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    Clinical Trial Results:
    The Effect of Tecfidera® (Dimethyl Fumarate, BG00012) on the Gut Microbiota as a Causal Factor for Gastro Intestinal Associated Adverse Events (TECONGUT)

    Summary
    EudraCT number
    2015-001197-18
    Trial protocol
    NO  
    Global end of trial date
    12 Jun 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Jan 2019
    First version publication date
    05 Jan 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NOR-BGT-14-10665
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02471560
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    250 Binney Street, Cambridge, Massachusetts, United States, 02142
    Public contact
    Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Study Medical Director, Biogen, clinicaltrials@biogen.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
    12 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jun 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to determine if dimethyl fumarate (DMF) causes changes in the abundance and diversity of commensal microbiota.
    Protection of trial subjects
    Subjects were treated according to clinical practice; protection of subjects was ensured by health care professional (HCP) as per clinical practice.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    03 Nov 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 36
    Worldwide total number of subjects
    36
    EEA total number of subjects
    36
    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)
    35
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 38 subjects were screened from 7 sites in Norway.

    Pre-assignment
    Screening details
    A total of 38 subjects were screened, 1 subject withdrew due to screening failure and 1 subject withdrew informed consent before study start.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Dimethyl Fumarate (DMF)
    Arm description
    Subjects followed the dosing schedule recommended by summary of product characteristics (SPC) for DMF i.e., 120 milligram (mg) two time daily (BID) orally for 7 days, followed by recommended dose of 240 mg BID.
    Arm type
    Experimental

    Investigational medicinal product name
    Dimethyl Fumarate
    Investigational medicinal product code
    Other name
    BG00012
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    DMF 120 mg capsules BID orally for 7 days, followed by recommended dose of 240 mg BID.

    Arm title
    Injectable (Multiple Sclerosis Disease Modifying Therapies)
    Arm description
    Subjects followed administration instructions and dosing schedule recommended in SPC.
    Arm type
    Experimental

    Investigational medicinal product name
    Multiple Sclerosis Disease Modifying Therapies (MS DMT)
    Investigational medicinal product code
    Other name
    IFNβ-1a, IFNβ-1b, Glatiramer Acetate
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered as recommended by SPC.

    Number of subjects in period 1
    Dimethyl Fumarate (DMF) Injectable (Multiple Sclerosis Disease Modifying Therapies)
    Started
    27
    9
    Completed
    22
    9
    Not completed
    5
    0
         Protocol Deviation
    1
    -
         Adverse Event
    3
    -
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dimethyl Fumarate (DMF)
    Reporting group description
    Subjects followed the dosing schedule recommended by summary of product characteristics (SPC) for DMF i.e., 120 milligram (mg) two time daily (BID) orally for 7 days, followed by recommended dose of 240 mg BID.

    Reporting group title
    Injectable (Multiple Sclerosis Disease Modifying Therapies)
    Reporting group description
    Subjects followed administration instructions and dosing schedule recommended in SPC.

    Reporting group values
    Dimethyl Fumarate (DMF) Injectable (Multiple Sclerosis Disease Modifying Therapies) Total
    Number of subjects
    27 9 36
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    45 (39 to 52) 44 (33 to 59) -
    Gender Categorical
    Units: Subjects
        Female
    19 7 26
        Male
    8 2 10

    End points

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    End points reporting groups
    Reporting group title
    Dimethyl Fumarate (DMF)
    Reporting group description
    Subjects followed the dosing schedule recommended by summary of product characteristics (SPC) for DMF i.e., 120 milligram (mg) two time daily (BID) orally for 7 days, followed by recommended dose of 240 mg BID.

    Reporting group title
    Injectable (Multiple Sclerosis Disease Modifying Therapies)
    Reporting group description
    Subjects followed administration instructions and dosing schedule recommended in SPC.

    Subject analysis set title
    DMF Subjects Without GIAE
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects who had received DMF and do not develop gastro-intestinal adverse event (GIAE).

    Subject analysis set title
    DMF Subjects With GIAE
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects who had received DMF and do develop GIAE.

