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Study to Investigate the Effects of Different Doses of S-adenosyl-L-methionine (SAMe) in Subjects With Nonalcoholic Fatty Liver Disease and Non-treated Matched Healthy Volunteers as Control Group (EXPO)

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ClinicalTrials.gov Identifier: NCT01754714
Recruitment Status : Completed
First Posted : December 21, 2012
Results First Posted : February 19, 2016
Last Update Posted : February 19, 2016
Sponsor:
Collaborator:
PPD
Information provided by (Responsible Party):
Abbott

Study Description
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Brief Summary:
Investigation the Effects of Different Doses of SAMe in Subjects with Nonalcoholic Fatty Liver Disease and non-treated matched healthy volunteers as control group

Condition or disease Intervention/treatment Phase
Non Alcoholic Fatty Liver Disease Drug: SAMe 1000 mg Drug: SAMe 1500 mg Drug: SAMe 2000 mg Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 108 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Open-label, Randomized, Parallel-Group, Exploratory Study to Investigate the Effects of Different Doses of S-adenosyl-L-methionine (SAMe) in Subjects With Nonalcoholic Steatohepatitis (NASH) and Non-treated Matched Healthy Volunteers as Control Group
Study Start Date : December 2012
Actual Primary Completion Date : September 2014
Actual Study Completion Date : September 2014

Resource links provided by the National Library of Medicine

Drug Information available for: Methionine

Arms and Interventions
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Arm Intervention/treatment
Experimental: 1000 mg SAMe (S-adenosyl-L-methionine) Drug: SAMe 1000 mg
1000 mg dose group: one 500 mg capsule fasting in the morning and one 500 mg capsule before dinner
Experimental: 1500 mg SAMe Drug: SAMe 1500 mg
1500 mg dose group: two 500 mg capsules fasting in the morning and one 500 mg capsule before dinner
Experimental: 2000 mg SAMe Drug: SAMe 2000 mg
2000 mg dose group: two 500 mg capsules fasting in the morning and two 500 mg capsules before dinner
No Intervention: No treatment


Outcome Measures
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Primary Outcome Measures :
  1. Methionine Elimination Half-life Measured in Blood. [ Time Frame: 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7* ]
    After the methionine load, blood samples will be obtained at 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours. Plasma will be analyzed for methionine.


Secondary Outcome Measures :
  1. Fasting Methionine Concentration of Average Methionine Concentration Versus Time Curve. [ Time Frame: 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7* ]
    After the methionine load, blood samples will be obtained at 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours. Plasma will be analyzed for methionine.

  2. 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test [ Time Frame: 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7* ]
    parameters cumulative percentage dose of 13 carbon recovered after 30, 60, 90 minutes (cPDR30, cPDR60, cPDR 90) will be evaluated

  3. Hepatic Panel (Liver Laboratory Parameters) [ Time Frame: change from baseline at 6 weeks ]
    Serum Total Bilirubin (STB), Serum Conjugated Bilirubin (SCB), liver-alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), Gamma Glutamyl Transpeptidase (GGT)

  4. Metabolic Panel (Metabolic Laboratory Parameters) [ Time Frame: change from baseline at 6 weeks ]
    Fasting lipid profile (cholesterol, HDL (High Density Lipoprotein), LDL (Low Density Lipoprotein)), amino acid profile, homeostasis model assessment (HOMA-R) and fasting glucose.

  5. The Metabolic Clearance Rate Measured in the Blood. [ Time Frame: 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7* ]
    After the methionine load, blood samples will be obtained at 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours. Plasma will be analyzed for methionine.

  6. Methionine Volume of Distribution at Week 7 (L) [ Time Frame: 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7* ]
    After the methionine load, blood samples will be obtained at 0.5, 1, 1.5, 3, 4, 5, 6, 7.5 and 9 hours. Plasma will be analyzed for methionine.

  7. 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test [ Time Frame: 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7* ]
    Peak

  8. 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test [ Time Frame: 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7* ]
    Time to peak

  9. Metabolic Panel (Metabolic Laboratory Parameters) [ Time Frame: Change from baseline at 6 weeks ]
    Fasting plasma insulin

  10. Metabolic Panel (Metabolic Laboratory Parameters) [ Time Frame: change from baseline at 6 weeks ]
    glycosylated hemoglobin (HbA1c)

  11. Metabolic Panel (Metabolic Laboratory Parameters) [ Time Frame: change from baseline at 6 weeks ]
    Adiponectin

  12. Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) [ Time Frame: change from baseline at 6 weeks ]
    C-reactive Protein (CRP)

  13. Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) [ Time Frame: change from baseline at 6 weeks ]
    glutathione in erythrocytes

  14. Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) [ Time Frame: change from baseline at 6 weeks ]
    oxidative stress marker (isoprostane level)

  15. Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) [ Time Frame: change from baseline at 6 weeks ]
    Caspase-cleaved cytokeratin (CK 18)

  16. Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) [ Time Frame: change from baseline at 6 weeks ]
    Hyaluronic acid

  17. Area Under Curve (AUC) of Average Methionine Concentration Versus Time Curve [ Time Frame: 0.5, 1, 1.5, 3, 4, 5, 6, 7.5 and 9 hours *at Week 7* ]
    After the methionine load, blood samples will be obtained at 0.5, 1, 1.5, 3, 4, 5, 6, 7.5 and 9 hours. Plasma will be analyzed for methionine.

