Trial of Hepaguard® in Adults With Nonalcoholic Steatohepatitis
Condition: Nonalcoholic Fatty Liver Disease
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
Study type: Interventional

Summary: 
      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: 
      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.
    

Intervention name(s): Phyllanthus urinaria; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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.
Other intervention name(s): Hepaguard®
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment