Placebo in nonalcoholic steatohepatitis: insight into natural history and implications for future clinical trials

Abstract

Background & aims: Changes in biochemical and histologic parameters related to nonalcoholic steatohepatitis (NASH) in placebo-treated patients may provide an insight into the natural history and help in defining treatment end points in NASH. The aim of our study was to assess the biochemical and histologic changes seen in the placebo arm of the randomized, placebo-controlled trials in adult patients with NASH.

Methods: Medline was searched (through May 2008) for studies published in the English language. Randomized, placebo-controlled trials of at least 6 months' duration in patients with NASH that provided biochemical and/or histologic data of the placebo arm were included. One investigator performed the literature search and data extraction. Two investigators independently confirmed that the studies met prespecified criteria. Pooled estimates of biochemical and histologic parameters associated with NASH were calculated.

Results: Five randomized controlled trials met the predefined criteria and included 162 placebo-treated and 189 active-treatment patients. The mean serum alanine and aspartate aminotransferase levels decreased on placebo. A 1-point improvement in steatosis, ballooning degeneration, lobular inflammation, NASH fibrosis, and combined inflammation scores was seen in 31%, 15%, 33%, 22%, and 32% of patients, respectively. A 2-point improvement in NASH histologic scores is rarely seen.

Conclusions: Serum alanine aminotransferase levels may decrease on placebo and is not a reliable measure of treatment response. Although a 1-point improvement is seen in a third of patients, a 2-point improvement in histologic parameters is rarely seen in the placebo arm and may be more reliable in assessing treatment response. These data may have important implications in designing future clinical trials in NASH.