    Primary: Change From Baseline in Gut Microbiota Composition in Subjects pre vs Post Initiation of DMF Treatment at Week 2

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    End point title
    Change From Baseline in Gut Microbiota Composition in Subjects pre vs Post Initiation of DMF Treatment at Week 2 [1]
    End point description
    End point type
    Primary
    End point timeframe
    Bseline, Week 2
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported.
    End point values
    Dimethyl Fumarate (DMF) Injectable (Multiple Sclerosis Disease Modifying Therapies)
    Number of subjects analysed
    27
    9
    Units: relative abundance of bacterial phyla
    median (inter-quartile range (Q1-Q3))
        Actinobacteria
    0.011 (0.005 to 0.02)
    0.024 (0.02 to 0.04)
        Bifidobacterium
    0.007 (0.001 to 0.01)
    0.015 (0.004 to 0.03)
        Firmicutes
    0.63 (0.52 to 0.77)
    0.589 (0.53 to 0.73)
        Bacteroidetes
    0.195 (0.15 to 0.44)
    0.359 (0.21 to 0.45)
        Firmicutes:Bacteroidetes-ratio
    2.26 (1.2 to 5.4)
    1.651 (1.18 to 3.72)
        Ruminococcacea
    0.32 (0.23 to 0.38)
    0.28 (0.17 to 0.35)
        Faecalibacterium
    0.055 (0.03 to 0.09)
    0.06 (0.04 to 0.10)
        Bacteroides
    0.14 (0.09 to 0.30)
    0.117 (0.09 to 0.24)
    No statistical analyses for this end point

    Primary: Change From Baseline in Gut Microbiota Composition in Subjects pre vs Post Initiation of DMF Treatment at Week 12

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    End point title
    Change From Baseline in Gut Microbiota Composition in Subjects pre vs Post Initiation of DMF Treatment at Week 12 [2]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported.
    End point values
    Dimethyl Fumarate (DMF) Injectable (Multiple Sclerosis Disease Modifying Therapies)
    Number of subjects analysed
    27
    9
    Units: relative abundance of bacterial phyla
    median (inter-quartile range (Q1-Q3))
        Actinobacteria
    0.016 (0.01 to 0.04)
    0.02 (0.008 to 0.03)
        Bifidobacterium
    0.012 (0.002 to 0.02)
    0.011 (0.004 to 0.03)
        Firmicutes
    0.679 (0.56 to 0.78)
    0.659 (0.46 to 0.72)
        Bacteroidetes
    0.246 (0.13 to 0.35)
    0.292 (0.23 to 0.49)
        Firmicutes:Bacteroidetes-ratio
    2.685 (1.51 to 6.35)
    2.253 (1.10 to 3.17)
        Ruminococcacea
    0.32 (0.27 to 0.41)
    0.25 (0.18 to 0.38)
        Faecalibacterium
    0.067 (0.04 to 0.11)
    0.06 (0.05 to 0.08)
        Bacteroides
    0.14 (0.07 to 0.23)
    0.165 (0.09 to 0.28)
    No statistical analyses for this end point

    Primary: Change From Baseline in Shannon Index in Subjects pre vs Post Initiation of DMF Treatment at Week 2

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    End point title
    Change From Baseline in Shannon Index in Subjects pre vs Post Initiation of DMF Treatment at Week 2 [3]
    End point description
    Shannon diversity index is a quantitative measure that reflects how many different types (such as species) are in a dataset (a community), and simultaneously takes into account how evenly the basic entities (such as individuals) are distributed among those types. A community with only one species would have Shannon’s index of 0. The higher the index, the more diverse a community.
    End point type
    Primary
    End point timeframe
    Baseline, Week 2
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported.
    End point values
    Dimethyl Fumarate (DMF) Injectable (Multiple Sclerosis Disease Modifying Therapies)
    Number of subjects analysed
    27
    9
    Units: shannon's diversity index
        median (inter-quartile range (Q1-Q3))
    6.54 (6.03 to 6.76)
    6.53 (5.80 to 7.09)
    No statistical analyses for this end point

    Primary: Change From Baseline in Shannon Index in Subjects pre vs Post Initiation of DMF Treatment at Week 12

