Efficacy and Safety of Berberine in Non-alcoholic Steatohepatitis

Non-alcoholic Steatohepatitis Clinical Trial

— EASYBEinNASH  

Official title:

Efficacy and Safety of Berberine in Non-alcoholic Steatohepatitis: a Multicentre, Randomised, Placebo-controlled Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03198572
• Other study ID #: 2016ZSLC04
• Status: Recruiting
• Phase: Phase 4
• Start date: August 16, 2017
• Est. completion date: July 30, 2024

Study information

• Verified date: August 2023
• Source: Fudan University
• Contact: Hong-Mei Yan
• Phone: 8613761666976
• Email: yan.hongmei[@]zs-hospital.sh.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the efficacy and safety of berberine treatment on Non-alcoholic Steatohepatitis.

Description:

This is a multicenter, double-blinded, randomized, placebo-controlled clinical trial to investigate the efficacy and safety of berberine on subjects with Non-alcoholic Steatohepatitis.Patients with biopsy-proven non-alcoholic steatohepatitis (NASH) from 18-65 years of age were enrolled. Patients should had no excessive alcohol intake or use of any hepatoprotective or hepatotoxicity medication within 3 months before enrollment.Patients will have an screening period 12 weeks, and a 48-week double-blinded treatment period.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: July 30, 2024
• Est. primary completion date: December 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

The inclusion criteria are as follows:

1. 18-75 years old, no limitation for ethnicity and gender.

2. BMI is no more than 40 kg/m2.

3. Patients with NASH based on liver biopsy obtained within 24 weeks before randomization. The histological evidence of NASH is defined as NAS =5 [] or NAS =4 with a minimum score of 1 for all of three components (steatosis, hepatocyte ballooning, and lobular inflammation), the diagnosis of NASH for EASYBEinNASH eligibility is based on reviews by three pathologists. If there are controversial pathologic diagnosis, at least 2 of the 3 pathologists are consistent with the pathologic diagnosis, which will be the final pathological diagnosis. If there are three different pathological diagnoses, it needs to be discussed and make a judgment by the chief pathologist to form the final pathology report.

4. For patients with impaired glucose metabolism, one of the three following conditions needs to be met. ? For patients diagnosed as impaired glucose regulation, they will be treated with lifestyle intervention without hypoglycemic drugs; ? For patients diagnosed as diabetes and treated with hypoglycemic drugs, the treatment regimen should not be changed and the dosage should remain stable for more than 2 months before randomization; ? For patients diagnosed as diabetes and treated with lifestyle intervention without hypoglycemic drugs, the treatment regimen should not be changed before randomization.

5. All participants agree to sign the informed consent form. Exclusion criteria

1. Excessive alcohol intake ( > 140 g per week for men and >70 g per week for women within 6 months before enrollment);

2. Liver enzymes (ALT or aspartate aminotransferase(AST) is 5 times higher than the upper limit of normal range;

3. Liver diseases caused by other reasons, such as alcohol abuse, viral hepatitis, drugs, auto-immune hepatitis, hereditary liver disease, liver cirrhosis, liver cancer, etc;

4. Biliary tract diseases, biliary obstructive disease, etc;

5. Other diseases that affect glucose and lipid metabolism, such as hypothyroidism, hyperthyroidism, hypercortisolism, etc;

6. Diabetic patients with poor blood glucose control: HbA1c >9.5%;

7. Use of drugs that may affect the outcome measures of this study 3 months before enrollment, including pioglitazone, GLP-1 receptor agonist, DPP-4 inhibitor, insulin, and glycyrrhizic acid preparation, etc;

8. Chronic kidney disease or severe renal impairment, defined as serum creatinine greater than 2.0mg/dL (176.8umol/L);

9. Life expectancy is no more than 5 years;

10. Pregnant or planning to become pregnant within the next 64 weeks for female participant;

11. Any situation that may affect the implementation or results of the study;

12. Continuous use of drugs that may affect steatohepatitis 3 months before enrollment, such as glucocorticoids, methotrexate, etc;

13. Subjects participated in other clinical trials in the past 4 weeks; The researchers did not think they were suitable for the study.

