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    Clinical Trial Results:
    A Multicenter, Randomized, Open-Label Study to Assess the Impact of Natalizumab versus Fingolimod on Central Nervous System Tissue Damage and Recovery in Active Relapsing-Remitting Multiple Sclerosis Subjects

    Summary
    EudraCT number
    		 2013-004622-29
    Trial protocol
    		 IT   CZ   GB   SE   ES   DE   DK  
    Global end of trial date
    17 May 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jun 2017
    First version publication date
    02 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    101MS408
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02342704
    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
    17 May 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 May 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to assess the effect of natalizumab compared to fingolimod on the evolution of new on-treatment T1-gadolinium-enhancing (Gd+) lesions to persistent black holes (PBH) over 52 weeks. The secondary objectives of this study in this study population are to assess the effect of natalizumab compared to fingolimod on: magnetic resonance imaging (MRI) measures of central nervous system (CNS) tissue destruction as measured by the number of new T1-Gd+ lesions; various other MRI measures of disease activity; No Evidence of Disease Activity (NEDA); Relapse on treatment over 52 weeks; The change in information processing speed as measured by the Symbol Digit Modalities Test (SDMT).
    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
    20 Nov 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
    Spain: 21
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    United States: 28
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Czech Republic: 40
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Italy: 4
    Worldwide total number of subjects
    111
    EEA total number of subjects
    80
    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)
    111
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 128 subjects were screened for this study, and 111 were enrolled. Three subjects were not randomized and did not receive any dose of study drug.

    Pre-assignment period milestones
    Number of subjects started
    		 111
    Number of subjects completed
    		 108

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Enrolled, not randomized: 3
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Natalizumab
    Arm description
    		 Open-label natalizumab 300 mg IV every 4 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    natalizumab
    Investigational medicinal product code
    BG00002
    Other name
    Tysabri
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects randomly assigned to the natalizumab group were to receive open-label natalizumab 300 mg IV infused over a 1-hour period (or per local label) every 4 weeks with the last dose planned for administration at Week 52.

    Arm title
    		 Fingolimod
    Arm description
    		 Open-label fingolimod 0.5 mg once daily orally
    Arm type
    		 Active comparator

    Investigational medicinal product name
    fingolimod
    Investigational medicinal product code
    FTY720
    Other name
    Gilenya
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects randomly assigned to the fingolimod group were to receive open-label fingolimod 0.5 mg orally once daily with the last dose planned to be administered at Week 52. Subjects were instructed to take their oral medication at the same time each day.

    Number of subjects in period 1 [1]
    		Natalizumab Fingolimod
    Started
    54
    54
    Completed
    1
    3
    Not completed
    53
    51
         Consent withdrawn by subject
    1
    -
         Physician decision
    -
    3
         Adverse event, non-fatal
    1
    3
         Sponsor Termination
    49
    43
         Not Specified
    -
    1
         Lost to follow-up
    2
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 111 subjects were enrolled. Three subjects were not randomized and did not receive any dose of study drug.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Natalizumab
    Reporting group description
    		 Open-label natalizumab 300 mg IV every 4 weeks

    Reporting group title
    Fingolimod
    Reporting group description
    		 Open-label fingolimod 0.5 mg once daily orally

    Reporting group values
    		 Natalizumab Fingolimod Total
    Number of subjects
    		 54 54 108
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38.19 ± 8.811 34.87 ± 8.731 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 37 38 75
        Male
    		 17 16 33

    End points

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    End points reporting groups
    Reporting group title
    Natalizumab
    Reporting group description
    		 Open-label natalizumab 300 mg IV every 4 weeks

    Reporting group title
    Fingolimod
    Reporting group description
    		 Open-label fingolimod 0.5 mg once daily orally

    Primary: Cumulative Number of ≥ 6-Month Confirmed T1-Hypointense Lesions Arising From New On-Treatment T1-Gadolinium-ENhancing (Gd+) Lesions

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    End point title
    		 Cumulative Number of ≥ 6-Month Confirmed T1-Hypointense Lesions Arising From New On-Treatment T1-Gadolinium-ENhancing (Gd+) Lesions [1]
    End point description
    End point type
    Primary
    End point timeframe
    Up to Week 52
    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: Descriptive statistics are presented, per protocol.
    End point values
    		 Natalizumab Fingolimod
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: lesions
    Notes
    [2] - Due to lack of data, this analysis was not done.
    [3] - Due to lack of data, this analysis was not done.
    No statistical analyses for this end point

