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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)

This study has been completed.
Sponsor:
Collaborator:
PPD
Information provided by (Responsible Party):
Abbott
ClinicalTrials.gov Identifier:
NCT01754714
First received: December 19, 2012
Last updated: January 22, 2016
Last verified: January 2016
  Purpose
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 Intervention Phase
Non Alcoholic Fatty Liver Disease
Drug: SAMe 1000 mg
Drug: SAMe 1500 mg
Drug: SAMe 2000 mg
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Abbott:

Primary Outcome Measures:
  • 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* ] [ Designated as safety issue: No ]
    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:
  • 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* ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7* ] [ Designated as safety issue: No ]
    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) [ Time Frame: change from baseline at 6 weeks ] [ Designated as safety issue: No ]
    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) [ Time Frame: change from baseline at 6 weeks ] [ Designated as safety issue: No ]
    Fasting lipid profile (cholesterol, HDL (High Density Lipoprotein), LDL (Low Density Lipoprotein)), amino acid profile, homeostasis model assessment (HOMA-R) and fasting glucose.

  • 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* ] [ Designated as safety issue: No ]
    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.

  • 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* ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7* ] [ Designated as safety issue: No ]
    Peak

  • 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* ] [ Designated as safety issue: No ]
    Time to peak

  • Metabolic Panel (Metabolic Laboratory Parameters) [ Time Frame: Change from baseline at 6 weeks ] [ Designated as safety issue: No ]
    Fasting plasma insulin

  • Metabolic Panel (Metabolic Laboratory Parameters) [ Time Frame: change from baseline at 6 weeks ] [ Designated as safety issue: No ]
    glycosylated hemoglobin (HbA1c)

  • Metabolic Panel (Metabolic Laboratory Parameters) [ Time Frame: change from baseline at 6 weeks ] [ Designated as safety issue: No ]
    Adiponectin

  • Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) [ Time Frame: change from baseline at 6 weeks ] [ Designated as safety issue: No ]
    C-reactive Protein (CRP)

  • Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) [ Time Frame: change from baseline at 6 weeks ] [ Designated as safety issue: No ]
    glutathione in erythrocytes

  • Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) [ Time Frame: change from baseline at 6 weeks ] [ Designated as safety issue: No ]
    oxidative stress marker (isoprostane level)

  • Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) [ Time Frame: change from baseline at 6 weeks ] [ Designated as safety issue: No ]
    Caspase-cleaved cytokeratin (CK 18)

  • Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers) [ Time Frame: change from baseline at 6 weeks ] [ Designated as safety issue: No ]
    Hyaluronic acid

  • 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* ] [ Designated as safety issue: No ]
    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.

  • Hepatic Panel (Liver Laboratory Parameters) [ Time Frame: change from baseline at 6 weeks ] [ Designated as safety issue: No ]
    ALT/AST ratio


Other Outcome Measures:
  • Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters) [ Time Frame: change from baseline at 6 weeks ] [ Designated as safety issue: No ]
    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) [ Time Frame: change from baseline at 6 weeks ] [ Designated as safety issue: No ]

    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.



Enrollment: 108
Study Start Date: December 2012
Study Completion Date: September 2014
Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years to 99 Years   (Adult, Senior)
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01754714

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

Responsible Party: Abbott
ClinicalTrials.gov Identifier: NCT01754714     History of Changes
Other Study ID Numbers: M13-397  2012-000975-18 
Study First Received: December 19, 2012
Results First Received: October 2, 2015
Last Updated: January 22, 2016
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by Abbott:
Steatohepatitis

Additional relevant MeSH terms:
Liver Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
Digestive System Diseases

ClinicalTrials.gov processed this record on December 08, 2016