Non Alcoholic Fatty Liver Disease
Conditions
Keywords
Steatohepatitis
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
Interventions
DRUGSAMe 1000 mg
1000 mg dose group: one 500 mg capsule fasting in the morning and one 500 mg capsule before dinner
DRUGSAMe 1500 mg
1500 mg dose group: two 500 mg capsules fasting in the morning and one 500 mg capsule before dinner
DRUGSAMe 2000 mg
2000 mg dose group: two 500 mg capsules fasting in the morning and two 500 mg capsules before dinner
Sponsors
PPD Development, LP
Abbott
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Methionine Elimination Half-life Measured in Blood. | 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
| Measure | Time frame | Description |
|---|---|---|
| Methionine Volume of Distribution at Week 7 (L) | 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. |
| Fasting Methionine Concentration of Average Methionine Concentration Versus Time Curve. | 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. |
| 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | 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 |
| Hepatic Panel (Liver Laboratory Parameters) | 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) |
| Metabolic Panel (Metabolic Laboratory Parameters) | 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. |
| Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) | change from baseline at 6 weeks | Caspase-cleaved cytokeratin (CK 18) |
| Area Under Curve (AUC) of Average Methionine Concentration Versus Time Curve | 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. |
| The Metabolic Clearance Rate Measured in the Blood. | 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. |
| Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | change from baseline at 6 weeks | C-reactive Protein (CRP) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | 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 ). |
| Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) | 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. |
Countries
France, Germany, Poland, Russia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) SAMe 1000 mg: 1000 mg dose group: one 500 mg capsule fasting in the morning and one 500 mg capsule before dinner | 27 |
| 1500 mg SAMe SAMe 1500 mg: 1500 mg dose group: two 500 mg capsules fasting in the morning and one 500 mg capsule before dinner | 27 |
| 2000 mg SAMe SAMe 2000 mg: 2000 mg dose group: two 500 mg capsules fasting in the morning and two 500 mg capsules before dinner | 26 |
| No Treatment no study drug was administered | 28 |
| Total | 108 |
Baseline characteristics
| Characteristic | 1000 mg SAMe (S-adenosyl-L-methionine) | 1500 mg SAMe | 2000 mg SAMe | No Treatment | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 3 Participants | 3 Participants | 7 Participants | 17 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants | 24 Participants | 23 Participants | 21 Participants | 91 Participants |
| Age, Continuous | 51.2 years STANDARD_DEVIATION 13.8 | 50.0 years STANDARD_DEVIATION 12.3 | 49.5 years STANDARD_DEVIATION 14.2 | 56.6 years STANDARD_DEVIATION 11.6 | 51.9 years STANDARD_DEVIATION 13.1 |
| Region of Enrollment France | 6 participants | 5 participants | 4 participants | 9 participants | 24 participants |
| Region of Enrollment Germany | 13 participants | 14 participants | 11 participants | 11 participants | 49 participants |
| Region of Enrollment Poland | 3 participants | 2 participants | 6 participants | 6 participants | 17 participants |
| Region of Enrollment Russian Federation | 5 participants | 6 participants | 5 participants | 2 participants | 18 participants |
| Sex: Female, Male Female | 15 Participants | 10 Participants | 9 Participants | 11 Participants | 45 Participants |
| Sex: Female, Male Male | 12 Participants | 17 Participants | 17 Participants | 17 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 27 | 4 / 27 | 7 / 24 | 2 / 28 |
| serious Total, serious adverse events | 0 / 27 | 0 / 27 | 0 / 24 | 1 / 28 |
Outcome results
Primary
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.
