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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    2012-000975-18
    Trial protocol
    DE  
    Global end of trial date
    25 Sep 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    13 Jul 2016
    Other versions
    Summary report(s)
    Abbott M-13 397-CSR synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    M13-397
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01754714
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Abbott Laboratories GmbH
    Sponsor organisation address
    Freundallee 9a, Hanover, Germany, 30173
    Public contact
    Suntje Sander-Struckmeier, Abbott, 0049 511 67500, suntje.sander@abbott.com
    Scientific contact
    Suntje Sander-Struckmeier, Abbott, 0049 511 67500, suntje.sander@abbott.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Jan 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Sep 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main 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.
    Protection of trial subjects
    All study investigators expressly agreed not to disclose the identity of the patients treated and to abide by the confidentiality rules as regards data and information to which they had access by participating in the study. All the data related to the participating patients were recorded and treated according to the regulatory law of data protection. All information obtained as a result of this study was considered confidential until the sponsor deemed it appropriate. The investigator could only inform on the study conduct and results to the sponsor, EC, and regulatory authorities.
    Background therapy
    None
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Nov 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 17
    Country: Number of subjects enrolled
    France: 24
    Country: Number of subjects enrolled
    Germany: 49
    Country: Number of subjects enrolled
    Russian Federation: 18
    Worldwide total number of subjects
    108
    EEA total number of subjects
    90
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    90
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients were recruited in 25 sites in Germany (10 sites), Poland (5 sites), Russia (5 sites) and France (5 sites) from 27 Dec 2012 to 25 Sep 2014.

    Pre-assignment
    Screening details
    During the screening period of 4 wks, NASH subjects were evaluated for eligibility: physical examination, pregnancy test, measurement of vital signs incl. body mass index, assessments of routine laboratory, review of their medical history, concomitant medication, AEs, demographics and alcohol consumption questionnaire.

    Period 1
    Period 1 title
    Baseline period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    1000 mg SAMe (Sadenosyl- L-methionine)
    Arm description
    SAMe 1000 mg: 1000 mg dose group: one 500 mg capsule fasting in the morning and one 500 mg capsule before dinner
    Arm type
    Experimental

    Investigational medicinal product name
    Sadenosyl- Lmethionine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The NASH subjects took the tablets while fasting, in the morning and before dinner.

    Arm title
    1500 mg SAMe
    Arm description
    SAMe 1500 mg: 1500 mg dose group: two 500 mg capsules fasting in the morning and one 500 mg capsule before dinner
    Arm type
    Experimental

    Investigational medicinal product name
    Sadenosyl- Lmethionine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The NASH subjects took the tablets while fasting, in the morning and before dinner.

    Arm title
    2000 mg SAMe
    Arm description
    SAMe 2000 mg: 2000 mg dose group: two 500 mg capsules fasting in the morning and two 500 mg capsules before dinner
    Arm type
    Experimental

    Investigational medicinal product name
    Sadenosyl- Lmethionine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The NASH subjects took the tablets while fasting, in the morning and before dinner.

    Arm title
    No Treatment
    Arm description
    No study drug was administered
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    1000 mg SAMe (Sadenosyl- L-methionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Started
    27
    27
    26
    28
    Completed
    27
    26
    24
    27
    Not completed
    0
    1
    2
    1
         No data for any postbaseline efficacy assessment
    -
    1
    -
    1
         Subject did not take investigational study drug
    -
    -
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    1000 mg SAMe (Sadenosyl- L-methionine)
    Reporting group description
    SAMe 1000 mg: 1000 mg dose group: one 500 mg capsule fasting in the morning and one 500 mg capsule before dinner

    Reporting group title
    1500 mg SAMe
    Reporting group description
    SAMe 1500 mg: 1500 mg dose group: two 500 mg capsules fasting in the morning and one 500 mg capsule before dinner

    Reporting group title
    2000 mg SAMe
    Reporting group description
    SAMe 2000 mg: 2000 mg dose group: two 500 mg capsules fasting in the morning and two 500 mg capsules before dinner

    Reporting group title
    No Treatment
    Reporting group description
    No study drug was administered

