Dataset Information

Treatment of nonalcoholic fatty liver disease in children: TONIC trial design.

ABSTRACT:

Background

Nonalcoholic 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.

Objectives

TONIC 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.

Design

TONIC 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.

Methods

Between 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.).

SUBMITTER: Lavine JE

PROVIDER: S-EPMC2936451 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Publications

Treatment of nonalcoholic fatty liver disease in children: TONIC trial design.

Lavine Joel E JE Schwimmer Jeffrey B JB Molleston Jean P JP Scheimann Ann O AO Murray Karen F KF Abrams Stephanie H SH Rosenthal Philip P Sanyal Arun J AJ Robuck Patricia R PR Brunt Elizabeth M EM Unalp Aynur A Tonascia James J

Contemporary clinical trials 20090915 1

<h4>Background</h4>Nonalcoholic 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.<h4>Objectives</h4>TONIC 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 ...[more]

PMID: 19761871

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Project description:ContextNonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in US children and adolescents and can present with advanced fibrosis or nonalcoholic steatohepatitis (NASH). No treatment has been established.ObjectiveTo determine whether children with NAFLD would improve from therapeutic intervention with vitamin E or metformin.Design, setting, and patientsRandomized, double-blind, double-dummy, placebo-controlled clinical trial conducted at 10 university clinical research centers in 173 patients (aged 8-17 years) with biopsy-confirmed NAFLD conducted between September 2005 and March 2010. Interventions Daily dosing of 800 IU of vitamin E (58 patients), 1000 mg of metformin (57 patients), or placebo (58 patients) for 96 weeks.Main outcome measuresThe primary outcome was sustained reduction in alanine aminotransferase (ALT) defined as 50% or less of the baseline level or 40 U/L or less at visits every 12 weeks from 48 to 96 weeks of treatment. Improvements in histological features of NAFLD and resolution of NASH were secondary outcome measures.ResultsSustained reduction in ALT level was similar to placebo (10/58; 17%; 95% CI, 9% to 29%) in both the vitamin E (15/58; 26%; 95% CI, 15% to 39%; P = .26) and metformin treatment groups (9/57; 16%; 95% CI, 7% to 28%; P = .83). The mean change in ALT level from baseline to 96 weeks was -35.2 U/L (95% CI, -56.9 to -13.5) with placebo vs -48.3 U/L (95% CI, -66.8 to -29.8) with vitamin E (P = .07) and -41.7 U/L (95% CI, -62.9 to -20.5) with metformin (P = .40). The mean change at 96 weeks in hepatocellular ballooning scores was 0.1 with placebo (95% CI, -0.2 to 0.3) vs -0.5 with vitamin E (95% CI, -0.8 to -0.3; P = .006) and -0.3 with metformin (95% CI, -0.6 to -0.0; P = .04); and in NAFLD activity score, -0.7 with placebo (95% CI, -1.3 to -0.2) vs -1.8 with vitamin E (95% CI, -2.4 to -1.2; P = .02) and -1.1 with metformin (95% CI, -1.7 to -0.5; P = .25). Among children with NASH, the proportion who resolved at 96 weeks was 28% with placebo (95% CI, 15% to 45%; 11/39) vs 58% with vitamin E (95% CI, 42% to 73%; 25/43; P = .006) and 41% with metformin (95% CI, 26% to 58%; 16/39; P = .23). Compared with placebo, neither therapy demonstrated significant improvements in other histological features.ConclusionNeither vitamin E nor metformin was superior to placebo in attaining the primary outcome of sustained reduction in ALT level in patients with pediatric NAFLD.Trial registrationclinicaltrials.gov Identifier: NCT00063635.

Project description:Aim: To investigate the intestinal flora of nonalcoholic fatty liver disease (NAFLD) in Chinese children and adolescents using metagenomic approach. Methods: All participants underwent magnetic resonance spectroscopy (MRS) to quantify liver fat content. Hepatic steatosis was defined as MRS proton density fat fraction (MRS-PDFF) >5%. A total of 58 children and adolescents were enrolled in this study, including 25 obese NAFLD patients, 18 obese non-NAFLD children, and 15 healthy children. Stool samples were collected and analyzed with metagenomics. We used Shannon index to reflect the alpha diversities of gut microbiota. Wilcoxon rank sum test and Kruskal-Wallis test were performed to evaluate alpha diversities between groups. At last, the differences of gut microbiota composition and functional annotations between obese with and without NAFLD and healthy children were assessed by Kruskal-Wallis test. Results: Significant differences in gut microbiota composition and functional annotations among three groups of children and adolescents have been observed. Deep sequencing of gut microbiota revealed high abundance of phylum Proteobacteria (Gammaproteobacteria) in obese NAFLD patients, comparing with the control group. Overall, obese children without NAFLD had less abundant Helicobacter and Helicobacter pylori. Compared to the control group, in obese children with NAFLD, the abundance of Bacteroidetes (Alistipes) were significantly reduced. Faecalibacterium prausnitzii was the only species representing a difference between obese children with and without NAFLD. There were not significant differences in terms of alpha diversity among three groups. Functional annotations demonstrated that several pathways were differentially enriched between groups, including metabolism of other amino acids, replication and repair, folding, sorting, degradation, and glycan biosynthesis and metabolism. Conclusion: Significantly differences are observed in gut microbiota composition and functional annotations between obese children with and without NAFLD in comparison to the healthy children group. The characteristic of gut microbiota in this study may contribute to a further understanding the gut-liver axis of pediatric NAFLD in China.

Dataset Information

Treatment of nonalcoholic fatty liver disease in children: TONIC trial design.

Background

Objectives

Design

Methods

Publications

Treatment of nonalcoholic fatty liver disease in children: TONIC trial design.

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