IL‐1 Receptor Antagonist in Combination with Pentoxifylline and Zinc for Severe Alcoholic Hepatitis: A Multicenter Randomized Double‐Bind Placebo‐Controlled Clinical Trial
Authors: Gyongyi Szabo, Mack Mitchell, Craig Mcclain, Srinivasan Dasarathy, Arthur Mccullough, Laura Nagy, Aimee Kroll-Desrosiers, Svetlana Radaeva, Bruce Barton, Aimee Kroll, Masatoshi Kudo, Ana Matilla, Armando Santoro, Ignacio Melero, Antonio Gracian, Mirelis Rivera Acosta, Su Choo, Anthony El-Khoueiry, Ryoko Kuromatsu, Bassel Rayes, Kazushi Numata, Yoshito Itoh, Francesco Di Costanzo, Oxana Crysler, Maria Reig, Yun Shen, Jaclyn Neely, Christine Cruz, Carlos Baccan, Bruno Sangro, H Gregorio Marañón, Michael Galambos, Aparna Goel, Andreas Kremer, Yvonne Dörffel, Paul Thuluvath, David Sheridan, Carmen Stanca, Christoph Berg, Lynsey Corless, Marcus-Alexander Woerns, Norman Gitlin, Monika Varga, David Jones, Joseph Odin, Charles Landis, Hemant Shah, Gianni Amato, Scott Rosenbusch, Rohit Loomba, Joel Neutel, David Bernard, Randall Severance, Rizwana Mohseni, Michael Dao, Satinder Saini, Carmen Margaritescu, Ken Homer, Brian Tran, Marianne Mancini, Hiroko Masamune, Brian Lian, Rohit Loomba -Gilead, David Bernard -Chear
Journal: Hepatology (2018)

Background: Severe alcoholic hepatitis (AH) with MELD > 20 and MDF > 32 is a serious condition with high short-term mortality.This study evaluated the safety and efficacy of the combination of recombinant human interleukin-1 receptor antagonist (anakinra), pentoxifylline (PTX) and zinc (Zn) sulfate in patients with AH.We aimed to target critical pathogenic elements of AH: inflammation (anakinra), protection from cellular injury (PTX) and gut leakiness (Zn).Methods: Subjects with clinical diagnosis of severe AH (MELD>20, MDF>32) were randomized to methyl prednisolone (32 mg orally daily for 28 days (PRED) or a combination of anakinra, 100 mg daily subcutaneously for 14 days plus PTX 400 mg orally 3 times daily for 28 days plus Zn 220 mg orally daily for 180 days (IL-1RA).Endpoints included mortality at 30, 90 and 180 days.A Cox proportional regression analysis was used to identify variables associated with mortality.Results: A total of 103 patients were enrolled over 4 years at 4 sites.Fifty-three patients were randomized into the IL-1RA and 50 to the PRED arms.At baseline, the mean age was 45.3±10.4years, 63% were males, 96% white, mean MELD 25.7±3.0(range 20-40).Baseline characteristics were comparable between treatment groups.Survival probability (Kaplan-Meier estimates) at 180day post randomization, the primary outcome, was 66.8% in the IL-1RA and 52.8% in the PRED group (HR=0.69;p=0.26).Survival at 30 days was similar between the IL-1RA (83.4%) and PRED groups (81.2%) (HR=0.91,p=0.85).Separation of the survival curves was noted by 90 days (IL-1RA: 69.7%; PRED: 55.8%; HR=0.69, p=0.28).Five subjects were lost to follow-up (IL-1RA:3; PRED:2).In Cox regression analysis, higher baseline MELD score was independently associated with mortality (p=0.003).No unexpected treatment-related severe adverse events were noted in either group.The incidence of infection was comparable in both groups.Survival at 180 days in subjects with initial MELD 20-25 (72.6%) was significantly higher than those with initial MELD 26-31 (45.2%) (HR=2.9,p=0.003).Both MELD strata showed non-significant treatment effects in favor of IL-1RA.Conclusion: A combination of anakinra, PTX and Zn provides comparable short-term and may provide long-term survival benefits compared to currently used PRED therapy in severe AH.Initial MELD is an important predictor of survival at 30, 90 and 180 days.