IL‐1 Receptor Antagonist in Combination with Pentoxifylline and Zinc for Severe Alcoholic Hepatitis: A Multicenter Randomized Double‐Bind Placebo‐Controlled Clinical Trial

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 45.310.4 years, 63% were males, 96% white, mean MELD 25.73.0 (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.