The Nonalcoholic Steatohepatitis (NASH) Clinical Research Network is launching its first two clinical trials for the study of NASH, a liver disease that resembles alcoholic liver disease but occurs in patients who drink little or no alcohol. NASH occurs most often in adults over the age of 40 who are overweight or have diabetes, insulin resistance (pre-diabetes), or hyperlipidemia (excess concentrations of fatty materials in the blood). NASH can also occur in children, the elderly, normal-weight, and non-diabetic persons.
The NASH Clinical Research Network and the clinical trial are funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), one of the National Institutes of Health (NIH).
NASH accounts for about 10 percent of newly diagnosed cases of chronic liver disease, and ranks as one of the leading causes of cirrhosis in the United States, following hepatitis C and alcoholic liver disease. Characteristics of the disease include abnormal liver enzyme levels, liver cell injury, inflammation and fibrosis in the liver, and excess amounts of fat stored in the liver. Though most people with NASH feel healthy and show no outward signs of a liver disease, NASH is progressive and can lead to cirrhosis and end-stage liver disease, which may require liver transplantation. The only way to distinguish NASH from other forms of fatty liver disease is with a liver biopsy.
"NASH has become a serious public health problem, because the incidence of NASH has risen with the increase of overweight and obesity in this country," 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 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 collected from observational studies and clinical trials on both adult and pediatric NASH patients, the Clinical Research Network will create a database of information to be used by researchers in the development of therapies for NASH. The Network also plans to encourage collaborations among clinical and basic researchers to generate information and develop ancillary studies using the resources of the database.
While there are currently no proven treatments for NASH, results from small pilot trials suggest that certain diabetes drugs improve liver enzyme levels and may slow or reverse the progression of NASH. Other pilot studies indicate that patients with this liver disease show improvement by following a regimen of balanced diet and exercise and also respond favorably to treatment with antioxidants such as vitamin E.
The first two clinical trials for the NASH Clinical Research Network will focus on the use of insulin-sensitizing agents and vitamin E for the treatment of NASH in adults and in children. The first clinical trial, the Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial is currently recruiting non-diabetic patients and will enroll 240 adults over 2 years into one of three treatment groups. Men and women aged 18 years and older will be assigned to either the vitamin E group, pioglitazone (an insulin-sensitizing agent) group, or placebo group. Potential patient volunteers will receive a standard oral glucose tolerance test after a 12-hour fast to rule out the presence of diabetes. Volunteers will also undergo liver biopsies at the start and the end of the trial.
"We believe that even in the absence of diabetes, drugs that improve insulin resistance may improve NASH. The PIVENS trial will test the possibility that both pioglitazone and vitamin E are effective treatments for NASH," says Arun Sanyal, M.D., co-chair, NASH CRN and principal investigator for the center at Virginia Commonwealth University in Richmond.
The second clinical trial, the "Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in Children" (TONIC) trial, will enroll 180 children with NAFLD to receive vitamin E, metformin (an insulin-sensitizing agent), or placebo over 18 months. The TONIC trial will begin recruitment in June 2005.
"Having a clear understanding of the pathogenesis of NASH and its natural history in both adults and children should translate into better treatments that slow or prevent NASH from progressing, ultimately improving the quality of life of patients with this liver disease," says Jay Hoofnagle, M.D., director, NIDDK Liver Disease Research Branch.
The eight clinical centers of the NASH Clinical Research Network recruiting patients 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 data.
The NASH Clinical Research Network and the PIVENS and TONIC clinical trials are funded by the NIDDK and an industry partner, Takeda Pharmaceuticals. Additional funding is provided by the National Institute of Child Health and Human Development, part of the NIH, an agency of the U.S. Department of Health and Human Services.