    Reporting group values
    1000 mg SAMe (Sadenosyl- L-methionine) 1500 mg SAMe 2000 mg SAMe No Treatment Total
    Number of subjects
    27 27 26 28 108
    Age categorical
    Units: Subjects
        <= 18 years
    0 0 0 0 0
        Between 18 and 65 years
    23 24 23 21 91
        >=65 years
    4 3 3 7 17
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    51.2 ± 13.8 50 ± 12.3 49.5 ± 14.2 56.6 ± 11.6 -
    Gender categorical
    Units: Subjects
        Female
    15 10 9 11 45
        Male
    12 17 17 17 63
    Region of Enrollment
    Units: Subjects
        Russian Federation
    5 6 5 2 18
        Poland
    3 2 6 6 17
        France
    6 5 4 9 24
        Germany
    13 14 11 11 49

    End points

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    End points reporting groups
    Reporting group title
    1000 mg SAMe (Sadenosyl- L-methionine)
    Reporting group description
    SAMe 1000 mg: 1000 mg dose group: one 500 mg capsule fasting in the morning and one 500 mg capsule before dinner

    Reporting group title
    1500 mg SAMe
    Reporting group description
    SAMe 1500 mg: 1500 mg dose group: two 500 mg capsules fasting in the morning and one 500 mg capsule before dinner

    Reporting group title
    2000 mg SAMe
    Reporting group description
    SAMe 2000 mg: 2000 mg dose group: two 500 mg capsules fasting in the morning and two 500 mg capsules before dinner

    Reporting group title
    No Treatment
    Reporting group description
    No study drug was administered

    Primary: 1. Methionine Elimination Half-life Measured in Blood

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    End point title
    1. Methionine Elimination Half-life Measured in Blood
    End point description
    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.
    End point type
    Primary
    End point timeframe
    9 hours
    End point values
    1000 mg SAMe (Sadenosyl- L-methionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Number of subjects analysed
    27
    26
    24
    27
    Units: hour
        arithmetic mean (standard deviation)
    4.29 ± 1.86
    4.66 ± 1.57
    4.25 ± 1.64
    4.26 ± 1.44
    Statistical analysis title
    Analysis of Methionine Half-life Measured in Blood
    Statistical analysis description
    The SAMe 1000 mg group was compared to the no treatment group, on the 95% CI interval for the difference in the least squares mean.
    Comparison groups
    1000 mg SAMe (Sadenosyl- L-methionine) v No Treatment
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.944
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.72
         upper limit
    0.77
    Statistical analysis title
    Analysis of Methionine Half-life Measured in Blood
    Statistical analysis description
    The SAMe 1500 mg group was compared to the no treatment group, on the 95% CI interval for the difference in the least squares mean.
    Comparison groups
    No Treatment v 1500 mg SAMe
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.899
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.82
         upper limit
    0.72
    Statistical analysis title
    Analysis of Methionine Half-life Measured in Blood
    Statistical analysis description
    The SAMe 2000 mg group was compared to the no treatment group, on the 95% CI interval for the difference in the least squares mean.
    Comparison groups
    No Treatment v 2000 mg SAMe
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.293
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.37
         upper limit
    1.2

    Secondary: 2. Fasting Methionine Concentration and Area Under Curve (AUC) of Average Methionine Concentration Versus Time Curve.

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    End point title
    2. Fasting Methionine Concentration and Area Under Curve (AUC) of Average Methionine Concentration Versus Time Curve.
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    9 hours
    End point values
    1000 mg SAMe (Sadenosyl- L-methionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Number of subjects analysed
    27
    26
    24
    27
    Units: mcg/mL
    arithmetic mean (standard deviation)
        methionine concentration at week 7 (mcg/mL)
    4.02 ± 0.92
    3.81 ± 0.67
    5.68 ± 10.13
    5.62 ± 8.53
        methionine AUC at week 7 (mcg*hr/mL)
    440.09 ± 149.96
    399.3 ± 148.9
    425.24 ± 231.88
    460.57 ± 135.63
    No statistical analyses for this end point