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    End point title
    Change From Baseline in Shannon Index in Subjects pre vs Post Initiation of DMF Treatment at Week 12 [4]
    End point description
    Shannon diversity index is a quantitative measure that reflects how many different types (such as species) are in a dataset (a community), and simultaneously takes into account how evenly the basic entities (such as individuals) are distributed among those types. A community with only one species would have Shannon’s index of 0. The higher the index, the more diverse a community.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported.
    End point values
    Dimethyl Fumarate (DMF) Injectable (Multiple Sclerosis Disease Modifying Therapies)
    Number of subjects analysed
    27
    9
    Units: shannon's diversity index
        median (inter-quartile range (Q1-Q3))
    6.49 (6.08 to 6.73)
    6.74 (5.89 to 7.08)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Gut Microbiota composition Between DMF Treated Subjects That do or do not Develop Gastro-intestinal (GI) Adverse Evenrs (AEs) as Measured by an Increase in the Gastrointestinal Symptom Rating Scale (GSRS) Score at Week 2 and 12

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    End point title
    Change From Baseline in Gut Microbiota composition Between DMF Treated Subjects That do or do not Develop Gastro-intestinal (GI) Adverse Evenrs (AEs) as Measured by an Increase in the Gastrointestinal Symptom Rating Scale (GSRS) Score at Week 2 and 12
    End point description
    GSRS is a self-reported questionnaire regarding GI symptoms comprising 15 items scored on a 7-point Likert scale. The 15 items can be grouped in 5 dimensions 1) abdominal pain (abdominal pain, gastric hunger pain, and nausea) 2) reflux (heartburn and acid regurgitation) 3) indigestion (borborygmus, bloating, eructation, and increased flatus) 4) diarrhea (diarrhea, loose stools, and urgency) and 5) constipation (constipation, hard stools, incomplete evacuation). A GI AE will be defined as an at least 2 point (>=2) increase from baseline in total score of any of the 5 dimensions in the GSRS. (maximum score per dimension is 3 items x 7 points = 21). Here, 'n' signifies that number of subjects evaluated for the specified bacterial composition.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 12
    End point values
    DMF Subjects Without GIAE DMF Subjects With GIAE
    Number of subjects analysed
    11 [5]
    10 [6]
    Units: relative abundance of bacterial phyla
    median (inter-quartile range (Q1-Q3))
        Actinobacteria: Baseline for Week 2 (n =11, 10)
    0.016 (0.012 to 0.032)
    0.022 (0.008 to 0.045)
        Actinobacteria: Change at Week 2 (n =11, 10)
    0.011 (0.005 to 0.022)
    0.011 (0.003 to 0.024)
        Actinobacteria: Baseline for Week 12 (n =10, 10)
    0.03 (0.013 to 0.046)
    0.01 (0.004 to 0.024)
        Actinobacteria: Change at Week 12 (n =10, 10)
    0.024 (0.009 to 0.048)
    0.011 (0.004 to 0.03)
        Bifidobacterium: Baseline for Week 2 (n =11, 10)
    0.011 (0.006 to 0.022)
    0.012 (0.005 to 0.038)
        Bifidobacterium: Change at Week 2 (n =11, 10)
    0.008 (0.003 to 0.014)
    0.005 (0 to 0.015)
        Bifidobacterium: Baseline for Week 12 (n =10, 10)
    0.016 (0.007 to 0.04)
    0.007 (0.002 to 0.018)
        Bifidobacterium: Change at Week 12 (n =10, 10)
    0.015 (0.004 to 0.028)
    0.008 (0.001 to 0.027)
        Firmicutes: Baseline for Week 2 (n =11, 10)
    0.546 (0.509 to 0.734)
    0.728 (0.536 to 0.787)
        Firmicutes: Change at Week 2 (n =11, 10)
    0.622 (0.533 to 0.799)
    0.686 (0.515 to 0.782)
        Firmicutes: Baseline for Week 12 (n =10, 10)
    0.632 (0.539 to 0.724)
    0.702 (0.521 to 0.843)
        Firmicutes: Change at Week 12 (n =10, 10)
    0.685 (0.597 to 0.784)
    0.715 (0.563 to 0.866)
        Bacteroidetes: Baseline for Week 2 (n =11, 10)
    0.388 (0.184 to 0.424)
    0.188 (0.151 to 0.294)
        Bacteroidetes: Change at Week 2 (n =11, 10)
    0.311 (0.138 to 0.437)
    0.192 (0.145 to 0.368)
        Bacteroidetes: Baseline for Week 12 (n =10, 10)
    0.319 (0.187 to 0.396)
    0.22 (0.089 to 0.426)
        Bacteroidetes: Change at Week 12 (n =10, 10)
    0.245 (0.151 to 0.29)
    0.221 (0.078 to 0.405)
        Faecalibacterium: Baseline for Week 2 (n =11, 10)
    0.036 (0.025 to 0.057)
    0.057 (0.033 to 0.094)
        Faecalibacterium: Change at Week 2 (n =11, 10)
    0.055 (0.037 to 0.072)
    0.058 (0.024 to 0.139)
        Faecalibacterium: Baseline for Week 12 (n =10, 10)
    0.044 (0.025 to 0.071)
    0.052 (0.027 to 0.094)
        Faecalibacterium: Change at Week 12 (n =10, 10)
    0.063 (0.035 to 0.117)
    0.071 (0.051 to 0.119)
        Bacteroides: Baseline for Week 2 (n =11, 10)
    0.304 (0.125 to 0.352)
    0.115 (0.065 to 0.162)
        Bacteroides: Change at Week 2 (n =11, 10)
    0.244 (0.088 to 0.379)
    0.14 (0.052 to 0.26)
        Bacteroides: Baseline for Week 12 (n =10, 10)
    0.25 (0.124 to 0.321)
    0.104 (0.028 to 0.311)
        Bacteroides: Change at Week 12 (n =10, 10)
    0.152 (0.074 to 0.224)
    0.107 (0.019 to 0.261)
    Notes
    [5] - Number of subjects analysed is the number of subjects evaluated for this endpoint.
    [6] - Number of subjects analysed is the number of subjects evaluated for this endpoint.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Gut Microbiota Composition in Subjects Treated With DMF Compared to Subjects Treated With an Alternative MS DMT at Week 2 and 12

