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    Clinical Trial Results:
    A Phase 4, Randomized, Double-Blind Study with a Safety Extension Period to Evaluate the Effect of Aspirin on Flushing Events in Subjects with Relapsing-Remitting Multiple Sclerosis Treated with Tecfidera™ (Dimethyl Fumarate) Delayed-Release Capsules

    Summary
    EudraCT number
    2013-001895-40
    Trial protocol
    IE  
    Global end of trial date
    11 Nov 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    17 Nov 2016
    First version publication date
    17 Nov 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    109MS406
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02090413
    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
    11 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to evaluate whether 150 mg enteric-coated aspirin (acetylsalicylic acid [ASA]) taken twice a day (BID) with dimethyl fumarate (DMF) administration or 75 mg enteric-coated ASA taken once daily in the morning (QAM) with DMF administration reduces the incidence and/or severity of flushing events in subjects with relapsing-remitting multiple sclerosis (RRMS) compared with ASA-placebo administered with DMF in the clinical practice setting. Secondary objectives of this study are to evaluate the safety and tolerability of DMF administered with and without enteric-coated ASA in the clinical practice setting; and to evaluate the impact of DMF administration on quality of life as measured by the Short Form 36 (SF-36®) and European Quality of Life – 5 Dimensions – 5 Levels (EQ-5D-5L) questionnaires.
    Protection of trial subjects
    Written informed consent was obtained from each subject prior to evaluations being performed for eligibility. Subjects were given adequate time to review the information in the informed consent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study. Through the informed consent process each subject was made aware of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken. Any side effects or other health issues occurring during the study were followed up by the study doctor. Subjects were able to stop taking part in the study at any time without giving any reason.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 May 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
    Ireland: 31
    Country: Number of subjects enrolled
    United Kingdom: 210
    Worldwide total number of subjects
    241
    EEA total number of subjects
    241
    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)
    240
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 241 subjects with RRMS were enrolled at 18 study sites across the UK and Ireland.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    All study staff were blinded to the subject treatment assignments throughout the Double-Blind Period of the study. To maintain the study blind, subject treatment assignments were not shared with the subjects, their families, or any member of the study team, either at the study site or at Biogen.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    DMF + ASA-Placebo BID
    Arm description
    DMF 120 mg taken twice daily (BID) for the first 7 days and 240 mg BID from Week 2 through Week 48. ASA-Placebo taken BID from Day 1 through Week 4. (Between Weeks 5 and 8, ASA was prohibited; between Weeks 9 and 48, ASA was allowed as needed.)
    Arm type
    Experimental

    Investigational medicinal product name
    Tecfidera
    Investigational medicinal product code
    BG00012
    Other name
    dimethyl fumarate, DMF
    Pharmaceutical forms
    Gastro-resistant capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    DMF was taken according to the prevailing product label; however, dose modifications were not allowed during the Double-Blind Period. During the Safety Extension Period, modification of theDMF dose was allowed at the discretion of the Investigator according to the prevailing product label.

    Investigational medicinal product name
    ASA-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects had to take blinded ASA/ASA-placebo with each dose of DMF for the first 28 days of the study, regardless of when the Week 4 Visit was performed. Missed doses were not made up.

    Arm title
    DMF + ASA 75 mg QAM
    Arm description
    DMF 120 mg BID for the first 7 days and 240 mg BID from Week 2 through Week 48. ASA 75 mg QAM and ASA-Placebo in the evening from Day 1 through Week 4. (Between Weeks 5 and 8, ASA was prohibited; between Weeks 9 and 48, ASA was allowed as needed.)
    Arm type
    Experimental

    Investigational medicinal product name
    Tecfidera
    Investigational medicinal product code
    BG00012
    Other name
    dimethyl fumarate, DMF
    Pharmaceutical forms
    Gastro-resistant capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    DMF was taken according to the prevailing product label; however, dose modifications were not allowed during the Double-Blind Period. During the Safety Extension Period, modification of the DMF dose was allowed at the discretion of the Investigator according to the prevailing product label.

