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    Clinical Trial Results:
    An 18-month, open-label, rater-blinded, randomized, multicenter, active-controlled, parallel-group pilot study to assess efficacy and safety of fingolimod in comparison to interferon beta-1b in treating the cognitive symptoms associated to relapsing-remitting multiple sclerosis and to assess possible relationship of these effects to regional brain atrophy

    Summary
    EudraCT number
    		 2010-023023-19
    Trial protocol
    		 IT   DE  
    Global end of trial date
    01 Sep 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Sep 2016
    First version publication date
    16 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CFTY720DIT01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01333501
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    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
    01 Sep 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate, by means of a specific cognitive test battery [Brief Repeatable Battery (BRB) and Delis-Kaplan Executive Function System scale - Sorting Test (DKEFS)], the slowing/reduction of cognitive dysfunction progression in RRMS patients after 18 months of treatment with fingolimod in comparison with interferon beta-1b treatment, and to evaluate which test of the battery was the most sensitive in detecting differences between treatment groups.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 May 2011
    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: 12
    Country: Number of subjects enrolled
    Italy: 145
    Worldwide total number of subjects
    157
    EEA total number of subjects
    157
    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)
    157
    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 number of total patients randomized in the study (157) together with the number of the safety population (patients who took at least one dose of study drug) (151). In the study there were 6 patients who were enrolled but who never took any dose of study drug.

    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
    		 Fingolimod
    Arm description
    		 0.5 mg in capsules for oral administration once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fingolimod
    Investigational medicinal product code
    FTY720
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg in capsules for oral administration once daily

    Arm title
    		 Interferon beta 1b
    Arm description
    		 250 μg injected s.c. every other day
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Interferon beta 1b
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Intravesical solution/solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    250 μg injected s.c. every other day

    Number of subjects in period 1
    		Fingolimod Interferon beta 1b
    Started
    106
    51
    Full Analysis Set (FAS)
    80 [1]
    28 [2]
    Safety Population
    104
    47
    Completed
    97
    30
    Not completed
    9
    21
         Adverse event, non-fatal
    3
    1
         Unsatisfactory therapeutic effect
    1
    7
         Abnormal laboratory value
    2
    1
         Withdrawn consent
    3
    12
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Total patients randomized in the study (157). Patients who took at least one dose of study drug are 151. The study there were 6 patients who were enrolled but who never took any dose of study drug
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Total patients randomized in the study (157). Patients who took at least one dose of study drug are 151. The study there were 6 patients who were enrolled but who never took any dose of study drug

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fingolimod
    Reporting group description
    		 0.5 mg in capsules for oral administration once daily

    Reporting group title
    Interferon beta 1b
    Reporting group description
    		 250 μg injected s.c. every other day

    Reporting group values
    		 Fingolimod Interferon beta 1b Total
    Number of subjects
    		 106 51 157
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 106 51 157
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 39.53 ( 9.28 ) 37.53 ( 9.27 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 68 32 100
        Male
    		 38 19 57

    End points

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    End points reporting groups
    Reporting group title
    Fingolimod
    Reporting group description
    		 0.5 mg in capsules for oral administration once daily

    Reporting group title
    Interferon beta 1b
    Reporting group description
    		 250 μg injected s.c. every other day

    Primary: Change from screening in Selective Reminding Test – Long-Term Storage (SRT-LTS) raw score

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    End point title
    		 Change from screening in Selective Reminding Test – Long-Term Storage (SRT-LTS) raw score
    End point description
    Brief Repeatable Battery (BRB)- widely used as a clinical and research tool, with 68% sensitivity and 85% specificity. It consists of the serial administration of 5 tests. One of the tests is SRT (Selective Reminding Test) for episodic memory (verbal learning and delayed recall). A word recalled on two consecutive trials is considered to have entered long-term storage (LTS) on the first of these trials and scored as LTS on all following trials. The total of the words in LTS of all six trials is then summed.
    End point type
    Primary
    End point timeframe
    Screening (-1month), 18 month
    End point values
    		 Fingolimod Interferon beta 1b
    Number of subjects analysed
    80
    28
    Units: raw score
        least squares mean (standard error)
    6.32 ( 1.33 )
    4.46 ( 2.28 )
    Statistical analysis title
    		 Change from screening in Selective Reminding Test
    Comparison groups
    Fingolimod v Interferon beta 1b
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.494
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.51
         upper limit
    		 7.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.7

