Silymarin for the Treatment of Non-Alcoholic Fatty Liver Disease (NAFLD)

A Randomised, Double-blind, Placebo-controlled, Phase II, Single-centre Study to Assess the Safety and Efficacy of Silymarin 700 mg Capsules TID for the Treatment of Non-Alcoholic Fatty Liver Disease (NAFLD)

This is a randomised study to examine whether high dose Sillymarin will be able to help improve fat-induced liver damage in the liver. The study hypothesis is that high dose Sillymarin will be able to reduce steato-hepatitis (fat-related liver inflammation) better than placebo.

Study Overview

• Status: Completed
• Conditions: Non-alcoholic Fatty Liver Disease
• Intervention / Treatment: Drug: Sillymarin; Drug: Placebo

Detailed Description

OBJECTIVES OF STUDY Primary Objectives

1. To assess the safety and adverse event profile of Silymarin compared to placebo.
2. To assess the efficacy of Silymarin as defined by an improvement in non-alcoholic steatosis (NAS) activity score by at least 30% from baseline compared to placebo.

Secondary Objectives

1. To compare NAS activity before and after Silymarin therapy.
2. To characterize changes in ALT and AST during Silymarin therapy.
3. To compare insulin resistance measured by HOMAr during Silymarin therapy.

• Study Type: Interventional
• Enrollment (Actual): 99
• Phase: Phase 2

Contacts and Locations

Study Locations

• Malaysia
  • Federal Territory
    • Kuala Lumpur, Federal Territory, Malaysia, 59100
      • University Malaya Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female 18 years of age or older.
• Diagnosed with NASH (refer to Section 5.2)
• AST and/or ALT greater than 40 IU/L.
• Must agree to adhere to alcohol consumption guideline.
• Weight gain//loss of no more than 10% between biopsy and screening or within 30 days of screening if the biopsy is performed during the screening period.
• No change in diabetic and/or lipid medications between biopsy and screening or within 30 days of screening if the biopsy is performed during the screening period

Exclusion Criteria:

• Use of silymarin or other milk thistle preparations for a period of 90 consecutive days or longer between biopsy and initial screening, or within 30 days prior to screening if the biopsy is performed during the screening period.

  • Use of other antioxidants or non-prescribed complementary alternative medications for a period of 90 consecutive days or longer between biopsy and initial screening, or within 30 days prior to screening if the biopsy is performed during the screening period.
  • Use of warfarin, metronidazole, or acetaminophen (greater than 2 grams per day) between screening and randomization.
  • Use of oral steroids for more than 14 days of screening or prior to randomization.
  • BMI ≥ 35 kg/m2 between screening and randomization.
  • Poorly-controlled diabetes (HbA1c > 8 %) between screening and randomization
  • Diabetes mellitus treated with oral agents other than the secretagogues or metformin between screening and randomization. Sitagliptin is allowed.
  • For patients using anti-hyperlipidemic agents or accepted anti-diabetic agents, any change of agent or dose between screening and randomization.
  • Radiologic imaging consistent with cirrhosis or portal hypertension.
  • Evidence of decompensated liver disease
  • Platelet count < 130 x 109 /L at screening.
  • History of bariatric surgery, or undergoing evaluation for bariatric surgery.
  • Known allergy/sensitivity to milk thistle or its preparations.
  • History of immunologically mediated disease
  • History of thyroid disease poorly controlled on prescribed medications.
  • History of solid organ or bone marrow transplantation.
  • Primary hepatic malignancy.
  • Secondary hepatic malignancy or extrahepatic malignancy.
  • Serum Creatinine of 176 μmol/L or greater or creatinine clearance (calculated according to Cockcroft-Gault) 60 mL/min or less, or on dialysis, at screening.
  • Severe illness or any other conditions that would make the patient, in the opinion of the investigator, unsuitable for the study.
  • Women with ongoing pregnancy or breast feeding, or contemplating pregnancy.
  • Women of childbearing potential who are not practicing an acceptable form of birth control.
  • Participation in a research drug trial within 30 days of screening.
  • Inability or unwillingness to give informed consent or abide by the study protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo capsules	Drug: Placebo; Placebo capsule with same appearances as study drug
Experimental: Sillymarin; Active component study medication	Drug: Sillymarin; Sillymarin is derived from the milk thistle plant, Silybum marianum, a herbal remedy that has been used for centuries for diseases of the liver. It is a complex mixture of 6 major flavonolignans (silybins A and B, isosilybins A and B, silychristin, and silydianin), as well as other minor polyphenolic compounds.; Other Names: Legalon

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To assess the efficacy of Silymarin as defined by an improvement in non-alcoholic steatosis (NAS) activity score by at least 30% from baseline compared to placebo	12 months

Secondary Outcome Measures

Outcome Measure	Time Frame
To assess the safety and adverse event profile of Silymarin compared to placebo	12 months

Other Outcome Measures

Outcome Measure	Time Frame
To characterize changes in ALT and AST during Silymarin therapy	12 months
To compare insulin resistance measured by HOMAr during Silymarin therapy.	12 months

Collaborators and Investigators

• Sponsor: University of Malaya
• Collaborators: Rottapharm
• Investigators: Principal Investigator: Sanjiv Mahadeva, MD, MRCP, University Malaya

Publications and helpful links

General Publications

• Wah Kheong C, Nik Mustapha NR, Mahadeva S. A Randomized Trial of Silymarin for the Treatment of Nonalcoholic Steatohepatitis. Clin Gastroenterol Hepatol. 2017 Dec;15(12):1940-1949.e8. doi: 10.1016/j.cgh.2017.04.016. Epub 2017 Apr 15.

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: December 4, 2013
• First Submitted That Met QC Criteria: December 4, 2013
• First Posted (Estimate): December 10, 2013

Study Record Updates

• Last Update Posted (Estimate): January 8, 2016
• Last Update Submitted That Met QC Criteria: January 6, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; sillymarin; randomised trial
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Antioxidants; Silymarin
• Other Study ID Numbers: LE13T0.01