gyula
AU - Howaldt, Stefanie
AU - Huber, Samuel
AU - Ibegbu, Ikechukwu
AU - Iborra Colomino, Maria Isabel
AU - Irving, Peter
AU - Isaacs, Kim
AU - Jagarlamudi, Kiran
AU - Jain, Rajesh
AU - Jankiel Miszputen, Sender
AU - Jansen, Jeroen
AU - Jones, Jennifer
AU - Karagiannis, John
AU - Karyotakis, Nicholas
AU - Kaser, Arthur
AU - Katz, Lior
AU - Katz, Seymour
AU - Katz, Leo
AU - Kaur, Nirmal
AU - Kazenaite, Edita
AU - Khanna, Reena
AU - Khurana, Sunil
AU - Kim, Joo Sung
AU - Kim, Young-Ho
AU - Kim, Sung Kook
AU - Kim, Sung Kook
AU - Klaus, Jochen
AU - Kleczkowski, Dariusz
AU - Kohout, Pavel
AU - Korczowski, Bartosz
AU - Kouklakis, Georgios
AU - Koutroubakis, Ioannis
AU - Krause, Richard
AU - Kristof, Tunde
AU - Kronborg, Ian
AU - Krummenerl, Annette
AU - Kupcinskas, Limas
AU - Laborda Molteni, Jorge
AU - Laharie, David
AU - Lahat-zok, Adi
AU - Lee, Jonghun
AU - Lee, Kang-Moon
AU - Leong, Rupert
AU - Levine, Henry
AU - Limdi, Jimmy
AU - Lindsay, James
AU - Lodhia, Nilesh
AU - Longman, Randy
AU - Lopez Serrano, Pilar
AU - Louis, Edouard
AU - Louzada Pereira, Maria Helena
AU - Lowe, John
AU - Lueth, Stefan
AU - Lukas, Milan
AU - Maconi, Giovanni
AU - Macrae, Finlay
AU - Madi-Szabo, Laszlo
AU - Mahadevan-Velayos, Uma
AU - Malluta, Everson Fernando
AU - Mana, Fazia
AU - Mannon, Peter
AU - Mantzaris, Gerasimos
AU - Marin Jimenez, Ignacio
AU - Martin Arranz, Maria Dolores
AU - Mateescu, Radu-Bogdan
AU - Mazzoleni, Felipe
AU - Meder, Agnieszka
AU - Melzer, Ehud
AU - Mertens, Jessica
AU - Mimidis, Konstantinos
AU - Mitchell, Brent
AU - Molnar, Tamas
AU - Moore, Gregory
AU - Morales Garza, Luis Alonso
AU - Mountifield, Reme
AU - Muls, Vinciane
AU - Murray, Charles
AU - Nagy, Bela
AU - Neurath, Markus
AU - Nguyen, Augustin
AU - Panaccione, Remo
AU - Pandak, William
AU - Panes Diaz, Julian
AU - Park, Jihye
AU - Pastorelli, Luca
AU - Patel, Bhaktasharan
AU - Peck-Radosavljevic, Markus
AU - Pecsi, Gyula
AU - Peerani, Farhad
AU - Perez Gisbert, Javier
AU - Pesta, Martin
AU - Petryka, Robert
AU - Peyrin-Biroulet, Laurent
AU - Phillips, Raymond
AU - Pierik, Marieke
AU - Pratha, Vijayalakshmi
AU - Prochazka, Vlastimil
AU - Racz, Istvan
AU - Radford-Smith, Graham
AU - Ramos Castañeda, Daniel
AU - Ramos Júnior, Odery
AU - Regula, Jaroslaw
AU - Reimund, Reimund
AU - Robbins, Bryan
AU - Roblin, Xavier
AU - Rogai, Francesca
AU - Rogler, Gerhard
AU - Rozciecha, Jerzy
AU - Rubin, David
AU - Ruiz Flores, Azalia Yuriria
AU - Rupinski, Maciej
AU - Rydzewska, Grazyna
AU - Saha, Sumona
AU - Saibeni, Simone
PY - 2022/2
Y1 - 2022/2
N2 - 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.
AB - 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.
KW - Etrolizumab
KW - ulcerative colitis
KW - inhibitors
KW - HICKORY
KW - Placebo-controlled trials
UR - http://www.scopus.com/inward/record.url?scp=85120731946&partnerID=8YFLogxK
U2 - 10.1016/S2468-1253(21)00298-3
DO - 10.1016/S2468-1253(21)00298-3
M3 - Article
C2 - 34798039
AN - SCOPUS:85120731946
SN - 2468-1253
VL - 7
SP - 128
EP - 140
JO - The Lancet Gastroenterology and Hepatology
JF - The Lancet Gastroenterology and Hepatology
IS - 2
ER -