    Primary: Change from screening in Selective Reminding Test – Consistent Long Term Retrieval (SRT-CLTR) raw score

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    End point title
    		 Change from screening in Selective Reminding Test – Consistent Long Term Retrieval (SRT-CLTR) raw score
    End point description
    Brief Repeatable Battery (BRB)- widely used as a clinical and research tool, with 68% sensitivity and 85% specificity. It consists of the serial administration of 5 tests. One of the tests is SRT (Selective Reminding Test) for episodic memory (verbal learning and delayed recall). A word recalled on two consecutive trials is considered to have entered long-term storage (LTS) on the first of these trials and scored as LTS on all following trials. The total of the words in LTS of all six trials is then summed. If a word in LTS is consistently recalled on all subsequent trials, it is then scored as Consistent Long Term Retrieval (CLTR). The total of the words in CLTR of all six trials is summed.
    End point type
    Primary
    End point timeframe
    Screening (-1month), 18 month
    End point values
    		 Fingolimod Interferon beta 1b
    Number of subjects analysed
    80
    28
    Units: Raw score
        least squares mean (standard error)
    5.93 ( 1.49 )
    3.96 ( 2.56 )
    Statistical analysis title
    		 Change from screening in (SRT-CLTR)
    Comparison groups
    Fingolimod v Interferon beta 1b
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5183
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.06
         upper limit
    		 7.99
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.03

    Primary: Change from screening in Spatial Recall Test (SPART) raw score

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    End point title
    		 Change from screening in Spatial Recall Test (SPART) raw score
    End point description
    Spatial Recall Test (SPART) for visuospatial learning and delayed recall.Spatial Recall Test (10/36): The spatial recall test assesses visuospatial learning and delayed recall (10/36-D). A checkerboard with ten checkers arranged in a pattern is shown to the subject for ten seconds. The subject is then asked to reproduce the same pattern with ten checkers on an empty checkerboard. The test includes three consecutive trials. The score is the total number of correct responses for the tree trials
    End point type
    Primary
    End point timeframe
    Screening (-1month), 18 month
    End point values
    		 Fingolimod Interferon beta 1b
    Number of subjects analysed
    80
    28
    Units: Raw score
        least squares mean (standard error)
    1.46 ( 0.52 )
    3.06 ( 0.89 )
    Statistical analysis title
    		 Change from screening in (SPART) raw score
    Comparison groups
    Fingolimod v Interferon beta 1b
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1334
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.69
         upper limit
    		 0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.05

    Primary: Change from screening in Symbol Digit Modalities Test (SDMT) raw score

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    End point title
    		 Change from screening in Symbol Digit Modalities Test (SDMT) raw score
    End point description
    Symbol Digit Modality Test (SDMT) for sustained attention and information processing speed. It presents a series of nine symbols, each of which is paired with a single digit labeled 1-9 in a key at the top of the sheet. The reminder of the page has a pseudo-randomized sequence of symbols, and the patient must respond with the digit associated with each of these as quickly as possible. The score is the number of correct answers in 90 seconds
    End point type
    Primary
    End point timeframe
    Screening (-1month), 18 month
    End point values
    		 Fingolimod Interferon beta 1b
    Number of subjects analysed
    80
    28
    Units: Raw score
        least squares mean (standard error)
    2.19 ( 1.12 )
    3.93 ( 1.93 )
    Statistical analysis title
    		 Change from screening in (SDMT) raw score
    Comparison groups
    Fingolimod v Interferon beta 1b
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4501
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.27
         upper limit
    		 2.81
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.29

    Primary: Change from screening in Paced Auditory Serial Addition Test – 3 seconds (PASAT 3) raw score

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    End point title
    		 Change from screening in Paced Auditory Serial Addition Test – 3 seconds (PASAT 3) raw score
    End point description
    Paced Auditory Serial Addition Test (PASAT) for working memory (and sustained attention and information processing speed). The patient hears a series of numbers from recordings that are presented at the rate of one every 3 seconds in the first part of the test (PASAT-3). The patient is asked to add each consecutive digit to the one immediately preceding it. Sixty-one digits are presented for each part, and each part has a maximum of 60 correct answers.
    End point type
    Primary
    End point timeframe
    Screening (-1month), 18 month
    End point values
    		 Fingolimod Interferon beta 1b
    Number of subjects analysed
    80
    28
    Units: Raw score
        least squares mean (standard error)
    7.14 ( 1.24 )
    6.68 ( 2.13 )
    Statistical analysis title
    		 Change from screening in (PASAT 3) raw score
    Comparison groups
    Fingolimod v Interferon beta 1b
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8561
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.57
         upper limit
    		 5.49
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.53