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    End point title
    Change From Baseline in Gut Microbiota Composition in Subjects Treated With DMF Compared to Subjects Treated With an Alternative MS DMT at Week 2 and 12
    End point description
    Here, 'n' signifies the number of subjects evaluated for specified bacterial composition.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 12
    End point values
    Dimethyl Fumarate (DMF) Injectable (Multiple Sclerosis Disease Modifying Therapies)
    Number of subjects analysed
    21 [7]
    9 [8]
    Units: delta values of relative abundance
    median (inter-quartile range (Q1-Q3))
        Change in Actinobacteria at Week 2 (n =21, 9)
    -0.006 (-0.026 to 0.002)
    -0.001 (-0.008 to 0.016)
        Change in Actinobacteria at Week 12 (n =20, 9)
    0 (-0.02 to 0.022)
    -0.002 (-0.02 to 0.002)
        Change in Bifidobacterium at Week 2 (n =21, 9)
    -0.002 (-0.013 to 0.001)
    -0.002 (-0.012 to 0.011)
        Change in Bifidobacterium at Week 12 (n =20, 9)
    0.001 (-0.015 to 0.013)
    -0.003 (-0.023 to 0.001)
        Change in Firmicutes at Week 2 (n =21, 9)
    0.011 (-0.06 to 0.078)
    0.001 (-0.069 to 0.032)
        Change in Firmicutes at Week 12 (n =20, 9)
    0.048 (0.002 to 0.088)
    -0.012 (-0.032 to 0.066)
        Change in Bacteroidetes at Week 2 (n =21, 9)
    -0.014 (-0.062 to 0.053)
    0.025 (-0.031 to 0.066)
        Change in Bacteroidetes at Week 12 (n =20, 9)
    -0.045 (-0.096 to -0.005)
    0.011 (-0.061 to 0.061)
        Change in Faecalibacterium at Week 2 (n =21, 9)
    0.004 (-0.009 to 0.033)
    -0.018 (-0.039 to 0.003)
        Change in Faecalibacterium at Week 12 (n =20, 9)
    0.021 (-0.001 to 0.046)
    -0.007 (-0.035 to 0.011)
        Change in Bacteroides at Week 2 (n =21, 9)
    -0.004 (-0.05 to 0.045)
    0.008 (-0.049 to 0.051)
        Change in Bacteroides at Week 12 (n =20, 9)
    -0.046 (-0.066 to -0.004)
    -0.005 (-0.017 to 0.054)
    Notes
    [7] - Number of subjects analysed is the number of subjects evaluated for this endpoint.
    [8] - Number of subjects analysed is the number of subjects evaluated for this endpoint.
    No statistical analyses for this end point

    Secondary: Baseline Differences in the Gut Microbiota composition Between DMF Treated Subjects That do or do not Develop GI AEs at Week 2 and 12

