Table 4.

Populations to study in clinical trials of NASH

Population	Comment
For advanced (stage 3–4) disease (mainly anti-fibrotic therapies)
Biopsy-based populations -NASH -Bridging fibrosis or cirrhosis	Biopsy-based populations: Biopsy remains gold standard despite several limitations
Non-biopsy based populations: -Steatosis (by MR spectroscopy or diffusion-weighted MR) -Elevated ALT (> 40 IU/L) or CK 18> (270 u/l) -Advanced fibrosis/cirrhosis by FDA-approved non-invasive method (e.g., elastography) -Absence of alternate cause of liver disease	Non-biopsy based populations: These represent alternate approaches to identification of NASH with advanced fibrosis. It is recommended that sponsors discuss with FDA during pre-IND process about these entry criteria
Populations may be enriched for risk of clinical outcomes by inclusion of subjects with: -MELD > 10 -HVPG > 10 mm Hg -High NAFLD fibrosis score or FIB4 Additional considerations: -fibrosis-related SNPs -type 2 diabetes	Enrichment of populations: Most useful when a liver-related clinical outcome or meeting minimal listing criteria for transplant (MELD of 15 or higher) is the primary endpoint Fibrosis-related SNPs may explain variability in treatment response and could be used as an ancillary entry criteria Type 2 diabetes affects clinical outcomes and should be accounted for by stratification or randomization
For early (stage 0–2) stage disease (anti-NASH therapies)
-Nonalcoholic steatohepatitis (biopsy-proven definite or borderline steatohepatitis) -Grade 2 or greater inflammation -Presence of ballooning with Mallory bodies -Stage 1–2 fibrosis -Persistently elevated ALT over last 6 months -Metabolic syndrome	This population has up to 20% probability of developing advanced fibrosis/cirrhosis within 4 years. Should be feasible to demonstrate reversal of steatohepatitis without fibrosis progression to bridging or cirrhosis within 1–2 years.