Evaluation via telephone was carried out at 3-, 9-, and 15-month intervals. UDCA and placebo were shipped to the participating medical centers and were handed to randomized patients upon entry into the study after 6 and 12 months. Regular

drug intake was determined by phone calls. Unused drugs were returned to the medical centers during visits, and this made calculation of patient compliance possible. Duplex ultrasonography was performed at entrance into the study and after 6, 12, and 18 Wnt antagonist months. Primary Criterion for Evaluation: The primary criterion for efficacy was an overall improvement of liver histology after 18 months. Pre-post differences of the sum scores were compared in each

group, and this was followed by a comparison of the UDCA and placebo groups. Secondary Criteria for Evaluation: The pre-post differences of each of four histological criteria were compared and this was followed by comparison of the UDCA and placebo groups. Further pre-post differences for the liver function tests and for the other clinical parameters were evaluated. Subgroup analyses comparing the secondary variables of the UDCA group with those of the placebo group included age (<50 years and ≥50 years), inflammation (sum score >7 points), improvement of alanine aminotransferase (ALT; by ≥50%), MCE body mass index (BMI; ≤30 kg/m2 and >30 kg/m2), and blood pressure (<130/85 mm Hg and ≥130/85 mm Hg). Because in the UDCA group only 10 patients

R788 and in the placebo group only 11 patients presented with type 2 diabetes, diabetes was not used for subgroup analysis. Symptoms such as fatigue, malaise, pruritis, right upper quadrant abdominal discomfort, right upper quadrant abdominal pain, and tenderness were assessed by the investigator on each visit. The sum scores of symptoms were determined according to a scale ranging from 0 to 3 (none, mild, moderate, and severe). The assessment of the safety and tolerability profile of UDCA included adverse events, laboratory data, liver biopsy, and ultrasonography. Adverse events were registered throughout the study and were coded according to MedDRA version 10.1, and the number of patients was compared between the treatment groups. Although our study was started 3 years before publication of the NAS,2 a second evaluation was performed according to the NAS, a score in which steatosis, lobular inflammation, and hepatocellular ballooning are used as variables. The definition of NASH according to the NAS was applied to all randomized patients, and the response to therapy was assessed with the NAS. Liver biopsy samples were obtained from 137 patients; 107 (78%) underwent biopsy a second time.