Silymarin in non-cirrhotics with non-alcoholic steatohepatitis: A randomized, double-blind, placebo controlled trial

• Published in: PloS one Vol. 14; no. 9; p. e0221683
• Main Authors: Navarro, Victor J, Belle, Steven H, D'Amato, Massimo, Adfhal, Nezam, Brunt, Elizabeth M, Fried, Michael W, Reddy, K Rajender, Wahed, Abdus S, Harrison, Stephen
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.09.2019; Public Library of Science (PLoS)
• Subjects: Adult; Analysis; Antioxidants; Antioxidants (Nutrients); Antioxidants - administration & dosage; Antioxidants - adverse effects; Biology and Life Sciences; Biopsy; Care and treatment; Cirrhosis; Clinical trials; Development and progression; Diabetes; Double-Blind Method; Double-blind studies; Drug dosages; Epidemiology; Fatty liver; Female; Fibrosis; Gastroenterology; Health care facilities; Hepatitis; Hepatology; Humans; Intention to Treat Analysis; Lipid peroxidation; Lipids; Liver; Liver cirrhosis; Liver diseases; Male; Medical centers; Medical research; Medical services; Medical treatment; Medicine; Medicine and Health Sciences; Middle Aged; Milk; Motivation; Non-alcoholic Fatty Liver Disease - drug therapy; Patients; People and Places; Public health; Randomization; Research and Analysis Methods; Resorcinols; Silymarin; Silymarin - administration & dosage; Silymarin - adverse effects; Statistical analysis; Treatment Outcome; United States > US; Pittsburgh Pennsylvania; Pennsylvania
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0221683

The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease and may be a treatment for NASH due to its antioxidant properties. We aimed to assess the safety and efficacy of higher than customary doses of silymarin in non-cirrhotic patients with NASH. This exploratory randomized double-blind placebo controlled multicenter Phase II trial tested a proprietary standardized silymarin preparation (Legalon®, Rottapharm|Madaus, Mylan) and was conducted at 5 medical centers in the United States. Eligible adult patients had liver biopsy within 12 months showing NASH without cirrhosis with NAFLD Activity Score (NAS) ≥4 per site pathologist's assessment. Participants were randomized to Legalon® 420 mg, 700 mg, or placebo t.i.d. for 48 weeks. The primary endpoint was histological improvement ≥2 points in NAS. Of 116 patients screened, 78 were randomized. There were no significant differences in adverse events among the treatment groups. After 48-50 weeks, 4/27 (15%) in the 700 mg dose, 5/26 (19%) participants randomized to 420 mg, and 3/25 (12%) of placebo recipients reached the primary endpoint (p = 0.79) among all randomized participants, indicating no benefit from silymarin in the intention to treat analysis Review by a central pathologist demonstrated that a substantial number of participants (49, 63%) did not meet histological entry criteria and that fibrosis stage improved most in the placebo treated group, although not significantly different from other groups. Silymarin (Legalon®) at the higher than customary doses tested in this study is safe and well tolerated. The effect of silymarin in patients with NASH remains inconclusive due to the substantial number of patients who entered the study but did not meet entry histological criteria, the lack of a statistically significant improvement in NAS of silymarin treated patients, and the unanticipated effect of placebo on fibrosis indicate the need for additional clinical trials. Trial Registration: clinicaltrials.gov, Identifier: NCT00680407.