Silymarin in non-cirrhotics with non-alcoholic steatohepatitis: A randomized, double-blind, placebo controlled trial
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...
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0221683 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0221683</identifier><identifier>PMID: 31536511</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>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</subject><ispartof>PloS one, 2019-09, Vol.14 (9), p.e0221683</ispartof><rights>COPYRIGHT 2019 Public Library of Science</rights><rights>2019 Navarro et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2019 Navarro et al 2019 Navarro et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-bf9311ad8bdc71f6c05aed62e1eac86cc2f1fac468890361374ea91f9ce6eefd3</citedby><cites>FETCH-LOGICAL-c692t-bf9311ad8bdc71f6c05aed62e1eac86cc2f1fac468890361374ea91f9ce6eefd3</cites><orcidid>0000-0002-8428-8528</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752871/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752871/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31536511$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Gluud, Lise Lotte</contributor><creatorcontrib>Navarro, Victor J</creatorcontrib><creatorcontrib>Belle, Steven H</creatorcontrib><creatorcontrib>D'Amato, Massimo</creatorcontrib><creatorcontrib>Adfhal, Nezam</creatorcontrib><creatorcontrib>Brunt, Elizabeth M</creatorcontrib><creatorcontrib>Fried, Michael W</creatorcontrib><creatorcontrib>Reddy, K Rajender</creatorcontrib><creatorcontrib>Wahed, Abdus S</creatorcontrib><creatorcontrib>Harrison, Stephen</creatorcontrib><creatorcontrib>Silymarin in NASH and C Hepatitis (SyNCH) Study Group</creatorcontrib><creatorcontrib>on behalf of the Silymarin in NASH and C Hepatitis (SyNCH) Study Group</creatorcontrib><title>Silymarin in non-cirrhotics with non-alcoholic steatohepatitis: A randomized, double-blind, placebo controlled trial</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.</description><subject>Adult</subject><subject>Analysis</subject><subject>Antioxidants</subject><subject>Antioxidants (Nutrients)</subject><subject>Antioxidants - administration & dosage</subject><subject>Antioxidants - adverse effects</subject><subject>Biology and Life Sciences</subject><subject>Biopsy</subject><subject>Care and treatment</subject><subject>Cirrhosis</subject><subject>Clinical trials</subject><subject>Development and progression</subject><subject>Diabetes</subject><subject>Double-Blind Method</subject><subject>Double-blind studies</subject><subject>Drug dosages</subject><subject>Epidemiology</subject><subject>Fatty liver</subject><subject>Female</subject><subject>Fibrosis</subject><subject>Gastroenterology</subject><subject>Health care facilities</subject><subject>Hepatitis</subject><subject>Hepatology</subject><subject>Humans</subject><subject>Intention to Treat Analysis</subject><subject>Lipid peroxidation</subject><subject>Lipids</subject><subject>Liver</subject><subject>Liver cirrhosis</subject><subject>Liver diseases</subject><subject>Male</subject><subject>Medical centers</subject><subject>Medical research</subject><subject>Medical services</subject><subject>Medical treatment</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Middle Aged</subject><subject>Milk</subject><subject>Motivation</subject><subject>Non-alcoholic Fatty Liver Disease - drug therapy</subject><subject>Patients</subject><subject>People and Places</subject><subject>Public health</subject><subject>Randomization</subject><subject>Research and Analysis Methods</subject><subject>Resorcinols</subject><subject>Silymarin</subject><subject>Silymarin - administration & dosage</subject><subject>Silymarin - adverse effects</subject><subject>Statistical analysis</subject><subject>Treatment Outcome</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkmuL1DAUhoso7rr6D0QLgiDYMZc2bf0gDIuXgYUFV_0a0vRkmiGTjEmqrr_ezE53mYKCJJDk5Dlvkjcny55itMC0xm82bvRWmMXOWVggQjBr6L3sFLeUFIwgev9ofpI9CmGDUEUbxh5mJxRXlFUYn2bxSpvrrfDa5qlbZwupvR9c1DLkP3UcbmLCSDc4o2UeIojoBtiJqKMOb_Nl7oXt3Vb_hv513ruxM1B0Rtu02hkhoXO5dDZ6Zwz0efRamMfZAyVMgCfTeJZ9_fD-y_mn4uLy4-p8eVFI1pJYdKqlGIu-6XpZY8UkqgT0jAAGIRsmJVFYCVmypmkRZcmVEkSLVSuBAaienmXPD7o74wKfDAuckLbENaKYJmJ1IHonNnzndbLimjuh-U3A-TUXPnlhgHelbIgC1DBSlRRUR2Unkaig7BpGmzZpvZtOG7st9BLSo4WZic53rB742v3grK5IU-Mk8GIS8O77CCH-48oTtRbpVtoql8TkVgfJlwyhkpSsrRO1-AuVWg9bnf4DlE7xWcKrWcL-z-BXXIsxBL66-vz_7OW3OfvyiB1AmDgEZ8aonQ1zsDyA0rsQPKg75zDi-4q_dYPvK55PFZ_Snh27fpd0W-L0D-8I_m4</recordid><startdate>20190919</startdate><enddate>20190919</enddate><creator>Navarro, Victor J</creator><creator>Belle, Steven H</creator><creator>D'Amato, Massimo</creator><creator>Adfhal, Nezam</creator><creator>Brunt, Elizabeth M</creator><creator>Fried, Michael W</creator><creator>Reddy, K Rajender</creator><creator>Wahed, Abdus S</creator><creator>Harrison, Stephen</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-8428-8528</orcidid></search><sort><creationdate>20190919</creationdate><title>Silymarin in non-cirrhotics with non-alcoholic steatohepatitis: A randomized, double-blind, placebo controlled trial</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-bf9311ad8bdc71f6c05aed62e1eac86cc2f1fac468890361374ea91f9ce6eefd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adult</topic><topic>Analysis</topic><topic>Antioxidants</topic><topic>Antioxidants (Nutrients)</topic><topic>Antioxidants - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Navarro, Victor J</au><au>Belle, Steven H</au><au>D'Amato, Massimo</au><au>Adfhal, Nezam</au><au>Brunt, Elizabeth M</au><au>Fried, Michael W</au><au>Reddy, K Rajender</au><au>Wahed, Abdus S</au><au>Harrison, Stephen</au><au>Gluud, Lise Lotte</au><aucorp>Silymarin in NASH and C Hepatitis (SyNCH) Study Group</aucorp><aucorp>on behalf of the Silymarin in NASH and C Hepatitis (SyNCH) Study Group</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Silymarin in non-cirrhotics with non-alcoholic steatohepatitis: A randomized, double-blind, placebo controlled trial</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2019-09-19</date><risdate>2019</risdate><volume>14</volume><issue>9</issue><spage>e0221683</spage><pages>e0221683-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>31536511</pmid><doi>10.1371/journal.pone.0221683</doi><tpages>e0221683</tpages><orcidid>https://orcid.org/0000-0002-8428-8528</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2019-09, Vol.14 (9), p.e0221683 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2294170313 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; 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 |
| title | Silymarin in non-cirrhotics with non-alcoholic steatohepatitis: A randomized, double-blind, placebo controlled trial |
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