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)

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

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

Study Overview

• Status: Completed
• Conditions: Non Alcoholic Fatty Liver Disease
• Intervention / Treatment: Drug: SAMe 1000 mg; Drug: SAMe 1500 mg; Drug: SAMe 2000 mg

• Study Type: Interventional
• Enrollment (Actual): 108
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Amiens, France, 80054
    • Site Reference ID 93914
  • Angers, France, 49933
    • Site Reference ID 93895
  • Bobigny, France, 93009
    • Site Reference ID 93894
  • Montpellier, France, 34295
    • Site Reference ID 93913
  • Nice, France, 06202
    • Site Reference ID 93916
  • Paris, France, 75012
    • Site Reference ID 93915
  • Paris, France, 75651
    • Site Reference ID 93893
  • Pessac, France, 33604
    • Site Reference ID 93896
• Germany
  • Bonn, Germany, 53127
    • Site Reference ID 93953
  • Frankfurt, Germany, 60594
    • Site Reference ID 93954
  • Freiburg, Germany, 79106
    • Site Reference ID 93935
  • Halle, Germany, 06120
    • Site Reference ID 93955
  • Hannover, Germany, 30625
    • Site Reference ID 93917
  • Homburg, Germany, 66424
    • Site Reference ID 93933
  • Leipzig, Germany, 04103
    • Site Reference ID 94015
  • Mainz, Germany, 55131
    • Site Reference ID 93918
  • Ulm, Germany, 89081
    • Site Reference ID 94014
• Poland
  • Bydgoszcz, Poland, 85-030
    • Site reference ID/Investigator # 109455
  • Chorzow, Poland, 41-500
    • Site Reference ID 93958
  • Krakow, Poland, 31-531
    • Site Reference ID 93973
  • Lodz, Poland, 91-347
    • Site Reference ID 93956
  • Myslowice, Poland, 41-400
    • Site Reference ID 93957
  • Warsaw, Poland, 02-507
    • Site Reference ID 93974
  • Wroclaw, Poland, 50-220
    • Site Reference ID 93975
• Russian Federation
  • Krasnoyarsk, Russian Federation, 660022
    • Site reference ID ORG-000905
  • Moscow, Russian Federation, 119435
    • Site reference ID ORG-000906
  • Nizhniy Novgorod, Russian Federation, 603126
    • Site reference ID ORG-000900
  • Novosibirsk, Russian Federation, 630084
    • Site reference ID ORG-000907
  • Omsk, Russian Federation, 644043
    • Site reference ID ORG-000903
  • Rostov-on-Don, Russian Federation, 344022
    • Site reference ID ORG-000920
  • Samara, Russian Federation, 443011
    • Site reference ID ORG-000904
  • Stavropol, Russian Federation, 355017
    • Site reference ID ORG-000901

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 97 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: No 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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 ).	change from baseline at 6 weeks
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.	change from baseline at 6 weeks

Collaborators and Investigators

• Sponsor: Abbott
• Collaborators: PPD

Study record dates

Study Major Dates

• Study Start: December 1, 2012
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: December 19, 2012
• First Submitted That Met QC Criteria: December 19, 2012
• First Posted (Estimate): December 21, 2012

Study Record Updates

• Last Update Posted (Estimate): February 19, 2016
• Last Update Submitted That Met QC Criteria: January 22, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: Steatohepatitis
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: M13-397; 2012-000975-18 (EudraCT Number)