SyNCH: Phase II Trial of Silymarin for Non-Cirrhotic Patients With Non-Alcoholic Steatohepatitis

• Sponsor: Madaus Inc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00680407
• Collaborator: University of Pennsylvania (Other), University of North Carolina (Other), Thomas Jefferson University (Other), Beth Israel Deaconess Medical Center (Other), Brooke Army Medical Center (U.S. Fed), University of Pittsburgh (Other)
• Enrollment: 78
• Locations: 6
• Arms: 3
• Duration (Months): 55
• Patients Per Site: 13
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Silymarin, also known as milk thistle, is an alternative medicine commonly found in health food and vitamin stores. People with liver disease sometimes use silymarin because it is thought to have liver protecting effects; however, this benefit has not been proven. The purpose of this research study is to determine the effectiveness of silymarin and assess the safety of different silymarin doses in patients with varying severity of liver disease compared to a placebo (lactose pill).

Following a screening visit, patients with histologically confirmed NASH will be randomized to either placebo or one of two active treatment groups of silymarin (Legalon®). One active treatment group will receive 420 mg, each dose given three times daily, the other active treatment group will receive 700 mg, each dose given three times daily. Patients will be treated for 48-50 weeks. Participation in this research study requires the patient to travel to the clinic for at least 11 visits so recruitment will be limited to a geographically restricted area around participating clinical centers. Liver biopsy must be performed up to 12 months prior to, and immediately after, the treatment phase.

Condition or Disease	Intervention/Treatment	Phase
Non-alcoholic Steatohepatitis	Other: Placebo; Drug: Silymarin 700 mg; Drug: Silymarin 420 mg	Phase 2

Detailed Description

This is a multicenter, randomized, double masked, placebo controlled Phase II trial to evaluate the safety and explore the efficacy of silymarin (Legalon®) compared with placebo on hepatic histology in patients with NASH (nonalcoholic steatohepatitis) after 48-50 weeks of therapy. This study was originally sponsored through a cooperative agreement (U01) award from the NCCAM and the NIDDK (RFA-AT-05-006: "Phase I/II Trials of Silymarin for Chronic Liver Diseases"), and now will continue with Madaus Inc. (Rottapharm Group) providing financial and regulatory support to the investigators. The broad aim of this study is to evaluate the safety and explore the efficacy of silymarin (Legalon®) in NASH patients and to form the basis for future studies which will establish its efficacy for treating patients with NASH. The specific objectives of this study are to determine the effect of silymarin (Legalon®) on the histologic NASH Activity Score (NAS), the liver enzymes, and HOMAr. The primary endpoint of the study is an improvement in the NAS by at least 2 points. Various secondary endpoints will be assessed, including the change in liver enzymes and HOMAr.

Study Design

• Study Type: Interventional
• Actual Enrollment: 78 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Placebo Controlled Study to Assess the Safety and Efficacy of Orally Administered Silymarin Preparation (Legalon®) for the Treatment of Non-Cirrhotic Patients With Non-Alcoholic Steatohepatitis
• Study Start Date: Apr 1, 2008
• Actual Primary Completion Date: Nov 1, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: silymarin 420 mg 420 mg Legalon (silymarin) three times daily	Drug: Silymarin 420 mg; 420 mg dose (5 pills, three times daily) for 48-50 week treatment period; Other Names: Legalon milk thistle
Experimental: silymarin 700 mg 700 mg of Legalon (silymarin) three times daily	Drug: Silymarin 700 mg; 700 mg dose (5 pills, three times daily) for 48-50 week treatment period; Other Names: Legalon milk thistle
Placebo Comparator: Placebo Placebo (lactose pill)	Other: Placebo; Placebo (5 pills, three times daily) for 48-50 week treatment period; Other Names: lactose pill

Outcome Measures

Primary Outcome Measures

1. Efficacy - Improvement by at Least 2 Points in Histology (NAS) [48-50 week treatment period]

   Histological Scoring System for Nonalcoholic Fatty Liver Disease ranges from 0-8 with the increase in number representing a worse outcome. Therefore the efficacy improvement was to be at least 2 points in lowering the score.

Secondary Outcome Measures

1. Safety - Occurrence of a Dose-limiting Toxicity [48-50 week treatment period]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age at least 18 years at screening.

• Informed consent signature.

• AST (aspartate aminotransferase) or ALT (alanine aminotransferase) greater than 40 IU/L within one year of screening and at least once during the screening period.

• The participant must agree to adhere to the alcohol consumption guidelines.