    Secondary: Cumulative Number of New T1-Gd+ Lesions

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    End point title
    		 Cumulative Number of New T1-Gd+ Lesions
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 12, Week 24
    End point values
    		 Natalizumab Fingolimod
    Number of subjects analysed
    47
    45
    Units: lesions
    arithmetic mean (standard deviation)
        From Baseline to Week 4
    0.62 ± 1.512
    1.69 ± 4.122
        From Baseline to Week 12
    0.68 ± 1.695
    2.27 ± 4.499
        From Baseline to Week 24
    0.72 ± 1.69
    2.6 ± 4.745
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Week 4
    Comparison groups
    Natalizumab v Fingolimod
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.126
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Week 4
    Comparison groups
    Natalizumab v Fingolimod
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3525
    Method
    		 negative binomial regression
    Confidence interval
    Statistical analysis title
    		 Statisical Analysis 3
    Statistical analysis description
    Week 12
    Comparison groups
    Natalizumab v Fingolimod
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0127
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Week 12
    Comparison groups
    Natalizumab v Fingolimod
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0299
    Method
    		 negative binomial regression
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Week 24
    Comparison groups
    Natalizumab v Fingolimod
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0123
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Week 24
    Comparison groups
    Natalizumab v Fingolimod
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0076
    Method
    		 negative binomial regression
    Confidence interval

    Secondary: Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 24

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    End point title
    		 Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 24
    End point description
    As assessed by magnetic resonance imaging (MRI).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Natalizumab Fingolimod
    Number of subjects analysed
    15
    16
    Units: percentage change
    arithmetic mean (standard deviation)
        T1 Lesion Volume Change
    0.5 ± 31.235
    1.81 ± 19.703
        T2 Lesion Volume Change
    0.08 ± 4.399
    3.32 ± 5.036
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    T1 Lesion Volume Change
    Comparison groups
    Natalizumab v Fingolimod
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5318
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    T2 Lesion Volume Change
    Comparison groups
    Natalizumab v Fingolimod
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0528
    Method
    		 Wilcoxon rank-sum test
    Confidence interval

    Secondary: Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 52

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    End point title
    		 Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 52
    End point description
    As assessed by MRI.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Natalizumab Fingolimod
    Number of subjects analysed
    0 [4]
    1 [5]
    Units: percentage change
    arithmetic mean (standard deviation)
        T1 Lesion Volume Change
    ±
    -15.31 ± 99999
        T2 Lesion Volume Change
    ±
    5.6 ± 99999
    Notes
    [4] - No subjects were evaluated at this time point.
    [5] - 99999=not applicable; only 1 subject was evaluated.
    No statistical analyses for this end point

    Secondary: Cumulative Number of New or Enlarging T2 Lesions

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    End point title
    		 Cumulative Number of New or Enlarging T2 Lesions
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Natalizumab Fingolimod
    Number of subjects analysed
    15
    16
    Units: lesions
        arithmetic mean (standard deviation)
    1.33 ± 2.469
    1.94 ± 2.205
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Natalizumab v Fingolimod
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2632
    Method
    		 Wilcoxon rank-sum test
    Confidence interval

    Secondary: Proportion of Subjects With No Evidence of Disease Activity (NEDA)

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    End point title
    		 Proportion of Subjects With No Evidence of Disease Activity (NEDA)
    End point description
    NEDA was defined as all of the following: no relapses; no 12-week confirmed disability progression based on Expanded Disability Status Scale (EDSS; defined as an increase of 1.0 or more on the EDSS from baseline of 1.0 or more, or an increase of 1.5 or more from a baseline score of 0) that was sustained for 12 weeks; no new T1-Gd+ lesions on brain MRI. No new or enlarging T2-hyperintense lesions.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Natalizumab Fingolimod
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: proportion of subjects
    Notes
    [6] - Due to lack of data, this analysis was not done.
    [7] - Due to lack of data, this analysis was not done.
    No statistical analyses for this end point

    Secondary: Time to First Relapse

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    End point title
    		 Time to First Relapse
    End point description
    A clinical relapse was defined as new or recurrent neurological symptoms, not associated with fever, lasting for at least 24 hours, and followed by a period of 30 days of stability or improvement.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Natalizumab Fingolimod
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: weeks
    Notes
    [8] - Due to lack of data, this analysis was not done.
    [9] - Due to lack of data, this analysis was not done.
    No statistical analyses for this end point

    Secondary: Cumulative Risk of Relapse

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    End point title
    		 Cumulative Risk of Relapse
    End point description
    A clinical relapse was defined as new or recurrent neurological symptoms, not associated with fever, lasting for at least 24 hours, and followed by a period of 30 days of stability or improvement.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Natalizumab Fingolimod
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: ratio
    Notes
    [10] - Due to lack of data, this analysis was not done.
    [11] - Due to lack of data, this analysis was not done.
    No statistical analyses for this end point

    Secondary: Time to Complete Recovery From First Relapse

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    End point title
    		 Time to Complete Recovery From First Relapse
    End point description
    12-week confirmed complete EDSS recovery from first on-treatment relapse is defined as an EDSS score that is equal to or lower than the last pre-relapse EDSS score and sustained for at least 12 weeks.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Natalizumab Fingolimod
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: days
    Notes
    [12] - Due to lack of data, this analysis was not done.
    [13] - Due to lack of data, this analysis was not done.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Symbol Digit Modalities Test (SDMT) at Week 24

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    End point title
    		 Change From Baseline in Symbol Digit Modalities Test (SDMT) at Week 24
    End point description
    The SDMT measures the time to pair abstract symbols with specific numbers. The test requires elements of attention, visuoperceptual processing, working memory, and psychomotor speed. The score is the number of correctly coded items from 0-110 in 90 seconds. The total score provides a measure of the speed and accuracy of symbol-digit substitution.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Natalizumab Fingolimod
    Number of subjects analysed
    14
    17
    Units: units on a scale
        arithmetic mean (standard deviation)
    3.79 ± 8.684
    3.24 ± 4.63
    No statistical analyses for this end point

