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    Clinical Trial Results:
    A Multicenter, Treatment-Blind Phase 3b Study to Evaluate Whether 6-Week Up-Titration in Tecfidera® Dose is Effective in Reducing the Incidence of Gastrointestinal Adverse Events in Patients With Multiple Sclerosis

    Summary
    EudraCT number
    2014-004562-22
    Trial protocol
    BE   CZ   HU   IT   DE  
    Global end of trial date
    08 Jan 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Dec 2016
    First version publication date
    29 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    109MS416
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02428231
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, Massachusetts, United States, 02142
    Public contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Biogen 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
    08 Jan 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jan 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to assess whether a 6-week titration (compared with a 1-week titration) is effective in reducing the incidence of dimethyl fumarate (DMF)-related gastrointestinal (GI) adverse events (AEs) in subjects with multiple sclerosis (MS). The secondary objective of this study is to assess whether a 6-week titration (compared with a 1-week titration) is effective in reducing the average severity and duration of GI symptoms over 12 weeks of DMF treatment in this study population.
    Protection of trial subjects
    Written informed consent was obtained from each subject prior to evaluations being performed for eligibility. Subjects were given adequate time to review the information in the informed consent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study. Through the informed consent process each subject was made aware of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken. Any side effects or other health issues occurring during the study were followed up by the study doctor. Subjects were able to stop taking part in the study at any time without giving any reason.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Apr 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
    United States: 34
    Country: Number of subjects enrolled
    Belgium: 23
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Czech Republic: 2
    Worldwide total number of subjects
    62
    EEA total number of subjects
    28
    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)
    62
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    This study included a 28-day screening period.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    All subjects remained blinded to the treatment assignment for the entire duration of the study. The study staff knew that all subjects were to receive placebo for the first 2 weeks; however, this information was not shared with the subjects in order to allow unbiased reporting of baseline GI symptoms. From Week 3 onwards, all study staff were blinded to the subject treatment assignments.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Standard Treatment (One-Week Titration)
    Arm description
    Following a 2-week placebo run-in baseline period, 120 mg DMF twice daily for 1 week, then 240 mg (as 2 120-mg capsules) DMF twice daily for 11 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    dimethyl fumarate
    Investigational medicinal product code
    BG00012
    Other name
    DMF, BG00012, Tecfidera
    Pharmaceutical forms
    Gastro-resistant capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Following the 2-week placebo baseline period, DMF was administered orally twice daily for 12 weeks as described in the arm description.

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo was administered twice daily during the 2-week baseline period. In addition, placebo capsules were administered with the 120-mg doses such that 2 capsules were administered at each dose.

    Arm title
    Slow Up-Titration (Six-Week Titration)
    Arm description
    Following a 2-week placebo run-in baseline period, 120 mg DMF once daily (morning dose) and placebo once daily (evening dose) for 2 weeks, then 120 mg DMF twice daily for 2 weeks, then 240 mg (as 2 120-mg capsules) DMF in the morning and 120 mg in the evening for 2 weeks, then 240 mg (as two 120-mg capsules) DMF twice daily for 6 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    dimethyl fumarate
    Investigational medicinal product code
    BG00012
    Other name
    DMF, BG00012, Tecfidera
    Pharmaceutical forms
    Gastro-resistant capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Following the 2-week placebo baseline period, DMF was given once daily for 2 weeks, then twice daily for remaining 10 weeks.

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo was administered twice daily during the 2-week baseline period and as the evening dose during Weeks 3 and 4. In addition, placebo capsules were administered with the 120-mg doses such that 2 capsules were administered at each dose.

    Number of subjects in period 1
    Standard Treatment (One-Week Titration) Slow Up-Titration (Six-Week Titration)
    Started
    30
    32
    Completed
    17
    15
    Not completed
    13
    17
         Adverse event, non-fatal
    3
    -
         Not specified
    10
    16
         Required symptomatic therapy
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard Treatment (One-Week Titration)
    Reporting group description
    Following a 2-week placebo run-in baseline period, 120 mg DMF twice daily for 1 week, then 240 mg (as 2 120-mg capsules) DMF twice daily for 11 weeks.

