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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., Competing Interests: Declaration of interests LP-B reports personal fees from AbbVie, Allergan, Alma, Amgen, Applied Molecular Transport, Arena, Biogen, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Enterome, Enthera, Ferring, Fresenius, Gilead, Hikma, InDex Pharmaceuticals, Janssen, Lilly, Merck Sharp & Dohme, Mylan, Nestle, Norgine, Oppilan, OSE Immunotherapeutics, Pfizer, Pharmacosmos, Roche/Genentech, Samsung Bioepis, Sandoz, Sterna, Tillotts, Sublimity, Takeda, and Vifor; consultation fees from Clinical Trials Mobile Application; and grants from AbbVie, Merck Sharp & Dohme, and Takeda outside the submitted work. AH reports personal fees from AbbVie, Arena, Celgene, Celltrion, Falk, Ferring, Janssen, Napp Pharmaceuticals, Pfizer, Pharmacosmos, Roche/Genentech, and Takeda, outside the submitted work. PB reports personal fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Hospira, Janssen, Merck Sharp & Dohme, Mundipharma, Pentax, Pfizer, PSI-CRO, Roche/Genentech, Sandoz, and Takeda; and grants from AbbVie, Amgen, Janssen, Mundipharma, Mylan, Pfizer, and Takeda, outside the submitted work. ML reports personal fees from AbbVie, Bristol Myers Squibb, Gilead, Lilly, Janssen, Pfizer, Prometheus, Roche/Genentech, Salix, Takeda, Target PharmaSolutions, UCB, Valeant; and grants from Pfizer and Takeda, outside the submitted work. MA reports personal fees as a speaker from Ferring, Janssen, Pfizer, Roche/Genentech, Takeda, and Tillotts; personal fees for advisory boards from Amgen, Bristol Meyers Squibb, Celltrion, Janssen, Novartis, Roche/Genentech, and Pfizer; and grants from Janssen and Roche/Genentech. PJ has no conflicts to disclose. AA reports personal fees from AbbVie, Allergan, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, Merck Sharp & Dohme, Mylan, Novartis, Pfizer, Roche/Genentech, Samsung Bioepis, Sandoz, and Takeda; and grants from Biogen, Merck Sharp & Dohme, Pfizer, and Takeda, outside the submitted work. EVLJr reports personal fees from AbbVie, Allergan, Amgen, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Calibr, Celgene, Celltrion Healthcare, Eli Lilly, Gilead, Iterative Scopes, Janssen, Ono Pharma, Pfizer, Roche/Genentech, Sun Pharmaceutical, Takeda, and UCB; grants from AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Gilead, Janssen, Pfizer, Robarts Clinical Trials, Roche/Genentech, Takeda, and UCB, outside the submitted work; he is the Chief Medical Editor of Healio Gastroenterology and Liver Disease (SLACK). EO-S, AS, AC, JP, and SL are employees of Roche/Genentech and receive Roche stock as a part of their compensation. ST and YSO were employees of Roche/Genentech at the time of this work and received salary and stock options during the time of this study. WJS reports personal fees from AbbVie, Abivax, AdMIRx, Alfasigma, Alimentiv, Alivio Therapeutics, Allakos, Allergan, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Avexegen Therapeutics, Bausch Health (Salix) Beigene, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Meyer Squibb, Celgene, Celltrion, Cellularity, Conatus Pharmaceuticals, Cosmo Pharmaceuticals, Escalier Biosciences, Ferring, Forbion, Equillium, Gilead Sciences, GlaxoSmithKline, Glenmark Pharmaceuticals, Gossamer Bio, Immunic (Vital Therapies), Incyte, InDex Pharmaceuticals, Intact Therapeutics, Janssen, Kyowa Kirin Pharmaceutical Research, Kyverna Therapeutics, Landos Biopharma, Lilly, Miraca Life Sciences, Nivalis Therapeutics, Novartis, Nutrition Science Partners, Oppilan Pharma, Otsuka, Pandion Therapeutics, Paul Hastings, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Provention Bio, Reistone Biopharma, Ritter Pharmaceuticals, Roche/Genentech, Seres Therapeutics, Shanghai Pharma Biotherapeutics, Shoreline Biosciences, Sienna Biopharmaceuticals, Sigmoid Biotechnologies, Sterna Biologicals, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Thetis Pharmaceuticals, TiGenix, Tillotts Pharma, UCB Pharma, Vendata Biosciences, Vivelix Pharmaceuticals, Vivreon Biosciences, Zealand Pharma; grants from AbbVie, Abivax, Alimentiv, Allakos, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene, Gilead Sciences, GlaxoSmithKline, Janssen, Lilly, Pfizer, Prometheus Biosciences, Roche/Genentech, Seres Therapeutics, Shire, Surrozen, Takeda, Theravance Biopharma; consultation fees from Allakos, Beigene, Gossamer Bio, Oppilan Pharma, Progenity, Prometheus Biosciences, Roche/Genentech, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivreon Biosciences, outside the submitted work; has served as a consultant for Iveric Bio and Oppilan Pharma; is an employee of Prometheus Biosciences and receives stocks/stock options from Iveric Bio, Oppilan Pharma, Progenity, Prometheus Biosciences, Ventyx Biosciences, and Vimalan Biosciences., (Copyright © 2022 Elsevier Ltd. 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