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    Clinical Trial Results:
    A 32-week, monocentric, exploratory, single arm study to assess immune function and MRI disease activity in patients with relapsing remitting multiple sclerosis (RRMS) transferred from previous treatment with Natalizumab to Gilenya® (Fingolimod)

    Summary
    EudraCT number
    2013-004616-21
    Trial protocol
    DE  
    Global end of trial date
    12 Feb 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Mar 2017
    First version publication date
    10 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CFTY720D2415T | V1.00 | 04-Dec-2013
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02325440
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Sponsor code: UKM12_0037
    Sponsors
    Sponsor organisation name
    Universitätsklinikum Münster
    Sponsor organisation address
    Albert-Schweitzer-Campus 1, Münster, Germany, 48149
    Public contact
    Head of Administrative Department, Universitätsklinikum Münster, 0049 251 835 5967, dorothee.kreuznacht@ukmuenster.de
    Scientific contact
    Coordinating Investigator, Universitätsklinikum Münster, 0049 25183444-52, LuisaHildegard.Klotz@ukmuenster.de
    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
    03 Feb 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluation of changes in the reconstitution of immune surveillance over time upon switching from natalizumab to fingolimod assessed by a change in the expression of CD49d. Evaluation of changes in the migratory capacity of immune cells/PBMCs upon switching from natalizumab to fingolimod in an in-vitro model of the blood-brain-barrier (BBB). Evaluation of changes in paraclinical disease activity over time upon switching from natalizumab to fingolimod assessed by MRI
    Protection of trial subjects
    Safety monitoring (adverse Events, serious adverse Events, adverse drug reactions) Continous assessment of laboratory values (blood/urine)
    Background therapy
    N/A
    Evidence for comparator
    N/A
    Actual start date of recruitment
    03 Mar 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
    Germany: 15
    Worldwide total number of subjects
    15
    EEA total number of subjects
    15
    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)
    15
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    15 patients were enrolled. The duration of the recruitment phase was one year. First patient was enrolled on 22-Apr-2014 (FPFV) and last patient was enrolled on 15-Apr-2015 (LPFV).

    Pre-assignment
    Screening details
    Suitable patients were selected by the investigator. 15 patients were screened. One of the patients was initially deemed screening failure, but re-screened at a later point of time and subsequently enrolled.

    Period 1
    Period 1 title
    Natalizumab - Washout
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Treatment arm
    Arm description
    One final dose of natalizumab 300mg followed by an 8-week washout phase
    Arm type
    Experimental

    Investigational medicinal product name
    Natalizumab
    Investigational medicinal product code
    EU/1/06/346/001
    Other name
    Tysabri
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    300 mg i.v. (once at baseline);

    Number of subjects in period 1
    Treatment arm
    Started
    15
    Completed
    15
    Period 2
    Period 2 title
    Fingolimod Treatment
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Treatment arm
    Arm description
    24-week treatment phase with fingolimod 0.5mg o.i.d.
    Arm type
    Experimental

    Investigational medicinal product name
    Fingolimod
    Investigational medicinal product code
    EU/1/11/677/001-005
    Other name
    Gilenya
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg p.o. (o.i.d)

    Number of subjects in period 2
    Treatment arm
    Started
    15
    Completed
    14
    Not completed
    1
         Serious adverse event
    1
    Period 3
    Period 3 title
    Follow-up
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Treatment arm
    Arm description
    Optional 8-week follow-up phase
    Arm type
    Optional follow-up

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    Treatment arm
    Started
    14
    Completed
    13
    Not completed
    1
         Rejection of optional follow-up phase
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Natalizumab - Washout
    Reporting group description
    -

    Reporting group values
    Natalizumab - Washout Total
    Number of subjects
    15 15
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    15 15
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    38.9 ± 9.2 -
    Gender categorical
    Units: Subjects
        Female
    11 11
        Male
    4 4
    Ethnicity
    Units: Subjects
        Caucasian
    15 15
    Weight
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    82.5 ± 22.5 -
    Body-Mass-Index (BMI)
    Body-Mass-Index (BMI)
    Units: kg/m2
        arithmetic mean (standard deviation)
    27.6 ± 7.5 -
    Height
    Height
    Units: cm
        arithmetic mean (standard deviation)
    172.9 ± 7.3 -

    End points

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    End points reporting groups
    Reporting group title
    Treatment arm
    Reporting group description
    One final dose of natalizumab 300mg followed by an 8-week washout phase
    Reporting group title
    Treatment arm
    Reporting group description
    24-week treatment phase with fingolimod 0.5mg o.i.d.
    Reporting group title
    Treatment arm
    Reporting group description
    Optional 8-week follow-up phase

    Subject analysis set title
    FAS (Baseline)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Full Analysis Set - Population (Baseline)

    Subject analysis set title
    FAS - (EOS; Immunology)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Full Analysis Set - Population (EOS | Immunology)

    Subject analysis set title
    FAS - (EOS | DTI)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Full Analysis Set - Population (EOS | DTI)

    Primary: Changes in expression of marker CD49d/CD4+ on peripheral blood mononuclear cells (PBMC) from week 0 to week 32

