Hepatitis
Conditions
Keywords
Insulin Resistance, Obesity, Fatty Liver, Cirrhosis, Diabetes, Pioglitazone, Thiazolidinediones, Peroxisome Proliferator-Advanced Receptor Gamma, PPAR Gama, Nonalcoholic Steatohepatitis, Hepatitis, Non-Alcoholic Steatohepatitis, NASH
Brief summary
Nonalcoholic steatohepatitis (NASH) is a common liver disease that resembles alcoholic hepatitis but occurs in persons who drink little or no alcohol. The etiology of NASH is unclear, but it is commonly associated with diabetes, obesity, and insulin resistance. Several pilot studies, including a study of pioglitazone at the NIH Clinical Center (01-DK-0130), have shown that the insulin-sensitizing thiazolidinediones lead to decreases in serum alanine aminotransferase (ALT) levels and improved liver histology. Once therapy is stopped, however, ALT levels rapidly return to pre-treatment values. Inaddition we are currently enrolling patients with NASH in a pilot study of metformin therapy for 48-weeks, however our results in 3 patients thus far have not been very encouraging. In the current study, patients who have completed the pilot study of pioglitazone and have been off therapy for 48 weeks will be offered re-treatment for 3 years. We also propose to treat patients who have not had a satisfactory response to metformin with pioglitazone for the same duration. After a repeat medical and metabolic evaluation and liver biopsy, patients with moderate-to-severe NASH (activity score greater than or equal to 4) will restart pioglitazone at a dose of 15 mg daily. If after 48 weeks, ALT levels are not normal or improved to the degree identified during the pilot study, the dose will be increased to 30 mg daily at the end of 3 years, all patients will undergo repeat medical and metabolic evaluation and liver biopsy. The primary end point will be improvement in liver histology. Secondary end points will be improvements in insulin sensitivity, reduction in visceral fat, liver volume, and liver biochemistry. The aim of this study is to evaluate whether long-term pioglitazone therapy can safely achieve and maintain biochemical and histological improvements in NASH. ...
Detailed description
Nonalcoholic steatohepatitis (NASH) is a common liver disease that resembles alcoholic hepatitis but occurs in persons who drink little or no alcohol. The etiology of NASH is unclear, but it is commonly associated with diabetes, obesity, and insulin resistance. Several pilot studies, including a study of pioglitazone at the NIH Clinical Center (01-DK-0130), have shown that the insulin-sensitizing thiazolidinediones lead to decreases in serum alanine aminotransferase (ALT) levels and improved liver histology. Once therapy is stopped, however, ALT levels rapidly return to pre-treatment values. Inaddition we are currently enrolling patients with NASH in a pilot study of metformin therapy for 48-weeks, however our results in 3 patients thus far have not been very encouraging. In the current study, patients who have completed the pilot study of pioglitazone and have been off therapy for 48 weeks will be offered re-treatment for 3 years. We also propose to treat patients who have not had a satisfactory response to metformin with pioglitazone for the same duration. After a repeat medical and metabolic evaluation and liver biopsy, patients with moderate-to-severe NASH (activity score greater than or equal to 4) will restart pioglitazone at a dose of 15 mg daily. If after 48 weeks, ALT levels are not normal or improved to the degree identified during the pilot study, the dose will be increased to 30 mg daily at the end of 3 years, all patients will undergo repeat medical and metabolic evaluation and liver biopsy. The primary end point will be improvement in liver histology. Secondary end points will be improvements in insulin sensitivity, reduction in visceral fat, liver volume, and liver biochemistry. The aim of this study is to evaluate whether long-term pioglitazone therapy can safely achieve and maintain biochemical and histological improvements in NASH.