    Investigational medicinal product name
    ASA-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects had to take blinded ASA/ASA-placebo with each dose of DMF for the first 28 days of the study, regardless of when the Week 4 Visit was performed. Missed doses were not made up.

    Investigational medicinal product name
    Enteric-coated ASA
    Investigational medicinal product code
    Other name
    aspirin
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects had to take blinded ASA/ASA placebo with each dose of DMF for the first 28 days of the study, regardless of when the Week 4 Visit was performed. Missed doses were not made up.

    Arm title
    DMF + ASA 150 mg BID
    Arm description
    DMF 120 mg BID for the first 7 days and 240 mg BID from Week 2 through Week 48. ASA 150 mg BID from Day 1 through Week 4. (Between Weeks 5 and 8, ASA was prohibited; between Weeks 9 and 48, ASA was allowed as needed.)
    Arm type
    Experimental

    Investigational medicinal product name
    Tecfidera
    Investigational medicinal product code
    BG00012
    Other name
    dimethyl fumarate, DMF
    Pharmaceutical forms
    Gastro-resistant capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    DMF was taken according to the prevailing product label; however, dose modifications were not allowed during the Double-Blind Period. During the Safety Extension Period, modification of the DMF dose was allowed at the discretion of the Investigator according to the prevailing product label.

    Investigational medicinal product name
    Enteric-coated ASA
    Investigational medicinal product code
    Other name
    aspirin
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects had to take blinded ASA/ASA-placebo with each dose of DMF for the first 28 days of the study, regardless of when the Week 4 Visit was performed. Missed doses were not made up.

    Number of subjects in period 1
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Started
    81
    80
    80
    Completed
    62
    60
    57
    Not completed
    19
    20
    23
         Investigator decision
    1
    1
    -
         Flushing event
    2
    -
    1
         Adverse event, non-fatal
    11
    15
    20
         Consent withdrawn by subject
    2
    2
    2
         Lost to follow-up
    1
    1
    -
         Not Specified
    2
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DMF + ASA-Placebo BID
    Reporting group description
    DMF 120 mg taken twice daily (BID) for the first 7 days and 240 mg BID from Week 2 through Week 48. ASA-Placebo taken BID from Day 1 through Week 4. (Between Weeks 5 and 8, ASA was prohibited; between Weeks 9 and 48, ASA was allowed as needed.)

    Reporting group title
    DMF + ASA 75 mg QAM
    Reporting group description
    DMF 120 mg BID for the first 7 days and 240 mg BID from Week 2 through Week 48. ASA 75 mg QAM and ASA-Placebo in the evening from Day 1 through Week 4. (Between Weeks 5 and 8, ASA was prohibited; between Weeks 9 and 48, ASA was allowed as needed.)

    Reporting group title
    DMF + ASA 150 mg BID
    Reporting group description
    DMF 120 mg BID for the first 7 days and 240 mg BID from Week 2 through Week 48. ASA 150 mg BID from Day 1 through Week 4. (Between Weeks 5 and 8, ASA was prohibited; between Weeks 9 and 48, ASA was allowed as needed.)

    Reporting group values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID Total
    Number of subjects
    81 80 80 241
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    40.17 ± 10.63 39.48 ± 8.48 40.16 ± 8.23 -
    Gender, Male/Female
    Units: participants
        Female
    59 62 60 181
        Male
    22 18 20 60

    End points

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    End points reporting groups
    Reporting group title
    DMF + ASA-Placebo BID
    Reporting group description
    DMF 120 mg taken twice daily (BID) for the first 7 days and 240 mg BID from Week 2 through Week 48. ASA-Placebo taken BID from Day 1 through Week 4. (Between Weeks 5 and 8, ASA was prohibited; between Weeks 9 and 48, ASA was allowed as needed.)