Time frame: 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7*
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) | Methionine Elimination Half-life Measured in Blood. | 4.29 hour | Standard Deviation 1.86 |
| 1500 mg SAMe | Methionine Elimination Half-life Measured in Blood. | 4.66 hour | Standard Deviation 1.57 |
| 2000 mg SAMe | Methionine Elimination Half-life Measured in Blood. | 4.25 hour | Standard Deviation 1.64 |
| No Treatment | Methionine Elimination Half-life Measured in Blood. | 4.26 hour | Standard Deviation 1.44 |
Secondary
13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test
Peak
Time frame: 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7*
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) | 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | 1.0972 Atom %C13 | Standard Deviation 0.0062 |
| 1500 mg SAMe | 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | 1.0964 Atom %C13 | Standard Deviation 0.0052 |
| 2000 mg SAMe | 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | 1.0964 Atom %C13 | Standard Deviation 0.0053 |
| No Treatment | 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | 1.0949 Atom %C13 | Standard Deviation 0.0045 |
Secondary
13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test
Time to peak
Time frame: 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7*
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) | 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | 70.0 minutes |
| 1500 mg SAMe | 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | 70.0 minutes |
| 2000 mg SAMe | 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | 70.0 minutes |
| No Treatment | 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | 70.0 minutes |
Secondary
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
Time frame: 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7*
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) | 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | 13C methionine breath test recovery at 30 min (%) | 0.93 percentage of recovery | Standard Deviation 0.73 |
| 1000 mg SAMe (S-adenosyl-L-methionine) | 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | 13C methionine breath test recovery at 90 min (%) | 6.69 percentage of recovery | Standard Deviation 2.75 |
| 1000 mg SAMe (S-adenosyl-L-methionine) | 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | 13C methionine breath test recovery at 60 min (%) | 3.66 percentage of recovery | Standard Deviation 1.99 |
| 1500 mg SAMe | 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | 13C methionine breath test recovery at 30 min (%) | 0.77 percentage of recovery | Standard Deviation 0.51 |
| 1500 mg SAMe | 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | 13C methionine breath test recovery at 90 min (%) | 6.60 percentage of recovery | Standard Deviation 2.56 |
| 1500 mg SAMe | 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | 13C methionine breath test recovery at 60 min (%) | 3.49 percentage of recovery | Standard Deviation 1.74 |
| 2000 mg SAMe | 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | 13C methionine breath test recovery at 60 min (%) | 3.61 percentage of recovery | Standard Deviation 1.78 |
| 2000 mg SAMe | 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | 13C methionine breath test recovery at 30 min (%) | 0.88 percentage of recovery | Standard Deviation 0.66 |
| 2000 mg SAMe | 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | 13C methionine breath test recovery at 90 min (%) | 6.68 percentage of recovery | Standard Deviation 2.48 |
| No Treatment | 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | 13C methionine breath test recovery at 30 min (%) | 0.69 percentage of recovery | Standard Deviation 0.55 |
| No Treatment | 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | 13C methionine breath test recovery at 90 min (%) | 5.74 percentage of recovery | Standard Deviation 2.56 |
| No Treatment | 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test | 13C methionine breath test recovery at 60 min (%) | 2.98 percentage of recovery | Standard Deviation 1.72 |
Secondary
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.
Time frame: 0.5, 1, 1.5, 3, 4, 5, 6, 7.5 and 9 hours *at Week 7*
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) | Area Under Curve (AUC) of Average Methionine Concentration Versus Time Curve | 440.09 mcg/mL | Standard Deviation 149.96 |
| 1500 mg SAMe | Area Under Curve (AUC) of Average Methionine Concentration Versus Time Curve | 399.30 mcg/mL | Standard Deviation 148.9 |
| 2000 mg SAMe | Area Under Curve (AUC) of Average Methionine Concentration Versus Time Curve | 425.24 mcg/mL | Standard Deviation 231.88 |
| No Treatment | Area Under Curve (AUC) of Average Methionine Concentration Versus Time Curve | 460.57 mcg/mL | Standard Deviation 135.63 |
Secondary
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.
