Table 2.
Primary Outcome and Changes in Histologic Features of the Liver after 96 Weeks of Treatment.
| Variable | Placebo | Vitamin E Pioglitazone | Pioglitazone | P Value* | |
|---|---|---|---|---|---|
| Vitamin E vs. Placebo |
Pioglitazone vs. Placebo |
||||
| Primary outcome† | |||||
| No. of subjects randomly assigned | 83 | 84 | 80 | ||
| Subjects with improvement (%) | 19 | 43 | 34 | 0.001 | 0.04 |
| Changes from baseline in histologic features | |||||
| No. of subjects with biopsy specimens at baseline and 96 wk |
72 | 80 | 70 | ||
| Steatosis | |||||
| Subjects with improvement (%) | 31 | 54 | 69 | 0.005 | <0.001 |
| Mean change in score | −0.1 | −0.7 | −0.8 | <0.001 | <0.001 |
| Lobular inflammation | |||||
| Subjects with improvement (%) | 35 | 54 | 60 | 0.02 | 0.004 |
| Mean change in score | −0.2 | −0.6 | −0.7 | 0.008 | <0.001 |
| Hepatocellular ballooning | |||||
| Subjects with improvement (%) | 29 | 50 | 44 | 0.01 | 0.08 |
| Mean change in score | −0.2 | −0.5 | −0.4 | 0.03 | 0.01 |
| Total NAFLD activity score (mean change) | −0.5 | −1.9 | −1.9 | <0.001 | <0.001 |
| Fibrosis‡ | |||||
| Subjects with improvement (%) | 31 | 41 | 44 | 0.24 | 0.12 |
| Mean change in score | −0.1 | −0.3 | −0.4 | 0.19 | 0.10 |
| Resolution of definite nonalcoholic steatohepatitis (% of subjects) |
21 | 36 | 47 | 0.05 | 0.001 |
P values were calculated with the use of the Mantel–Haenszel chi-square test, stratified according to clinic, for the primary outcome; Fisher’s exact test for the binary secondary outcomes; and analysis-of-covariance models, regressing change from baseline to 96 weeks on treatment group and baseline value of the outcome, for secondary outcome scores.
The primary outcome was an improvement in histologic findings, which required improvement by 1 or more points in the hepatocellular ballooning score; no increase in the fibrosis score; and either a decrease in the activity score for non-alcoholic fatty liver disease to a score of 3 points or less or a decrease in the activity score of at least 2 points, with at least a 1-point decrease in either the lobular inflammation or steatosis score. A total of 11 subjects in the placebo group, 4 in the vitamin E group, and 10 in the pioglitazone group had missing histologic data at week 96, and the results for these subjects were imputed as a lack of improvement. The NAFLD activity score was assessed on a scale of 0 to 8, with higher scores indicating more severe disease; the components of this measure include steatosis (assessed on a scale of 0 to 3), lobular inflammation (assessed on a scale of 0 to 3), and hepatocellular ballooning (assessed on a scale of 0 to 2).
Fibrosis was assessed on a scale of 0 to 4, with higher scores indicating more severe fibrosis.