    Reporting group title
    DMF + ASA 75 mg QAM
    Reporting group description
    DMF 120 mg BID for the first 7 days and 240 mg BID from Week 2 through Week 48. ASA 75 mg QAM and ASA-Placebo in the evening from Day 1 through Week 4. (Between Weeks 5 and 8, ASA was prohibited; between Weeks 9 and 48, ASA was allowed as needed.)

    Reporting group title
    DMF + ASA 150 mg BID
    Reporting group description
    DMF 120 mg BID for the first 7 days and 240 mg BID from Week 2 through Week 48. ASA 150 mg BID from Day 1 through Week 4. (Between Weeks 5 and 8, ASA was prohibited; between Weeks 9 and 48, ASA was allowed as needed.)

    Primary: Percentage of Subjects Reporting Overall Flushing Events During the First 4 Weeks of Treatment, as Assessed by the Modified Global Flushing Severity Scale (MGFSS)

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    End point title
    Percentage of Subjects Reporting Overall Flushing Events During the First 4 Weeks of Treatment, as Assessed by the Modified Global Flushing Severity Scale (MGFSS) [1]
    End point description
    Subject-reported flushing events during the first 4 weeks of treatment, recorded on the hand-held subject reporting device (eDiary) as assessed by MGFSS. The MGFSS measures the side effects related to flushing during the past 24 hours. Flushing means redness, warmth, tingling or itching of the skin. Each question is rated on a scale from 0 (no flushing side effects) to 10 (extreme flushing side effects). Day 1 data are not included in the analysis because MGFSS question refers to last 24 hours flushing score.
    End point type
    Primary
    End point timeframe
    Day 2 to Week 4
    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 for this end point, per protocol.
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    80
    79
    80
    Units: percentage of subjects
    number (not applicable)
        Weeks 1-4 combined; n=80, 79, 80
    90
    92.4
    88.8
        Week 1; n=80, 77, 80
    83.8
    85.7
    83.8
        Week 2; n=77, 76, 79
    76.6
    61.8
    69.6
        Week 3; n=74, 74, 76
    73
    55.4
    53.9
        Week 4; n=72, 71, 71
    59.7
    54.9
    54.9
    Attachments
    Untitled (Filename: Table 7_Statistical Analyses for Endpoint 1.pdf)
    No statistical analyses for this end point

    Primary: Percentage of Subjects Reporting Overall Flushing Events During the First 4 Weeks of Treatment, as Assessed by the Modified Flushing Severity Scale (MFSS)

