Nonalcoholic Steatohepatitis MedDRA version: 17.0 Level: PT Classification code 10053219 Term: Non-alcoholic steatohepatitis System Organ Class: 10019805 - Hepatobiliary disorders
Conditions
Interventions
Trade Name: TRANSMETIL
Product Name: TRANSMETIL 500 mg
Pharmaceutical Form: Gastro-resistant tablet
INN or Proposed INN: Ademetionine 1,4-butanedisulfonate
CAS Number: [29908-03-0]
Other descriptive
Sponsors
Abbott Laboratories GmbH
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: NASH subjects Signed Informed Consent - Age = 18 years - Subjects diagnosed with NAFLD based on one of the following approaches: 1. Subjects with non-alcoholic steatohepatitis based on histology in medical history within the last 3 years and the subjects have to be in a stable metabolic condition since histology for NASH: - No major treatment changes indicative for improvement of NASH, e.g. stop of anti-diabetes drug(s) - No significant change in body weight (> 10 % weight reduction) 2. Subjects with non-alcoholic steatosis or steatohepatitis based on histology (> 3 years) in medical history and - Ultrasound ( 25 kg/m2 3. Subjects diagnosed with NAFLD without histology, based on: - Ultrasound ( 25 kg/m2 and - At least one of the following metabolic risk factors: - Impaired fasting glucose (serum glucose >6.1 mmol/l) or type 2 diabetes or Hypertension or Dyslipidemia Healthy volunteers - Signed Informed Consent - Subjects = 18 years - Subjects must be in good health as determined by vital signs, medical history, physical examination, serum/urine biochemistry and hematology. - No findings in ultrasound of the liver indicative for liver disease Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 101 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 34
Exclusion criteria
Exclusion criteria: NASH subjects ? Subjects with extrahepatic biliary obstruction ? Subjects with primary sclerosing cholangitis ? Subjects with primary biliary cirrhosis ? Any cancer within the past 5 years and/or basal cell carcinoma and squamous cell carcinoma of the skin within the past 2 years ? History of active substance abuse within 1 year ? Renal impairment ? Known hypersensitivity to the active substance or methionine or any of the inactive ingredients ? Known genetic defects affecting the methionine cycle and/or causing homocystinuria and/or hyperhomocysteinemia ? Subjects on total parenteral nutrition in the year prior to screening ? Subjects after or planned for bariatric surgery ? Extrahepatic cholestasis ? Subjects with ALT and/or AST > 5 ULN ? Subject with STB > 5 ULN ? Subjects after or on the waiting list for liver transplantation ? Subjects with history of viral hepatitis, evidence of autoimmune liver disease, Wilson´s disease, hemochromatosis oand /or Alpha-1-antitrypsin deficiency ? HIV positive ? Known heart failure ? Current or history of significant alcohol consumption ? Clinical or histological evidence of cirrhosis F4 ? History of biliary diversion ? Subjects with uncontrolled diabetes mellitus defined by HbA1c > 8.0 % at screening. ? Concomitant medication of B12, folate, betaine or choline ? Concomitant treatment with glitazone within the past year ? Subjects with known folate or B12 deficiency ? History of major depression DSM-IV or bipolar disease ? Women with positive urine pregnancy test during screening or unwillingness to use an effective form of birth control ? Breastfeeding women ? Any condition that does not justify the patient’s inclusion into the study ? Investigational drug intake within 1 month prior to the study ? Active, serious medical disease with life-expectancy less than five years ? Uncooperative attitude or reasonable likelihood for non-compliance with the protocol or any other reason that 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 Healthy volunteers ? Subjects with clinically relevant evidence of cardiovascular, gastrointestinal/hepatic, renal, neurologic/psychiatric or emotional, respiratory, urogenital, hematologic/immunologic, HEENT, dermatologic/connective tissue, musculoskeletal, metabolic/nutritional, drug hypersensitivity, (drug) allergy, endocrine, major surgery or other relevant diseases as revealed by medical history, physical examination, and laboratory assessments which may interfere with the absorption, distribution, metabolism or elimination of drugs or constitute a risk factor when taking the study medication. ? BMI > 27 kg/m2 ? Subject with elevated caspase-cleaved Cytokeratin 18 fragments > 100 U/L ? Subjects with known genetic defects affecting the methionine cycle and/or causing homocystinuria and/or hyperhomocysteinemia ? Subjects with hypersensitivity against methionine ? Concomitant medication of B12, folate, betaine or choline ? Concomitant treatment with glitazone within the past year ? Subjects with known folate or B12 deficiency ? Any form of malignancy within the past 5 years and/or basal cell carcinoma and squamous cell carcinoma of the skin within the past 2 years. ? Subjects with a history of symptomati
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: NASH subjects The primary objective of this study is to explore the effects of different doses of SAMe on the liver using the methionine tolerance test. The primary efficacy parameter will be the methionine elimination half-life measured in blood. Healthy volunteers Primary Objective: The healthy volunteer group will serve as control group to establish the reference values for the methionine tolerance test.;Secondary Objective: To explore: • The effect of different doses of SAMe using the methionine tolerance test and 13C-methionine breath test • Different doses of SAMe on: ? Hepatic panel: serum total bilirubin, serum conjugated bilirubin, alanine aminotransferase, alkaline phosphatase, total bile acids, aspartate aminotransferase, GGT, ALT/AST ratio ? Metabolic panel: fasting lipid profile, amino acid profile, homeostasis model assessment, fasting plasma insulin, fasting glucose, glycosylated hemoglobin and adiponectin ? Immunological/antioxidant panel ? fibrosis /apoptosis panel: caspase-cleaved cytokeratin 18, hyaluronic acid, ActiTest/Fibrotest: score 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, GGT, STB and ALT. • The efficacy of different doses of SAMe on clinical global impression • The efficacy of different doses of SAMe on EQ5/D ;Primary end point(s): Methionine tolerance test: The primary efficacy parameter of the methionine tolerance test will be the methionine eliminiation half-life measured in blood.;Timepoint(s) of evaluation of this end point: After 6 weeks of treatment. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Methionine tolerance test: The secondary efficacy parameter of this test will be the fasting methionine concentration and AUC of average methionine concentration versus time curve, the metabolic clearance rate and volume of distribution measured in blood. 13C Methionine breath test: An additional secondary efficacy parameter will be the methionine breath test that will determine the effect of different doses of SAMe on the liver. The parameters cPDR30, cPDR60, cPDR 90, peak and time to peak will be evaluated. The breath test will be performed one day after the methionine loading test at the start and at the end of trial. Breath test parameter will be measured by the non-continuous breath test device. ;Timepoint(s) of evaluation of this end point: After 6 weeks of treatment. | — |
Countries
Germany
Contacts
Public ContactRegulatory Affairs
Abbott House
Outcome results
None listed