A Preliminary Study to Evaluate Cysteamine Therapy in Human Subjects With Non-Alcoholic Steatohepatitis (NASH)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00799578
Recruitment Status : Completed
First Posted : December 1, 2008
Results First Posted : January 31, 2014
Last Update Posted : January 31, 2014
Raptor Pharmaceuticals Corp.
Information provided by (Responsible Party):
Joel Lavine, University of California, San Diego

Brief Summary:
The purpose of this study is to determine whether cysteamine will effectively reduce or reverse the biologic markers of steatohepatitis in patients.

Condition or disease Intervention/treatment Phase
Fatty Liver Drug: Cysteamine Phase 1 Phase 2

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Detailed Description:

Non-alcoholic fatty liver disease (NAFLD) steatohepatitis represents a spectrum of disease occurring in the absence of alcohol abuse. It is characterized by the presence of steatosis and may represent a hepatic manifestation of the metabolic syndrome (including obesity, diabetes and hypertriglyceridemia). NAFLD is linked to insulin resistance, it causes liver disease in adults and children and may ultimately lead to cirrhosis (Skelly et al., 2002). The histologic spectrum of NAFLD ranges from the relatively benign isolated predominantly macrovesicular steatosis (i.e., nonalcoholic fatty liver or NAFL) to steatohepatitis (NASH) (Angulo, & Lindor, 2002). The latter is characterized by the histologic presence of steatosis, cytological ballooning, scattered inflammation and pericellular fibrosis(Contos & Sanyal, 2002). Estimates of prevalence among children can be inferred from pediatric obesity data and the knowledge that 85% of children with NAFLD are obese. Data from the National Health and Nutrition Examination Survey has revealed a threefold rise in the prevalence of childhood and adolescent obesity over the past 35 years; data from 2000 suggests that 14-16% children between 6-19yrs age are obese with a BMI >95% (Fishbein, Miner, Mogren & Chalekson, 2003), and also the fact that 85% of children with NAFLD are obese.

Treatment of NASH currently revolves around the reduction of the two main pathogenetic factors, namely, fat accumulation within the liver and excessive accumulation of free radicals causing oxidative stress. Glutathione (gamma-glutamyl-cysteinyl-glycine; GSH) is a major endogenous antioxidant and its depletion is implicated in the development of hepatocellular injury (Wu, Fang, Yang, Lupton & Turner, 2004). Glutathione itself is does not enter easily into cells, even when given in large amounts. However, glutathione precursors do enter into cells and have been shown to be effective in the treatment of conditions such as acetaminophen toxicity by preventing significant GSH depletion (Prescott & Critchley, 1983). Examples of GSH precursors include cysteine, N-acetylcysteine, methionine and other sulphur-containing compounds such as cysteamine (Prescott, Park & Proudfoot, 1976). Studies have demonstrated that orally and intravenously administered cysteamine in mice and humans is effective in acetaminophen-induced hepatocellular injury (Prescott, 1972; Prescott, Stewart & Proudfoot, 1978; Mitchell, Thorgeirsson, Potter, Jollow & Keiser, 1974). Another study where N-acetylcysteine was used to treat NASH over a period of 4-12 weeks demonstrated improved amniotransferase levels (Pamuk & Sonsuz, 2003), suggesting that increasing GSH levels may have a hepato-protective role and may be useful in the treatment of NASH. A possible mode of action of cysteamine is that it might react with extracellular cystine to form cysteine which then is readily taken up into the cell and transformed into GSH.

Recent studies have suggested that the essential amino acid cysteine is a major limiting factor for GSH synthesis and that factors (e.g., insulin and growth factors) that stimulate cysteine uptake by cells generally result in increased intracellular GSH levels (Lyons et al., 2000; Lu, 2000).

Cysteamine, a GSH precursor, is currently available and is used in the treatment of cystinosis, an intra-lysosomalcystine storage disorder. In cystinosis, cysteamine acts by converting cystine to cysteine and cysteine-cysteamine mixed disulfide which are the both able to leave the lysosome through the cysteine and lysine porters respectively (Gahl, Theone & Shneider, 2002). Within the cytosol the mixed disulfide can be reduced by its reaction with glutathione and the cysteine released can be used for further GSH synthesis. The synthesis of GSH from cysteine is catalyzed by two enzymes, gamma-glutamylcysteine synthetase and GSH synthetase. This pathway occurs in almost all cell types, with the liver being the major producer and exporter or GSH. The reduced cysteine-cysteamine mixed disulfide will also release cysteamine, which, in theory is then able to re-enter the lysosome, bind more cystine and repeat the process (Dohil et al., 2006). In a recent study in children with cystinosis, enteral administration of cysteamine resulted in increased plasma cysteamine levels, which subsequently caused prolonged efficacy in the lowering of leukocyte cystine levels (Dohil et al., 2006). This may have been due to "re-cycling" of cysteamine when adequate amounts of drug reached the lysosome. If cysteamine does act in this fashion, then GSH production may also be significantly enhanced.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 13 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Study Start Date : October 2008
Actual Primary Completion Date : June 2009
Actual Study Completion Date : January 2010

Arm Intervention/treatment
Experimental: Cystagon-EC Drug: Cysteamine
Drug is in enteric-coated capsule form. The dosage will begin at 1g/m-squared body surface area with a maximum dose of 1000mg twice daily. Treatment period is 3-6 months.

Primary Outcome Measures :
  1. Normalization or >50% of Serum ALT Levels From Baseline [ Time Frame: 6 months ]

Information from the National Library of Medicine

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Ages Eligible for Study:   10 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Biopsy confirmed diagnosis of non-alcoholic steatohepatitis (within past 12 months)
  • Ages 10 yrs and older
  • Must swallow tablets on a regular basis
  • ALT level >60 iu/L

Exclusion Criteria:

  • Subjects with known hypersensitivity to cysteamine
  • History, currently or within the past 3 months, of the following conditions:
  • Pancreatitis
  • Inflammatory bowel disease
  • Malabsorption
  • Unstable heart disease, e.g., myocardial infarction, heart failure, arrhythmias.
  • Unstable diabetes mellitus
  • Any bleeding disorder.
  • Zollinger-Ellison syndrome
  • Malignant disease
  • Subjects whom maybe pregnant or have health issues that make it unsafe for them participate, or whose concomitant medical problems preclude them from committing to the study schedule.
  • No specific NASH medical therapy for 3 months such as vitamin E, s-adenosyl methionine or metformin or other NAFLD study drugs.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00799578

United States, California
University of California, San Diego School of Medicine General Clinic Research Center
San Diego, California, United States, 92103-8203
Sponsors and Collaborators
Joel Lavine
Raptor Pharmaceuticals Corp.

Additional Information:

Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Joel Lavine, Professor, University of California, San Diego Identifier: NCT00799578     History of Changes
Other Study ID Numbers: 07-1699
First Posted: December 1, 2008    Key Record Dates
Results First Posted: January 31, 2014
Last Update Posted: January 31, 2014
Last Verified: December 2013

Keywords provided by Joel Lavine, University of California, San Diego:
NASH, NAFLD,nonalcoholic steatohepatitis

Additional relevant MeSH terms:
Fatty Liver
Non-alcoholic Fatty Liver Disease
Liver Diseases
Digestive System Diseases
Cystine Depleting Agents
Molecular Mechanisms of Pharmacological Action