Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological diagnosis in which more than 5% of hepatocytes demonstrate macrovesicular steatosis in an individual without significant history of alcohol intake. NAFLD has become the most common cause of chronic liver disease in children in the United States, and encompasses a range of severity from bland steatosis to nonalcoholic steatohepatitis (NASH) that may ultimately result in advanced fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD was selected as the histologic entry criterion for this study because of a lack of knowledge about the natural history in the pediatric subset.

Treatment approaches to NAFLD in adults and children target reduction in insulin resistance and oxidative stress. Based on pediatric pilot data demonstrating potential efficacy of metformin or vitamin E, the NASH Clinical Research Network (NASH CRN), initiated a phase 3, multicenter, randomized, double-blinded, placebo-controlled trial evaluating vitamin E or metformin for the Treatment of NAFLD in Children (TONIC). The purpose of this study was to determine if therapeutic modification of insulin resistance or oxidative stress leads to improvement in serum or histologic indicators of liver injury or quality of life.

173 eligible patients were randomized in permuted blocks of treatments stratified by clinical center. Patients were assigned in a 1:1:1 ratio to 1 of 3 groups for 96 weeks of treatment, either (1) oral metformin (500 mg twice daily) and vitamin E placebo twice daily, (2) vitamin E (400 IU twice daily) and metformin placebo twice daily, or (3) vitamin E placebo and metformin placebo, each twice daily.

The complete TONIC data is now available.

The objective of TONIC was to determine whether 96 weeks of treatment with either metformin or vitamin E leads to sustained reduction in serum ALT in nondiabetic children with NAFLD compared to treatment with placebo.

Primary:

• Sustained reduction in ALT level, defined as 50% or less of the baseline level or 40 U/L or less at each visit from 48 to 96 weeks of treatment

Secondary:

• Change in serum AST, GGT, and alkaline phosphatase levels
• Change in histologic feature scores determined by standardized scoring of liver biopsies at baseline and after 96 weeks of treatment
• Improvement in liver fibrosis, lobular inflammation, ballooning degradation, and steatosis scores
• Change in body mass index
• Change in insulin resistance indices
• Change in serum vitamin E levels
• Change in serum cytokine and fibrosis marker levels
• Change in serum lipid profile
• Change in Quality of Life (QOL) scores – physical and psychosocial

• Age 8 to 17 years
• Histologic evidence of NAFLD (more than 5% steatosis) within a 6-month period before randomization
• ALT level > 60 U/L on two separate occasions at least 30 days apart but no more than 12 months (365 days) apart. One of these measures must be obtained at the TONIC clinical center during screening for TONIC. The other measure may be historic (i.e., obtained prior to initiation of screening in TONIC)
• Randomized within 16 weeks (112 days) of starting screening
• Exclusion: diabetes mellitus, cirrhosis, monogenic inborn errors of metabolism, pregnancy, viral hepatitis, alcohol use, and other causes of chronic liver disease

Neither vitamin E nor metformin was superior to placebo in attaining the primary outcome of sustained reduction in ALT level in patients with pediatric NAFLD.

The resolution of NASH was significantly greater in children treated with vitamin E than with placebo. This was mainly attributable to significant improvement in hepatocellular ballooning by vitamin E treatment, which also occurred in the metformin treated patients. Vitamin E treatment also significantly improved NAFLD activity score. (JAMA. 2011 April 27; 305(16): 1659–1668.)