Institution: University of Massachusetts Medical School PI: Gyongyi Szabo ABSTRACT of the original application: 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 GCSF 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. Blinding-related changes to the clinical protocol: In response to the review of the original application that pointed out the value of double-blinding, we have amended the protocol to double-blind all 3 arms of the study. The DASH clinical trial was double-blinded using ?placebo? syringes containing saline identical to those containing anakinra and double-blinded capsules containing oral medications. Similar double-blinding will be done for GCSF. For the first 5 days of the study, each subject will receive twice daily S.Q. injections of either GCSF BID; anakinra QD and saline QD (anakinra/Zn group) or saline BID (prednisone group). After the first 5 days, the injections will be given once daily for an additional 9 days, either anakinra or saline (GCSF group and prednisone group). In the revised protocol, each subject will receive a daily injection of anakinra/placebo for 2 weeks; daily oral medications (methyl-prednisolone or zinc) for 30 days followed by daily zinc or placebo for an additional 60 days and an injection of GCSF or saline on day 1 and day 5. We estimate that each kit will cost ~$500 in addition to the originally submitted budget to prepare based on our experience in the DASH trial. There will also be additional costs to the IDS pharmacy (part of the DCC) for distribution of the kits. Conducting the trial in a double-blind fashion will require monitoring changes in the size of the spleen for all subjects, not just those on the GCSF arm of the trial. This requirement is based on guidance from FDA for the ongoing trial of GCSF in AH.
The Alcoholic Hepatitis Network project, AlcHepNet, comprised of nine leading partner institutions in the field, will examine new and promising treatments for severe liver damage caused by alcohol. Further, the network will collect and organize patient information, associated data, and samples that can help shed greater light on this disease. Combined, these two approaches will improve treatment and how we care for patients with this devastating liver condition. !