Related Conditions & MeSH terms

• Fatty Liver
• Non-alcoholic Fatty Liver Disease
• Non-alcoholic Steatohepatitis

Intervention

Behavioral:
• Lifestyle intervention
Lifestyle intervention is consisted of diet control and aerobic exercise. calorie restriction: to subtract 500 kcal from daily calorie intake aerobic exercise: medium intensity aerobic exercise for more than 150 min per week with heart rate around 50-70% of the maximal heart rate.

Drug:
• Placebo
placebo tablets 0.5 tid, 30 minutes before each meal, for 48weeks
• Berberine
Berberine tablets 0.5 tid, 30 minutes before each meal, for 48weeks

Locations

Country	Name	City	State
China	The Affiliated Hospital of Hangzhou Normal University	Hangzhou
China	Department of Endocrinology and Metabolism,Shanghai 6th People's Hospital	Shanghai	Shanghai
China	Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine	Shanghai
China	Xinhua Hospital, Shanghai Jiao Tong University School of Medicine	Shanghai
China	Tianjin Third Central Hospital	Tianjin
China	Xinjiang Medical University	Urumqi

Sponsors (7)

Lead Sponsor	Collaborator
Fudan University	Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, The Affiliated Hospital of Hangzhou Normal University, Tianjin Third Central Hospital, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Xinjiang Medical University

Country where clinical trial is conducted

China, 

References & Publications (31)

Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, Hazlehurst JM, Guo K; LEAN trial team; Abouda G, Aldersley MA, Stocken D, Gough SC, Tomlinson JW, Brown RM, Hubscher SG, Newsome PN. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016 Feb 13;387(10019):679-690. doi: 10.1016/S0140-6736(15)00803-X. Epub 2015 Nov 20. — View Citation

Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, Gastaldelli A, Tio F, Pulcini J, Berria R, Ma JZ, Dwivedi S, Havranek R, Fincke C, DeFronzo R, Bannayan GA, Schenker S, Cusi K. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006 Nov 30;355(22):2297-307. doi: 10.1056/NEJMoa060326. — View Citation

Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004 Dec;40(6):1387-95. doi: 10.1002/hep.20466. — View Citation

Cali AM, Zern TL, Taksali SE, de Oliveira AM, Dufour S, Otvos JD, Caprio S. Intrahepatic fat accumulation and alterations in lipoprotein composition in obese adolescents: a perfect proatherogenic state. Diabetes Care. 2007 Dec;30(12):3093-8. doi: 10.2337/dc07-1088. Epub 2007 Aug 23. — View Citation

Cao Y, Pan Q, Cai W, Shen F, Chen GY, Xu LM, Fan JG. Modulation of Gut Microbiota by Berberine Improves Steatohepatitis in High-Fat Diet-Fed BALB/C Mice. Arch Iran Med. 2016 Mar;19(3):197-203. — View Citation

Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012 Jun;55(6):2005-23. doi: 10.1002/hep.25762. No abstract available. — View Citation

Chalasani NP, Sanyal AJ, Kowdley KV, Robuck PR, Hoofnagle J, Kleiner DE, Unalp A, Tonascia J; NASH CRN Research Group. Pioglitazone versus vitamin E versus placebo for the treatment of non-diabetic patients with non-alcoholic steatohepatitis: PIVENS trial design. Contemp Clin Trials. 2009 Jan;30(1):88-96. doi: 10.1016/j.cct.2008.09.003. Epub 2008 Sep 10. — View Citation

Eckel RH, Jakicic JM, Ard JD, de Jesus JM, Houston Miller N, Hubbard VS, Lee IM, Lichtenstein AH, Loria CM, Millen BE, Nonas CA, Sacks FM, Smith SC Jr, Svetkey LP, Wadden TA, Yanovski SZ; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014 Jul 1;63(25 Pt B):2960-84. doi: 10.1016/j.jacc.2013.11.003. Epub 2013 Nov 12. No abstract available. Erratum In: J Am Coll Cardiol. 2014 Jul 1;63(25 Pt B):3027-3028. — View Citation

Garcia-Monzon C, Martin-Perez E, Iacono OL, Fernandez-Bermejo M, Majano PL, Apolinario A, Larranaga E, Moreno-Otero R. Characterization of pathogenic and prognostic factors of nonalcoholic steatohepatitis associated with obesity. J Hepatol. 2000 Nov;33(5):716-24. doi: 10.1016/s0168-8278(00)80301-3. Erratum In: J Hepatol 2001 Jan;34(1):180. — View Citation