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    End point title
    Percentage of Subjects Reporting Overall Flushing Events During the First 4 Weeks of Treatment, as Assessed by the Modified Flushing Severity Scale (MFSS)
    End point description
    Subject-reported flushing events during the first 4 weeks of treatment recorded on the eDiary as assessed by MFSS. MFSS questionnaire measures the side effects related to flushing following drug administration. Flushing means redness, warmth, tingling or itching of the skin. This questionnaire relates only to the period of time since the investigational drug was administered and was to be completed within 10 hours of taking the study drug (2 times/day). Each question is rated on a scale from 0 (no flushing side effects) to 10 (extreme flushing side effects).
    End point type
    Primary
    End point timeframe
    Day 1 to Week 4
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    80
    78
    80
    Units: percentage of subjects
    number (not applicable)
        Overall flushing events
    91.3
    96.2
    96.3
        Overall redness events
    90
    88.5
    88.8
        Overall warmth events
    92.5
    97.4
    97.5
        Overall tingling events
    81.3
    87.2
    86.3
        Overall itching events
    87.5
    79.5
    76.3
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Overall flushing events
    Comparison groups
    DMF + ASA-Placebo BID v DMF + ASA 75 mg QAM
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Difference in percentage
    Point estimate
    4.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.6
         upper limit
    12.4
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Overall flushing events
    Comparison groups
    DMF + ASA-Placebo BID v DMF + ASA 150 mg BID
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Difference in percentage
    Point estimate
    5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.5
         upper limit
    12.5
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Overall redness events
    Comparison groups
    DMF + ASA-Placebo BID v DMF + ASA 75 mg QAM
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Difference in percentage
    Point estimate
    -1.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.2
         upper limit
    8.1
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Overall redness events
    Comparison groups
    DMF + ASA-Placebo BID v DMF + ASA 150 mg BID
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Difference in percentage
    Point estimate
    -1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.8
         upper limit
    8.3
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    Overall warmth events
    Comparison groups
    DMF + ASA-Placebo BID v DMF + ASA 75 mg QAM
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Difference in percentage
    Point estimate
    4.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.8
         upper limit
    11.7
    Statistical analysis title
    Statistical Analysis 6
    Statistical analysis description
    Overall warmth events
    Comparison groups
    DMF + ASA-Placebo BID v DMF + ASA 150 mg BID
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Difference in percentage
    Point estimate
    5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.7
         upper limit
    11.7
    Statistical analysis title
    Statistical Analysis 7
    Statistical analysis description
    Overall tingling events
    Comparison groups
    DMF + ASA-Placebo BID v DMF + ASA 75 mg QAM
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Difference in percentage
    Point estimate
    5.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.4
         upper limit
    17.3
    Statistical analysis title
    Statistical Analysis 8
    Statistical analysis description
    Overall tingling events
    Comparison groups
    DMF + ASA-Placebo BID v DMF + ASA 150 mg BID
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Difference in percentage
    Point estimate
    5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.4
         upper limit
    16.4
    Statistical analysis title
    Statistical Analysis 9
    Statistical analysis description
    Overall itching events
    Comparison groups
    DMF + ASA-Placebo BID v DMF + ASA 75 mg QAM
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Difference in percentage
    Point estimate
    -8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -19.5
         upper limit
    3.5
    Statistical analysis title
    Statistical Analysis 10
    Statistical analysis description
    Overall itching events
    Comparison groups
    DMF + ASA-Placebo BID v DMF + ASA 150 mg BID
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Difference in percentage
    Point estimate
    -11.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -23.1
         upper limit
    0.6

    Primary: Worst Severity Scores of Overall Flushing During the First 4 Weeks of Treatment, as Assessed by MGFSS

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    End point title
    Worst Severity Scores of Overall Flushing During the First 4 Weeks of Treatment, as Assessed by MGFSS [2]
    End point description
    Worst severity of subject-reported flushing events during the first 4 weeks of treatment recorded on the eDiary as assessed by MGFSS. The MGFSS measures the side effects related to flushing during the past 24 hours. Flushing means redness, warmth, tingling or itching of the skin. Each question is rated on a scale from 0 (no flushing side effects) to 10 (extreme flushing side effects). Day 1 data are not included in the analysis because MGFSS question refers to last 24 hours flushing score.
    End point type
    Primary
    End point timeframe
    Day 2 to Week 4
    Notes
    [2] - 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 for this end point, per protocol.
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    80
    79
    80
    Units: units on a scale
        arithmetic mean (standard deviation)
    4.36 ± 2.66
    3.99 ± 2.63
    3.93 ± 2.47
    No statistical analyses for this end point

    Primary: Worst Severity Scores of Overall Flushing During the First 4 Weeks of Treatment, as Assessed by MFSS

