Trial Information

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

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:

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.