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

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

Official Title
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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

Conditions
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Non Alcoholic Fatty Liver Disease

Intervention / Treatment
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* Drug: SAMe 1000 mg
* Drug: SAMe 1500 mg
* Drug: SAMe 2000 mg


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1000 mg SAMe (S-adenosyl-L-methionine)<br> | Drug: SAMe 1000 mg<br>* 1000 mg dose group: one 500 mg capsule fasting in the morning and one 500 mg capsule before dinner<br>|
| Experimental: 1500 mg SAMe<br> | Drug: SAMe 1500 mg<br>* 1500 mg dose group: two 500 mg capsules fasting in the morning and one 500 mg capsule before dinner<br>|
| Experimental: 2000 mg SAMe<br> | Drug: SAMe 2000 mg<br>* 2000 mg dose group: two 500 mg capsules fasting in the morning and two 500 mg capsules before dinner<br>|
| No Intervention: No treatment<br> | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Methionine Elimination Half-life Measured in Blood. | 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. | 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7* | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fasting Methionine Concentration of Average Methionine Concentration Versus Time Curve. | 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. | 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7* | 
| 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | parameters cumulative percentage dose of 13 carbon recovered after 30, 60, 90 minutes (cPDR30, cPDR60, cPDR 90) will be evaluated | 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7* | 
| Hepatic Panel (Liver Laboratory Parameters) | Serum Total Bilirubin (STB), Serum Conjugated Bilirubin (SCB), liver-alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), Gamma Glutamyl Transpeptidase (GGT) | change from baseline at 6 weeks | 
| Metabolic Panel (Metabolic Laboratory Parameters) | Fasting lipid profile (cholesterol, HDL (High Density Lipoprotein), LDL (Low Density Lipoprotein)), amino acid profile, homeostasis model assessment (HOMA-R) and fasting glucose. | change from baseline at 6 weeks | 
| The Metabolic Clearance Rate Measured in the Blood. | 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. | 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7* | 
| Methionine Volume of Distribution at Week 7 (L) | 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. | 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7* | 
| 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | Peak | 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7* | 
| 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | Time to peak | 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7* | 
| Metabolic Panel (Metabolic Laboratory Parameters) | Fasting plasma insulin | Change from baseline at 6 weeks | 
| Metabolic Panel (Metabolic Laboratory Parameters) | glycosylated hemoglobin (HbA1c) | change from baseline at 6 weeks | 
| Metabolic Panel (Metabolic Laboratory Parameters) | Adiponectin | change from baseline at 6 weeks | 
| Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | C-reactive Protein (CRP) | change from baseline at 6 weeks | 
| Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | glutathione in erythrocytes | change from baseline at 6 weeks | 
| Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | oxidative stress marker (isoprostane level) | change from baseline at 6 weeks | 
| Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) | Caspase-cleaved cytokeratin (CK 18) | change from baseline at 6 weeks | 
| Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) | Hyaluronic acid | change from baseline at 6 weeks | 
| Area Under Curve (AUC) of Average Methionine Concentration Versus Time Curve | 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. | 0.5, 1, 1.5, 3, 4, 5, 6, 7.5 and 9 hours *at Week 7* | 
| Hepatic Panel (Liver Laboratory Parameters) | ALT/AST ratio | change from baseline at 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Steatohepatitis