Interventions
Pts receive drug in a dose of 15 mg daily for at least 1 year; the dose is escalated to 30 mg daily if serum ALT levels do not fall to normal by the 1 year pt; if pts have a biochemical response, drug is continued for 3 years,
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: Completion of a 48-week course of pioglitazone in protocol 01-DK-0130 or completion of 48-weeks of metformin in protocol 03-DK-0233. At least 48 weeks of follow up on no thiazolidinedione therapy after completion of protocol 01-DK-0130. At least 24-weeks follow up on no metformin theray after completion of protocol 03-DK-0233. Written informed consent. Patients who participated in protocol 01-DK-0130 will also have to meet the following inclusion criteria: Demonstrated improvements in liver histology and/or serum ALT levels during the 48-week course of pioglitazone therapy in protocol 01-DK-0130. Elevations in serum ALT levels. Liver biopsy showing NASH with a total NASH activity score of at least 4 (of a total possible score of 16) including a score of at least 1 each for parenchyma inflammation, cellular injury and steatosis on liver biopsy taken 48 weeks after stopping pioglitazone. Willingness to receive pioglitazone for 3 years. Patients who participated in protocol 03-DK-0233 will also have to me the following inclusion criteria: Demonstrated no significant improvement in liver histology and/or serum ALT levels during the 48-week course of metformin treatment in protocol 03-DK-0233. Elevations in serum ALT levels. Liver biopsy showing NASH with a total activity score of at least 4 (of a total possible score of 16) including a score of at least 1 each for parenchymal inflammation, cellular injury and steatosis on liver biopsy taken at the end of the 48-week course of metofrmin.
Exclusion criteria
Evidence of another form of liver disease (these largely will have been excluded based upon enrollment in the previous study, 01-DK-0130 and 03-DK-0233). Hepatitis B as defined as presence of hepatitis B surface antigen (HBsAg). Hepatitis C as defined by presence of hepatitis C virus (HCV) RNA in serum. Autoimmune hepatitis as defined by anti-nuclear antibody (ANA) of 1:160 or greater and liver histology consistent with autoimmune hepatitis or previous response to immunosuppressive therapy. Autoimmune cholestatic liver disorders as defined by elevation of alkaline phosphatase and anti-mitochondrial antibody of greater than 1:80 or liver histology consistent with primary biliary cirrhosis or elevation of alkaline phosphatase and liver histology consistent with sclerosing cholangitis. e. Wilson disease as defined by ceruloplasmin below the limits of normal and liver histology consistent with Wilson disease. Alpha-1-antitrypsin deficiency as defined by alpha-1-antitrypsin level less than normal and liver histology consistent with alpha-1-antitrypsin deficiency. Hemochromatosis as defined by presence of 3+ or 4 iron on liver biopsy stain and homozygosity for C282Y or compound heterozygosity for C282Y/H63D. Drug-induced liver disease as defined on the basis of typical exposure and history. Bile duct obstruction as shown by imaging studies. History of excess alcohol ingestion, averaging more than 30 gm/day (3 drinks per day) in the previous 10 years, or history of alcohol intake averaging greater than 10 gm/day (1 drink per day: 7 drinks per week) in the previous one year. Contraindications to liver biopsy: platelet counts less than 75,000/mm(3) or prothrombin time greater than 16 seconds. Decompensated liver disease, Child-Pugh score greater than or equal to 7 points. History of gastrointestinal bypass surgery or ingestion of drugs known to produce hepatic steatosis including corticosteroids, high-dose estrogens, methotrexate, tetracycline or amiodarone in the previous 6 months. Preexistent diabetes mellitus or the development of diabetes mellitus during the study requiring the use of another drug in addition to pioglitazone for glycaemic control. Diabetes being as defined by: fasting plasma glucose of greater than or equal to 126 mg/dl on two separate occasions, or diabetic symptoms with a random plasma glucose of greater than or equal to 200 mg/dl. Use of anti-diabetic drugs, including insulin, biguanides, sulfonylureas, or thiazolidinediones