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    Clinical Trial Results:
    A Phase 4 Multicenter, Open-Label, Single Arm Study to Evaluate Switching From BRACET/Gilenya® to Natalizumab in Subjects With Relapsing Forms of Multiple Sclerosis (MS)

    Summary
    EudraCT number
    2013-005586-39
    Trial protocol
    DE  
    Global end of trial date
    04 Nov 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    11 May 2017
    First version publication date
    11 May 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    101MS409
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02241785
    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
    04 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Nov 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to determine the efficacy of natalizumab (Tysabri, BG00002) in participants with relapsing forms of multiple sclerosis (MS) who have failed Gilenya or BRACET (Betaseron, Rebif, Avonex, Copaxone, Extavia, Tecfidera) as measured by the proportion of participants with no evidence of disease activity (NEDA) at Year 1. The secondary objectives in this study population are: change in total T1 hypointense and total T2 hyperintense lesion volume; proportion of participants with NEDA at Year 2; evaluation of the impact of natalizumab on annualized relapse rate (ARR); and change in Multiple Sclerosis Impact Scale-29 (MSIS-29) physical impact score.
    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
    18 Sep 2014
    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: 47
    Worldwide total number of subjects
    47
    EEA total number of subjects
    0
    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)
    47
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The study included a 43-day screening period.

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

    Arms
    Arm title
    Natalizumab
    Arm description
    natalizumab 300 mg intravenously (IV) every 4 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    natalizumab
    Investigational medicinal product code
    BG00002
    Other name
    Tysabri
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received 1 open-label Tysabri 300 mg infusion every 4 weeks with the last dose planned to be administered at Week 104.

    Number of subjects in period 1
    Natalizumab
    Started
    47
    Completed
    0
    Not completed
    47
         Sponsor Termination
    43
         Adverse event, non-fatal
    1
         Consent withdrawn by subject
    1
         Lost to follow-up
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Natalizumab
    Reporting group description
    natalizumab 300 mg intravenously (IV) every 4 weeks

    Reporting group values
    Natalizumab Total
    Number of subjects
    47 47
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    47 47
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    41.9 ± 10.43 -
    Gender, Male/Female
    Units: Subjects
        Female
    34 34
        Male
    13 13

    End points

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    End points reporting groups
    Reporting group title
    Natalizumab
    Reporting group description
    natalizumab 300 mg intravenously (IV) every 4 weeks

    Primary: Proportion of Subjects With No Evidence of Disease Activity (NEDA) From Reset Baseline (Week 8) to Week 56

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    End point title
    Proportion of Subjects With No Evidence of Disease Activity (NEDA) From Reset Baseline (Week 8) to Week 56 [1]
    End point description
    The proportion of subjects with NEDA, defined as follows: no Expanded Disability Status Scale (EDSS) progression (12-week sustained); no relapses; no gadolinium enhancing (Gd+) lesions; no new or enlarging T2 hyperintense lesions over 48 weeks after resetting the Baseline at Week 8 to remove contribution of combined unique active (CUA) lesions that occurred prior to Week 8, when natalizumab was not yet active. The EDSS quantifies disability in 8 functional systems. The final EDSS score is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) in half-point increments. The limited number of subjects enrolled and the early termination of the study resulted in efficacy data not collected, and efficacy outcomes not analyzed, as per the pre-specified plan of analysis.
    End point type
    Primary
    End point timeframe
    Reset Baseline (Week 8) to Week 56
    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 limited number of subjects enrolled and the early termination of the study resulted in efficacy data not collected, and efficacy outcomes not analyzed, as per the pre-specified plan of analysis.
    End point values
    Natalizumab
    Number of subjects analysed
    0 [2]
    Units: proportion of subjects
    Notes
    [2] - Efficacy data not collected and outcomes not analyzed, as per the pre-specified plan of analysis.
    No statistical analyses for this end point

    Secondary: Change in T1 Unenhancing Lesion Volume and T2 Lesion Volume From Baseline (Day -1) to Reset Baseline (Week 8)

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    End point title
    Change in T1 Unenhancing Lesion Volume and T2 Lesion Volume From Baseline (Day -1) to Reset Baseline (Week 8)
    End point description
    As measured by magnetic resonance imaging.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -1) to Reset Baseline (Week 8)
    End point values
    Natalizumab
    Number of subjects analysed
    43
    Units: cc
    arithmetic mean (standard deviation)
        Change in T1 Unenhancing Lesion Volume
    0.11 ± 0.65
        Change in T2 Lesion Volume
    0.01 ± 1.76
    No statistical analyses for this end point

    Secondary: Proportion of Subjects With NEDA From Week 8 (Reset Baseline) to Week 104

