Treatment of nonalcoholic fatty liver disease in children: TONIC trial design |
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| Authors: | Joel E. Lavine Jeffrey B. Schwimmer Jean P. Molleston Ann O. Scheimann Karen F. Murray Stephanie H. Abrams Philip Rosenthal Arun J. Sanyal Patricia R. Robuck Elizabeth M. Brunt Aynur Ünalp James Tonascia |
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| Affiliation: | 1. University of California San Diego, La Jolla, CA, USA;2. Indiana University School of Medicine, Indianapolis, IN, USA;3. Johns Hopkins Hospital, Baltimore, MD, USA;4. Seattle Children''s, Seattle, WA, USA;5. Baylor College of Medicine, Houston, TX, USA;6. University of California San Francisco, CA, USA;7. Virginia Commonwealth University, Richmond, VA, USA;8. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA;9. Washington University School of Medicine, St. Louis, MO, USA;10. The Johns Hopkins University, Bloomberg School of Public Health, 615 North Wolfe Street, Room W5010, Baltimore, Maryland 21205, USA |
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| Abstract: | BackgroundNonalcoholic fatty liver disease (NAFLD) in children can lead to steatohepatitis, cirrhosis, and end-stage liver disease. The cause of NAFLD is unknown, but it is commonly associated with obesity, insulin resistance, and dyslipidemia.ObjectivesTONIC is conducted to test whether treatment with metformin, an insulin sensitizer, or vitamin E, a naturally available antioxidant, will lead to improvements in biochemical and histological features of nondiabetic children with biopsy-proven NAFLD.DesignTONIC is a randomized, multicenter, double-masked, placebo-controlled trial of 96 weeks of treatment with metformin or vitamin E. The primary outcome measure chosen for the trial is improvement in serum alanine aminotransferase (ALT) levels with treatment as compared to placebo. An improvement in ALT is defined as reduction in serum ALT levels to below 50% of the baseline values or into the normal range (40 U/L or less) during the last 48 weeks of treatment. Histological improvement is defined by changes in liver histology between a baseline and end-of-treatment liver biopsy in regards to (1) steatohepatitis, (2) NAFLD Activity Score, consisting of scores for steatosis, lobular inflammation, and hepatocellular injury (ballooning), and (3) fibrosis score.MethodsBetween September 2005 and September 2007, 173 children were enrolled into TONIC at 10 clinical centers in the United States. Participants were randomized to receive either metformin (500 mg b.i.d.), vitamin E (400 IU b.i.d.), or placebo for 96 weeks. This protocol was approved by all participating center Institutional Review Boards (IRBs) and an independent Data and Safety Monitoring Board (DSMB). (ClinicalTrials.gov number, NCT00063635.) |
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