Gupte P, Amarapurkar D, Agal S, Baijal R, Kulshrestha P, Pramanik S, Patel N, Madan A, Amarapurkar A, Hafeezunnisa. Non-alcoholic steatohepatitis in type 2 diabetes mellitus. J Gastroenterol Hepatol. 2004 Aug;19(8):854-8. doi: 10.1111/j.1440-1746.2004.03312.x. — View Citation

Hamaguchi M, Kojima T, Takeda N, Nakagawa T, Taniguchi H, Fujii K, Omatsu T, Nakajima T, Sarui H, Shimazaki M, Kato T, Okuda J, Ida K. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med. 2005 Nov 15;143(10):722-8. doi: 10.7326/0003-4819-143-10-200511150-00009. — View Citation

Kistler KD, Brunt EM, Clark JM, Diehl AM, Sallis JF, Schwimmer JB; NASH CRN Research Group. Physical activity recommendations, exercise intensity, and histological severity of nonalcoholic fatty liver disease. Am J Gastroenterol. 2011 Mar;106(3):460-8; quiz 469. doi: 10.1038/ajg.2010.488. Epub 2011 Jan 4. — View Citation

Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ; Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005 Jun;41(6):1313-21. doi: 10.1002/hep.20701. — View Citation

Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, Wang Y, Wang Z, Si S, Pan H, Wang S, Wu J, Wang Y, Li Z, Liu J, Jiang JD. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med. 2004 Dec;10(12):1344-51. doi: 10.1038/nm1135. Epub 2004 Nov 7. — View Citation

Kotronen A, Yki-Jarvinen H. Fatty liver: a novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2008 Jan;28(1):27-38. doi: 10.1161/ATVBAHA.107.147538. Epub 2007 Aug 9. — View Citation

Li Z, Xue J, Chen P, Chen L, Yan S, Liu L. Prevalence of nonalcoholic fatty liver disease in mainland of China: a meta-analysis of published studies. J Gastroenterol Hepatol. 2014 Jan;29(1):42-51. doi: 10.1111/jgh.12428. — View Citation

Lin SC, Ang B, Hernandez C, Bettencourt R, Jain R, Salotti J, Richards L, Kono Y, Bhatt A, Aryafar H, Lin GY, Valasek MA, Sirlin CB, Brouha S, Loomba R. Cardiovascular risk assessment in the treatment of nonalcoholic steatohepatitis: a secondary analysis of the MOZART trial. Therap Adv Gastroenterol. 2016 Mar;9(2):152-61. doi: 10.1177/1756283X15621232. — View Citation

Marchesini G, Moscatiello S, Di Domizio S, Forlani G. Obesity-associated liver disease. J Clin Endocrinol Metab. 2008 Nov;93(11 Suppl 1):S74-80. doi: 10.1210/jc.2008-1399. — View Citation

Musso G, Gambino R, Cassader M, Pagano G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology. 2010 Jul;52(1):79-104. doi: 10.1002/hep.23623. — View Citation

Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 2011 Dec;43(8):617-49. doi: 10.3109/07853890.2010.518623. Epub 2010 Nov 2. — View Citation

Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, Dasarathy S, Diehl AM, Hameed B, Kowdley KV, McCullough A, Terrault N, Clark JM, Tonascia J, Brunt EM, Kleiner DE, Doo E; NASH Clinical Research Network. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015 Mar 14;385(9972):956-65. doi: 10.1016/S0140-6736(14)61933-4. Epub 2014 Nov 7. Erratum In: Lancet. 2015 Mar 14;385(9972):946. Lancet. 2016 Apr 16;387(10028):1618. — View Citation

Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves JW, Hill MN, Jones DH, Kurtz T, Sheps SG, Roccella EJ; Council on High Blood Pressure Research Professional and Public Education Subcommittee, American Heart Association. Recommendations for blood pressure measurement in humans: an AHA scientific statement from the Council on High Blood Pressure Research Professional and Public Education Subcommittee. J Clin Hypertens (Greenwich). 2005 Feb;7(2):102-9. doi: 10.1111/j.1524-6175.2005.04377.x. No abstract available. — View Citation

Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010 May 6;362(18):1675-85. doi: 10.1056/NEJMoa0907929. Epub 2010 Apr 28. — View Citation

