Browsing by Author "Mitchell, Mack C."

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    Design of a multicenter randomized clinical trial for treatment of Alcohol-Associated Hepatitis
    (Elsevier, 2023-01-18) Tu, Wanzhu; Gawrieh, Samer; Dasarathy, Srinivasan; Mitchell, Mack C.; Simonetto, Douglas A.; Patidar, Kavish R.; McClain, Craig J.; Bataller, Ramon; Szabo, Gyongyi; Tang, Qing; Barton, Bruce A.; Radaeva, Svetlana; Sanyal, Arun J.; Shah, Vijay; Alcoholic Hepatitis Network (AlcHepNet) Investigators; Biostatistics, School of Public Health
    Background: Mortality is high for severe alcohol-associated hepatitis (AH). Corticosteroids are the standard of care for patients without contraindications. Recent data showed that interleukin-1β receptor antagonist anakinra attenuated inflammation and liver damage. We designed a multicenter, double-blind, randomized controlled trial to assess the safety and efficacy of anakinra compared to prednisone. Methods: Patients meeting the clinical and biochemical criteria for severe AH with MELD scores between 20 and 35 were recruited at eight clinical sites. Eligible patients enrolled in the study were randomized to anakinra, 100 mg subcutaneous injection for 14 days, plus zinc sulfate 220 mg for 90 days, vs. prednisone 40 mg PO daily for 30 days. Matching placebos for anakinra, zinc, and prednisone were provided to mask the treatment. Participants were followed for 180 days. The primary outcome was overall survival at 90 days. An unadjusted log-rank test was used to compare the survival of the two treatments in the first 90 days. Between July 10, 2020, and March 4, 2022, we screened 1082 patients with severe AH, and 147 eligible patients were enrolled and randomized. The average baseline MELD score was 25 [range 20-35], Maddrey discriminant function (MDF) was 59.4 [range 20.2-197.5]. The mean aspartate transaminase (AST)-to-alanine transaminase (ALT) ratio was 3.5. The baseline characteristics were not statistically different between the two treatment groups. Conclusions: The study provided a direct comparison of the survival benefits and safety profiles of anakinra plus zinc vs. prednisone in patients with severe AH.
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    Parental liver disease mortality is associated with unfavorable outcomes in patients with alcohol-associated hepatitis
    (Wolters Kluwer, 2025-05-23) Tu, Wanzhu; Gawrieh, Samer; Nephew, Lauren; McClain, Craig; Tang, Qing; Dasarathy, Srinivasan; Vatsalya, Vatsalya; Simonetto, Douglas A.; Kettler, Carla; Szabo, Gyongyi; Barton, Bruce; Yu, Yunpeng; Kamath, Patrick S.; Sanyal, Arun J.; Nagy, Laura; Mitchell, Mack C.; Liangpunsakul, Suthat; Shah, Vijay H.; Chalasani, Naga; Bataller, Ramon; AlcHepNet Investigators; Medicine, School of Medicine
    Background: How parental alcohol use disorder and liver disease-related mortality influence the risk and the outcomes of alcohol-associated hepatitis (AH) in the offspring is unknown. Methods: We analyzed data from 2 prospective observational studies of AH cases and heavy drinking controls (HDCs). Family history of parental alcohol use disorder and liver disease mortality was assessed at the study entry. Logistic regression and Cox proportional hazard models were used to assess the influences of family history on AH development and outcome. Results: Data from 1356 participants in two prospective cohorts (926 AH cases and 430 HDC) were combined and analyzed. Parental alcohol use disorder was found in 56.9% of AH cases and 61.1% of HDC; parental death due to liver disease was reported in 7.5% of AH cases and 5.7% of HDC. Multivariable logistic regression showed that parental liver disease-related mortality was associated with more than a doubled risk of AH development in the offspring after controlling for their demographic characteristics and drinking behavior (OR=2.26, 95% CI: [1.22, 4.20]). Moreover, among the AH cases, having a parent die of liver disease significantly increased the 90-day mortality of study participants after adjusting for the effects of other risk factors (HR=2.26, 95% CI: [1.05, 4.86]). Conclusions: The study highlights the influences of parental death due to liver disease on AH development and mortality. Identifying patients at risk of AH through family history might help facilitate discussions on reducing alcohol consumption.
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    Standard Definitions and Common Data Elements for Clinical Trials in Patients With Alcoholic Hepatitis: Recommendation From the NIAAA Alcoholic Hepatitis Consortia
    (Elsevier, 2016-04) Crabb, David W.; Bataller, Naga; Chalasani, Naga P.; Kamath, Patrick S.; Lucey, Michael; Mathurin, Philippe; McClain, Craig; McCullough, Arthur; Mitchell, Mack C.; Morgan, Timothy R.; Department of Medicine, IU School of Medicine
    Heavy drinkers are at risk for a spectrum of histologic alcohol-related liver injury: steatosis, alcoholic steatohepatitis (ASH), alcohol-related fibrosis, and cirrhosis. Alcoholic hepatitis (AH), the clinical entity associated with severe ASH, has high short-term mortality. The standard-of-care therapy, prednisolone, has limited efficacy and many side effects; no other treatment has consistently shown survival benefit. The National Institute on Alcohol Abuse and Alcoholism (NIAAA)-funded Alcoholic Hepatitis Consortia carry out translational research on pathophysiologic mechanisms, genetic and environmental risk factors, phase II clinical trials, and development of biomarkers. The consortia members were convened by the National Institutes of Health to address diagnostic criteria and practical issues related to clinical AH research, and to develop a set of common data elements to harmonize ongoing and future trials. This was accomplished through 3 face-to-face meetings of the investigators and representatives of the National Institutes of Health, and subsequent electronic communications over the course of 6 months. Evidence for the recommendations was based on published trials and observational data from several of the consortia members. A draft manuscript was iteratively reviewed by members of the consortia. The goal was to reach agreements on recommendations and definitions that could facilitate trial design, and simultaneously be tested by research groups pooling their data. The recommendations made here are specifically directed to achieve better uniformity in clinical trials, rather than serving as clinical practice guidelines.