Treating Nonalcoholic Steatohepatitis With Pioglitazone

December 14, 2012 updated by: Jay Hoofnagle, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Long-Term Treatment of Nonalcoholic Steatohepatitis With Pioglitazone

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.

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Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

18

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Pioglitazone
Drug: Actos (Pioglitazone)
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,

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Patients With Improvement in Liver Histology
Time Frame: 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.
48 weeks

Secondary Outcome Measures

Outcome Measure
Time Frame
Number of Patients With Impaired Glucose Tolerance After Treatment
Time Frame: 48 weeks
48 weeks
Mean Increase of Insulin Sensitivity Index
Time Frame: 48 weeks
48 weeks
Average Increase in Weight After Treatment
Time Frame: 48 weeks
48 weeks
Mean BMI Change
Time Frame: 48 weeks
48 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

  • Principal Investigator: Jay Hoofnagle, MD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2003

Primary Completion (Actual)

February 1, 2009

Study Completion (Actual)

February 1, 2009

Study Registration Dates

First Submitted

June 12, 2003

First Submitted That Met QC Criteria

June 12, 2003

First Posted (Estimate)

June 13, 2003

Study Record Updates

Last Update Posted (Estimate)

December 19, 2012

Last Update Submitted That Met QC Criteria

December 14, 2012

Last Verified

December 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 030212
  • 03-DK-0212

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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