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    End point title
    Worst Severity Scores of Overall Flushing During the First 4 Weeks of Treatment, as Assessed by MFSS [3]
    End point description
    Worst severity of subject-reported flushing events during the first 4 weeks of treatment recorded on the eDiary as assessed by MFSS. MFSS questionnaire measures the side effects related to flushing following drug administration. Flushing means redness, warmth, tingling or itching of the skin. This questionnaire relates only to the period of time since the investigational drug was administered and was to be completed within 10 hours of taking the study drug (2 times/day). Each question is rated on a scale from 0 (no flushing side effects) to 10 (extreme flushing side effects).
    End point type
    Primary
    End point timeframe
    Day 1 to Week 4
    Notes
    [3] - 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 for this end point, per protocol.
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    80
    78
    80
    Units: units on a scale
    arithmetic mean (standard deviation)
        Overall flushing
    4.84 ± 2.77
    4.73 ± 2.43
    4.78 ± 2.53
        Redness
    4.83 ± 2.69
    4.65 ± 2.73
    4.34 ± 2.67
        Warmth
    5.03 ± 2.54
    4.88 ± 2.38
    4.9 ± 2.46
        Tingling
    3.31 ± 2.38
    3.62 ± 2.53
    3.3 ± 2.3
        Itching
    3.7 ± 2.55
    3.64 ± 2.76
    3.23 ± 2.66
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reporting Overall Flushing Events During Weeks 5-8 and Weeks 9-12 of Treatment, as Assessed by MGFSS

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    End point title
    Percentage of Subjects Reporting Overall Flushing Events During Weeks 5-8 and Weeks 9-12 of Treatment, as Assessed by MGFSS
    End point description
    Subject-reported flushing events during Weeks 5-8 and Weeks 9-12 of the study recorded on the eDiary as assessed by MGFSS. The MGFSS measures the side effects related to flushing during the past 24 hours. Flushing means redness, warmth, tingling or itching of the skin. Each question is rated on a scale from 0 (no flushing side effects) to 10 (extreme flushing side effects).
    End point type
    Secondary
    End point timeframe
    Week 5 to Week 12
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    80
    79
    80
    Units: percentage of subjects
    number (not applicable)
        Weeks 5-8 combined; n=71, 71, 70
    74.6
    73.2
    80
        Weeks 9-12 combined; n=67, 62, 65
    61.2
    67.7
    76.9
    Attachments
    Untitled (Filename: Table 42_ Statistical Analyses for Endpoint 5.pdf)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reporting Overall Flushing Events During Weeks 5-8 and Weeks 9-12 of Treatment, as Assessed by MFSS

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    End point title
    Percentage of Subjects Reporting Overall Flushing Events During Weeks 5-8 and Weeks 9-12 of Treatment, as Assessed by MFSS
    End point description
    Subject-reported flushing events during Weeks 5-8 and Weeks 9-12 of the study recorded on the eDiary as assessed by MFSS. MFSS questionnaire measures the side effects related to flushing following drug administration. Flushing means redness, warmth, tingling or itching of the skin. This questionnaire relates only to the period of time since the investigational drug was administered and was to be completed within 10 hours of taking the study drug (2 times/day). Each question is rated on a scale from 0 (no flushing side effects) to 10 (extreme flushing side effects).
    End point type
    Secondary
    End point timeframe
    Week 5 to Week 12
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    80
    78
    80
    Units: percentage of subjects
    number (not applicable)
        Overall Flushing, Weeks 5-8 combined; n=71, 70, 70
    80.3
    82.9
    84.3
        Overall Flushing, Weeks 9-12 combined;n=68, 65, 65
    66.2
    69.2
    78.5
        Redness, Weeks 5-8 combined; n=71, 70, 70
    77.5
    75.7
    81.4
        Redness, Weeks 9-12 combined; n=68, 65, 65
    70.6
    61.5
    73.8
        Warmth, Weeks 5-8 combined; n=71, 70, 70
    80.3
    80
    82.9
        Warmth, Weeks 9-12 combined; n=68, 65, 65
    70.6
    70.8
    75.4
        Tingling, Weeks 5-8 combined; n=71, 70, 70
    57.7
    55.7
    71.4
        Tingling, Weeks 9-12 combined; n=68, 65, 65
    54.4
    49.2
    61.5
        Itching, Weeks 5-8 combined; n=71, 70, 70
    54.9
    64.3
    64.3
        Itching, Weeks 9-12 combined; n=68, 65, 65
    48.5
    52.3
    56.9
    Attachments
    Untitled (Filename: Table 44_ Statistical Analyses for Endpoint 6_overall flushing.pdf)
    Untitled (Filename: Table 44_ Statistical Analyses for Endpoint 6_redness.pdf)
    Untitled (Filename: Table 44_ Statistical Analyses for Endpoint 6_warmth.pdf)
    Untitled (Filename: Table 44_ Statistical Analyses for Endpoint 6_tingling.pdf)
    Untitled (Filename: Table 44_ Statistical Analyses for Endpoint 6_itching.pdf)
    No statistical analyses for this end point