    Secondary: 3. 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test

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    End point title
    3. 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test
    End point description
    Parameters cumulative percentage dose of 13 carbon recovered after 30, 60, 90 minutes (cPDR30, cPDR60, cPDR 90) will be evaluated.
    End point type
    Secondary
    End point timeframe
    90 minutes
    End point values
    1000 mg SAMe (Sadenosyl- L-methionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Number of subjects analysed
    27
    26
    24
    27
    Units: percentage of recovery
    arithmetic mean (standard deviation)
        13C methionine breath test recovery at 30 min (%)
    0.93 ± 0.73
    0.77 ± 0.51
    0.88 ± 0.66
    0.69 ± 0.55
        13C methionine breath test recovery at 60 min (%)
    3.66 ± 1.99
    3.49 ± 1.74
    3.61 ± 1.78
    2.98 ± 1.72
        13C methionine breath test recovery at 90 min (%)
    6.69 ± 2.75
    6.6 ± 2.56
    6.68 ± 2.48
    5.74 ± 2.56
    No statistical analyses for this end point

    Secondary: 4. Hepatic Panel (Liver Laboratory Parameters)

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    End point title
    4. Hepatic Panel (Liver Laboratory Parameters)
    End point description
    Serum Total Bilirubin (STB), Serum Conjugated Bilirubin (SCB), liver-alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), Gamma Glutamyl Transpeptidase (GGT), ALT/AST ratio
    End point type
    Secondary
    End point timeframe
    change from baseline at 6 weeks
    End point values
    1000 mg SAMe (Sadenosyl- L-methionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Number of subjects analysed
    27
    26
    24
    27
    Units: U/L
    arithmetic mean (standard deviation)
        ALP
    1.9 ± 7.9
    -0.1 ± 13.7
    3.4 ± 24.1
    -6 ± 16.9
        ALT
    -6.2 ± 19.5
    -6.3 ± 23.5
    -4.9 ± 32.2
    -11.9 ± 33.4
        AST
    -5.1 ± 15.7
    -3 ± 16.5
    -1.2 ± 10.7
    -11.6 ± 27.7
        GGT
    -1.1 ± 33.7
    -10.6 ± 62.7
    -2.7 ± 35.7
    -12.3 ± 48.1
        ALT/AST ratio
    -0.02 ± 0.23
    0.01 ± 0.21
    0.03 ± 0.18
    -0.01 ± 0.27
    No statistical analyses for this end point

    Secondary: 5. Metabolic Panel (Metabolic Laboratory Parameters)

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    End point title
    5. Metabolic Panel (Metabolic Laboratory Parameters)
    End point description
    Fasting lipid profile (cholesterol, HDL (High Density Lipoprotein), LDL (Low Density Lipoprotein)), amino acid profile, homeostasis model assessment (HOMA-R) and fasting glucose.
    End point type
    Secondary
    End point timeframe
    change from baseline at 6 weeks
    End point values
    1000 mg SAMe (Sadenosyl- L-methionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Number of subjects analysed
    27
    26
    24
    27
    Units: mmol/L
    arithmetic mean (standard deviation)
        Cholesterol (mmol/L)
    -0.131 ± 0.593
    0.046 ± 0.921
    -0.265 ± 0.601
    -0.134 ± 0.659
        HDL (mmol/L)
    -0.094 ± 0.166
    -0.046 ± 0.254
    -0.098 ± 0.169
    -0.065 ± 0.155
        LDL (mmol/L)
    0.125 ± 0.452
    0.182 ± 0.762
    -0.202 ± 0.589
    -0.112 ± 0.558
        HOMA-R (mmol/L)
    0.837 ± 13.232
    0.127 ± 3.763
    -1.549 ± 13.321
    3.434 ± 10.837
        Glucose (mmol/L)
    -0.068 ± 0.968
    0.49 ± 1.486
    -0.163 ± 1.009
    -0.121 ± 1.61
    No statistical analyses for this end point

    Secondary: 6. The Metabolic Clearance Rate Measured in the Blood.

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    End point title
    6. The Metabolic Clearance Rate Measured in the Blood.
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    9 hours
    End point values
    1000 mg SAMe (Sadenosyl- L-methionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Number of subjects analysed
    27
    26
    24
    27
    Units: L/h
        arithmetic mean (standard deviation)
    8.86 ± 2.93
    9.83 ± 3.27
    10.05 ± 4.32
    8.23 ± 2.3
    No statistical analyses for this end point

    Secondary: 7. Methionine Volume of Distribution at Week 7 (L)

