Trial of Hepaguard® in Adults With Nonalcoholic Steatohepatitis

Study Overview
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Brief Summary
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Nonalcoholic fatty liver disease is one of the most common chronic liver diseases worldwide. Nonalcoholic steatohepatitis (NASH) is the active form of the disease which runs a progressive course and may result in liver cirrhosis and liver cancer. However, there is yet proven treatment for this disorder. In cell line and animal studies, we have shown that Phyllanthus urinaria can ameliorate NASH by reducing oxidative stress and lipid accumulation. Phyllanthus (Hepaguard) has been used widely by patients with chronic liver diseases, but the efficacy in NASH has not been confirmed in humans. This study is divided into two parts. In part 1, 60 patients with histology-confirmed NASH will be randomized to receive Hepaguard or placebo for 24 weeks to test the efficacy. Endpoints will be assessed at week 24. The aim of part 2 is to test the durability of Hepaguard. Forty patients originally on Hepaguard will be randomized again to continue Hepaguard for another 24 weeks or stop the treatment. The endpoints at week 48 will be further analyzed.

Detailed Description
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Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in affluent countries. Patients with nonalcoholic steatohepatitis (NASH), a severe form of NAFLD characterized by ballooning, lobular inflammation and liver fibrosis, have increased mortality rate and risk of cardiovascular disease. Besides, some patients progress to cirrhosis and may even develop hepatocellular carcinoma. In long-term studies, up to 13% of NAFLD patients died of hepatic complications.(1) Owing to westernization of lifestyle, NAFLD is also increasing dramatically in Asia. In a population screening study in Shanghai using ultrasonography, 15% of adult Chinese was found to suffer from NAFLD.(2) Among Chinese patients with NAFLD, significant necroinflammation and liver fibrosis are not uncommon.(3-5) These patients also often have progression of liver fibrosis with time.(6) Since NASH is closely related to type 2 diabetes and obesity, a logical approach would be to improve these metabolic parameters.(7, 8) Observational studies suggest that regular exercise and weight reduction benefit NASH patients. At present, there is no registered drug for the treatment of NASH. Although insulin sensitizers such as pioglitazone and rosiglitazone may improve the metabolic profile and hepatic necroinflammation,(9, 10) the effects are not durable.(11) Weight gain and cardiovascular complications also limit the use of these agents.(12, 13) More effective and better tolerated treatment is urgently needed. Phyllanthus urinaria (Hepaguard®) is commonly used by patients with various chronic liver diseases.(14-16) Phyllanthus has excellent safety profile. In in vitro and in vivo models of NAFLD, Phyllanthus reduces hepatic steatosis, necroinflammation and fibrosis.(16) Oxidative stress and lipid accumulation are ameliorated. Whether the same beneficial effects apply to humans is unclear. References: Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005;129:113-21. Fan JG, Zhu J, Li XJ, Chen L, Li L, Dai F, Li F, Chen SY. Prevalence of and risk factors for fatty liver in a general population of Shanghai, China. J Hepatol 2005;43:508-14. Wong VW, Chan HL, Hui AY, Chan KF, Liew CT, Chan FK, Sung JJ. Clinical and histological features of non-alcoholic fatty liver disease in Hong Kong Chinese. Aliment Pharmacol Ther 2004;20:45-9. Wong VW, Wong GL, Chim AM, Tse AM, Tsang SW, Hui AY, Choi PC, Chan AW, So WY, Chan FK, Sung JJ, Chan HL. Validation of the NAFLD fibrosis score in a Chinese population with low prevalence of advanced fibrosis. Am J Gastroenterol 2008;103:1682-8. Wong VW, Wong GL, Tsang SW, Hui AY, Chan AW, Choi PC, Chim AM, Chu S, Chan FK, Sung JJ, Chan HL. Metabolic and histological features of non-alcoholic fatty liver disease patients with different serum alanine aminotransferase levels. Aliment Pharmacol Ther 2009;29:387-96. Hui AY, Wong VW, Chan HL, Liew CT, Chan JL, Chan FK, Sung JJ. Histological progression of non-alcoholic fatty liver disease in Chinese patients. Aliment Pharmacol Ther 2005;21:407-13. Wong VW, Hui AY, Tsang SW, Chan JL, Tse AM, Chan KF, So WY, Cheng AY, Ng WF, Wong GL, Sung JJ, Chan HL. Metabolic and adipokine profile of Chinese patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2006;4:1154-61. Wong VW, Hui AY, Tsang SW, Chan JL, Wong GL, Chan AW, So WY, Cheng AY, Tong PC, Chan FK, Sung JJ, Chan HL. Prevalence of undiagnosed diabetes and postchallenge hyperglycaemia in Chinese patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2006;24:1215-22. 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;355:2297-307. Ratziu V, Giral P, Jacqueminet S, Charlotte F, Hartemann-Heurtier A, Serfaty L, Podevin P, Lacorte JM, Bernhardt C, Bruckert E, Grimaldi A, Poynard T. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology 2008;135:100-10. Lutchman G, Modi A, Kleiner DE, Promrat K, Heller T, Ghany M, Borg B, Loomba R, Liang TJ, Premkumar A, Hoofnagle JH. The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hepatology 2007;46:424-9. Balas B, Belfort R, Harrison SA, Darland C, Finch J, Schenker S, Gastaldelli A, Cusi K. Pioglitazone treatment increases whole body fat but not total body water in patients with non-alcoholic steatohepatitis. J Hepatol 2007;47:565-70. Juurlink DN, Gomes T, Lipscombe LL, Austin PC, Hux JE, Mamdani MM. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. BMJ 2009;339:b2942. Wang M, Cheng H, Li Y, Meng L, Zhao G, Mai K. Herbs of the genus Phyllanthus in the treatment of chronic hepatitis B: observations with three preparations from different geographic sites. J Lab Clin Med 1995;126:350-2. Chan HL, Sung JJ, Fong WF, Chim AM, Yung PP, Hui AY, Fung KP, Leung PC. Double-blinded placebo-controlled study of Phyllanthus urinaris for the treatment of chronic hepatitis B. Aliment Pharmacol Ther 2003;18:339-45. Shen B, Yu J, Wang S, Chu ES, Wong VW, Zhou X, Lin G, Sung JJ, Chan HL. Phyllanthus urinaria ameliorates the severity of nutritional steatohepatitis both in vitro and in vivo. Hepatology 2008;47:473-83.