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    End point title
    Baseline Differences in the Gut Microbiota composition Between DMF Treated Subjects That do or do not Develop GI AEs at Week 2 and 12
    End point description
    Here, 'n' signifies the number of subjects evaluated for specified bacterial composition.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 12
    End point values
    DMF Subjects Without GIAE DMF Subjects With GIAE
    Number of subjects analysed
    12
    12
    Units: relative abundance of bacterial phyla
    median (inter-quartile range (Q1-Q3))
        Change in Actinobacteria at Week 2 (n =12, 12)
    0.015 (0.012 to 0.031)
    0.021 (0.008 to 0.035)
        Change in Actinobacteria at Week 12 (n =10, 11)
    0.03 (0.013 to 0.046)
    0.011 (0.004 to 0.023)
        Change in Bifidobacterium at Week 2 (n =12, 12)
    0.011 (0.005 to 0.02)
    0.012 (0.003 to 0.031)
        Change in Bifidobacterium at Week 12 (n =10, 11)
    0.016 (0.007 to 0.04)
    0.008 (0.002 to 0.017)
        Change in Firmicutes at Week 2 (n =12, 12)
    0.545 (0.51 to 0.724)
    0.708 (0.528 to 0.767)
        Change in Firmicutes at Week 12 (n =10, 11)
    0.632 (0.539 to 0.724)
    0.734 (0.524 to 0.835)
        Change in Bacteroidetes at Week 2 (n =12, 12)
    0.39 (0.186 to 0.466)
    0.206 (0.171 to 0.372)
        Change in Bacteroidetes at Week 12 (n =10, 11)
    0.319 (0.187 to 0.396)
    0.184 (0.092 to 0.424)
        Change in Faecalibacterium at Week 2 (n =12, 12)
    0.037 (0.025 to 0.063)
    0.056 (0.031 to 0.088)
        Change in Faecalibacterium at Week 12 (n =10, 11)
    0.044 (0.025 to 0.071)
    0.039 (0.029 to 0.093)
        Change in Bacteroides at Week 2 (n =12, 12)
    0.308 (0.125 to 0.408)
    0.124 (0.078 to 0.21)
        Change in Bacteroides at Week 12 (n =10, 11)
    0.25 (0.124 to 0.321)
    0.108 (0.031 to 0.306)
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Gut Microbiota Composition of DMF Treated Subjects After Resolution of GI AEs vs. During GI AE Occurrences at Week 2 and 12

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    End point title
    Change From Baseline in the Gut Microbiota Composition of DMF Treated Subjects After Resolution of GI AEs vs. During GI AE Occurrences at Week 2 and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 12
    End point values
    Dimethyl Fumarate (DMF) Injectable (Multiple Sclerosis Disease Modifying Therapies)
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: relative abundance of bacterial phyla
        median (standard deviation)
    ±
    ±
    Notes
    [9] - Data was not collected for the endpoint due to low number of subjects analysed.
    [10] - Data was not collected for the endpoint due to low number of subjects analysed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start to last visit (Up to Week 12)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Multiple Sclerosis Disease Modifying Therapies (MS DMT)
    Reporting group description
    Subjects followed administration instructions and dosing schedule recommended in SPC.

    Reporting group title
    Dimethyl Fumarate (DMF)
    Reporting group description
    Subjects followed the dosing schedule recommended by summary of product characteristics (SPC) for DMF i.e., 120 milligram (mg) two time daily (BID) orally for 7 days, followed by recommended dose of 240 mg BID.

    Serious adverse events
    Multiple Sclerosis Disease Modifying Therapies (MS DMT) Dimethyl Fumarate (DMF)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 27 (3.70%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Relapsing-remitting multiple sclerosis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Multiple Sclerosis Disease Modifying Therapies (MS DMT) Dimethyl Fumarate (DMF)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 9 (88.89%)
    15 / 27 (55.56%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 9 (0.00%)
    4 / 27 (14.81%)
         occurrences all number
    0
    4
    Hot Flush
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Monoparesis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Injection site rash
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Hunger
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Nausea
         subjects affected / exposed
    0 / 9 (0.00%)
    4 / 27 (14.81%)
         occurrences all number
    0
    3
    Diarrhoea
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Lip oedema
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Abdominal discomfort
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Dermatitis contact
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    12 Jun 2017
    Due to poor recruitment level in the study, it was decided to stop recruitment before the target number of subjects was reached.
    -

    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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