• Have a liver biopsy performed within 12 months of randomization demonstrating features consistent with NASH without cirrhosis; NAS score of at least 4. Historical biopsy must include one Trichrome and one H&E slide, otherwise the biopsy must be redone.

• No change in diabetic medications or insulin sensitizers (if applicable) between biopsy and screening or during the screening period.

• Weight loss/gain of no more than 10% between biopsy and screening, or within 30 days of screening if the biopsy is performed during the screening period.

• Negative urine pregnancy test (for women of childbearing potential) documented within the 24-hour period prior to the first dose of study medication. Females of childbearing potential must be using two reliable forms of effective contraception during the study (while on study drug and during follow-up).

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 such as vitamin E, vitamin C, glutathione, alpha-tocopherol, or non-prescribed complementary alternative medications (including dietary supplements, megadose vitamins, herbal preparations, and special teas) within 30 days prior to screening. A multivitamin at standard doses will be allowed.

• Use of silymarin or other antioxidants or non-prescribed complementary alternative medications (as above) during the screening period or patient unwilling to refrain from taking these medications through completion of the study.

• BMI > 45 kg/m2 between screening and randomization.

• Type 2 diabetes treated with oral agents other than the secretagogues or metformin; these include, thiazolidinediones, alpha-glucosidase inhibitors, exenatide, pramlintide between screening and randomization. Januvia (sitagliptin) is allowed.

• Evidence of poorly-controlled diabetes (defined as HbA1c > 8% in patients with diabetes) between screening and randomization.

• Known allergy/sensitivity to milk thistle or its preparations.

• Use of drugs associated with a clinical or histological picture consistent with fatty liver disease or NASH for more than 12 consecutive weeks in the 1 year prior to screening; these include amiodarone, tamoxifen, methotrexate, glucocorticoids, anabolic steroids, tetracyclines, estrogens at doses greater than those used for hormone replacement, valproate/valproic acid.

• For patients using antihyperlipidemic agents or accepted anti-diabetic agents, any change of agent or dose from screening through randomization.

• Use of warfarin, metronidazole, or acetaminophen (greater than 2 grams per day) from screening through randomization.

• Lactose intolerance defined as patient reported inability to tolerate milk products.

• History of other chronic liver disease, including metabolic diseases, documented by appropriate test(s).

• Previous liver biopsy that demonstrated presence of cirrhosis.

• Radiologic imaging consistent with cirrhosis or portal hypertension.

• Clinical or histological evidence of cirrhosis or, in the opinion of the investigator, the inability to safely obtain a liver biopsy due to technical reasons, such as body habitus.

• Evidence of decompensated liver disease defined as any of the following: serum albumin <3.2 g/dl, total bilirubin > 1.5 mg/dl, or PT/INR (Prothrombin Time/International Normalized Ratio) > 1.3 times normal at screening, or history or presence of ascites or encephalopathy, or bleeding from esophageal varices.

• Platelet count < 130,000/mm3 at screening.

• Serum creatinine of 2.0 mg/dL or greater or CrCl ≤ 60cc/min, or on dialysis, at screening. The creatinine clearance (CrCl) will be calculated according to Cockcroft-Gault.

• Average alcohol consumption of more than one drink or equivalent (>12 grams) per day or more than two (2) drinks on any one day over the 30 days prior to screening. Patients who met either criterion more than 30 days prior to screening must have consumed a monthly average of 12 grams or less per day of alcohol for at least six months prior to screening.

• Evidence of drug abuse in the year prior to screening or prior to randomization.

• History of immunologically mediated disease (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, severe psoriasis, rheumatoid arthritis) that could affect the assessment of biomarkers of inflammation.

• History of solid organ or bone marrow transplantation.

• History of thyroid disease poorly controlled on prescribed medications.

• Use of oral steroids for more than 14 days within 30 days of screening or prior to randomization.

• Primary hepatic malignancy.

• Secondary hepatic malignancy (metastatic disease) or extrahepatic malignancy.

• Women with ongoing pregnancy or breast feeding, or contemplating pregnancy.

• History of bariatric surgery, or undergoing evaluation for bariatric surgery.

• Participation in a research drug trial, exclusive of the SyNCH Phase I trial, within 30 days of screening.

• History or other evidence of severe illness or any other conditions that would make the patient, in the opinion of the investigator, unsuitable for the study (such as poorly controlled psychiatric disease, coronary artery disease, or active gastrointestinal conditions that might interfere with drug absorption).

