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


OBJECTIVE
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.


METHODS
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.).
Lavine
Joel E
JE
University of California San Diego, La Jolla, CA, USA.
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
D000293:Adolescent; D000410:Alanine Transaminase / Q000097:blood; D002648:Child; D004311:Double-Blind Method; D005234:Fatty Liver / Q000188:drug therapy* / Q000201:enzymology; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008111:Liver Function Tests; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D018579:Patient Selection; D012107:Research Design; D014810:Vitamin E / Q000627:therapeutic use*
D007004:Hypoglycemic Agents; D014810:Vitamin E; D008687:Metformin; D000410:Alanine Transaminase