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    End point title
    Proportion of Subjects With NEDA From Week 8 (Reset Baseline) to Week 104
    End point description
    Proportion of subjects with NEDA from Week 8 (Reset Baseline) to Week 104 (with no 12-week confirmed EDSS progression determined at Week 116). NEDA was defined as follows: no EDSS progression (12-week sustained); no relapses; no Gd+ lesions; no new or enlarging T2 hyperintense lesions over 48 weeks after resetting the Baseline at Week 8 to remove contribution of CUA lesions that occurred prior to Week 8, when natalizumab was not yet active. The EDSS quantifies disability in 8 functional systems. The final EDSS score is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) in half-point increments. The limited number of subjects enrolled and the early termination of the study resulted in efficacy data not collected, and efficacy outcomes not analyzed, as per the pre-specified plan of analysis.
    End point type
    Secondary
    End point timeframe
    from Week 8 (Reset Baseline) to Week 104
    End point values
    Natalizumab
    Number of subjects analysed
    0 [3]
    Units: proportion of subjects
    Notes
    [3] - Efficacy data not collected and outcomes not analyzed, as per the pre-specified plan of analysis.
    No statistical analyses for this end point

    Secondary: Pre- and Post-Natalizumab Infusion Annualized Relapse Rate (ARR) Comparison at Month 12

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    End point title
    Pre- and Post-Natalizumab Infusion Annualized Relapse Rate (ARR) Comparison at Month 12
    End point description
    An MS relapse was defined as the onset of new or recurrent neurological symptoms lasting at least 24 hours, accompanied by new objective abnormalities on a neurological examination, and not explained solely by non-MS processes such as fever, infection, severe stress, or drug toxicity. 95% confidence interval is based on a Poisson regression model.
    End point type
    Secondary
    End point timeframe
    From 12 months prior to natalizumab infusion and 12 months post-natalizumab infusion
    End point values
    Natalizumab
    Number of subjects analysed
    47
    Units: relapses per subject-year
    number (confidence interval 95%)
        12 months pre-natalizumab infusion
    1.553 (1.306 to 1.847)
        12 months post-natalizumab infusion
    0.159 (0.076 to 0.331)
    No statistical analyses for this end point

    Secondary: Change in MSIS-29 Physical Impact Scores from Baseline (Day -1) to Reset Baseline (Week 8)

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    End point title
    Change in MSIS-29 Physical Impact Scores from Baseline (Day -1) to Reset Baseline (Week 8)
    End point description
    The MSIS-29 is a brief self-administered MS-specific instrument measuring physical (20 items) and mental/psychological (9 items) impact of MS. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 to 100, where high scores indicate worse health.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -1) to Reset Baseline (Week 8)
    End point values
    Natalizumab
    Number of subjects analysed
    45
    Units: units on a scale
        arithmetic mean (standard deviation)
    -2.53 ± 12.42
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From Screening through end of study. Duration of study treatment was up to 13 months.
    Adverse event reporting additional description
    SAEs only were collected. Events were not coded by MedDRA.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    events not coded
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Natalizumab
    Reporting group description
    natalizumab 300 mg IV every 4 weeks

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: The limited number of subjects enrolled and the early termination of the study resulted in serious adverse events data only being collected, as per the pre-specified plan of analysis.
    Serious adverse events
    Natalizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 47 (4.26%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Syncopal episode
         subjects affected / exposed
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Natalizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 47 (0.00%)

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jul 2014
    The primary reasons for this amendment are to amend the term “free(dom) from measured disease activity (FMDA)” to “no evidence of disease activity (NEDA)”, to allow sufficient time for MRI scan processing and determination of acceptability prior to Tysabri dosing, and to update procedures for the EDSS examination. In addition, minor revisions were made to study procedures to either clarify procedures or for consistency with other study procedures.
    12 Aug 2014
    The primary reason for this amendment to is to correct the version number listed on the Synopsis of the previous version.
    29 Oct 2014
    The primary reasons for this amendment are to remove the MS cognition composite battery assessments from the protocol, add the time period for the natalizumab infusion, change the number of participating sites from 50 to 30, revise the number of subjects from 200 to 130, revise the number of subjects in the exploratory DTI substudy from 70 to 50, revise the inclusion criteria for lymphocytes to be at or above the lower limit of normal instead of within the normal limits (the LLN value is also provided), revise the exclusion criteria to exclude Tysabri “or any of its ingredients”.
    23 Jul 2015
    The primary reason for this amendment is to reduce the time required for subjects to have been on Gilenya® or BRACET at Screening and to increase the period during which disease activity can be observed prior to Screening for entry into the study.

    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.
    As a result of early study termination and limited available data, no meaningful conclusions can be drawn.
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