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    End point title
    7. Methionine Volume of Distribution at Week 7 (L)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    9 hours
    End point values
    1000 mg SAMe (Sadenosyl- L-methionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Number of subjects analysed
    27
    26
    24
    27
    Units: liter
        arithmetic mean (standard deviation)
    54.4 ± 18.43
    62.84 ± 14.04
    64.58 ± 17.77
    53.98 ± 15.21
    No statistical analyses for this end point

    Secondary: 8. 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test

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    End point title
    8. 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test
    End point description
    Peak
    End point type
    Secondary
    End point timeframe
    90 minutes
    End point values
    1000 mg SAMe (Sadenosyl- L-methionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Number of subjects analysed
    27
    26
    24
    27
    Units: Atom %C13
        arithmetic mean (standard deviation)
    1.0972 ± 0.0062
    1.0964 ± 0.0052
    1.0964 ± 0.0053
    1.0949 ± 0.0045
    No statistical analyses for this end point

    Secondary: 9. 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test

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    End point title
    9. 13 Carbon (Natural, Stable Isotope of Carbon) Methionine Breath Test
    End point description
    Time to peak
    End point type
    Secondary
    End point timeframe
    90 minutes
    End point values
    1000 mg SAMe (Sadenosyl- L-methionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Number of subjects analysed
    27
    26
    24
    27
    Units: minutes
        median (inter-quartile range (Q1-Q3))
    70 (50 to 80)
    70 (60 to 90)
    70 (50 to 80)
    70 (60 to 90)
    No statistical analyses for this end point

    Secondary: 10. Metabolic Panel (Metabolic Laboratory Parameters)

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    End point title
    10. Metabolic Panel (Metabolic Laboratory Parameters)
    End point description
    Fasting plasma insulin
    End point type
    Secondary
    End point timeframe
    Change from baseline at 6 weeks
    End point values
    1000 mg SAMe (Sadenosyl- L-methionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Number of subjects analysed
    27
    26
    24
    27
    Units: pmol/L
        arithmetic mean (standard deviation)
    0.3 ± 191
    -13.6 ± 115.5
    -13.1 ± 248
    69.1 ± 309
    No statistical analyses for this end point

    Secondary: 11. Metabolic Panel (Metabolic Laboratory Parameters)

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    End point title
    11. Metabolic Panel (Metabolic Laboratory Parameters)
    End point description
    glycosylated hemoglobin (HbA1c)
    End point type
    Secondary
    End point timeframe
    change from baseline at 6 weeks
    End point values
    1000 mg SAMe (Sadenosyl- L-methionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Number of subjects analysed
    27
    26
    24
    27
    Units: percentage
        arithmetic mean (standard deviation)
    -0.08 ± 0.28
    -0.06 ± 0.36
    -0.05 ± 0.32
    0.02 ± 0.33
    No statistical analyses for this end point

    Secondary: 12. Metabolic Panel (Metabolic Laboratory Parameters)

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    End point title
    12. Metabolic Panel (Metabolic Laboratory Parameters)
    End point description
    Adiponectin
    End point type
    Secondary
    End point timeframe
    change from baseline at 6 weeks
    End point values
    1000 mg SAMe (Sadenosyl- L-methionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Number of subjects analysed
    27
    26
    24
    27
    Units: mcg/mL
        arithmetic mean (standard deviation)
    0.754 ± 4.191
    0.425 ± 1.199
    0.219 ± 1.661
    -0.045 ± 1.515
    No statistical analyses for this end point

    Secondary: 13. Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters)

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    End point title
    13. Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters)
    End point description
    C-reactive Protein (CRP)
    End point type
    Secondary
    End point timeframe
    change from baseline at 6 weeks
    End point values
    1000 mg SAMe (Sadenosyl- L-methionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Number of subjects analysed
    27
    26
    24
    27
    Units: nmol/L
        arithmetic mean (standard deviation)
    -0.79 ± 15.51
    -0.8 ± 14.9
    -8.02 ± 20.4
    -4.8 ± 12.28
    No statistical analyses for this end point

    Secondary: 14. Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters)

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    End point title
    14. Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters)
    End point description
    glutathione in erythrocytes
    End point type
    Secondary
    End point timeframe
    change from baseline at 6 weeks
    End point values
    1000 mg SAMe (Sadenosyl- L-methionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Number of subjects analysed
    27
    26
    24
    27
    Units: mcmol/g
        arithmetic mean (standard deviation)
    -0.24 ± 2.06
    -0.21 ± 1.01
    0.05 ± 1.41
    -0.3 ± 1.33
    No statistical analyses for this end point