    Primary: Change from screening in Paced Auditory Serial Addition Test – 2 (PASAT 2) raw score

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    End point title
    		 Change from screening in Paced Auditory Serial Addition Test – 2 (PASAT 2) raw score
    End point description
    Paced Auditory Serial Addition Test (PASAT) for working memory (and sustained attention and information processing speed). The patient hears a series of numbers from recordings that are presented at the rate of one every 2 seconds in the second part of the test (PASAT-2). The patient was asked to add each consecutive digit to the one immediately preceding it. Sixty-one digits are presented for each part, and each part has a maximum of 60 correct answers.
    End point type
    Primary
    End point timeframe
    Screening (-1month), 18 month
    End point values
    		 Fingolimod Interferon beta 1b
    Number of subjects analysed
    80
    28
    Units: Raw score
        least squares mean (standard error)
    4.79 ( 1.25 )
    4.42 ( 2.14 )
    Statistical analysis title
    		 Change from screening in (PASAT 2) raw score
    Comparison groups
    Fingolimod v Interferon beta 1b
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8858
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.67
         upper limit
    		 5.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.53

    Primary: Change from screening in Selective Reminding Test – delayed recall (SRT-D) raw score

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    End point title
    		 Change from screening in Selective Reminding Test – delayed recall (SRT-D) raw score
    End point description
    The tests SRT (Selective Reminding Test) for episodic memory (verbal learning and delayed recall). The Delayed SRT test is the total number of words recalled after a delayed period
    End point type
    Primary
    End point timeframe
    Screening (-1month), 18 month
    End point values
    		 Fingolimod Interferon beta 1b
    Number of subjects analysed
    80
    28
    Units: Raw score
        least squares mean (standard error)
    0.57 ( 0.23 )
    0.39 ( 0.4 )
    Statistical analysis title
    		 Change from screening in (SRT-D) raw score
    Comparison groups
    Fingolimod v Interferon beta 1b
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7119
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.76
         upper limit
    		 1.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.47

    Primary: Change from screening in Spatial Recall Test – delayed recall (SPART-D)

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    End point title
    		 Change from screening in Spatial Recall Test – delayed recall (SPART-D)
    End point description
    Spatial Recall Test (SPART) for visuospatial learning and delayed recall.Spatial Recall Test (10/36): The spatial recall test assesses visuospatial learning and delayed recall (10/36-D). A checkerboard with ten checkers arranged in a pattern was shown to the subject for ten seconds. The subject was then asked to reproduce the same pattern with ten checkers on an empty checkerboard. The test includes three consecutive trials. The score was the total number of correct responses for the tree trials
    End point type
    Primary
    End point timeframe
    Screening (-1month), 18 month
    End point values
    		 Fingolimod Interferon beta 1b
    Number of subjects analysed
    80
    28
    Units: Raw score
        least squares mean (standard error)
    0.41 ( 0.21 )
    0.44 ( 0.36 )
    Statistical analysis title
    		 Change from screening in (SPART-D)
    Comparison groups
    Fingolimod v Interferon beta 1b
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9496
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.86
         upper limit
    		 0.81
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.42

    Primary: Change from screening in Word List Generation (WLG)

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    End point title
    		 Change from screening in Word List Generation (WLG)
    End point description
    Word List Generation (COWAT/WLG): The COWAT assesses verbal fluency on semantic stimulus by asking the patient to produce as many words as possible belonging to a semantic category in 90 seconds. The score was the number of correct words
    End point type
    Primary
    End point timeframe
    Screening (-1month), 18 month
    End point values
    		 Fingolimod Interferon beta 1b
    Number of subjects analysed
    80
    28
    Units: Raw score
        least squares mean (standard error)
    0.39 ( 0.58 )
    0.24 ( 0.99 )
    Statistical analysis title
    		 Change from screening in (WLG)
    Comparison groups
    Fingolimod v Interferon beta 1b
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8944
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.18
         upper limit
    		 2.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.18

    Primary: Change from screening in Delis-Kaplan Executive Function System (DKEFS) condition 1: free sorting, confirmed correct sort- card set 1+2