    Reporting group title
    Slow Up-Titration (Six-Week Titration)
    Reporting group description
    Following a 2-week placebo run-in baseline period, 120 mg DMF once daily (morning dose) and placebo once daily (evening dose) for 2 weeks, then 120 mg DMF twice daily for 2 weeks, then 240 mg (as 2 120-mg capsules) DMF in the morning and 120 mg in the evening for 2 weeks, then 240 mg (as two 120-mg capsules) DMF twice daily for 6 weeks.

    Reporting group values
    Standard Treatment (One-Week Titration) Slow Up-Titration (Six-Week Titration) Total
    Number of subjects
    30 32 62
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    30 32 62
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    45.5 ( 11.77 ) 42.5 ( 11.12 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    22 21 43
        Male
    8 11 19

    End points

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    End points reporting groups
    Reporting group title
    Standard Treatment (One-Week Titration)
    Reporting group description
    Following a 2-week placebo run-in baseline period, 120 mg DMF twice daily for 1 week, then 240 mg (as 2 120-mg capsules) DMF twice daily for 11 weeks.

    Reporting group title
    Slow Up-Titration (Six-Week Titration)
    Reporting group description
    Following a 2-week placebo run-in baseline period, 120 mg DMF once daily (morning dose) and placebo once daily (evening dose) for 2 weeks, then 120 mg DMF twice daily for 2 weeks, then 240 mg (as 2 120-mg capsules) DMF in the morning and 120 mg in the evening for 2 weeks, then 240 mg (as two 120-mg capsules) DMF twice daily for 6 weeks.

    Primary: Proportion of Participants With a Worsening in Severity of Gastrointestinal (GI) Adverse Events (AEs) on the Gastrointestinal Symptom Rating Scale (GSRS)

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    End point title
    Proportion of Participants With a Worsening in Severity of Gastrointestinal (GI) Adverse Events (AEs) on the Gastrointestinal Symptom Rating Scale (GSRS) [1]
    End point description
    The GSRS is a weekly recall scale to rate the severity of GI symptoms in participants. It has been modified for daily recall in this study. The severity of each of the 15 questions of the GSRS have a number assigned from 0 (no discomfort at all) to 6 (very severe discomfort).
    End point type
    Primary
    End point timeframe
    from Week 2 (Baseline) to Week 14
    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: The planned efficacy analyses were not performed due to early study termination.
    End point values
    Standard Treatment (One-Week Titration) Slow Up-Titration (Six-Week Titration)
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: participants
    Notes
    [2] - The planned efficacy analyses were not performed due to early study termination.
    [3] - The planned efficacy analyses were not performed due to early study termination.
    No statistical analyses for this end point

    Secondary: Average Change From Baseline in GSRS Scores During DMF Treatment

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    End point title
    Average Change From Baseline in GSRS Scores During DMF Treatment
    End point description
    Average change from baseline in GSRS scores over the 12 weeks of DMF treatment as measured by the total change in GSRS scores from baseline divided by the total number of days with GSRS scores recorded. The GSRS is a weekly recall scale to rate the severity of GI symptoms in participants. It has been modified for daily recall in this study. The severity of each of the 15 questions of the GSRS have a number assigned from 0 (no discomfort at all) to 6 (very severe discomfort).
    End point type
    Secondary
    End point timeframe
    Week 2 (Baseline), Week 14
    End point values
    Standard Treatment (One-Week Titration) Slow Up-Titration (Six-Week Titration)
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: units on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [4] - The planned efficacy analyses were not performed due to early study termination.
    [5] - The planned efficacy analyses were not performed due to early study termination.
    No statistical analyses for this end point

    Secondary: Time to First Worsening From Baseline in GSRS Score

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    End point title
    Time to First Worsening From Baseline in GSRS Score
    End point description
    The GSRS is a weekly recall scale to rate the severity of GI symptoms in participants. It has been modified for daily recall in this study. The severity of each of the 15 questions of the GSRS have a number assigned from 0 (no discomfort at all) to 6 (very severe discomfort).
    End point type
    Secondary
    End point timeframe
    Week 2 (Baseline), Week 14
    End point values
    Standard Treatment (One-Week Titration) Slow Up-Titration (Six-Week Titration)
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: days
    Notes
    [6] - The planned efficacy analyses were not performed due to early study termination.
    [7] - The planned efficacy analyses were not performed due to early study termination.
    No statistical analyses for this end point