Time frame: 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7*
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) | Fasting Methionine Concentration of Average Methionine Concentration Versus Time Curve. | 4.02 mcg/mL | Standard Deviation 0.92 |
| 1500 mg SAMe | Fasting Methionine Concentration of Average Methionine Concentration Versus Time Curve. | 3.81 mcg/mL | Standard Deviation 0.67 |
| 2000 mg SAMe | Fasting Methionine Concentration of Average Methionine Concentration Versus Time Curve. | 5.68 mcg/mL | Standard Deviation 10.13 |
| No Treatment | Fasting Methionine Concentration of Average Methionine Concentration Versus Time Curve. | 5.62 mcg/mL | Standard Deviation 8.53 |
Secondary
Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers)
Hyaluronic acid
Time frame: change from baseline at 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) | Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) | 4.67 ng/mL | Standard Deviation 48.52 |
| 1500 mg SAMe | Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) | 2.03 ng/mL | Standard Deviation 32.26 |
| 2000 mg SAMe | Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) | 9.40 ng/mL | Standard Deviation 59.63 |
| No Treatment | Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) | 3.02 ng/mL | Standard Deviation 46.56 |
Secondary
Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers)
Caspase-cleaved cytokeratin (CK 18)
Time frame: change from baseline at 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) | Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) | -126.8 U/L | Standard Deviation 401.1 |
| 1500 mg SAMe | Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) | -136.6 U/L | Standard Deviation 257.3 |
| 2000 mg SAMe | Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) | -47.0 U/L | Standard Deviation 157.3 |
| No Treatment | Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) | -143.2 U/L | Standard Deviation 532.5 |
Secondary
Hepatic Panel (Liver Laboratory Parameters)
ALT/AST ratio
Time frame: change from baseline at 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) | Hepatic Panel (Liver Laboratory Parameters) | -0.02 Ratio | Standard Deviation 0.23 |
| 1500 mg SAMe | Hepatic Panel (Liver Laboratory Parameters) | 0.01 Ratio | Standard Deviation 0.21 |
| 2000 mg SAMe | Hepatic Panel (Liver Laboratory Parameters) | 0.03 Ratio | Standard Deviation 0.18 |
| No Treatment | Hepatic Panel (Liver Laboratory Parameters) | -0.01 Ratio | Standard Deviation 0.27 |
Secondary
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)
Time frame: change from baseline at 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) | Hepatic Panel (Liver Laboratory Parameters) | ALP | 1.9 U/L | Standard Deviation 7.9 |
| 1000 mg SAMe (S-adenosyl-L-methionine) | Hepatic Panel (Liver Laboratory Parameters) | ALT | -6.2 U/L | Standard Deviation 19.5 |
| 1000 mg SAMe (S-adenosyl-L-methionine) | Hepatic Panel (Liver Laboratory Parameters) | AST | -5.1 U/L | Standard Deviation 15.7 |
| 1000 mg SAMe (S-adenosyl-L-methionine) | Hepatic Panel (Liver Laboratory Parameters) | GGT | -1.1 U/L | Standard Deviation 33.7 |
| 1500 mg SAMe | Hepatic Panel (Liver Laboratory Parameters) | ALT | -6.3 U/L | Standard Deviation 23.5 |
| 1500 mg SAMe | Hepatic Panel (Liver Laboratory Parameters) | AST | -3.0 U/L | Standard Deviation 16.5 |
| 1500 mg SAMe | Hepatic Panel (Liver Laboratory Parameters) | GGT | -10.6 U/L | Standard Deviation 62.7 |
| 1500 mg SAMe | Hepatic Panel (Liver Laboratory Parameters) | ALP | -0.1 U/L | Standard Deviation 13.7 |
| 2000 mg SAMe | Hepatic Panel (Liver Laboratory Parameters) | AST | -1.2 U/L | Standard Deviation 10.7 |
| 2000 mg SAMe | Hepatic Panel (Liver Laboratory Parameters) | ALT | -4.9 U/L | Standard Deviation 32.2 |
| 2000 mg SAMe | Hepatic Panel (Liver Laboratory Parameters) | GGT | -2.7 U/L | Standard Deviation 35.7 |
| 2000 mg SAMe | Hepatic Panel (Liver Laboratory Parameters) | ALP | 3.4 U/L | Standard Deviation 24.1 |
