Clinical Trial Launched For Treatment Of Liver Disease In Children

The Treatment of Nonalcoholic Fatty LiverDisease (NAFLD) in Children (TONIC) trial will enroll 180 boys andgirls, ages 8-15 years with NAFLD. The participants will receivevitamin E, or metformin (an insulin-sensitizing drug), or placebo over2 years. There are no weight cut-offs or percentiles for the childrenparticipating in TONIC. However, more than ninety percent of thechildren are expected to be obese. Volunteers need a baseline biopsythat demonstrates NAFLD to be eligible for the study. Children withdiabetes and other chronic liver diseases will be excluded from TONIC.

Whilesimilar to alcoholic liver disease, NAFLD, occurs in persons who drinklittle to no alcohol. NAFLD is associated with overweight and obesityand occurs in a high proportion of persons with diabetes. But, it canalso occur in adults and children who are normal weight withoutdiabetes. Although there seems to be an association between obesity andliver injury, current research does not support a causal link ortrigger from obesity to liver injury. TONIC investigators hope touncover the underlying conditions that contribute to the developmentand progression of NAFLD in children.

Once considered a diseaseof adults over 40, NAFLD is increasingly reported in children.Determining population-based prevalence numbers for NAFLD is difficult.These numbers depend on the age group being studied, the racial/ethnicmix of the study, and the methods used to assess fatty liver, whichinclude serum enzyme readings, ultrasound, and magnetic resonanceimaging (MRI). However, researchers in a nationwide school-basedpopulation study found that about 23 percent of obese 17-year-olds hadabnormal serum enzyme levels, an indicator of NAFLD. The major featurein NAFLD is the accumulation of fat in the liver. Patients withinflammation and liver injury along with fat in the liver are said tohave NASH. Most patients with fatty liver disease feel well and do notexperience symptoms.

NAFLD can be a precursor to NASH, which mayprogress to cirrhosis. When complications such as cirrhosis cannot becontrolled with treatment or when the liver becomes so damaged fromscarring that it completely stops functioning, a liver transplant isnecessary. Researchers are concerned that the disease may progress inchildren and increase their risk for cirrhosis, liver failure, anddeath as adults, particularly if they drink alcohol or contract viralhepatitis.

A liver biopsy is the only way to accuratelydistinguish NASH from simple fatty liver disease. Most of the childrenwith the disease are overweight and insulin-resistant, with boys morecommonly affected than girls. Mexican-American children appear to havea greater risk for NASH than black and white children.

“The risein the rates of NAFLD in children likely mirrors the increase inobesity, making it the most prevalent liver disease in Americanchildren today,” says Joel E. Lavine, M.D., Ph.D., chair, NASH-CRNPediatric Sub-committee and principal investigator for the center atthe University of California, San Diego.

Currently, there are nosafe or effective drugs recommended to treat children or adults withthis liver disease. Results from small pilot studies using metformin orantioxidants for children with NAFLD appear to improve liver enzymelevels and may delay or possibly prevent the progression of NASH. Thechildren participating in the TONIC trial will receive metformin as atreatment option because extensive safety and efficacy data exists onthe use of this drug for the treatment of type 2 diabetes in children.

“Asthe first randomized, controlled trial for children with NAFLD, TONICprovides researchers and NIDDK a platform to conduct rigorous studieson how safe and effective vitamin E and metformin are in treatingchildren with this liver disease,” says Patricia Robuck, Ph.D., M.P.H.,project scientist for the NASH Clinical Research Network and directorof the Clinical Trials Program within the Division of DigestiveDiseases and Nutrition at the NIDDK.

The adult trial,Pioglitazone versus Vitamin E versus Placebo for the Treatment ofNondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS), wasinitiated earlier this year and will recruit 240 adults with NASH intothree treatment groups: vitamin E group, pioglitazone (aninsulin-sensitizing drug) group, or placebo group. Volunteers willundergo liver biopsies at the start and the end of the trial. Patientenrollment is ongoing.

“The NASH Clinical Research Network andits two randomized controlled trials offer opportunities to learn moreabout the cause and natural history of this liver disease, which willadvance treatments and improve patient outcomes,” says Jay Hoofnagle,M.D., director, NIDDK Liver Disease Research Branch.

The NASHClinical Research Network, consisting of eight clinical centers and adata coordinating center, was formed in September 2002 to conductresearch on the natural history, pathogenesis, and treatment of NASH.With the information gathered from the observational studies andclinical trials involving both adults and children with NASH/NAFLD, theClinical Research Network will create a database of information to beused by researchers in the development of treatments for this liverdisease.

The eight clinical centers of the NASH Clinical ResearchNetwork recruiting patients for both the TONIC and PIVENS trialsinclude: Case Western Reserve University in Cleveland; Duke UniversityMedical Center in Raleigh-Durham (adult site)/ Johns Hopkins Universityin Baltimore (pediatric site); Indiana University in Indianapolis; St.Louis University in Missouri; University of California in San Diego;University of California in San Francisco; University of Washington inSeattle; and Virginia Commonwealth University in Richmond. The JohnsHopkins University Bloomberg School of Public Health in Baltimoreprovides coordination of the research network studies.

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Information for the centers is available at http://www.nashcrn.com.
For general information about NASH, visit http://digestive.niddk.nih.gov/ddiseases/pubs/nash/.

The NASH Clinical Research Network, the TONIC trial, and the PIVENStrial are funded by the National Institute of Diabetes and Digestiveand Kidney Diseases (NIDDK), part of the National Institutes of Health(NIH). The National Institute of Child Health and Human Development,part of the NIH, an agency of the U.S. Department of Health and HumanServices, provides additional funding.