Original article—liver, pancreas, and biliary tract
Placebo in Nonalcoholic Steatohepatitis: Insight Into Natural History and Implications for Future Clinical Trials

https://doi.org/10.1016/j.cgh.2008.07.013Get rights and content

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.

Section snippets

Retrieval of Clinical Trials

The Medline database was searched for articles written in English through May of 2008. Indexing terms included nonalcoholic steatohepatitis or NASH in combination with randomized controlled trials, and nonalcoholic fatty liver disease or NAFLD (nonalcoholic fatty liver disease) in combination with randomized controlled trials. A manual review of the bibliographies of seminal primary and review articles also was performed to identify additional studies.

Criteria for study inclusion in the

Results

Seven studies met the specified criteria on initial screening. We excluded one study because of the short follow-up period11 and a second study because patients had nonalcoholic fatty liver disease and not exclusively NASH.12 Of 5 clinical trials in the pooled analysis, 2 were conducted in North America,13, 14 and 1 each in Switzerland,15 Iran,16 and France.17 Of the 5 studies deemed eligible, 4 were multicenter studies,13, 14, 15, 17 and 1 was a single-center study.16 The quality indicators

Discussion

The main finding of this pooled analysis is that serum ALT and AST levels declined in placebo-treated patients with NASH. Similar reductions were seen in mean changes in NASH-associated histologic parameters. The greatest decline in mean histologic scores was seen in the steatosis score, which was statistically significant. The overall decrease in these parameters was small, but depending on how an outcome measure is defined it may become statistically significant. A 1-point reduction in any of

Conclusions

Serum ALT and AST levels change during follow-up evaluation in NASH patients and may not reflect histologic improvement. Minor improvements in NASH-associated histologic scores are seen in up to a third of patients, although a 2-point improvement in steatosis, ballooning degeneration, or lobular inflammation rarely is seen in placebo-treated individuals. These data have important implications for designing and reporting future clinical trials in NASH and suggest a need for standardization of

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This study was supported by the intramural research programs of the National institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute, National Institutes of Health.

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