| No Treatment | Hepatic Panel (Liver Laboratory Parameters) | GGT | -12.3 U/L | Standard Deviation 48.1 |
| No Treatment | Hepatic Panel (Liver Laboratory Parameters) | ALT | -11.9 U/L | Standard Deviation 33.4 |
| No Treatment | Hepatic Panel (Liver Laboratory Parameters) | ALP | -6.0 U/L | Standard Deviation 16.9 |
| No Treatment | Hepatic Panel (Liver Laboratory Parameters) | AST | -11.6 U/L | Standard Deviation 27.7 |
Secondary
Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters)
C-reactive Protein (CRP)
Time frame: change from baseline at 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | -0.79 nmol/L | Standard Deviation 15.51 |
| 1500 mg SAMe | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | -0.80 nmol/L | Standard Deviation 14.9 |
| 2000 mg SAMe | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | -8.02 nmol/L | Standard Deviation 20.4 |
| No Treatment | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | -4.80 nmol/L | Standard Deviation 12.8 |
Secondary
Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters)
glutathione in erythrocytes
Time frame: change from baseline at 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | -0.24 mcmol/g | Standard Deviation 2.06 |
| 1500 mg SAMe | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | -0.21 mcmol/g | Standard Deviation 1.01 |
| 2000 mg SAMe | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | 0.05 mcmol/g | Standard Deviation 1.41 |
| No Treatment | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | -0.30 mcmol/g | Standard Deviation 1.33 |
Secondary
Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters)
oxidative stress marker (isoprostane level)
Time frame: change from baseline at 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | -0.223 ng/mg Crea | Standard Deviation 0.801 |
| 1500 mg SAMe | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | 0.116 ng/mg Crea | Standard Deviation 0.699 |
| 2000 mg SAMe | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | 0.290 ng/mg Crea | Standard Deviation 0.691 |
| No Treatment | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | -0.223 ng/mg Crea | Standard Deviation 0.641 |
Secondary
Metabolic Panel (Metabolic Laboratory Parameters)
Adiponectin
Time frame: change from baseline at 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) | Metabolic Panel (Metabolic Laboratory Parameters) | 0.754 mcg/mL | Standard Deviation 4.191 |
| 1500 mg SAMe | Metabolic Panel (Metabolic Laboratory Parameters) | 0.425 mcg/mL | Standard Deviation 1.199 |
| 2000 mg SAMe | Metabolic Panel (Metabolic Laboratory Parameters) | 0.219 mcg/mL | Standard Deviation 1.661 |
| No Treatment | Metabolic Panel (Metabolic Laboratory Parameters) | 0.045 mcg/mL | Standard Deviation 1.515 |
Secondary
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.
Time frame: change from baseline at 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) | Metabolic Panel (Metabolic Laboratory Parameters) | HOMA-R | 0.837 mmol/L | Standard Deviation 13.232 |
| 1000 mg SAMe (S-adenosyl-L-methionine) | Metabolic Panel (Metabolic Laboratory Parameters) | HDL | -0.094 mmol/L | Standard Deviation 0.166 |
| 1000 mg SAMe (S-adenosyl-L-methionine) | Metabolic Panel (Metabolic Laboratory Parameters) | Glucose | -0.068 mmol/L | Standard Deviation 0.968 |
| 1000 mg SAMe (S-adenosyl-L-methionine) | Metabolic Panel (Metabolic Laboratory Parameters) | LDL | 0.125 mmol/L | Standard Deviation 0.452 |
| 1000 mg SAMe (S-adenosyl-L-methionine) | Metabolic Panel (Metabolic Laboratory Parameters) | Cholesterol | -0.131 mmol/L | Standard Deviation 0.593 |
| 1500 mg SAMe | Metabolic Panel (Metabolic Laboratory Parameters) | LDL | 0.182 mmol/L | Standard Deviation 0.762 |
| 1500 mg SAMe | Metabolic Panel (Metabolic Laboratory Parameters) | HOMA-R | 0.127 mmol/L | Standard Deviation 3.763 |
| 1500 mg SAMe | Metabolic Panel (Metabolic Laboratory Parameters) | Glucose | 0.490 mmol/L | Standard Deviation 1.486 |