Official Title
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A Randomized,Placebo-controlled,Double-blind Trial of Phyllanthus Urinaria (Hepaguard®) in Adults With Nonalcoholic Steatohepatitis

Conditions
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Nonalcoholic Fatty Liver Disease

Intervention / Treatment
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* Drug: Phyllanthus urinaria
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or above, Histologic NAFLD activity score 3, Written informed consent Exclusion Criteria: Positive hepatitis B surface antigen, or anti-hepatitis C virus antibody, or histologic features of an alternative liver disease, Alcohol consumption above 30g per week in men or 20g per week in women, Serum alanine aminotransferase above 10 times the upper limit of normal, Liver decompensation, Evidence of hepatocellular carcinoma currently or in the past 5 years, Type 1 diabetes or insulin treatment, Use of investigational drugs in the last 12 weeks, Terminal illness or cancer

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Hepaguard<br> | Drug: Phyllanthus urinaria<br>* Subjects meeting the inclusion and exclusion criteria will be randomized (2:1) to receive oral Hepaguard 1 g three times daily or placebo of identical appearance. At week 24, subjects receiving active Hepaguard will be randomized (1:1) to continue Hepaguard for another 24 weeks or stop treatment.<br>* Other names: Hepaguard®;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Subjects meeting the inclusion and exclusion criteria will be randomized (2:1) to receive oral Hepaguard 1 g three times daily or placebo of identical appearance.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Histologic NAFLD activity score |  | week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ALT normalization |  | week 24 & week 48 | 
| Metabolic endpoints |  | Weeks 12, 24, 36 and 48 | 
| Changes in magnetic resonance spectroscopy |  | Weeks 24 and 48 | 
| Liver stiffness measurement |  | Weeks 24 and 48 | 
| Biomarkers of NASH and liver fibrosis |  | Weeks 12, 24, 36 and 48 |