Schwimmer JB, Pardee PE, Lavine JE, Blumkin AK, Cook S. Cardiovascular risk factors and the metabolic syndrome in pediatric nonalcoholic fatty liver disease. Circulation. 2008 Jul 15;118(3):277-83. doi: 10.1161/CIRCULATIONAHA.107.739920. Epub 2008 Jun 30. — View Citation

Shen L. Treatment implication from the potential association between nonalcoholic fatty liver disease and cardiovascular disease. Hepatology. 2011 Jul;54(1):377-8. doi: 10.1002/hep.24213. No abstract available. — View Citation

Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010 Sep 30;363(14):1341-50. doi: 10.1056/NEJMra0912063. No abstract available. — View Citation

Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, Harrison SA. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011 Jan;140(1):124-31. doi: 10.1053/j.gastro.2010.09.038. Epub 2010 Sep 19. — View Citation

Yan HM, Xia MF, Wang Y, Chang XX, Yao XZ, Rao SX, Zeng MS, Tu YF, Feng R, Jia WP, Liu J, Deng W, Jiang JD, Gao X. Efficacy of Berberine in Patients with Non-Alcoholic Fatty Liver Disease. PLoS One. 2015 Aug 7;10(8):e0134172. doi: 10.1371/journal.pone.0134172. eCollection 2015. — View Citation

Yuan X, Wang J, Tang X, Li Y, Xia P, Gao X. Berberine ameliorates nonalcoholic fatty liver disease by a global modulation of hepatic mRNA and lncRNA expression profiles. J Transl Med. 2015 Jan 27;13:24. doi: 10.1186/s12967-015-0383-6. — View Citation

Zhang Y, Li X, Zou D, Liu W, Yang J, Zhu N, Huo L, Wang M, Hong J, Wu P, Ren G, Ning G. Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J Clin Endocrinol Metab. 2008 Jul;93(7):2559-65. doi: 10.1210/jc.2007-2404. Epub 2008 Apr 8. — View Citation

Zhang Z, Li B, Meng X, Yao S, Jin L, Yang J, Wang J, Zhang H, Zhang Z, Cai D, Zhang Y, Ning G. Berberine prevents progression from hepatic steatosis to steatohepatitis and fibrosis by reducing endoplasmic reticulum stress. Sci Rep. 2016 Feb 9;6:20848. doi: 10.1038/srep20848. — View Citation

* Note: There are 31 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Improvement in histologic features of nonalcoholic steatohepatitis by NAFLD activity score (NAS)	A separate system of scoring the histological features of nonalcoholic fatty liver disease (NAFLD) called the NAFLD Activity Score (NAS) was used. An improvement in histologic findings require an improvement by 1 or more points in the hepatocellular ballooning score; no increase in the fibrosis score; and either a decrease in the activity score for nonalcoholic fatty liver disease to a score of 3 or less or a decrease in the activity score of at least 2 points, with at least a 1-point decrease in either the lobular inflammation or steatosis score.	48 weeks
Secondary	Improvement in the composites of NAFLD activity scores for steatosis, lobular inflammation, hepatocellular ballooning	NAFLD activity score (NAS) is composed of steatosis (scale of 0 to 3), lobular inflammation (scale of 0 to 3), hepatocellular ballooning (scale of 0 to 2). Alteration in each component of NAS is measured.	48 weeks
Secondary	Improvement in liver histological fibrosis staging	Fibrosis staging was measured as following criteria: 0=none, 1=perisinusoidal or periportal fibrosis, 2=perisinusoidal and portal/periportal fibrosis, 3=bridging fibrosis, and 4=cirrhosis.the definition of fibrosis stages improvement requires at least one stage.	48 weeks
Secondary	Resolution of NASH	Resolution of NASH was defined as a diagnosis of no steatohepatitis at 48 weeks among those with possible or definite NASH at baseline.	48 weeks
Secondary	Change in anthropometric measures	including BMI etc	48 weeks
Secondary	Change in blood biochemistry	including serum aminotransferase levels etc	48 weeks
Secondary	Change in liver fat content	liver fat content determined by 1H MRS (in part of clinical centers)	48 weeks
Secondary	Change in serum cytokeratin 18 (CK-18) in U/L	serum cytokeratin 18 (CK-18) in U/L	48 weeks