• Inability or unwillingness to give informed consent or abide by the study protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beth Isreal Deaconess Medical Center	Boston	Massachusetts	United States	02215
2	University of North Carolina - Chapel Hill	Chapel Hill	North Carolina	United States	27599
3	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
4	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
5	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
6	Brooke Army Medical Center	San Antonio	Texas	United States	78234

Sponsors and Collaborators

• Madaus Inc
• University of Pennsylvania
• University of North Carolina
• Thomas Jefferson University
• Beth Israel Deaconess Medical Center
• Brooke Army Medical Center
• University of Pittsburgh

Investigators

• Principal Investigator: Michael Fried, MD, University of North Carolina, Chapel Hill
• Principal Investigator: Victor Navarro, MD, Thomas Jefferson University
• Principal Investigator: Nezam Afdhal, MD, Beth Israel Deaconess Medical Center
• Principal Investigator: K. Rajender Reddy, MD, University of Pennsylvania
• Principal Investigator: Steven H. Belle, PhD, University of Pittsburgh
• Principal Investigator: Stephen A. Harrison, MD, Brooke Army Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Madaus Inc
• ClinicalTrials.gov Identifier: NCT00680407
• Other Study ID Numbers: U01AT003566-02; IND 105,461 (orig. IND 74,887)
• First Posted: May 20, 2008
• Last Update Posted: Jul 17, 2019
• Last Verified: Jul 1, 2019

• Keywords provided by Madaus Inc: NASH; non-alcoholic steatohepatitis
• Additional relevant MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease; Silymarin

Study Results

Participant Flow

Recruitment Details	Patients were recruited at 5 sites; first observation April 30, 2008, last observation Nov 12, 2012.

Arm/Group Title	Silymarin 420 mg	Silymarin 700 mg	Placebo
Arm/Group Description	420 mg Legalon (silymarin) three times daily Silymarin 420 mg: 420 mg dose (5 pills, three times daily) for 48-50 week treatment period	700 mg of Legalon (silymarin) three times daily Silymarin 700 mg: 700 mg dose (5 pills, three times daily) for 48-50 week treatment period	Placebo (lactose pill) Placebo: Placebo (5 pills, three times daily) for 48-50 week treatment period
Period Title: Overall Study
STARTED	26	27	25
COMPLETED	18	22	22
NOT COMPLETED	8	5	3

Baseline Characteristics

Arm/Group Title	Silymarin 420 mg	Silymarin 700 mg	Placebo	Total
Arm/Group Description	420 mg Legalon (silymarin) three times daily Silymarin 420 mg: 420 mg dose (5 pills, three times daily) for 48-50 week treatment period	700 mg of Legalon (silymarin) three times daily Silymarin 700 mg: 700 mg dose (5 pills, three times daily) for 48-50 week treatment period	Placebo (lactose pill) Placebo: Placebo (5 pills, three times daily) for 48-50 week treatment period	Total of all reporting groups
Overall Participants	26	27	25	78
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.3 (10.83)	48.2 (11.43)	49.51 (10.89)	48.3 (10.95)
Sex: Female, Male (Count of Participants)
Female	13 50%	9 33.3%	11 44%	33 42.3%
Male	13 50%	18 66.7%	14 56%	45 57.7%

Outcome Measures

1. Primary Outcome

Title	Efficacy - Improvement by at Least 2 Points in Histology (NAS)
Description	Histological Scoring System for Nonalcoholic Fatty Liver Disease ranges from 0-8 with the increase in number representing a worse outcome. Therefore the efficacy improvement was to be at least 2 points in lowering the score.
Time Frame	48-50 week treatment period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Silymarin 420 mg	Silymarin 700 mg	Placebo
Arm/Group Description	420 mg Legalon (silymarin) three times daily Silymarin 420 mg: 420 mg dose (5 pills, three times daily) for 48-50 week treatment period	700 mg of Legalon (silymarin) three times daily Silymarin 700 mg: 700 mg dose (5 pills, three times daily) for 48-50 week treatment period	Placebo (lactose pill) Placebo: Placebo (5 pills, three times daily) for 48-50 week treatment period
Measure Participants	26	27	25
Number [participants]	5 19.2%	4 14.8%	3 12%

