The Nonalcoholic Steatohepatitis (NASH) Clinical Research Network has launched its second clinical trial to study NASH, a liver disease that resembles alcoholic liver disease but occurs in patients who drink little or no alcohol. The first trial, launched in January of this year, focuses on adults, while the second trial studies the disease in children.
The NASH Clinical Research Network and its clinical trials are funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
The Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in Children (TONIC) trial will enroll 180 boys and girls, ages 8-15 years with NAFLD. The participants will receive vitamin E, or metformin (an insulin-sensitizing drug), or placebo over 2 years. There are no weight cut-offs or percentiles for the children participating in TONIC. However, more than ninety percent of the children are expected to be obese. Volunteers need a baseline biopsy that demonstrates NAFLD to be eligible for the study. Children with diabetes and other chronic liver diseases will be excluded from TONIC.
While similar to alcoholic liver disease, NAFLD, occurs in persons who drink little to no alcohol. NAFLD is associated with overweight and obesity and occurs in a high proportion of persons with diabetes. But, it can also occur in adults and children who are normal weight without diabetes. Although there seems to be an association between obesity and liver injury, current research does not support a causal link or trigger from obesity to liver injury. TONIC investigators hope to uncover the underlying conditions that contribute to the development and progression of NAFLD in children.
Once considered a disease of 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/ethnic mix of the study, and the methods used to assess fatty liver, which include serum enzyme readings, ultrasound, and magnetic resonance imaging (MRI). However, researchers in a nationwide school-based population study found that about 23 percent of obese 17-year-olds had abnormal serum enzyme levels, an indicator of NAFLD. The major feature in NAFLD is the accumulation of fat in the liver. Patients with inflammation and liver injury along with fat in the liver are said to have NASH. Most patients with fatty liver disease feel well and do not experience symptoms.
NAFLD can be a precursor to NASH, which may progress to cirrhosis. When complications such as cirrhosis cannot be controlled with treatment or when the liver becomes so damaged from scarring that it completely stops functioning, a liver transplant is necessary. Researchers are concerned that the disease may progress in children and increase their risk for cirrhosis, liver failure, and death as adults, particularly if they drink alcohol or contract viral hepatitis.
A liver biopsy is the only way to accurately distinguish NASH from simple fatty liver disease. Most of the children with the disease are overweight and insulin-resistant, with boys more commonly affected than girls. Mexican-American children appear to have a greater risk for NASH than black and white children.
"The rise in the rates of NAFLD in children likely mirrors the increase in obesity, making it the most prevalent liver disease in American children today," says Joel E. Lavine, M.D., Ph.D., chair, NASH-CRN Pediatric Sub-committee and principal investigator for the center at the University of California, San Diego.
Currently, there are no safe or effective drugs recommended to treat children or adults with this liver disease. Results from small pilot studies using metformin or antioxidants for children with NAFLD appear to improve liver enzyme levels and may delay or possibly prevent the progression of NASH. The children participating in the TONIC trial will receive metformin as a treatment option because extensive safety and efficacy data exists on the use of this drug for the treatment of type 2 diabetes in children.
"As the first randomized, controlled trial for children with NAFLD, TONIC provides researchers and NIDDK a platform to conduct rigorous studies on how safe and effective vitamin E and metformin are in treating children with this liver disease," says Patricia Robuck, Ph.D., M.P.H., project scientist for the NASH Clinical Research Network and director of the Clinical Trials Program within the Division of Digestive Diseases and Nutrition at the NIDDK.
The adult trial, Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS), was initiated earlier this year and will recruit 240 adults with NASH into three treatment groups: vitamin E group, pioglitazone (an insulin-sensitizing drug) group, or placebo group. Volunteers will undergo liver biopsies at the start and the end of the trial. Patient enrollment is ongoing.
"The NASH Clinical Research Network and its two randomized controlled trials offer opportunities to learn more about the cause and natural history of this liver disease, which will advance treatments and improve patient outcomes," says Jay Hoofnagle, M.D., director, NIDDK Liver Disease Research Branch.
The NASH Clinical Research Network, consisting of eight clinical centers and a data coordinating center, was formed in September 2002 to conduct research on the natural history, pathogenesis, and treatment of NASH. With the information gathered from the observational studies and clinical trials involving both adults and children with NASH/NAFLD, the Clinical Research Network will create a database of information to be used by researchers in the development of treatments for this liver disease.
The eight clinical centers of the NASH Clinical Research Network recruiting patients for both the TONIC and PIVENS trials include: Case Western Reserve University in Cleveland; Duke University Medical Center in Raleigh-Durham (adult site)/ Johns Hopkins University in 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 in Seattle; and Virginia Commonwealth University in Richmond. The Johns Hopkins University Bloomberg School of Public Health in Baltimore provides coordination of the research network studies.