at the time of enrollment or in the previous 48 weeks. Significant systemic or major illnesses other than liver disease, including congestive heart failure, coronary artery disease, cerebrovascular disease, pulmonary disease, renal failure, organ transplantation, serious psychiatric disease, malignancy that, in the opinion of the investigator would preclude treatment with pioglitazone and adequate follow up. Positive test for anti-HIV. Active substance abuse, such as alcohol, inhaled or injection drugs within the previous one year. Pregnancy or inability to practice adequate contraception in women of childbearing potential. Evidence of hepatocellular carcinoma: alpha-fetoprotein levels greater than 200 ng/ml and/or liver mass on imaging study that is suggestive of liver cancer. Any other conditions, which, in the opinion of the investigators would impede competence or compliance or possibility, hinder completion of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Improvement in Liver Histology | 48 weeks | A histological response was defined as a reduction in the NASH activity index by 3 points or more with improvements of at least 1 point each in steatosis, parenchymal inflammation, and hepatocellular injury. |
Secondary
| Measure | Time frame |
|---|---|
| Number of Patients With Impaired Glucose Tolerance After Treatment | 48 weeks |
| Mean Increase of Insulin Sensitivity Index | 48 weeks |
| Average Increase in Weight After Treatment | 48 weeks |
| Mean BMI Change | 48 weeks |
Countries
United States
Participant flow
Recruitment details
Between March 2001 and April 2002, 25 patients suspected of having NASH were evaluated, and 18 were enrolled in the study after screening.
Participants by arm
| Arm | Count |
|---|---|
| Pioglitazone Patients receive Pioglitazone in a dose of 15 mg daily for at least 1 year; the dose is escalated to 30 mg daily if serum Alanine transaminase levels do not fall to normal by the 1 year pt; if patients have a biochemical response, drug is continued for 3 years. | 18 |
| Total | 18 |
Baseline characteristics
| Characteristic | Pioglitazone |
|---|---|
| 2-hr glucose diabetes mellitus <=200 mg/dL | 16 participants |
| 2-hr glucose diabetes mellitus >200 mg/dL | 2 participants |
| 2-hr glucose (Impaired glucose tolerance) 140-199 mg/dL | 11 participants |
| 2-hr glucose (Impaired glucose tolerance) other | 7 participants |
| Age Continuous | 46 years STANDARD_DEVIATION 11 |
| Fasting glucose 110-125 mg/dL | 2 participant |
| Fasting glucose other | 16 participant |
| Metabolic syndrome No | 11 participants |
| Metabolic syndrome Yes | 7 participants |
| Obesity Distribution BMI<=30 | 7 participants |
| Obesity Distribution BMI>30 | 11 participants |
| Race/Ethnicity, Customized Hispanic | 3 participants |
| Race/Ethnicity, Customized Mixed | 2 participants |
| Race/Ethnicity, Customized White | 13 participants |
| Region of Enrollment United States | 18 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 14 / 18 |
| serious Total, serious adverse events | 0 / 18 |
Outcome results
Primary
Number of Patients With Improvement in Liver Histology
A histological response was defined as a reduction in the NASH activity index by 3 points or more with improvements of at least 1 point each in steatosis, parenchymal inflammation, and hepatocellular injury.
Time frame: 48 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone | Number of Patients With Improvement in Liver Histology | 12 participants |
Secondary
Average Increase in Weight After Treatment
Time frame: 48 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pioglitazone | Average Increase in Weight After Treatment | 3.5 kg |
Secondary
Mean BMI Change
Time frame: 48 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | Mean BMI Change | 1.3 kg/m2 | Standard Deviation 1.7 |
p-value: 0.004paired t-test
Secondary
Mean Increase of Insulin Sensitivity Index
Time frame: 48 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | Mean Increase of Insulin Sensitivity Index | 126 percentage | Standard Deviation 78 |
Secondary
Number of Patients With Impaired Glucose Tolerance After Treatment
Time frame: 48 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone | Number of Patients With Impaired Glucose Tolerance After Treatment | 6 participants |