    Secondary: Time to Recovery to Baseline From Last Occurrence of Worst GSRS Score

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    End point title
    Time to Recovery to Baseline From Last Occurrence of Worst GSRS Score
    End point description
    The GSRS is a weekly recall scale to rate the severity of GI symptoms in participants. It has been modified for daily recall in this study. The severity of each of the 15 questions of the GSRS have a number assigned from 0 (no discomfort at all) to 6 (very severe discomfort).
    End point type
    Secondary
    End point timeframe
    Week 2 (Baseline), Week 14
    End point values
    Standard Treatment (One-Week Titration) Slow Up-Titration (Six-Week Titration)
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: days
    Notes
    [8] - The planned efficacy analyses were not performed due to early study termination.
    [9] - The planned efficacy analyses were not performed due to early study termination.
    No statistical analyses for this end point

    Secondary: Average Change From Baseline in GSRS Scores to the End of Weeks 4, 6, 8, 10, 12, and 14

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    End point title
    Average Change From Baseline in GSRS Scores to the End of Weeks 4, 6, 8, 10, 12, and 14
    End point description
    Average change from baseline to end of DMF treatment in the GSRS. The GSRS is a weekly recall scale to rate the severity of GI symptoms in participants. It has been modified for daily recall in this study. The severity of each of the 15 questions of the GSRS have a number assigned from 0 (no discomfort at all) to 6 (very severe discomfort).
    End point type
    Secondary
    End point timeframe
    Week 2 (Baseline), Weeks 4, 6, 8, 10, 12, 14
    End point values
    Standard Treatment (One-Week Titration) Slow Up-Titration (Six-Week Titration)
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: units on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [10] - The planned efficacy analyses were not performed due to early study termination.
    [11] - The planned efficacy analyses were not performed due to early study termination.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study through Week 14 plus 2 weeks (±5 days) follow-up. Serious events were collected from time of informed consent and non-serious events were collected from the first dose and throughout the study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    6-Week Titration Arm
    Reporting group description
    Following a 2-week placebo run-in baseline period, 120 mg DMF once daily (morning dose) and placebo once daily (evening dose) for 2 weeks, then 120 mg DMF twice daily for 2 weeks, then 240 mg (as 2 120-mg capsules) DMF in the morning and 120 mg in the evening for 2 weeks, then 240 mg (as two 120-mg capsules) DMF twice daily for 6 weeks.

    Reporting group title
    Standard 1-Week Titration Arm
    Reporting group description
    Following a 2-week placebo run-in baseline period, 120 mg DMF twice daily for 1 week, then 240 mg (as 2 120-mg capsules) DMF twice daily for 11 weeks.

    Serious adverse events
    6-Week Titration Arm Standard 1-Week Titration Arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 30 (6.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastrointestinal infection
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    6-Week Titration Arm Standard 1-Week Titration Arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 32 (43.75%)
    18 / 30 (60.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    6 / 32 (18.75%)
    7 / 30 (23.33%)
         occurrences all number
    9
    11
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 32 (12.50%)
    2 / 30 (6.67%)
         occurrences all number
    5
    2
    Multiple sclerosis relapse
         subjects affected / exposed
    1 / 32 (3.13%)
    3 / 30 (10.00%)
         occurrences all number
    1
    3
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 30 (6.67%)
         occurrences all number
    2
    2
    Rash
         subjects affected / exposed
    1 / 32 (3.13%)
    3 / 30 (10.00%)
         occurrences all number
    1
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Infections and infestations
    Cystitis
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 30 (6.67%)
         occurrences all number
    2
    2
    Gastroenteritis viral
         subjects affected / exposed
    3 / 32 (9.38%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 32 (9.38%)
    3 / 30 (10.00%)
         occurrences all number
    4
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Mar 2015
    A global amendment was issued on 16 March 2015 to clarify only 1 strength of capsule was to be administered (120 mg), clarify clinical laboratory test results from screening had to be reviewed before the baseline visit, and extend the period of time men had to use contraceptives to 90 days after the last dose of study treatment. In addition, administrative and other minor changes were included.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The Sponsor decided to terminate the study as a result of an evaluation of ongoing development programs.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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