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    End point title
    Changes in expression of marker CD49d/CD4+ on peripheral blood mononuclear cells (PBMC) from week 0 to week 32
    End point description
    First co-primary endpoint: Difference in the expression of marker CD49d (mean fluorescence intensity [MFI]) between the measurement at EOS (week 32) and the baseline value (week 0)
    End point type
    Primary
    End point timeframe
    32 weeks
    End point values
    FAS (Baseline) FAS - (EOS; Immunology)
    Number of subjects analysed
    14
    14 [1]
    Units: Mean Fluorescence Intensity (MFI)
        arithmetic mean (standard deviation)
    6.03 ± 1.05
    10.11 ± 3.71
    Notes
    [1] - Data for one patient in the FAS was missing at week 32 (EOS)
    Statistical analysis title
    Paired t-test
    Statistical analysis description
    Paired t-test with a significance level of 0.05%
    Comparison groups
    FAS (Baseline) v FAS - (EOS; Immunology)
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    t-test, 2-sided
    Confidence interval

    Primary: Changes in migratory capacity of immune cells/peripheral blood mononuclear cells (PBMCs) in an in-vitro model of the blood-brain-barrier (BBB) from week 0 to week 32

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    End point title
    Changes in migratory capacity of immune cells/peripheral blood mononuclear cells (PBMCs) in an in-vitro model of the blood-brain-barrier (BBB) from week 0 to week 32
    End point description
    Second co-primary endpoint: Difference between migratory capacities of unstimulated CD4+ cells at EOS (week 32) compared to baseline (week 0)
    End point type
    Primary
    End point timeframe
    32 weeks
    End point values
    FAS (Baseline) FAS - (EOS; Immunology)
    Number of subjects analysed
    14
    14 [2]
    Units: Fluorescence intensity
        arithmetic mean (standard deviation)
    1.44 ± 0.54
    3.33 ± 2.71
    Notes
    [2] - Data for one patient in the FAS was missing at week 32 (EOS)
    Statistical analysis title
    Paired t-test
    Statistical analysis description
    Paired t-test with a significance level of 0.05%
    Comparison groups
    FAS (Baseline) v FAS - (EOS; Immunology)
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.028
    Method
    t-test, 2-sided
    Confidence interval

    Secondary: MRI Disease activity - Number of new Gd+ lesions from week 0 to week 32

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    End point title
    MRI Disease activity - Number of new Gd+ lesions from week 0 to week 32
    End point description
    Number of new Gd+ lesions counted from baseline until EOS
    End point type
    Secondary
    End point timeframe
    32 weeks
    End point values
    FAS - (EOS; Immunology)
    Number of subjects analysed
    15 [3]
    Units: Number of new Gd+ lesions
        median (inter-quartile range (Q1-Q3))
    3 (0 to 6)
    Notes
    [3] - Data for one patient at one visit missing | Reason: Study discontinuation
    No statistical analyses for this end point

    Secondary: MRI disease activity - Number of new T2w lesions from week 0 to week 32

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    End point title
    MRI disease activity - Number of new T2w lesions from week 0 to week 32
    End point description
    Number of new T2w lesions counted from baseline until EOS.
    End point type
    Secondary
    End point timeframe
    32 weeks
    End point values
    FAS - (EOS; Immunology)
    Number of subjects analysed
    15 [4]
    Units: Number of new T2w lesions
        median (inter-quartile range (Q1-Q3))
    1 (0 to 5)
    Notes
    [4] - Data for one patient at one visit missing | Reason: Study discontinuation
    No statistical analyses for this end point

    Secondary: MRI disease activity - Change in DTI fractional anisotropy from week 0 to week 32

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    End point title
    MRI disease activity - Change in DTI fractional anisotropy from week 0 to week 32
    End point description
    Change in DTI fractional anisotropy from baseline to EOS
    End point type
    Secondary
    End point timeframe
    32 weeks
    End point values
    FAS (Baseline) FAS - (EOS | DTI)
    Number of subjects analysed
    10
    10 [5]
    Units: DTI fractional anisotropy
        median (inter-quartile range (Q1-Q3))
    0.29 (0.28 to 0.3)
    0.29 (0.29 to 0.3)
    Notes
    [5] - Data for five patients in the FAS were missing at week 32 (EOS)
    Statistical analysis title
    Paired t-test
    Statistical analysis description
    Paired t-test with a significance level of 0.05%
    Comparison groups
    FAS (Baseline) v FAS - (EOS | DTI)
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.975
    Method
    t-test, 2-sided
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were recorded from baseline (week 0) until end of follow-up phase (week 40)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Safety Set
    Reporting group description
    Full-Analysis-Set = Safety Set

    Serious adverse events
    Safety Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 15 (20.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Nuclear magnetic resonance imaging brain abnormal
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 15 (6.67%)
         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
    Safety Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 15 (100.00%)
    Vascular disorders
    Thrombophlebitis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    4
    Pyrexia
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Depression
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Concussion
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Peroneal nerve injury
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Post lumbar puncture syndrome
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Blood triglycerides increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Nuclear magnetic resonance imaging brain abnormal
         subjects affected / exposed
    7 / 15 (46.67%)
         occurrences all number
    15
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    4
    Nervous system disorders
    Cervicobrachial syndrome
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    6 / 15 (40.00%)
         occurrences all number
    13
    Multiple sclerosis relapse
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Muscle spasticity
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Eye disorders
    Vision blurred
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    Enteritis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Stomatitis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    2
    Toothache
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Micturition urgency
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Skin fissures
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    3
    Pain in extremity
         subjects affected / exposed
    3 / 15 (20.00%)
         occurrences all number
    3
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Dental fistula
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    2
    Herpes simplex
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    4
    Nasopharyngitis
         subjects affected / exposed
    13 / 15 (86.67%)
         occurrences all number
    24
    Oral herpes
         subjects affected / exposed
    2 / 15 (13.33%)
         occurrences all number
    4
    Periodontitis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    4 / 15 (26.67%)
         occurrences all number
    6

    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? No

    Limitations and caveats

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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/26099927
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