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

Non Alcoholic Fatty Liver Disease Clinical Trial

— EXPO  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01754714
• Other study ID #: M13-397
• Secondary ID: 2012-000975-18
• Status: Completed
• Phase: Phase 3
• First received: December 19, 2012
• Last updated: January 22, 2016
• Start date: December 2012
• Est. completion date: September 2014

Study information

• Verified date: January 2016
• Source: Abbott
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 108
• Est. completion date: September 2014
• Est. primary completion date: September 2014
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 99 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Fatty Liver
• Liver Diseases
• Non Alcoholic Fatty Liver Disease

Intervention

Drug:
• SAMe 1000 mg
1000 mg dose group: one 500 mg capsule fasting in the morning and one 500 mg capsule before dinner
• SAMe 1500 mg
1500 mg dose group: two 500 mg capsules fasting in the morning and one 500 mg capsule before dinner
• SAMe 2000 mg
2000 mg dose group: two 500 mg capsules fasting in the morning and two 500 mg capsules before dinner

Locations

Country	Name	City	State
France	Site Reference ID 93914	Amiens
France	Site Reference ID 93895	Angers
France	Site Reference ID 93894	Bobigny
France	Site Reference ID 93913	Montpellier
France	Site Reference ID 93916	Nice
France	Site Reference ID 93893	Paris
France	Site Reference ID 93915	Paris
France	Site Reference ID 93896	Pessac
Germany	Site Reference ID 93953	Bonn
Germany	Site Reference ID 93954	Frankfurt
Germany	Site Reference ID 93935	Freiburg
Germany	Site Reference ID 93955	Halle
Germany	Site Reference ID 93917	Hannover
Germany	Site Reference ID 93933	Homburg
Germany	Site Reference ID 94015	Leipzig
Germany	Site Reference ID 93918	Mainz
Germany	Site Reference ID 94014	Ulm
Poland	Site reference ID/Investigator # 109455	Bydgoszcz
Poland	Site Reference ID 93958	Chorzow
Poland	Site Reference ID 93973	Krakow
Poland	Site Reference ID 93956	Lodz
Poland	Site Reference ID 93957	Myslowice
Poland	Site Reference ID 93974	Warsaw
Poland	Site Reference ID 93975	Wroclaw
Russian Federation	Site reference ID ORG-000905	Krasnoyarsk
Russian Federation	Site reference ID ORG-000906	Moscow
Russian Federation	Site reference ID ORG-000900	Nizhniy Novgorod
Russian Federation	Site reference ID ORG-000907	Novosibirsk
Russian Federation	Site reference ID ORG-000903	Omsk
Russian Federation	Site reference ID ORG-000920	Rostov-on-Don
Russian Federation	Site reference ID ORG-000904	Samara
Russian Federation	Site reference ID ORG-000901	Stavropol

Sponsors (2)

Lead Sponsor	Collaborator
Abbott	PPD

Countries where clinical trial is conducted

France,  Germany,  Poland,  Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters)	Cytokine profile ( Interleukin-6, IL-8, IL-10 (IL), Tumor Necrosis Factor (TNF -a), monocyte chemoattractant protein (MCP-1), and Granulocyte-colony stimulating factor (G-CSF ).	change from baseline at 6 weeks	No
Other	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	No
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.	0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7*	No
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.	0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7*	No
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	0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7*	No
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)	change from baseline at 6 weeks	No
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.	change from baseline at 6 weeks	No
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.	0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7*	No
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.	0.5, 1, 1.5, 3, 4.5, 6, 7.5 and 9 hours*at Week 7*	No
Secondary	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*	No
Secondary	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*	No
Secondary	Metabolic Panel (Metabolic Laboratory Parameters)	Fasting plasma insulin	Change from baseline at 6 weeks	No
Secondary	Metabolic Panel (Metabolic Laboratory Parameters)	glycosylated hemoglobin (HbA1c)	change from baseline at 6 weeks	No
Secondary	Metabolic Panel (Metabolic Laboratory Parameters)	Adiponectin	change from baseline at 6 weeks	No
Secondary	Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters)	C-reactive Protein (CRP)	change from baseline at 6 weeks	No
Secondary	Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters)	glutathione in erythrocytes	change from baseline at 6 weeks	No
Secondary	Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters)	oxidative stress marker (isoprostane level)	change from baseline at 6 weeks	No
Secondary	Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers)	Caspase-cleaved cytokeratin (CK 18)	change from baseline at 6 weeks	No
Secondary	Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers)	Hyaluronic acid	change from baseline at 6 weeks	No
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.	0.5, 1, 1.5, 3, 4, 5, 6, 7.5 and 9 hours *at Week 7*	No
Secondary	Hepatic Panel (Liver Laboratory Parameters)	ALT/AST ratio	change from baseline at 6 weeks	No