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    End point title
    		 Change from screening in Delis-Kaplan Executive Function System (DKEFS) condition 1: free sorting, confirmed correct sort- card set 1+2
    End point description
    The Delis-Kaplan Executive Function System – Sorting Test is one of the nine tests presented in the DKEFS manual and explores the patient’s executive abilities. It has a standard form (version A, administered at screening and Month-18 visit) and an alternate form (version B, administered at Month-9 visit). The standard form consists of the practice card set, card set 1 and card set 2. The alternate form consists of the same practice card set, card set 3 and card set 4. The DKFES test consisted of two testing procedures: free sorting and sort recognition. In free sorting, six scores were obtained: Confirmed Correct sorts for card sets 1 and 2 (or 3 and 4 for version B), sum of confirmed Correct Sorts, Free Sorting Description score for card set 1 and 2 (or 3 and 4 for version B) and sum of Free Sorting Description scores. In sort recognition, a description score for card set 1 and 2 (or 3 and 4 for version B) was obtained, as well as the sum of description scores of both sets.
    End point type
    Primary
    End point timeframe
    Screening (-1month), 18 month
    End point values
    		 Fingolimod Interferon beta 1b
    Number of subjects analysed
    80
    28
    Units: Raw score
        least squares mean (standard error)
    0.57 ( 0.31 )
    0.82 ( 0.48 )
    Statistical analysis title
    		 Change from screening in (DKEFS) condition 1
    Comparison groups
    Fingolimod v Interferon beta 1b
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6757
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.42
         upper limit
    		 0.92
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.59

    Primary: Change from screening in DKEFS condition 1: free sorting, free sorting, description score, card set 1+2

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    End point title
    		 Change from screening in DKEFS condition 1: free sorting, free sorting, description score, card set 1+2
    End point description
    The Delis-Kaplan Executive Function System – Sorting Test is one of the nine tests presented in the DKEFS manual and explores the patient’s executive abilities. It has a standard form (version A, administered at screening and Month-18 visit) and an alternate form (version B, administered at Month-9 visit). The standard form consists of the practice card set, card set 1 and card set 2. The alternate form consists of the same practice card set, card set 3 and card set 4. The DKFES test consisted of two testing procedures: free sorting and sort recognition. In free sorting, six scores were obtained: Confirmed Correct sorts for card sets 1 and 2 (or 3 and 4 for version B), sum of confirmed Correct Sorts, Free Sorting Description score for card set 1 and 2 (or 3 and 4 for version B) and sum of Free Sorting Description scores. In sort recognition, a description score for card set 1 and 2 (or 3 and 4 for version B) was obtained, as well as the sum of description scores of both sets.
    End point type
    Primary
    End point timeframe
    Screening (-1month), 18 month
    End point values
    		 Fingolimod Interferon beta 1b
    Number of subjects analysed
    80
    28
    Units: Raw score
        least squares mean (standard error)
    1.52 ( 1.23 )
    3.69 ( 1.92 )
    Statistical analysis title
    		 Change from screening in DKEFS condition 1
    Comparison groups
    Fingolimod v Interferon beta 1b
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3585
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.82
         upper limit
    		 2.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.34

    Primary: Change from screening in DKEFS condition 2: sort recognition, sort recognition description score- card set 1+2

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    End point title
    		 Change from screening in DKEFS condition 2: sort recognition, sort recognition description score- card set 1+2
    End point description
    The Delis-Kaplan Executive Function System – Sorting Test is one of the nine tests presented in the DKEFS manual and explores the patient’s executive abilities. It has a standard form (version A, administered at screening and Month-18 visit) and an alternate form (version B, administered at Month-9 visit). The standard form consists of the practice card set, card set 1 and card set 2. The alternate form consists of the same practice card set, card set 3 and card set 4. The DKFES test consisted of two testing procedures: free sorting and sort recognition. In free sorting, six scores were obtained: Confirmed Correct sorts for card sets 1 and 2 (or 3 and 4 for version B), sum of confirmed Correct Sorts, Free Sorting Description score for card set 1 and 2 (or 3 and 4 for version B) and sum of Free Sorting Description scores. In sort recognition, a description score for card set 1 and 2 (or 3 and 4 for version B) was obtained, as well as the sum of description scores of both sets.
    End point type
    Primary
    End point timeframe
    Screening (-1month), 18 month
    End point values
    		 Fingolimod Interferon beta 1b
    Number of subjects analysed
    80
    28
    Units: Raw score
        least squares mean (standard error)
    2.15 ( 1.9 )
    7.38 ( 2.97 )
    Statistical analysis title
    		 Change from screening in DKEFS condition 2
    Comparison groups
    Fingolimod v Interferon beta 1b
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.161
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -5.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.62
         upper limit
    		 2.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.69

