Nonalcoholic fatty liver disease (NAFLD) is a growing cause of end-stage liver disease. Despite many advances, there remains an unmet need to better understand the variable clinical course of affected subjects, the factors driving such variability and develop effective treatment to prevent cirrhosis due to nonalcoholic steatohepatitis (NASH). The NIDDK NASH Clinical Research Network (CRN) has performed four clinical trials, numerous ancillary studies and enrolled 3000+ subjects in to a prospective cohort database-2 study with protocol-mandated follow up, bio-sample collection and adjudicated outcomes assessment; this cohort has been followed up to 10+ years and outcomes are beginning to be seen. In this competitive renewal application from the VCU adult clinical center and the Emory University pediatric center, we will build on the gains from the current cycle by performing studies with the following aims: (1) To actively participate in NASH CRN activities and recruit/retain adult and pediatric subjects in ongoing and future consortium-wide and ancillary studies e.g. database-2 and STOP- NAFLD. These studies will generate critically needed outcomes data needed for biomarker development, holistic modeling of disease progression and to inform the design of long-term clinical trials. (2) To establish and lead ?The NAFLD Atlas (TNA)? to guide models of disease development and progression, identification of novel biomarkers and Precision Medicine approaches for NASH. Here we provide a vision to integrate the clinical, laboratory, genomic, transcriptomic and lipidomic data being obtained by the CRN with histological- and clinical- outcomes data. This approach, analogous to the cancer genome atlas for cancers, will permit unprecedented multi-dimensional analytic approaches to accelerate the identification of new diagnostic and prognostic markers, new targets for pharmaceutical interventions and Precision Medicine approaches for the prevention and treatment of NASH. The infrastructure required for data formatting, storage, integrity, analytics and visualization for both CRN and the greater research community is outlined along with a viable ?modular? funding model. Key external collaborators with the required skills and experience have joined this effort. (3) To lead and perform a NASH CRN-wide prospective, randomized, double-blind placebo-controlled clinical trial of Pioglitazone and Vitamin E (rrr ?-tocopherol, 800 IU/day) in those with NASH with bridging fibrosis (PIVENS II). The premise for this trial includes the unmet need for therapies that prevent cirrhosis the driver of liver outcomes in NASH, the available data to support a role for pioglitazone and vitamin E for NASH and their independent mechanisms of action making them suitable for combination in a trial. The primary endpoint is the proportion of subjects who progress to cirrhosis; the trial population is selected based on their high risk of such progression and thus likelihood of benefit. Together, the proposed studies will further all of the objectives of RFA-DK-18-505 for continuation of the NASH CRN by participation in ongoing CRN activities, creation of the NAFLD atlas for the entire research community and delivery of therapeutic options to prevent cirrhosis in those at highest risk.

Public Health Relevance

The aims of this proposal are to actively participate in CRN activities, create the NAFLD atlas which will integrate multiple ?Omics? data with metadata and link these to outcomes and by perform a clinical trial to test the ability of a combination of pioglitazone and vitamin E to prevent cirrhosis in those with NASH and bridging fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK061731-19
Application #
10016239
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Sherker, Averell H
Project Start
2002-05-20
Project End
2024-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
19
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Middleton, Michael S; Van Natta, Mark L; Heba, Elhamy R et al. (2018) Diagnostic accuracy of magnetic resonance imaging hepatic proton density fat fraction in pediatric nonalcoholic fatty liver disease. Hepatology 67:858-872
Africa, Jonathan A; Behling, Cynthia A; Brunt, Elizabeth M et al. (2018) In Children With Nonalcoholic Fatty Liver Disease, Zone 1 Steatosis Is Associated With Advanced Fibrosis. Clin Gastroenterol Hepatol 16:438-446.e1
Ajmera, Veeral; Belt, Patricia; Wilson, Laura A et al. (2018) Among Patients With Nonalcoholic Fatty Liver Disease, Modest Alcohol Use Is Associated With Less Improvement in Histologic Steatosis and Steatohepatitis. Clin Gastroenterol Hepatol 16:1511-1520.e5
Vuppalanchi, Raj; Siddiqui, Mohammad S; Van Natta, Mark L et al. (2018) Performance characteristics of vibration-controlled transient elastography for evaluation of nonalcoholic fatty liver disease. Hepatology 67:134-144
Loomba, Rohit; Sanyal, Arun J; Kowdley, Kris V et al. (2018) Factors Associated With Histologic Response in Adult Patients With Nonalcoholic Steatohepatitis. Gastroenterology :
Brunt, Elizabeth M; Kleiner, David E; Wilson, Laura A et al. (2018) Improvements in Histologic Features and Diagnosis associated with Improvement in Fibrosis in NASH: Results from the NASH Clinical Research Network Treatment Trials. Hepatology :
Chalasani, Naga; Abdelmalek, Manal F; Loomba, Rohit et al. (2018) Relationship Between Three Commonly Used Non-invasive Fibrosis Biomarkers and Improvement in Fibrosis Stage in Patients With NASH. Liver Int :
Harlow, Kathryn E; Africa, Jonathan A; Wells, Alan et al. (2018) Clinically Actionable Hypercholesterolemia and Hypertriglyceridemia in Children with Nonalcoholic Fatty Liver Disease. J Pediatr 198:76-83.e2
Perito, Emily R; Ajmera, Veeral; Bass, Nathan M et al. (2017) Association Between Cytokines and Liver Histology in Children with Nonalcoholic Fatty Liver Disease. Hepatol Commun 1:609-622
Newton, Kimberly P; Feldman, Haruna S; Chambers, Christina D et al. (2017) Low and High Birth Weights Are Risk Factors for Nonalcoholic Fatty Liver Disease in Children. J Pediatr 187:141-146.e1

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