Project Details
Description
PROJECT SUMMARY/ABSTRACT
Alcoholic hepatitis (AH) is a leading cause of liver-related morbidity and mortality with a remarkable paucity of
effective therapeutics. This application represents a coordinated submission of several NIAAA-funded
consortia that have come together as the Alcoholic Hepatitis Network (AlcHepNet). Collectively, the network
will synergize efforts and expertise to better understand AH and develop novel effective and safe therapies for
severe AH. Buttressing that goal, the overarching aims of this new consortium are to: 1) perform studies to
better understand the pathogenesis and main determinants of outcomes, particularly in severe AH; 2) identify
novel targets for therapy of AH, and 3) perform phase 2B studies of compounds that are already FDA
approved and available and can be repurposed as safe and effective therapies for severe AH. Under the
umbrella of these larger aims, the aims of this AlcHepNet proposal are to: Aim 1. Conduct a prospective,
multicenter, observational study of patients with AH and suitable controls that serves as the
foundation for conducting novel mechanistic and therapeutic studies. We will consolidate and extend our
longitudinal database containing 1) clinical and laboratory information and 2) bio-sample repository from
subjects with AH of varying severity and matched controls. This database will serve three functions: (a) provide
unique information on the outcomes and pathobiology of AH, (b) support translational research designed to
identify novel targets for treatment, and (c) serve as a catalyst to develop systems biology-based, informatics-
integrated databases that will serve as a resource for all researchers interested in AH; Aim 2. Perform a
multicenter, prospective, randomized phase 2B clinical trial of granulocyte colony stimulating factor G-
CSF versus Anakinra (plus zinc) versus standard medical therapy with Prednisone in patients with
severe AH. This aim will test the hypothesis that both active treatment arms with G-CSF and the IL-1 receptor
antagonist Anakinra (plus zinc) are superior to the standard of care (i.e. Prednisone) in patients with severe
AH. The choice of these agents is based on: 1) literature demonstrating a role for inflammation and
inflammasome activation in severe AH, 2) several pilot studies demonstrating therapeutic benefit with G-CSF,
and 3) interim analysis of an ongoing trial suggesting a mortality benefit with Anakinra in patients with AH. This
phase 2B efficacy trial will be conducted across nine clinical centers and coordinated by two Data Coordinating
Centers (DCCs). The primary endpoint will be mortality at Day 90. The investigators and the AlcHepNet are
uniquely positioned to perform the proposed study given the substantial breadth, depth, and history of
expertise related to AH, clinical trial conduct, and related therapeutic development. By testing promising
therapies for AH and collecting well-annotated patient samples and datasets, this proposal will have a strong
and lasting impact on the field.
Status | Finished |
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Effective start/end date | 8/1/18 → 6/30/23 |
Funding
- National Institute on Alcohol Abuse and Alcoholism: $380,152.00
- National Institute on Alcohol Abuse and Alcoholism: $380,152.00
- National Institute on Alcohol Abuse and Alcoholism: $380,152.00
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