    Secondary: Change from screening in the Volume of total T2 lesions

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    End point title
    		 Change from screening in the Volume of total T2 lesions
    End point description
    Change in volume of total T2-weighted lesions by visit were summarized. Negative values indicate improvement (reduction in lesion volume) and positive values worsening (increase in lesion volume
    End point type
    Secondary
    End point timeframe
    Screening (-1 month), 18 months
    End point values
    		 Fingolimod Interferon beta 1b
    Number of subjects analysed
    68
    27
    Units: mm3
        arithmetic mean (standard deviation)
    176.25 ( 1355.31 )
    711.81 ( 1584.42 )
    No statistical analyses for this end point

    Secondary: Change from screening in Montgomery-Asberg Depression Rating Scale (MADRS)

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    End point title
    		 Change from screening in Montgomery-Asberg Depression Rating Scale (MADRS)
    End point description
    MADRS measures the overall severity of depressive symptoms. The MADRS had a 10-item checklist. Items are rated on a scale of 0-6, for a total numeric range of scores from 0 (depressive symptoms absent) to 60 (numerically highest level of depressive symptoms).
    End point type
    Secondary
    End point timeframe
    Screening (-1month), 18 month
    End point values
    		 Fingolimod Interferon beta 1b
    Number of subjects analysed
    80
    28
    Units: Raw score
        least squares mean (standard error)
    -0.77 ( 0.79 )
    0.13 ( 1.31 )
    No statistical analyses for this end point

    Secondary: Changes in quality of life, by means of the Multiple Sclerosis Quality of Life (MSQoL-54)

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    End point title
    		 Changes in quality of life, by means of the Multiple Sclerosis Quality of Life (MSQoL-54)
    End point description
    A 54 question measure covers 12 domains; assesses mental and physical health. Each domain score is converted into a 0-100 score based on individual item responses; higher scores=better health status. The physical health composite score is a weighted average of the physical health scales, such as physical function, health perceptions, and energy. The mental health composite score is a weighted average of the mental health scales, such as overall quality of life, cognitive function, and health distress
    End point type
    Secondary
    End point timeframe
    Baseline, 18 months
    End point values
    		 Fingolimod Interferon beta 1b
    Number of subjects analysed
    80
    28
    Units: Score
    least squares mean (standard error)
        Mental health composite score
    4.76 ( 2.01 )
    -2.31 ( 3.36 )
        Physical health composite score
    -1.8 ( 1.41 )
    -4.75 ( 2.46 )
    No statistical analyses for this end point

    Secondary: Changes from baseline in Fatigue Impact Scale (mFIS, total score and scores of the 3 individual domains).

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    End point title
    		 Changes from baseline in Fatigue Impact Scale (mFIS, total score and scores of the 3 individual domains).
    End point description
    Modified Fatigue Impact Scale (mFIS) questionnaire is described at each time point to evaluate fatigue by means of usual descriptive statistics. Three domains were also defined: Physical Subscale (sum of items 4, 6, 7, 10, 13, 14, 17, 20, 21 and therefore ranging from 0 to 36), Cognitive Subscale (sum of items 1, 2, 3, 5, 11, 12, 15, 16, 18, 19 and therefore ranging from 0 to 40) and Psychosocial Subscale (sum of items 8, 9 and therefore ranging from 0 to 8). Finally, the mFIS total score was computed as the sum of scores for each item.
    End point type
    Secondary
    End point timeframe
    Baseline, 18 months
    End point values
    		 Fingolimod Interferon beta 1b
    Number of subjects analysed
    80
    28
    Units: Score
        least squares mean (standard error)
    0.46 ( 0.86 )
    4.34 ( 1.43 )
    No statistical analyses for this end point