    Secondary: 15. Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters)

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    End point title
    15. Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters)
    End point description
    oxidative stress marker (isoprostane level)
    End point type
    Secondary
    End point timeframe
    change from baseline at 6 weeks
    End point values
    1000 mg SAMe (Sadenosyl- L-methionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Number of subjects analysed
    27
    26
    24
    27
    Units: ng/mg Crea
        arithmetic mean (standard deviation)
    -0.223 ± 0.801
    0.116 ± 0.699
    0.29 ± 0.691
    -0.223 ± 0.641
    No statistical analyses for this end point

    Secondary: 16. Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers)

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    End point title
    16. Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers)
    End point description
    Caspase-cleaved cytokeratin (CK 18)
    End point type
    Secondary
    End point timeframe
    change from baseline at 6 weeks
    End point values
    1000 mg SAMe (Sadenosyl- L-methionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Number of subjects analysed
    27
    26
    24
    27
    Units: U/L
        arithmetic mean (standard deviation)
    -126.8 ± 401.1
    -136.6 ± 257.3
    -47 ± 157.3
    -143.4 ± 532.5
    No statistical analyses for this end point

    Secondary: 17. Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers)

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    End point title
    17. Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers)
    End point description
    Hyaluronic acid
    End point type
    Secondary
    End point timeframe
    change from baseline at 6 weeks
    End point values
    1000 mg SAMe (Sadenosyl- L-methionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Number of subjects analysed
    27
    26
    24
    27
    Units: ng/mL
        arithmetic mean (standard deviation)
    4.67 ± 48.52
    2.03 ± 32.26
    9.4 ± 59.63
    3.02 ± 46.56
    No statistical analyses for this end point

    Secondary: 18. Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters)

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    End point title
    18. Immunological/Anti-oxidant Panel (Immunological and Anti-oxidant Laboratory Parameters)
    End point description
    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 ).
    End point type
    Secondary
    End point timeframe
    change from baseline at 6 weeks
    End point values
    1000 mg SAMe (Sadenosyl- L-methionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Number of subjects analysed
    27 [1]
    26
    24 [2]
    27 [3]
    Units: pg/mL
    arithmetic mean (standard deviation)
        IL-6
    0.0603 ± 2.0263
    -0.9254 ± 6.4599
    -1.3194 ± 4.5779
    0.1597 ± 1.6243
        IL-8
    -14.41 ± 41.07
    0.65 ± 13.37
    -78.73 ± 187.51
    -6.17 ± 16.94
        IL-10
    0.27 ± 0
    -0.045 ± 0.106
    -0.3 ± 0
    1.6 ± 1.146
        TNF-alpha
    -0.127 ± 0.414
    -1.083 ± 4.782
    -0.601 ± 2.136
    -0.187 ± 1.114
        MCP-1
    -29.75 ± 154.75
    -20.6 ± 79.71
    -40.15 ± 96.21
    -44.51 ± 114.85
        G-CSF
    -20 ± 52.8
    -0.5 ± 9.7
    20 ± 0
    0 ± 0
    Notes
    [1] - SD IL-10 not calculated as there was data of only 1 patient available.
    [2] - SD IL-10 and G-CSF not calculated as there was data of only 1 patient available.
    [3] - G-CSF not calculated as there was no data of patients available.
    No statistical analyses for this end point

    Secondary: 19. Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers)

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    End point title
    19. Fibrosis and Apoptosis Markers (Fibrosis and Apoptosis Laboratory Markers)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    change from baseline at 6 weeks
    End point values
    1000 mg SAMe (Sadenosyl- L-methionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Number of subjects analysed
    27
    26
    24
    27
    Units: scores on a scale
    arithmetic mean (standard deviation)
        ActiTest Score
    -0.017 ± 0.098
    -0.022 ± 0.137
    -0.002 ± 0.168
    -0.042 ± 0.096
        Fibrotest Score
    0.036 ± 0.097
    0.028 ± 0.093
    0.05 ± 0.125
    0.02 ± 0.068
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Each subject was evaluated from screening through the safety follow-up telephone call and in the event of premature study termination.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    1000 mg SAMe (Sadenosyl- Lmethionine)
    Reporting group description
    SAMe 1000 mg: 1000 mg dose group: one 500 mg capsule fasting in the morning and one 500 mg capsule before dinner

