Nikhil Vergis, Vishal Patel, Karolina Bogdanowicz, Justyna Czyzewska-Khan, Rosemary Keshinro, Francesca Fiorentino, Emily Day, Paul Middleton, Stephen Atkinson, Thomas Tranah, Mary Cross, Daphne Babalis, Neil Foster, Emma Lord, Alberto Quaglia, Josephine Lloyd, Robert Goldin, William Rosenberg, Richard Parker, Paul Richardson, Steven Masson, Gavin Whitehouse, Cyril Sieberhagan, David Patch, Nikolai Naoumov, Ashwin Dhanda, Ewan Forrest, Mark Thursz
{"title":"IL-1 Signal Inhibition in Alcohol-Related Hepatitis: a randomised, double-blind, placebo-controlled trial of canakinumab.","authors":"Nikhil Vergis, Vishal Patel, Karolina Bogdanowicz, Justyna Czyzewska-Khan, Rosemary Keshinro, Francesca Fiorentino, Emily Day, Paul Middleton, Stephen Atkinson, Thomas Tranah, Mary Cross, Daphne Babalis, Neil Foster, Emma Lord, Alberto Quaglia, Josephine Lloyd, Robert Goldin, William Rosenberg, Richard Parker, Paul Richardson, Steven Masson, Gavin Whitehouse, Cyril Sieberhagan, David Patch, Nikolai Naoumov, Ashwin Dhanda, Ewan Forrest, Mark Thursz","doi":"10.1016/j.cgh.2024.07.025","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and aim: </strong>Short-term mortality in alcohol-related hepatitis (AH) is high and no current therapy results in durable benefit. A role for IL-1ß has been demonstrated in the pathogenesis of alcohol-induced steatohepatitis. This study explored the safety and efficacy of canakinumab (CAN), a monoclonal antibody targeting IL-1ß, in the treatment of patients with AH.</p><p><strong>Methods: </strong>Participants with biopsy-confirmed AH and discriminant function ≥32 but MELD ≤27 were randomly allocated 1:1 to receive either CAN 3mg/kg or placebo (PBO). Liver biopsies were taken before, and 28 days after treatment. The primary endpoint was the overall histological improvement in inflammation analysed by modified Intention-To-Treat (mITT).</p><p><strong>Results: </strong>Fifty-seven participants were randomised: 29 to CAN and 28 to PBO. Two participants had histology that did not corroborate the clinical diagnosis. Of the remaining 55 participants, paired histology data was evaluable from 48 participants. In CAN-treated participants, 14/24 (58%) demonstrated histological improvement compared to 10/24 (42%) in the PBO group (p=0.25). There was no improvement in prognostic scores of liver function. Four of the 55 participants (7%) died within 90 days; 2 in each group. The number of serious adverse events was similar between CAN vs PBO. In post-hoc exploratory analyses after adjustment for baseline prognostic factors, CAN therapy was associated with overall histological improvement (p=0.04).</p><p><strong>Conclusion: </strong>CAN therapy in severe AH participants with MELD≤27 did not alter biochemical or clinical outcomes compared to PBO. Non-significant histological improvements did not translate into clinical benefit.</p>","PeriodicalId":10347,"journal":{"name":"Clinical Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":11.6000,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Gastroenterology and Hepatology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.cgh.2024.07.025","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background and aim: Short-term mortality in alcohol-related hepatitis (AH) is high and no current therapy results in durable benefit. A role for IL-1ß has been demonstrated in the pathogenesis of alcohol-induced steatohepatitis. This study explored the safety and efficacy of canakinumab (CAN), a monoclonal antibody targeting IL-1ß, in the treatment of patients with AH.
Methods: Participants with biopsy-confirmed AH and discriminant function ≥32 but MELD ≤27 were randomly allocated 1:1 to receive either CAN 3mg/kg or placebo (PBO). Liver biopsies were taken before, and 28 days after treatment. The primary endpoint was the overall histological improvement in inflammation analysed by modified Intention-To-Treat (mITT).
Results: Fifty-seven participants were randomised: 29 to CAN and 28 to PBO. Two participants had histology that did not corroborate the clinical diagnosis. Of the remaining 55 participants, paired histology data was evaluable from 48 participants. In CAN-treated participants, 14/24 (58%) demonstrated histological improvement compared to 10/24 (42%) in the PBO group (p=0.25). There was no improvement in prognostic scores of liver function. Four of the 55 participants (7%) died within 90 days; 2 in each group. The number of serious adverse events was similar between CAN vs PBO. In post-hoc exploratory analyses after adjustment for baseline prognostic factors, CAN therapy was associated with overall histological improvement (p=0.04).
Conclusion: CAN therapy in severe AH participants with MELD≤27 did not alter biochemical or clinical outcomes compared to PBO. Non-significant histological improvements did not translate into clinical benefit.
期刊介绍:
Clinical Gastroenterology and Hepatology (CGH) is dedicated to offering readers a comprehensive exploration of themes in clinical gastroenterology and hepatology. Encompassing diagnostic, endoscopic, interventional, and therapeutic advances, the journal covers areas such as cancer, inflammatory diseases, functional gastrointestinal disorders, nutrition, absorption, and secretion.
As a peer-reviewed publication, CGH features original articles and scholarly reviews, ensuring immediate relevance to the practice of gastroenterology and hepatology. Beyond peer-reviewed content, the journal includes invited key reviews and articles on endoscopy/practice-based technology, health-care policy, and practice management. Multimedia elements, including images, video abstracts, and podcasts, enhance the reader's experience. CGH remains actively engaged with its audience through updates and commentary shared via platforms such as Facebook and Twitter.