|NASH Clinical Research Network Launches Trial for Treatment
of Liver Disease in Children
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), one of the National Institutes of Health (NIH).
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.
Contact 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 PIVENS trial
are funded by the National Institute of Diabetes and Digestive and 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 Human Services, provides additional funding.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U. S. Department of Health and Human Services. It is the primary Federal
agency for conducting and supporting basic, clinical, and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.