Objective and design: The study aimed at assessing the therapeutic efficacy and safety of metadoxine versus placebo on the ultrasonographic and histological features of non-alcoholic steatohepatitis (NASH).
Subjects: 134 subjects with biopsy-confirmed NASH were randomized to receive metadoxine 500 mg two times daily (n = 75) or placebo (n = 59) added to the standard of care, over 16 weeks.
Efficacy endpoints: Originally, the primary efficacy endpoint was the composite of: reduction in the steatosis by ≥1 grade, reduction in hepatic necro-inflammation by ≥1 grade and ALT normalization. Since >50% of patients refused the second biopsy, it was decided to analyze only the individual parameters.
Results: There was no significant difference between the treatment and the placebo groups in either liver histology or ALT or AST. Overall, as expected both groups showed reduction in serum ALT and AST compared to baseline. Compared to placebo (9 out 54), patients on metadoxine (34 out of 75) had significantly higher rates of improvement in 1-point in steatosis grade on ultrasound (P-value <0.001). Safety and tolerability did not differ between treatments.
Conclusion: Metadoxine is not effective in improvement of liver histology or serum ALT or AST in patients with NASH. However, there was significant improvement of steatosis assessed by ultrasound. To properly estimate the effects on histology and transaminases, further studies of longer duration and at higher doses are needed.
Keywords: ALD, alcoholic liver disease; ALT, alanine transaminase; ANCOVA, analysis of covariance; AST, aspartate transaminase; ATP, adenosine triphosphate; GGT, gamma-glutamyl transferase; GSH, glutathione; HOMA-IR, homeostasis model assessment for insulin resistance; ITT, intention to treat; MRI, magnetic resonance imaging; MRS, MR spectroscopy; NADH, nicotinamide adenine dinucleotide; NAFLD, non-alcoholic fatty liver disease; NASH; NASH, non-alcoholic steatohepatitis; PDFF, proton-density fat-fraction; RCTs, randomized clinical trials; RIQ, range interquartile; TNF, tumor necrosis factors; controlled clinical trial; metadoxine.