2. Secondary Outcome

Title	Safety - Occurrence of a Dose-limiting Toxicity
Time Frame	48-50 week treatment period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Silymarin 420 mg	Silymarin 700 mg	Placebo
Arm/Group Description	420 mg Legalon (silymarin) three times daily Silymarin 420 mg: 420 mg dose (5 pills, three times daily) for 48-50 week treatment period	700 mg of Legalon (silymarin) three times daily Silymarin 700 mg: 700 mg dose (5 pills, three times daily) for 48-50 week treatment period	Placebo (lactose pill) Placebo: Placebo (5 pills, three times daily) for 48-50 week treatment period
Measure Participants	26	27	25
Number [participants]	2 7.7%	0 0%	0 0%

3. Post-Hoc Outcome

Title	Efficacy - Improvement by at Least 2 Points in Histology (NAS) - With NAS Without Cirrhosis
Description	This outcome measure excludes the substantial percentage (62.8%) of patients with baseline biopsies that were deemed ineligible (per inclusion criteria) by the central pathologist due to NAS <4 or absence of NASH (nonalcoholic steatohepatitis) (n=34), NASH with presence of cirrhosis (n=1), or slides unavailable/not evaluable for reading (n=14).
Time Frame	48-50 week treatment period

Outcome Measure Data

Analysis Population Description

Subgroup of ITT (Intent to Treat) Patients with NASH and without cirrhosis population

Arm/Group Title	Silymarin 420 mg	Silymarin 700 mg	Placebo
Arm/Group Description	420 mg Legalon (silymarin) three times daily Silymarin 420 mg: 420 mg dose (5 pills, three times daily) for 48-50 week treatment period	700 mg of Legalon (silymarin) three times daily Silymarin 700 mg: 700 mg dose (5 pills, three times daily) for 48-50 week treatment period	Placebo (lactose pill) Placebo: Placebo (5 pills, three times daily) for 48-50 week treatment period
Measure Participants	10	9	10
Number [participants]	3 11.5%	4 14.8%	1 4%

Adverse Events

Arm/Group Title	Silymarin 420 mg		Silymarin 700 mg		Placebo
Arm/Group Description	420 mg Legalon (silymarin) three times daily Silymarin 420 mg: 420 mg dose (5 pills, three times daily) for 48-50 week treatment period		700 mg of Legalon (silymarin) three times daily Silymarin 700 mg: 700 mg dose (5 pills, three times daily) for 48-50 week treatment period		Placebo (lactose pill) Placebo: Placebo (5 pills, three times daily) for 48-50 week treatment period
All Cause Mortality
	Silymarin 420 mg		Silymarin 700 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Silymarin 420 mg		Silymarin 700 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/26 (3.8%)		2/27 (7.4%)		1/25 (4%)
Blood and lymphatic system disorders
LOW PLATELET COUNT	0/26 (0%)	0	1/27 (3.7%)	1	0/25 (0%)	0
Hepatobiliary disorders
ACUTE HEMATOMA POST TREATMENT LIVER BIOPSY	1/26 (3.8%)	1	0/27 (0%)	0	0/25 (0%)	0
Musculoskeletal and connective tissue disorders
BACK SURGERY L5/S1	0/26 (0%)	0	0/27 (0%)	0	1/25 (4%)	1
Nervous system disorders
HOSPITALIZED FOR SEVERE HEADACHE	0/26 (0%)	0	1/27 (3.7%)	1	0/25 (0%)	0
Other (Not Including Serious) Adverse Events
	Silymarin 420 mg		Silymarin 700 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/26 (65.4%)		14/27 (51.9%)		11/25 (44%)
Cardiac disorders
Cardiac	3/26 (11.5%)		1/27 (3.7%)		2/25 (8%)
Gastrointestinal disorders
Gasto-intestinal	5/26 (19.2%)		4/27 (14.8%)		4/25 (16%)
General disorders
Headache	2/26 (7.7%)		1/27 (3.7%)		2/25 (8%)
Investigations
Hyperglycemia	1/26 (3.8%)		2/27 (7.4%)		0/25 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal	2/26 (7.7%)		1/27 (3.7%)		4/25 (16%)
Nervous system disorders
Depression	1/26 (3.8%)		2/27 (7.4%)		1/25 (4%)
Psychiatric disorders
Neurological	0/26 (0%)		1/27 (3.7%)		2/25 (8%)
Renal and urinary disorders
Urological	1/26 (3.8%)		1/27 (3.7%)		2/25 (8%)
Respiratory, thoracic and mediastinal disorders
Respiratory	2/26 (7.7%)		3/27 (11.1%)		2/25 (8%)
Skin and subcutaneous tissue disorders
Dermatologic	0/26 (0%)		2/27 (7.4%)		1/25 (4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.