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

Abstract

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.

Conflict of interest statement

The authors confirm the following competing interests: Victor Navarro, M.D. No conflicts relevant to this trial; Steven H. Belle, Ph.D. No conflicts relevant to this trial; Massimo D’Amato, M.D. Dr. D’Amato was an employee of the Italian subsidiary of the Rottapharm|Madaus, now Mylan, manufacturer of the silymarin formulation used in the study, at the time of the study, but left Rottapharm|Madaus to join Rottapharm Biotech in 2014 and participated in the preparation of the manuscript as an independent scientist. Rottapharm Biotech is an independent company from Mylan, does not market Legalon nor any sylimarin formulation and as corporate entity had no role in the conception, design and performance of this study, nor in the decision to submit the manuscript for publication; Nezam Afdhal, M.D. Dr. Afdhal serves as a consultant/advisory board member for Merck, Gilead, Echosens, Ligand, Jannsen, and Shionogi. He is Director, TRIO Heathcare. He owns stock or stock options in Sprinbank, Allurion, and TRIO; Elizabeth M. Brunt, M.D. Dr. Brunt was compensated by Rottapharm|Madaus for her review of the liver biopsies; Michael W. Fried, M.D. Dr. Fried receives research grants paid to his institution from AbbVie, BMS, Gilead, Merck. He serves as an unpaid consultant to AbbVie, BMS, Merck, and TARGET PharmaSolutions and owns stock in TARGET PharmaSolutions, which is held in an independently managed trust; K. Rajender Reddy, M.D. Dr. Reddy serves on the Scientific Advisory Board-Gilead, Merck, Abbvie, BMS, Spark Therapeutics. Research Support (Paid to the University of Pennsylvania)-Gilead, Merck, Abbvie, BMS, Conatus, Mallinckrodt, Intercept, Exact Sciences. DSMB-Novartis; Abdus S. Wahed, PhD: No conflicts relevant to this trial; Stephen Harrison, M.D. Consultant/Advisory board for Prometic, Innovate, Gelesis, CiVi, Contravir, Cymabay, Galectin, Northsea, Hightide, Madrigal, Metacrine, NGM, Cirius, Akero, Terns, Viking, Blade, Poxel, 3v Bio, Axcella, Merck, Gilead, Intercept, Genfit, Novo Nordisk, Echosens, Perspectum, Novartis and Medpace. Research support from Gilead, Novo Nordisk, BMS, Pfizer, Novartis, Cymabay, NGM, Axcella, Hightide, Conatus, Galectin, Intercept, Genfit, Akero, Metacrine, Cirius, Contravir, Madrigal, Enyo, Northsea. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Displayed is patient enrollment.

Of the 116 patients assessed for eligibility, 38 failed screening, and 78 underwent randomization (25 to Placebo, 26 to 420 mg, and 27 to 700 mg); this group comprised the intention to treat study population. Twenty-nine of the 78 randomized patients actually met histological criteria for NASH, as determined by the study pathologist (BB). Specifically, 34 biopsies showed an NAS