    Reporting group title
    1500 mg SAMe
    Reporting group description
    SAMe 1500 mg: 1500 mg dose group: two 500 mg capsules fasting in the morning and one 500 mg capsule before dinner

    Reporting group title
    2000 mg SAMe
    Reporting group description
    SAMe 2000 mg: 2000 mg dose group: two 500 mg capsules fasting in the morning and two 500 mg capsules before dinner

    Reporting group title
    No Treatment
    Reporting group description
    No study drug was administered

    Serious adverse events
    1000 mg SAMe (Sadenosyl- Lmethionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 28 (3.57%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Head injury
    Additional description: head injury and neck injury before start of treatment
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    1000 mg SAMe (Sadenosyl- Lmethionine) 1500 mg SAMe 2000 mg SAMe No Treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 27 (25.93%)
    4 / 27 (14.81%)
    7 / 24 (29.17%)
    2 / 28 (7.14%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    0 / 28 (0.00%)
         occurrences all number
    2
    2
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    3 / 24 (12.50%)
    2 / 28 (7.14%)
         occurrences all number
    0
    1
    3
    2
    Diarrhoea
         subjects affected / exposed
    3 / 27 (11.11%)
    2 / 27 (7.41%)
    4 / 24 (16.67%)
    0 / 28 (0.00%)
         occurrences all number
    3
    2
    4
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Mar 2012
    1. The inclusion criteria regarding the diagnosis of NASH were modified without impacting the scientific value of the study and reliability of the indication. The rationale for this change was that the diagnosis of NASH was modified to take local clinical practice into account without impacting the reliability of the diagnosis of fatty liver disease. 2. The change in exclusion criterion was required due to change in the inclusion criterion. The rationale for this change was that the exclusion criterion of BMI> 40 kg/m2 was removed. 3. The current emergency telephone and fax number of the CRO were added. The rationale for this change was that details of CRO were added which were so far documented in a separate instruction to the sites.
    13 Aug 2012
    1. The dose of the stable isotope (methyl-13C)-labeled methionine to be administered during the 13C-methionine breath test was changed from “2 mg/kg body weight” to “200 mg.” The rationale for this change was that a standardized test kit of 200 mg substrate was recommended by the manufacturer of the 13C-methionine breath test instead of dosing per kg body weight.
    21 Sep 2012
    Inclusion and exclusion criteria altered, clarification that the fibrosis/apoptosis marker CK 18 was to be assessed, Pioglitazone treatment prohibited, removal of text on dietary assessments, text on the Methionine Tolerance Test added, the row ‘Collect study drug’ in the flow chart of study assessments for NASH subjects was changed from Visit 5b to Visit 5a, text added to Section 7.1, text added to Section 8.1, text on recording of the dietary assessment was replaced by text on a protein equilibration diet, ‘Dietary assessment/recording’ in the flow charts of study assessments was changed to ‘Protein equilibration diet/recording’, name change of Abbott Products GmbH to Abbott Laboratoires GmbH.
    06 May 2013
    The study design was changed to an open-label study instead of a double-blind study and the placebo group was replaced by a group of subjects receiving no treatment. Russia was added to the recruiting countries. The 400 mg SAMe capsules were replaced by 500 mg tablets, which affected the dose groups; i.e., 800 mg was changed to 1000 mg, and 1600 mg was to be changed to 1500 mg. Name change of Drug Supply Management. In Sections 7.2 and 7.4 of the protocol, “Drug Supply Management” was changed to “Clinical Supply management.” In the Synopsis heading for the ‘Name of Sponsor’ was changed from “Abbott Laboratoires GmbH” to Abbott Laboratories GmbH.” Change in text on statistical analysis on fixed factors in ANCOVA, blinding, and subject samples. Coeliac disease was added as an exclusion criterion. A BMI of 25 kg/m2 was added as an exclusion criterion instead of BMI of 27 kg/m2. Details on the packaging and labeling were no longer to be specified in the Packaging and Labeling Specifications. Capsule formulation was changed to tablet formulation.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    14 May 2013
    The study design was changed to an open-label study instead of a double-blind study and the placebo group was replaced by a group of subjects receiving no treatment.
    30 Sep 2013

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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