    Secondary: Change from screening in the Number of new T2 lesions

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    End point title
    		 Change from screening in the Number of new T2 lesions
    End point description
    New T2 lesions at a specific visit were assessed relative to the previous visit scan. The total number of lesions (visit 8 to 18 month) is calculated as the sum of the number of lesions.
    End point type
    Secondary
    End point timeframe
    Screening (-1month), 18 month
    End point values
    		 Fingolimod Interferon beta 1b
    Number of subjects analysed
    80
    28
    Units: Number
        arithmetic mean (standard deviation)
    1.25 ( 2.05 )
    3.33 ( 4.44 )
    No statistical analyses for this end point

    Secondary: Change from screening in the Volume of total T1 hypointense lesions

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    End point title
    		 Change from screening in the Volume of total T1 hypointense lesions
    End point description
    Volume of hypointense post-gadolinium T1 lesion component was measured by MRI scan. Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) by-visit interaction.
    End point type
    Secondary
    End point timeframe
    Screening (-1month), 18 month
    End point values
    		 Fingolimod Interferon beta 1b
    Number of subjects analysed
    80
    28
    Units: mm3
        arithmetic mean (standard deviation)
    391.96 ( 986.85 )
    213.93 ( 312.24 )
    No statistical analyses for this end point

    Secondary: Change from screening in the Number of T1 Gd+ enhancing lesions

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    End point title
    		 Change from screening in the Number of T1 Gd+ enhancing lesions
    End point description
    Total number of post-baseline Gd-enhanced lesions is calculated as a sum of all Gd-enhanced lesions seen on post-baseline scans per visit. Real (not per slice) lesions are counted in this analysis
    End point type
    Secondary
    End point timeframe
    Screening (-1month), 18 month
    End point values
    		 Fingolimod Interferon beta 1b
    Number of subjects analysed
    80
    28
    Units: Number
        arithmetic mean (standard deviation)
    -0.64 ( 1.27 )
    0.59 ( 3.98 )
    No statistical analyses for this end point

    Secondary: Change from screening in the Percentage of Brain volume change

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    End point title
    		 Change from screening in the Percentage of Brain volume change
    End point description
    Calculations of brain volume change were performed using the structural image evaluation of normalized atrophy (SIENA), software included in the Functional Magnetic Resonance Imaging of the Brain (FMRIB) software library. SIENA is a fully automated method for estimating temporal brain volume change.
    End point type
    Secondary
    End point timeframe
    Screening (-1month), 18 month
    End point values
    		 Fingolimod Interferon beta 1b
    Number of subjects analysed
    80
    28
    Units: percentage
        arithmetic mean (standard deviation)
    -0.6 ( 0.83 )
    -0.96 ( 0.71 )
    No statistical analyses for this end point

    Secondary: changes in the Environmental Status Scale score (ESS)

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    End point title
    		 changes in the Environmental Status Scale score (ESS)
    End point description
    The Environmental Status Scale (ESS) is used to quickly evaluate a patient for handicap. It was derived from a measure of socio-economic status. It consists of seven parameters: (1) actual work status, (2) financial and economic status, (3) personal residence or home, (4) personal assistance required, (5) transportation, (6) community services, (7) social activity. Each parameter has a single score from minimum 0 to maximum 5. ESS score is the sum of the points for all 7 parameters: minimum score: 0; maximum score: 35. The higher the score the greater the handicap
    End point type
    Secondary
    End point timeframe
    Baseline, 18 month
    End point values
    		 Fingolimod Interferon beta 1b
    Number of subjects analysed
    80
    28
    Units: Score
        arithmetic mean (standard deviation)
    1.08 ( 3.45 )
    0.91 ( 1.98 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Interferon beta 1b
    Reporting group description
    		 Interferon beta 1b

    Reporting group title
    Fingolimod 0.5 mg
    Reporting group description
    		 Fingolimod 0.5 mg

