Nonalcoholic steatohepatitis (NASH) is a common liver disease associated with obesity and diabetes. NASH is a progressive disorder that can lead to cirrhosis and liver failure, and there is no definitive treatment. Insulin resistance and oxidative stress (resulting in lipid peroxidation) are considered to be the two most important mechanisms in the pathogenesis of NASH.

PIVENS hypothesized that pioglitazone and vitamin E will lead to improvement in hepatic histology in nondiabetic adults with biopsy proven NASH through changes in insulin resistance or oxidative stress. Before and post-treatment liver biopsies were read centrally in a masked fashion for an assessment of steatohepatitis and a NAFLD Activity Score (NAS) consisting of steatosis, lobular inflammation, and hepatocyte ballooning.

PIVENS enrollment started in January 2005 and ended in January 2007 with 247 patients randomized to receive either pioglitazone (30 mg q.d.), vitamin E (800 IU q.d.), or placebo for 96 weeks. Participants were followed for an additional 24 weeks after stopping the treatment. Both at the initial evaluation and at the completion of treatment 96 weeks later, subjects underwent an assessment of body weight, height, and waist and hip circumferences, and blood samples were obtained for routine biochemical tests and assessment of fasting levels of lipids, glucose, and insulin. Body composition was assessed with the use of dual-energy x-ray absorptiometry. The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) was administered for the assessment of quality of life.

The complete PIVENS data is now available.

The objective of PIVENS was to evaluate whether 96 weeks of treatment with either pioglitazone or vitamin E lowers NASH activity as determined from hepatic histology in nondiabetic adults with NASH compared to treatment with placebo.

Primary:

• Improvement in NASH activity defined as either an improvement in NAFLD Activity Score (NAS) by 2 or more in at least two NAS features, or a post-treatment NAS of 3 or less, and improvement in hepatocyte ballooning by 1 or more, and no worsening of fibrosis

Secondary

• Improvement in overall NAFLD activity score
• Improvement in liver fibrosis, lobular inflammation, hepatocellular ballooning, and steatosis scores
• Change in serum aminotransferase levels
• Change in anthropometric measurements (weight, BMI, waist to hip ratio, waist circumference, triceps skin fold thickness, upper arm circumference, body composition)
• Change in insulin resistance (assessed by HOMA)
• Change in serum vitamin E levels
• Change in cytokines, leptin, fibrosis markers, and lipid profile
• Change in HR-QOL scores

• Histologic evidence of NASH based on a liver biopsy obtained within 6 months of randomization (NALFD score of 5 or more, and score of at least 1 for hepatocellular ballooning)
• Age 18 years or older
• Exclusion: significant alcohol consumption, cirrhosis, hepatitis C, and other liver diseases, heart failure, diabetes, taking drugs known to cause steatohepatitis

Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis, but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant. There were significant benefits of pioglitazone for some of the secondary outcomes including resolution of steatohepatitis, decrease in mean aminotransferase levels, and improvement in insulin resistance.

(Contemp Clin Trials. 2009 January; 30(1): 88–96.) (N Engl J Med 2010; 362:1675-1685.)