  18. Hepatic Panel (Liver Laboratory Parameters) [ Time Frame: change from baseline at 6 weeks ]
    ALT/AST ratio


Other Outcome Measures:
  1. Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) [ Time Frame: change from baseline at 6 weeks ]
    Cytokine profile ( Interleukin-6, IL-8, IL-10 (IL), Tumor Necrosis Factor (TNF -α), monocyte chemoattractant protein (MCP-1), and Granulocyte-colony stimulating factor (G-CSF ).

  2. Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) [ Time Frame: change from baseline at 6 weeks ]

    Non-invasive test for liver disease (ActiTest)/Fibrotest

    FibroTest® : diagnoses hepatic fibrosis ActiTest® : assesses viral necro-inflammatory activity Scores between 0 and 1, the higher the score the worse

    The FibroTest score is calculated from the results of a six-parameter blood test, combining six serum markers with the age and gender of the patient:Alpha-2-macroglobulin, Haptoglobin, Apolipoprotein A1, Gamma-glutamyl transpeptidase (GGT), Total bilirubin, and Alanine transaminase (ALT). ALT is used in a second assessment called ActiTest that is part of FibroTest.



Eligibility Criteria
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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria

  • Subjects with non-alcoholic steatohepatitis based on histology in medical history within the last 3 years
  • Subjects in a stable metabolic condition since histology for NASH (Non-alcoholic Steatohepatitis)

Exclusion Criteria

  • Subjects with extrahepatic biliary obstruction
  • Subjects with primary sclerosing cholangitis (PSC)
  • Subjects with primary biliary cirrhosis (PBC)
  • Any form of malignancy within the past 5 years and/or basal cell carcinoma and squamous cell carcinoma of the skin within the past two years
  • History of active substance abuse (oral, inhaled or injected) within one year prior to the study
  • Subjects with renal impairment (creatinine level of >2.0 mg/dL)
  • Subjects with a known hypersensitivity to the active substance (ademetionine) or methionine or to any of the inactive ingredients
  • Subjects with known genetic defects affecting the methionine cycle and/or causing homocystinuria and/or hyperhomocysteinemia (e.g., cystathionine beta-synthase deficiency, Vitamin B12 metabolism defect)
  • Subjects on total parenteral nutrition in the year prior to screening
  • Subjects after or planned for bariatric surgery (jejunoileal bypass or gastric weight loss surgery)
  • Extrahepatic cholestasis (proven by ultrasound)
  • Subjects with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 5 upper limit of normal (ULN)
  • Subject with serum total bilirubin (STB) > 5 ULN
  • Subjects after liver transplantation and subjects on the waiting list for liver transplantation
  • Subjects with any of the following disease in medical history:
  • Viral hepatitis (serum positive HBcAb (hepatitis B core antibody) or Hepatitis C Virus (HCV) ribonucleic acid (RNA)
  • Evidence of autoimmune liver disease
  • Wilson's disease
  • Hemochromatosis
  • Alpha-1-antitrypsin deficiency
  • Known positivity for antibody to human immunodeficiency virus (HIV)
  • Known heart failure of New York heart Association class 3 or 4
  • Current or history of significant alcohol consumption for a period of more than three consecutive months within five years prior to screening (significant alcohol consumption is defined as > 3 U (unit)/day for men and > 2 U/day for women, on average) or binge drinking or inability to reliably quantify alcohol consumption.
  • Clinical or histological evidence of cirrhosis F4
  • Subjects with history of biliary diversion
  • Subjects with uncontrolled diabetes mellitus defined by HbA1c (hemoglobin A1c) > 8.0 % at screening
  • Concomitant medication of B12, folate, betaine or choline
  • Concomitant treatment with glitazone within the past year prior to the study
  • Subjects with known folate or B12 deficiency
  • BMI (body mass index) > 40 kg/m2
  • History of major depression diagnostic and statistical manual of mental disorders (DSM-IV) or bipolar disease
  • Women of childbearing potential: positive urine pregnancy test during screening or unwillingness to use an effective form of birth control during the study.
  • Breastfeeding women
  • Any condition that, in the opinion of the investigator, does not justify the patient's inclusion into the study
  • Investigational drug intake within one month prior to the study
  • Active, serious medical disease with likely life-expectancy less than five years
  • Uncooperative attitude or reasonable likelihood for non-compliance with the protocol or any other reason that, in the investigator's opinion, prohibits the inclusion of the subject into the study
  • Legal incapacity or limited legal capacity, or who are incarcerated.
  • Inability to return for scheduled visits.
  • Inability to understand and follow the requirements of the protocol in the local language
Contacts and Locations
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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 ClinicalTrials.gov identifier (NCT number): NCT01754714


Locations
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Sponsors and Collaborators
Abbott
PPD
Investigators
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Study Director: Suntje Sander-Struckmeier, PhD Abbott
More Information
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Responsible Party: Abbott
ClinicalTrials.gov Identifier: NCT01754714    
Other Study ID Numbers: M13-397
2012-000975-18 ( EudraCT Number )
First Posted: December 21, 2012    Key Record Dates
Results First Posted: February 19, 2016
Last Update Posted: February 19, 2016
Last Verified: January 2016
Keywords provided by Abbott:
Steatohepatitis
Additional relevant MeSH terms:
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Liver Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
Digestive System Diseases