| 1500 mg SAMe | Metabolic Panel (Metabolic Laboratory Parameters) | HDL | -0.046 mmol/L | Standard Deviation 0.254 |
| 1500 mg SAMe | Metabolic Panel (Metabolic Laboratory Parameters) | Cholesterol | 0.046 mmol/L | Standard Deviation 0.921 |
| 2000 mg SAMe | Metabolic Panel (Metabolic Laboratory Parameters) | LDL | -0.202 mmol/L | Standard Deviation 0.589 |
| 2000 mg SAMe | Metabolic Panel (Metabolic Laboratory Parameters) | Cholesterol | -0.265 mmol/L | Standard Deviation 0.601 |
| 2000 mg SAMe | Metabolic Panel (Metabolic Laboratory Parameters) | HDL | -0.098 mmol/L | Standard Deviation 0.169 |
| 2000 mg SAMe | Metabolic Panel (Metabolic Laboratory Parameters) | HOMA-R | -1.549 mmol/L | Standard Deviation 13.321 |
| 2000 mg SAMe | Metabolic Panel (Metabolic Laboratory Parameters) | Glucose | -0.163 mmol/L | Standard Deviation 1.009 |
| No Treatment | Metabolic Panel (Metabolic Laboratory Parameters) | HOMA-R | 3.432 mmol/L | Standard Deviation 10.837 |
| No Treatment | Metabolic Panel (Metabolic Laboratory Parameters) | HDL | -0.075 mmol/L | Standard Deviation 0.188 |
| No Treatment | Metabolic Panel (Metabolic Laboratory Parameters) | Cholesterol | -0.134 mmol/L | Standard Deviation 0.659 |
| No Treatment | Metabolic Panel (Metabolic Laboratory Parameters) | LDL | -0.112 mmol/L | Standard Deviation 0.558 |
| No Treatment | Metabolic Panel (Metabolic Laboratory Parameters) | Glucose | -0.121 mmol/L | Standard Deviation 1.61 |
Secondary
Metabolic Panel (Metabolic Laboratory Parameters)
Fasting plasma insulin
Time frame: Change from baseline at 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) | Metabolic Panel (Metabolic Laboratory Parameters) | 0.3 pmol/L | Standard Deviation 191 |
| 1500 mg SAMe | Metabolic Panel (Metabolic Laboratory Parameters) | -13.6 pmol/L | Standard Deviation 115.5 |
| 2000 mg SAMe | Metabolic Panel (Metabolic Laboratory Parameters) | -13.1 pmol/L | Standard Deviation 248 |
| No Treatment | Metabolic Panel (Metabolic Laboratory Parameters) | 69.1 pmol/L | Standard Deviation 309 |
Secondary
Metabolic Panel (Metabolic Laboratory Parameters)
glycosylated hemoglobin (HbA1c)
Time frame: change from baseline at 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) | Metabolic Panel (Metabolic Laboratory Parameters) | -0.08 Percentage | Standard Deviation 0.28 |
| 1500 mg SAMe | Metabolic Panel (Metabolic Laboratory Parameters) | -0.06 Percentage | Standard Deviation 0.36 |
| 2000 mg SAMe | Metabolic Panel (Metabolic Laboratory Parameters) | -0.05 Percentage | Standard Deviation 0.32 |
| No Treatment | Metabolic Panel (Metabolic Laboratory Parameters) | 0.02 Percentage | Standard Deviation 0.33 |
Secondary
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.
Time frame: 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7*
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) | Methionine Volume of Distribution at Week 7 (L) | 54.40 L | Standard Deviation 18.43 |
| 1500 mg SAMe | Methionine Volume of Distribution at Week 7 (L) | 62.84 L | Standard Deviation 14.04 |
| 2000 mg SAMe | Methionine Volume of Distribution at Week 7 (L) | 64.58 L | Standard Deviation 17.77 |
| No Treatment | Methionine Volume of Distribution at Week 7 (L) | 8.23 L | Standard Deviation 53.98 |
Secondary
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.
Time frame: 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7*
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) | The Metabolic Clearance Rate Measured in the Blood. | 8.86 L/h | Standard Deviation 2.93 |
| 1500 mg SAMe | The Metabolic Clearance Rate Measured in the Blood. | 9.83 L/h | Standard Deviation 3.27 |
| 2000 mg SAMe | The Metabolic Clearance Rate Measured in the Blood. | 10.05 L/h | Standard Deviation 4.32 |
| No Treatment | The Metabolic Clearance Rate Measured in the Blood. | 8.23 L/h | Standard Deviation 2.3 |
Other Pre-specified
Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers)
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.
