| Outcome Measures: |
Primary: The proportion of pioglitazone-treated patients relative to placebo achieving an improvement of ≥2 points in non-alcoholic fatty liver disease activity score (NAS) without an increase in fibrosis stage., The proportion of patients with liver histological improvement of ≥2 points in non-alcoholic fatty liver disease activity score (NAS) with a ≥1-point reduction in either ballooning or lobular inflammation and no increase in fibrosis stage by NASH CRN scoring criteria., 72 weeks of treatment | Secondary: Resolution of NASH without worsening of liver fibrosis., The proportion of pioglitazone-treated patients achieving NASH resolution, defined as hepatocellular ballooning score of 0 and lobular NASH CRN scoring criteria. inflammation score of 0-1, with no increase in fibrosis stage., 72 weeks|Proportion of patients with improvement in the activity component of steatosis-activity-fibrosis (SAF) score., Proportion of patients with improvement in the activity component of steatosis-activity-fibrosis (SAF) score., 72 weeks.|Proportion of patients with NAS improvement (0-8)., The proportion of pioglitazone-treated patients achieving NAS improvement compared to placebo by NASH CRN scoring criteria., 72 weeks.|Mean NAS change (0-8)., Defined as the mean change in the NAS score by NASH CRN scoring criteria., 72 weeks.|Proportion of patients with a change of the individual components of the NAS score (steatosis, lobular inflammation and ballooning) by at least 1 point., Defined as the proportion of patients with a change in steatosis, ballooning or inflammation by NASH CRN scoring criteria., 72 weeks|Mean change of the individual components of the NAS, Defined as the mean change in steatosis, ballooning or inflammation by NASH CRN scoring criteria., 72 weeks|Fibrosis improvement., Defined as the proportion of patients with ≥1-stage decrease in fibrosis with no worsening of lobular inflammation or hepatocellular ballooning by NASH CRN scoring criteria., 72 weeks.|Improvement of fibrosis by at least 2 stages., Defined as the proportion of patients with an improvement of fibrosis by 2 stages by NASH CRN scoring criteria., 72 weeks.|Improvement of fibrosis AND resolution of NASH as a composite endpoint., Defined as the proportion of patients with improvement in both endpoints being met in the same subject by NASH CRN scoring criteria., 72 weeks.|No worsening of fibrosis AND no worsening of NASH, Defined as the proportion of patients with no worsening of fibrosis AND no worsening of ballooning or inflammation by NASH CRN scoring criteria., 72 weeks.|Progression of liver fibrosis., Defined by the proportion of patients with progression \>1 stage in liver fibrosis by NASH CRN scoring criteria., 72 weeks|Mean change in liver fibrosis, Defined as he mean change in liver fibrosis by NASH CRN scoring criteria., 72 weeks. | Other: Liver fibrosis by imaging., Measured by magnetic resonance elastography., 72 weeks.|Intrahepatic triglyceride content, Measured by magnetic resonance imaging, 72 weeks.|CAP (controlled attenuation parameter) and vibration controlled transient elastography (VCTE), Measurement of CAP and VCTE by Fibroscan., 72 weeks.|Liver cT1 MRI mapping (Liver Multiscan), A measurement of liver disease actvitiy, 72 weeks.|Atlas imaging, An integrated MRI body fat distribution; cardiovascular and abdominal organ measurement., 72 weeks.|biomarkers of liver fibrosis, FIB-4, NFS, APRI, PRO-C3, 72 weeks.|Insulin sensitivity, Defined as an improvement in HOMA (fasting plasma glucose x fasting plasma insulin)., 72 weeks|Adipose tissue insulin sensitivity (Adipo-IR), Defined as an improvement in Adipo-IR (fasting plasma free fatty acids x fasting plasma insulin), 72 weeks|Lipid profile, Defined as an improvement in any one of the following parameters: plasma total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and lipoproteins., 72 weeks.|Glycemic control, Fasting plasma glucose and Hba1c, 72 weeks.
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