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    Summary
    EudraCT Number:2012-000975-18
    Sponsor's Protocol Code Number:M13-397
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-07-03
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2012-000975-18
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to investigate the Effects of Different Doses of the drug product S-adenosyl-L-methionine (SAMe) in patients with Nonalcoholic Steatohepatitis (NASH) and in healthy volunteers as control group
    A.4.1Sponsor's protocol code numberM13-397
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAbbott Laboratories GmbH
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAbbott Products GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAbbott House
    B.5.2Functional name of contact pointRegulatory Affairs
    B.5.3 Address:
    B.5.3.1Street AddressVanwall Road
    B.5.3.2Town/ cityMaidenhead
    B.5.3.3Post codeSL6 4XE
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number0044 01628 644346
    B.5.5Fax number0044 01628 644330
    B.5.6E-mailPETeamEPDRA@abbott.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name TRANSMETIL
    D.2.1.1.2Name of the Marketing Authorisation holderABBOTT S.r.l.- S.R.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTRANSMETIL 500 mg
    D.3.4Pharmaceutical form Gastro-resistant tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAdemetionine 1,4-butanedisulfonate
    D.3.9.1CAS number [29908-03-0]
    D.3.9.3Other descriptive nameAdemetionine SD4, SAMe SD4, Ade-SD4, SAMe 1,4-
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Nonalcoholic Steatohepatitis
    E.1.1.1Medical condition in easily understood language
    Fatty liver disease not associated with excessive alcohol intake
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level PT
    E.1.2Classification code 10053219
    E.1.2Term Non-alcoholic steatohepatitis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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.
    E.2.2Secondary objectives of the trial
    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
    E.2.3Trial contains a sub-study No
    E.3Principal 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 (< 3 months prior to study start) displaying a bright echo
    pattern compatible with steatosis and
    - BMI > 25 kg/m2
    3. Subjects diagnosed with NAFLD without histology, based on:
    - Ultrasound (< 3 months prior to study start) displaying a bright echo
    pattern compatible with steatosis and
    - BMI > 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
    E.4Principal 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 symptomatic orthostatic hypotension or vasovagal syncope.
     Subjects with a history or family history of seizures (excluding childhood febrile seizures)
     Subjects who have been treated with SAMe before.
     Subjects who have taken one single dose of an investigational drug within 30 days or multiple doses of an investigational drug within 60 days prior to dosing. Subjects should not have participated in more than three clinical studies in the past year.
     Subjects who have provided a blood donation in the past 2 months
     Subjects who consume on average more than 3 (for males) 2 (for females) glasses per day of beer, wine or equivalent or who have a history of alcoholism or drug abuse
     Use of alcoholic beverages within 48 hours prior to first dosing and/or test positive for alcohol
     Subjects with known drug abuse
     Subjects who are known to have serum hepatitis or who are carriers of the Hepatitis B core antigen or are carriers of antibodies to hepatitis C virus or to HIV1 or HIV2
     Subjects may not be employees of the clinical site nor related to the study staff in any way
     Subjects who in the opinion of the investigator should not participate in 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
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 6 weeks of treatment.
    E.5.2Secondary 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.
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 6 weeks of treatment.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    No-treatment arm
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA29
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    End of trial will be a safety follow-up telephone call that will take place 30 days plus up to 3 days after the last visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days18
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days18
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 101
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 34
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state95
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 135
    F.4.2.2In the whole clinical trial 135
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    No approved treatment option is available for NASH patients therefore after the end of this exploratory trial no further medication will be provided to the trial subjects. Following the end of this study the sponsor plans to run a long-term study with the objective of establishing the efficacy and safety of SAMe in patients with NASH, the results of which may contribute to the establishment of a standard of care therapy for this indication.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-09-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-08-21
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-09-29
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