Etrolizumab for maintenance therapy in patients with moderately to severely active ulcerative colitis (LAUREL): a randomised, placebo-controlled, double-blind, phase 3 study
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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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | The Lancet Gastroenterology and Hepatology |
| Vol/bind | 7 |
| Udgave nummer | 1 |
| Sider (fra-til) | 28-37 |
| Antal sider | 10 |
| ISSN | 2468-1253 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
This study was funded by F Hoffmann-La Roche. Third-party medical writing assistance was provided by Stacie Dilks (ApotheCom, San Diego, CA, USA), and was funded by F Hoffmann-La Roche. We thank the patients and study staff who participated in this study. We also thank Gaohong She and Gizette Sperinde (Genentech, South San Francisco, CA, USA) for their valuable contribution to pharmacokinetic and immunogenicity analyses and language.
Funding Information:
SV reports grants from AbbVie, Johnson & Johnson, Pfizer, and Takeda; and consulting or speaking fees from AbbVie, Arena Pharmaceuticals, Avaxia, Boehringer Ingelheim, Celgene, Dr Falk Pharma, Ferring, Galapagos, Gilead, Hospira, Janssen, Mundipharma, Merck Sharp & Dohme (MSD), Pfizer, ProDigest, Progenity, Prometheus, Robarts Clinical Trials, Roche/Genentech, Second Genome, Shire, Takeda, Theravance, and Tillotts Pharma. PLL reports personal fees from AbbVie, Amgen, Arena Pharmaceuticals, Fresenius Kabi, Gilead, Janssen, Merck, Mylan, Pfizer, Roche Genentech, Takeda, Tillotts, and Viatris; and grants from AbbVie and Pfizer. TR reports personal fees from AbbVie, Arena, Bristol Myers Squibb (BMS), Ferring, Gilead, Gossamer Bio, Intercept Pharmaceuticals, Janssen, Lilly, Pfizer, Prometheus, Rebiotix, and Takeda, outside the submitted work; and personal and consultation fees from Roche/Genentech, during the conduct of the study. SH has served as a consultant for AbbVie, Allergan, Amgen, Arena, Boehringer Ingelheim, BMS, Celgene, Celltrion, Gilead, GlaxoSmithKline (GSK), Janssen, Lilly, Merck, Nestle, Novartis, Pfizer, Progenity, Prometheus, Receptos, Roche/Genentech, Salix, Samsung Bioepis, Seres Therapeutics, Takeda, TiGenex, UCB Pharma, and VHsquared; performs clinical research for AbbVie, Allergan, Amgen, Celgene, GSK, Janssen, Lilly, Novartis, Pfizer, Prometheus, Receptos, Roche/Genentech, Takeda, UCB Pharma, and VHsquared; and has served as a speaker for AbbVie, Janssen, Pfizer, and Takeda. BB reports personal fees from AbbVie, Alimentiv, Allergan, Amgen, AMT, BMS, Celgene, Ferring, Fresenius Kabi, Gilead, Iterative Scopes, Janssen, Merck, Microbiome Insights, Mylan, Novartis, Pendopharm, Pfizer, Protagonist, Roche/Genentech, and Takeda; grants from AbbVie, Alvine, Amgen, Boehringer Ingelheim, BMS, Celgene, GSK, Janssen, Merck, Qu Biologics, and Roche/Genentech; and stock options from Qu Biologics. RK reports personal fees from AbbVie, Alimentiv (formerly Robarts Clinical Trials), Amgen, Encycle Therapeutics, Innomar, Gilead, Janssen, Lilly, Merck, Pendopharm, Pfizer, Roche/Genentech, Shire, and Takeda, outside of the submitted work. KI reports personal fees from Janssen Research; grants from Target IBD, Eli Lilly, and Takeda, outside of the submitted work; and grants from Roche/Genentech, during the conduct of the study. HT, AC, JP, CE, and WZ are employees of Roche/Genentech and receive Roche stocks as a part of their compensation. AK, YSO, and ST were employees of Roche/Genentech at the time of this work, and received salary and stock options during the time of this study. BGF reports personal fees from AbbVie, AgomAB Therapeutics, Allakos, Allergan, Amgen, Applied Molecular Transport, Aptevo, AstraZeneca MedImmune, Atlantic Pharma, BiomX Israel, Boehringer Ingelheim, BMS, Calypso Biotech, Celgene, Celltech, Connect BioPharma, Disc Medicine, Everest Clinical Research Corp, Galapagos, Galen Atlantica, Gilead, GSK, Gossamer Pharma, InDex Pharmaceuticals, Janssen, Kyowa Hakko Kirin, Leadiant, Lilly, Lument, Merck, Millennium, Mylan, Nestle, NextBiotix, Novartis, Origo Biopharma, Pandion Therapeutics, Par'limmune, Parvus Therapeutics, Pfizer, Prometheus, Protagonist, Qu Biologics, Receptos Celgene, Rebiotix, Roche/Genentech, Salix Pharmaceuticals, Sandoz, Sanofi, Surrozen, Takeda, Tillotts, UCB Pharma, VHsquared, Viatris, Ysios, and Zealand Pharma; grants from AbbVie, Amgen, AstraZeneca MedImmune, Atlantic Pharma, Boehringer Ingelheim, Celgene, Celltech, Gilead, GSK, Janssen, Pfizer, Roche/Genentech, Takeda, and Tillotts, outside of the submitted work; and is the Senior Scientific Director at Alimentiv (formerly Robarts Clinical Trials). SS declares no competing interests.
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© 2022 Elsevier Ltd
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