Time frame: change from baseline at 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) | Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) | ActiTest Score | -0.017 scores on a scale | Standard Deviation 0.098 |
| 1000 mg SAMe (S-adenosyl-L-methionine) | Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) | Fibrotest Score | 0.036 scores on a scale | Standard Deviation 0.097 |
| 1500 mg SAMe | Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) | Fibrotest Score | 0.028 scores on a scale | Standard Deviation 0.093 |
| 1500 mg SAMe | Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) | ActiTest Score | -0.022 scores on a scale | Standard Deviation 0.137 |
| 2000 mg SAMe | Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) | ActiTest Score | -0.002 scores on a scale | Standard Deviation 0.168 |
| 2000 mg SAMe | Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) | Fibrotest Score | 0.050 scores on a scale | Standard Deviation 0.125 |
| No Treatment | Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) | ActiTest Score | -0.042 scores on a scale | Standard Deviation 0.096 |
| No Treatment | Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) | Fibrotest Score | 0.020 scores on a scale | Standard Deviation 0.068 |
Other Pre-specified
Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters)
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 ).
Time frame: change from baseline at 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1000 mg SAMe (S-adenosyl-L-methionine) | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | G-CSF: n= (5,4,1,0) | -20.0 pg/mL | Standard Deviation 52.8 |
| 1000 mg SAMe (S-adenosyl-L-methionine) | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | TNF-alpha: n= (24,24,20,27) | -0.127 pg/mL | Standard Deviation 0.414 |
| 1000 mg SAMe (S-adenosyl-L-methionine) | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | IL-8: n= (8,6,7,9) | -14.41 pg/mL | Standard Deviation 41.07 |
| 1000 mg SAMe (S-adenosyl-L-methionine) | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | IL-10: n= (1,2,1,2) | 0.270 pg/mL | — |
| 1000 mg SAMe (S-adenosyl-L-methionine) | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | MCP-1: n= (27,25,24,27) | -29.75 pg/mL | Standard Deviation 154.75 |
| 1000 mg SAMe (S-adenosyl-L-methionine) | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | IL-6: n= (27,24,23,27) | 0.0603 pg/mL | Standard Deviation 2.0263 |
| 1500 mg SAMe | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | MCP-1: n= (27,25,24,27) | -20.60 pg/mL | Standard Deviation 79.71 |
| 1500 mg SAMe | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | G-CSF: n= (5,4,1,0) | -0.5 pg/mL | Standard Deviation 9.7 |
| 1500 mg SAMe | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | IL-8: n= (8,6,7,9) | 0.65 pg/mL | Standard Deviation 13.37 |
| 1500 mg SAMe | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | IL-6: n= (27,24,23,27) | -0.9254 pg/mL | Standard Deviation 6.4599 |
| 1500 mg SAMe | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | IL-10: n= (1,2,1,2) | -0.045 pg/mL | Standard Deviation 0.106 |
| 1500 mg SAMe | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | TNF-alpha: n= (24,24,20,27) | -1.083 pg/mL | Standard Deviation 4.782 |
| 2000 mg SAMe | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | IL-6: n= (27,24,23,27) | -1.3194 pg/mL | Standard Deviation 4.5779 |
| 2000 mg SAMe | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | IL-8: n= (8,6,7,9) | -78.73 pg/mL | Standard Deviation 187.51 |
| 2000 mg SAMe | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | MCP-1: n= (27,25,24,27) | -40.15 pg/mL | Standard Deviation 96.21 |
| 2000 mg SAMe | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | TNF-alpha: n= (24,24,20,27) | -0.601 pg/mL | Standard Deviation 2.136 |
| 2000 mg SAMe | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | G-CSF: n= (5,4,1,0) | 20.0 pg/mL | — |
| 2000 mg SAMe | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | IL-10: n= (1,2,1,2) | -0.300 pg/mL | — |
| No Treatment | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | G-CSF: n= (5,4,1,0) | NA pg/mL | — |
| No Treatment | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | IL-6: n= (27,24,23,27) | 0.1597 pg/mL | Standard Deviation 1.6243 |
| No Treatment | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | IL-8: n= (8,6,7,9) | -6.17 pg/mL | Standard Deviation 16.94 |
| No Treatment | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | IL-10: n= (1,2,1,2) | 1.600 pg/mL | Standard Deviation 1.146 |
| No Treatment | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | TNF-alpha: n= (24,24,20,27) | -0.187 pg/mL | Standard Deviation 1.114 |
| No Treatment | Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) | MCP-1: n= (27,25,24,27) | -44.51 pg/mL | Standard Deviation 114.85 |