Report on the AASLD/EASL Joint Workshop on Clinical Trial Endpoints in NAFLD

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a global public health concern. Its natural history, the development of nonalcoholic steatohepatitis (NASH) and fibrosis, is highly variable, prone to endogenous (e.g., genetics, microbiota) and exogenous (e.g., nutrition, alcohol, physical activity) disease modifiers, and can fluctuate over time. The complexity of its pathophysiology is reflected by the multitude of pharmacological targets in development. NASH clinical trials have provided valuable insight that is applicable to future trial design. Endpoints for NASH have evolved over the past decade and will continue to be refined. Currently accepted endpoints for conditional approval include resolution of NASH without worsening of fibrosis and/or improvement in fibrosis without worsening of NASH by standardized evaluation of paired liver histology. In pediatric NASH, practical obstacles, pubertal hormonal changes, and stringent safety requirements mandate adaptations in trial design. In adult patients with NASH‐related cirrhosis, clinical events (e.g. decompensation, hepatocellular carcinoma, transplantation, death) are more prevalent and thereby are viable primary endpoints. Consideration of the natural fluctuation of disease, the clinical implication of the chosen primary endpoint, and factors that may affect placebo response will facilitate an accurate determination of efficacy of emerging therapeutics for NASH. Conclusion: The June 2018 American Association for the Study of Liver Diseases and European Association for the Study of the Liver joint workshop on NAFLD endpoints summarized important findings from ongoing and completed trials, defined the scientific evidence supporting distinct endpoints, and provided guidance for future trial design.

Effect of Weight Loss Medications on Hepatic Steatosis and Steatohepatitis: A Systematic Review

“…Studies that were double-blind with an active or placebo comparator were considered to be of highest quality. Given the variable natural history of NAFLD, a robust placebo response is present in studies of NAFLD and NASH (3,73), such that studies without a comparator were considered to be of lowest quality. Optimal endpoints for studies of NAFLD and NASH are currently the subject of much discussion (3).…”

“…Consequently, understanding the possible hepatic effects of currently used weight loss medications is important to aid clinicians in selecting appropriate therapy for individuals who desire weight loss medication and also have NAFLD. The current "gold standard" endpoints for improvement in NAFLD in clinical trials are either (A) resolution of steatohepatitis without worsening of fibrosis or (B) improvement in fibrosis without worsening of steatohepatitis, both requiring assessment by liver biopsy (3). None of the literature reviewed herein utilized these endpoints, which are specific to treatment trials of NAFLD.…”

Phase 3 drug pipelines in the treatment of non‐alcoholic steatohepatitis

“…Third, paired liver biopsies are required to evaluate treatment efficacy in phase 3 trials. 30 Non-invasive tests reflecting fibrosis progression or regression should be established. It is expected that fibrosis markers or imaging modalities will replace liver biopsies.…”

“…First, these primary outcomes are variable across studies (Table ). According to the report on the American Association for the Study of Liver diseases/European Association for the Study of the Liver joint workshop on clinical end‐points in NASH, the currently accepted end‐points for conditional approval include NASH resolution without worsening fibrosis and/or improvement in fibrosis by at least one stage with no worsening of NASH by paired biopsies . Second, fibrosis stages in enrolled patients are variable (from stage 1 to cirrhosis).…”

“…Primary end‐points must be different according to fibrosis stage. Third, paired liver biopsies are required to evaluate treatment efficacy in phase 3 trials . Non‐invasive tests reflecting fibrosis progression or regression should be established.…”