    Secondary: Change From Baseline in SDMT at Week 52

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    End point title
    		 Change From Baseline in SDMT at Week 52
    End point description
    The SDMT measures the time to pair abstract symbols with specific numbers. The test requires elements of attention, visuoperceptual processing, working memory, and psychomotor speed. The score is the number of correctly coded items from 0-110 in 90 seconds. The total score provides a measure of the speed and accuracy of symbol-digit substitution.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Natalizumab Fingolimod
    Number of subjects analysed
    0 [14]
    9
    Units: units on a scale
        arithmetic mean (standard deviation)
    ±
    2.11 ± 8.492
    Notes
    [14] - No subjects were evaluated at this time point.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 64 weeks.
    Adverse event reporting additional description
    Treatment-emergent adverse events are presented.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Natalizumab
    Reporting group description
    		 Open-label natalizumab 300 mg IV every 4 weeks

    Reporting group title
    Fingolimod
    Reporting group description
    		 Open-label fingolimod 0.5 mg once daily orally

    Serious adverse events
    		 Natalizumab Fingolimod
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 54 (3.70%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Migraine with aura
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 54 (1.85%)
         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
    		 Natalizumab Fingolimod
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 54 (25.93%)
    23 / 54 (42.59%)
    Investigations
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 54 (0.00%)
    5 / 54 (9.26%)
         occurrences all number
    0
    5
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 54 (0.00%)
    3 / 54 (5.56%)
         occurrences all number
    0
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 54 (11.11%)
    4 / 54 (7.41%)
         occurrences all number
    21
    12
    Hypoaesthesia
         subjects affected / exposed
    0 / 54 (0.00%)
    3 / 54 (5.56%)
         occurrences all number
    0
    3
    Multiple sclerosis relapse
         subjects affected / exposed
    1 / 54 (1.85%)
    8 / 54 (14.81%)
         occurrences all number
    4
    16
    Migraine
         subjects affected / exposed
    0 / 54 (0.00%)
    3 / 54 (5.56%)
         occurrences all number
    0
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 54 (0.00%)
         occurrences all number
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    3 / 54 (5.56%)
    1 / 54 (1.85%)
         occurrences all number
    3
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 54 (1.85%)
    3 / 54 (5.56%)
         occurrences all number
    1
    4
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 54 (1.85%)
    5 / 54 (9.26%)
         occurrences all number
    2
    10
    Urinary tract infection
         subjects affected / exposed
    2 / 54 (3.70%)
    3 / 54 (5.56%)
         occurrences all number
    2
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jul 2014
    - A tertiary endpoint for atrophy was revised and a tertiary endpoint for magnetization transfer ratio (MTR) was added. - “Freedom from Measured Disease Activity” was replaced with “No Evidence of Disease Activity”. - The “abstinence” description under contraceptives was revised with language consistent with the Medicines and Healthcare Products Regulatory Agency. -The definition of End of Study was revised to be consistent with other similar protocols.
    13 Oct 2014
    - The number of study visits during which study assessments were collected was decreased for subjects with MS. - Inclusion criteria were revised such that subjects on certain therapies at study screening were required to have at least 9 T2-hyperintense lesions on a brain MRI scan instead of 2 T2-hyperintense lesions, and subjects who were DMT naïve at study screening must have had at least 2 disabling relapses within 1 year prior to study screening instead of 2 unspecified relapses. - Exclusion criteria for subjects with relapsing MS were expanded. Additional criteria were added to exclude a history of congenital QT prolongation and unexplained hypokalemia, and any current therapy with drugs that prolong the corrected QT interval or are potent inducers of CYP450. - Exclusion criteria for subjects with MS were expanded; exclusion criteria for healthy volunteers were expanded. - Absolute lymphocyte count was added to the list of hematology assessments. - Treatment precautions with fingolimod were expanded. - Disallowed concomitant therapy was expanded; cautionary text was added for concomitant administration of certain therapies in patients with relevant risk factors. - Hematology assessments at certain weeks were eliminated. - Blood chemistry assessments at certain weeks were eliminated for natalizumab subjects but retained for fingolimod subjects; an additional blood chemistry assessment was added at Week 4 for fingolimod subjects. - Urinalysis assessments were eliminated for all subjects. - Pulmonary function test at Screening was revised. - Vital sign assessments for fingolimod subjects were eliminated from certain weeks. - Discontinuation of study treatment was expanded to include MS subjects who developed any contraindications to fingolimod and natalizumab, as well as any medical conditions described in the warnings and precautions of the 2 study treatments that made the subject unsuitable for study participation in the opinion of the Investigator.
    01 May 2015
    - Clarification of the requirements in inclusion criteria #5 and #6 to expand the list of permitted prior DMTs - Reduction of the time required for a subject to be on a DMT at screening - Inclusion of potential subjects who had highly-active disease.

    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
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