Non-alcoholic SteatohepatitisPhase 2SyNCHNCT00680407
Phase II Trial of Silymarin for Non-Cirrhotic Patients With Non-Alcoholic Steatohepatitis
A Phase 2 study testing Silymarin 700 mg and Silymarin 420 mg in people with Non-alcoholic Steatohepatitis, run by Madaus Inc at 6 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Non-alcoholic Steatohepatitis
- What is being tested?
- Silymarin 700 mg and Silymarin 420 mg
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 78 participants
- Where
- 6 sitesUnited States
- Study dates
- Apr 2008to Nov 2012
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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).
Who cannot join
- 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.
Show all 31Show fewer
- 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.
Trial locations and contacts
6 sites in 1 country.
6 sites in 1 country
United States6 sites
Beth Isreal Deaconess Medical Center
Boston, Massachusetts, 02215
University of North Carolina - Chapel Hill
Chapel Hill, North Carolina, 27599
University of Pennsylvania
Philadelphia, Pennsylvania, 19104
Thomas Jefferson University
Philadelphia, Pennsylvania, 19107
University of Pittsburgh
Pittsburgh, Pennsylvania, 15213
Brooke Army Medical Center
San Antonio, Texas, 78234
About this study
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
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.
Read the 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.
- Conditions
- Non-alcoholic Steatohepatitis
- Being tested
- Placebo, Silymarin 700 mg, Silymarin 420 mg
- Keywords
- NASH, non-alcoholic steatohepatitis
- Medical subject headings
- Non-alcoholic Fatty Liver Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PlaceboOther
Also called lactose pill
Placebo (5 pills, three times daily) for 48-50 week treatment period
Silymarin 700 mgDrug
Also called Legalon, milk thistle
700 mg dose (5 pills, three times daily) for 48-50 week treatment period
Silymarin 420 mgDrug
Also called Legalon, milk thistle
420 mg dose (5 pills, three times daily) for 48-50 week treatment period
| Study group | Role | What they receive |
|---|---|---|
| silymarin 420 mg | Experimental | 420 mg Legalon (silymarin) three times daily Receives: Drug: Silymarin 420 mg |
| silymarin 700 mg | Experimental | 700 mg of Legalon (silymarin) three times daily Receives: Drug: Silymarin 700 mg |
| Placebo | Placebo comparator | Placebo (lactose pill) Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Efficacy - Improvement by at Least 2 Points in Histology (NAS)
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.
Measured: 48-50 week treatment period
Secondary outcomes (1)
Safety - Occurrence of a Dose-limiting Toxicity
Measured: 48-50 week treatment period
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 May 2008 (estimated)
- Study startApr 2008
- Primary completionNov 2012
- Study completionNov 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Non-alcoholic SteatohepatitisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 78 participants (actual)
Sponsor and investigators
- Lead sponsor
- Madaus Inc
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- University of Pennsylvania, University of North Carolina, Thomas Jefferson University, Beth Israel Deaconess Medical Center, Brooke Army Medical Center, University of Pittsburgh
- Responsible party
- Sponsor
- Investigators
- Michael Fried, MD, Principal investigator, University of North Carolina, Chapel HillVictor Navarro, MD, Principal investigator, Thomas Jefferson UniversityNezam Afdhal, MD, Principal investigator, Beth Israel Deaconess Medical CenterK. Rajender Reddy, MD, Principal investigator, University of PennsylvaniaSteven H. Belle, PhD, Principal investigator, University of PittsburghStephen A. Harrison, MD, Principal investigator, Brooke Army Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00680407
- Sponsor's protocol ID
- U01AT003566-02
- Other IDs
- IND 105,461 (orig. IND 74,887)
- Acronym
- SyNCH
- Status last verified
- Jul 2019
- First submitted
- 15 May 2008
- Last updated
- 17 Jul 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Navarro VJ, Belle SH, D'Amato M, Adfhal N, Brunt EM, Fried MW, Reddy KR, Wahed AS, Harrison S; Silymarin in NASH and C Hepatitis (SyNCH) Study Group. Silymarin in non-cirrhotics with non-alcoholic steatohepatitis: A randomized, double-blind, placebo controlled trial. PLoS One. 2019 Sep 19;14(9):e0221683. doi: 10.1371/journal.pone.0221683. eCollection 2019.
PubMed 31536511
Study at a glance
From the registry record, last updated by the sponsor on 17 Jul 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00680407
- Acronym / sponsor ID
- SyNCH / U01AT003566-02
- Conditions
- Non-alcoholic Steatohepatitis
- Keywords
- NASH, non-alcoholic steatohepatitis
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 78 participants (actual)
- Lead sponsor
- Madaus IncIndustry (pharma, biotech, devices)
- Collaborators
- University of Pennsylvania, University of North Carolina, Thomas Jefferson University, Beth Israel Deaconess Medical Center, Brooke Army Medical Center, University of Pittsburgh
- Study start
- Apr 2008
- Primary completion
- Nov 2012 (actual)
- Study completion
- Nov 2012 (actual)
- First posted
- 20 May 2008 (estimated)
- Results
- Posted 29 Jan 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| silymarin 420 mg | Experimental | Drug: Silymarin 420 mg420 mg Legalon (silymarin) three times daily |
| silymarin 700 mg | Experimental | Drug: Silymarin 700 mg700 mg of Legalon (silymarin) three times daily |
| Placebo | Placebo comparator | Other: PlaceboPlacebo (lactose pill) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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.
Key exclusion criteria (31 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PlaceboAlso: lactose pillPlacebo (5 pills, three times daily) for 48-50 week treatment period | Other | Placebo |
| Silymarin 700 mgAlso: Legalon, milk thistle700 mg dose (5 pills, three times daily) for 48-50 week treatment period | Drug | silymarin 700 mg |
| Silymarin 420 mgAlso: Legalon, milk thistle420 mg dose (5 pills, three times daily) for 48-50 week treatment period | Drug | silymarin 420 mg |
Primary outcome
Efficacy - Improvement by at Least 2 Points in Histology (NAS)
Time frame: 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.
1 secondary outcome
Safety - Occurrence of a Dose-limiting Toxicity
Time frame: 48-50 week treatment period
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Jul 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 31536511Navarro VJ, Belle SH, D'Amato M, Adfhal N, Brunt EM, Fried MW, Reddy KR, Wahed AS, Harrison S; Silymarin in NASH and C Hepatitis (SyNCH) Study Group. Silymarin in non-cirrhotics with non-alcoholic steatohepatitis: A randomized, double-blind, placebo controlled trial. PLoS One. 2019 Sep 19;14(9):e0221683. doi: 10.1371/journal.pone.0221683. eCollection 2019.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michael Fried, MD principal investigator
University of North Carolina, Chapel Hill
Victor Navarro, MD principal investigator
Thomas Jefferson University
Nezam Afdhal, MD principal investigator
Beth Israel Deaconess Medical Center
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Silymarin 700 mg and Silymarin 420 mg in people with Non-alcoholic Steatohepatitis, run by Madaus Inc at 6 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Jul 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 29 Jan 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Efficacy - Improvement by at Least 2 Points in Histology (NAS) (time frame: 48-50 week treatment period). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00680407, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jul 2019.