Treatment of Nonalcoholic Steatohepatitis With Pioglitazone
This study will evaluate the effectiveness of pioglitazone, a new diabetes medicine, on decreasing insulin resistance and improving liver disease in patients with nonalcoholic steatohepatitis (NASH). NASH is a chronic liver disease with unknown cause that involves fat accumulation and inflammation in the liver, leading to liver cirrhosis in 10 to 15 percent of patients and significant liver scarring in another 30 percent. Although similar to a condition that affects people who drink excessive amounts of alcohol, NASH occurs in people who drink only minimal or no alcohol. It is most often seen in patients with insulin resistance. Pioglitazone decreases insulin resistance and improves blood lipid (fat) levels, so that it may improve liver disease in NASH.
Patients with NASH 18 years of age or older may be eligible for this study. Candidates will be screened with a medical history and physical examination and routine blood tests. They will see a dietitian for counseling on diet and weight reduction, if needed. They will stop taking any medications for liver disease and take a daily multivitamin pill. After 2 months, those eligible for participation will be enrolled in the study.
Participants will be admitted to the Clinical Center for 2 to 3 days for a complete medical history, physical examination, blood tests, urinalysis, chest X-ray, electrocardiogram, abdominal ultrasound and a liver biopsy. After the diagnosis of NASH is confirmed, the following procedures will be performed:
- Echocardiography - imaging test using sound waves shows the heart structure and function
- Resting metabolic rate - measures amount of oxygen (and calories) used to maintain body functions at rest. While lying down, the patient wears a clear plastic hood over the head for 20 minutes while the amount of oxygen used is measured.
- Magnetic resonance imaging (MRI) scans - shows the size of the liver and other organs. The patient lies on a table in a metal cylinder that contains a magnetic field (the scanner) for no more than 30 minutes while the organs are imaged.
- Dual energy X-ray absorptiometry (DEXA) scan measures whole body composition, including amount of fat. The patient lies under an X-ray scanning machine for about 2 minutes.
- Oral glucose tolerance test (OGTT) - measures blood sugar and insulin levels. The patient drinks a very sweet drink containing glucose (sugar), after which blood samples are collected at various intervals during the 3-hour test. The blood is drawn through a catheter (thin plastic tube) placed in the arm before the test begins.
- Intravenous glucose tolerance test (IVGTT) - determines how the tissues respond to insulin and glucose. Glucose is injected into a vein, followed by a short infusion of insulin. Blood samples are collected through a catheter at various intervals during the 3-hour test.
When the above procedures are completed, patients start taking pioglitazone by mouth once a day for 48 weeks, keeping track of the medication and any side effects. They will be seen at the clinic every 2 weeks for the first month and then every 4 weeks for the rest of the treatment period. The visits will include an interview and examination by a physician and blood draw for laboratory tests. Female patients will have a pregnancy test at each clinic visit. At the end of the treatment period patients will be admitted to the Clinical Center for a repeat medical evaluation that will include the procedures described above.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Primary Purpose: Treatment
|Official Title:||Treatment of Nonalcoholic Steatohepatitis With Pioglitazone|
|Study Start Date:||March 2001|
|Estimated Study Completion Date:||March 2004|
Nonalcoholic steatohepatitis (NASH) is a clinicopathological entity that is being recognized more frequently in recent years. It is characterized by histologic changes that are similar to alcoholic hepatitis, but in the absence of excessive alcohol consumption. It is typically associated with type 2 diabetes mellitus, obesity and dyslipidemia and insulin resistance. It may progress and cause severe hepatic fibrosis and cirrhosis in significant numbers of patients. Currently, there is no effective therapy for this condition. In this pilot, open label study, we propose to treat 30 patients with nonalcoholic hepatitis with pioglitazone for 48 weeks. Pioglitazone has been shown to improve insulin sensitivity, the possible underlying mechanism of nonalcoholic steatohepatitis. Pioglitazone is an antidiabetic drug that belongs to thiazolidinedione group. The mechanism of action is thought to be mediated by activation of peroxisome proliferator-activated receptors-gamma (PPAR-gamma). After an initial evaluation of insulin sensitivity, fat distribution and liver biopsy, patients will receive 30 mg of pioglitazone, orally for 48 weeks. Patients will be monitored at regular intervals for symptoms of liver disease, side effects of pioglitazone, serum biochemical and metabolic indices. At 48 weeks, patients will have a repeat medical evaluation and liver biopsy. Pre and post treatment liver histology, fat distribution and insulin sensitivity will be compared. The primary end point of successful therapy will be improvement in hepatic histology as determined by reduction of at least three points in NASH activity score. Secondary end points will be improvement in insulin sensitivity, reduction in visceral fat, liver volume and liver biochemistry.
|United States, Maryland|
|National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)|
|Bethesda, Maryland, United States, 20892|