Hepatitis Clinical Trial
Official title:
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.
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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Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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