    Serious adverse events
    		 Interferon beta 1b Fingolimod 0.5 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 47 (2.13%)
    9 / 104 (8.65%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Blood glucose abnormal
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic brain injury
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Uterine polypectomy
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 104 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 104 (0.96%)
         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
    		 Interferon beta 1b Fingolimod 0.5 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 47 (46.81%)
    44 / 104 (42.31%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 47 (2.13%)
    9 / 104 (8.65%)
         occurrences all number
    1
    11
    Blood triglycerides increased
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 104 (0.00%)
         occurrences all number
    3
    0
    Transaminases increased
         subjects affected / exposed
    4 / 47 (8.51%)
    4 / 104 (3.85%)
         occurrences all number
    5
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 47 (8.51%)
    11 / 104 (10.58%)
         occurrences all number
    4
    12
    Multiple sclerosis relapse
         subjects affected / exposed
    4 / 47 (8.51%)
    2 / 104 (1.92%)
         occurrences all number
    5
    2
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    5 / 47 (10.64%)
    1 / 104 (0.96%)
         occurrences all number
    5
    1
    Pyrexia
         subjects affected / exposed
    4 / 47 (8.51%)
    6 / 104 (5.77%)
         occurrences all number
    4
    6
    Psychiatric disorders
    Depression
         subjects affected / exposed
    3 / 47 (6.38%)
    7 / 104 (6.73%)
         occurrences all number
    3
    8
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 47 (6.38%)
    3 / 104 (2.88%)
         occurrences all number
    3
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 47 (6.38%)
    4 / 104 (3.85%)
         occurrences all number
    8
    9
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    2 / 47 (4.26%)
    7 / 104 (6.73%)
         occurrences all number
    2
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Feb 2012
    1.Germany was included as participating country in the study. Two more sites were added in Italy. 2. Implementation of CHMP recommendations concerning intensified cardiovascular monitoring during treatment start and upon re-initiation of treatment with fingolimod. These recommendations were considered necessary after Novartis had informed the European Medicines Agency of the unexplained sudden death of a 59-year-old female patient with multiple sclerosis in the United States of America within 24 hours of taking the first dose of fingolimod. Six other cases of unexplained death had also been reported, three of which were sudden. In addition, other reports included three deaths due to heart attack and one due to disruption of heart rhythm. At the time of its authorization, no cases of sudden or unexplained death had been reported in studies with fingolimod. However, fingolimod is known to cause transient bradycardia and may be associated with atrioventricular block after the first dose, as stated in the current Summary of Product Characteristics. 3. A new study objective was included concerning the evaluation of how the Symbol Symbol Transcode Test (SSTT) correlates with the results of the BRB or D-KEFS. The SSTT was to be administered only in a subgroup of patients/sites, namely new patients/sites included in Germany. 4. Eligibility criteria were updated to exclude patients with an acute relapse of MS and to better clarify the exclusions relevant to patients presenting with chronic diseases of the immune system. In addition, further details were added concerning prohibited previous treatments and related timelines. As the study drug was already marketed in Germany and Italy, exclusion criterion n. 24 was also modified to exclude patients previously treated with fingolimod, regardless of the participation in a previous clinical trial.
    07 Sep 2012
    In April 2012, the CHMP completed the review of fingolimod cardiovascular safety data that started following the case of sudden death mentioned in Amendment 1. The overall positive benefit-risk profile of Gilenya was confirmed and final recommendations for the use of the drug were released. The major changes made to the protocol are summarized below: Exclusion criteria related to cardiovascular conditions were updated. 2. Exclusion of patients taking medications that lower heart rate was added. 3. Appendix 1 “Guidance for observation of patients taking their first dose of fingolimod and for management of bradycardia” was updated to reflect final CHMP recommendations
    04 Mar 2013
    The protocol was amended in order to add the option for patients completing study CFTY720DIT01 to be included in protocol CFTY720DIT07, an open label study aimed at providing access to fingolimod to patients who benefited from treatment or did not have adequate alternative treatment options, but who did not have access to reimbursement from the Italian National Health Service. Long-term safety and tolerability data was also to be collected in a population of patients different from the then current indications. In addition, the age upper limit of 55 years previously indicated in inclusion criterion n.2 was extended to 60 years. Finally, the Gilenya Pregnancy Exposure Registry was introduced, an observational study to evaluate the effect of fingolimod on pregnancy, to which any patient taking fingolimod that became pregnant during the course of this study was encouraged to participate in.
    18 Nov 2013
    Study CFTY720DIT07 mentioned in Amendment 3 initially called for the enrollment of roughly 200 patients. It was however later demonstrated that the number of patients who needed to continue therapy were actually not more than 40, a number not compatible with the study objectives, especially due to the reduced significance of the tolerability and safety data emerging from such a limited number of cases. The need to guarantee therapeutic continuity in situations like these can be more simply and adequately met through a compassionate use program, as per Ministerial Decree May 8, 2003. Novartis decided to provide the drug for compassionate use, on an individual basis, to guarantee therapeutic continuity to patients in treatment with fingolimod who were present for their end of study visit. The protocol was updated also with cumulative data from clinical studies in line with Investigator Brochure v.16.

    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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