    Secondary: Worst Severity Scores of Overall Flushing During Weeks 5-8 and Weeks 9-12 of the Study, as Assessed by MGFSS

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    End point title
    Worst Severity Scores of Overall Flushing During Weeks 5-8 and Weeks 9-12 of the Study, as Assessed by MGFSS
    End point description
    Worst severity of subject-reported flushing events during Weeks 5-8 and Weeks 9-12 of the study recorded on the eDiary as assessed by MGFSS. The MGFSS measures the side effects related to flushing during the past 24 hours. Flushing means redness, warmth, tingling or itching of the skin. Each question is rated on a scale from 0 (no flushing side effects) to 10 (extreme flushing side effects).
    End point type
    Secondary
    End point timeframe
    Week 5 to Week 12
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    80
    79
    80
    Units: units on a scale
    arithmetic mean (standard deviation)
        Weeks 5-8 combined; n=71, 71, 70
    3 ± 2.61
    2.83 ± 2.4
    3.47 ± 2.64
        Weeks 9 to 12 combined; n=67, 62, 65
    2.43 ± 2.72
    2.81 ± 2.76
    2.95 ± 2.5
    No statistical analyses for this end point

    Secondary: Worst Severity Scores of Overall Flushing During Weeks 5-8 and Weeks 9-12 of the Study, as Assessed by MFSS

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    End point title
    Worst Severity Scores of Overall Flushing During Weeks 5-8 and Weeks 9-12 of the Study, as Assessed by MFSS
    End point description
    Worst severity of subject-reported flushing events during Weeks 5-8 and Weeks 9-12 of the study recorded on the eDiary as assessed by MFSS. MFSS questionnaire measures the side effects related to flushing following drug administration. Flushing means redness, warmth, tingling or itching of the skin. This questionnaire relates only to the period of time since the investigational drug was administered and was to be completed within 10 hours of taking the study drug (2 times/day). Each question is rated on a scale from 0 (no flushing side effects) to 10 (extreme flushing side effects).
    End point type
    Secondary
    End point timeframe
    Week 5 to Week 12
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    80
    78
    80
    Units: units on a scale
    arithmetic mean (standard deviation)
        Overall Flushing, Weeks 5-8 combined; n=71, 70, 70
    3.37 ± 2.8
    3.24 ± 2.57
    3.57 ± 2.45
        Overall Flushing, Weeks 9-12 combined;n=68, 65, 65
    2.5 ± 2.65
    3.15 ± 2.98
    3.45 ± 2.74
        Redness, Weeks 5-8 combined; n=71, 70, 70
    3.27 ± 2.9
    2.83 ± 2.54
    3.51 ± 2.58
        Redness, Weeks 9-12 combined; n=68, 65, 65
    2.57 ± 2.55
    2.75 ± 3.13
    3.4 ± 2.93
        Warmth, Weeks 5-8 combined; n=71, 70, 70
    3.3 ± 2.71
    3.11 ± 2.45
    3.49 ± 2.54
        Warmth, Weeks 9-12 combined; n=68, 65, 65
    2.66 ± 2.52
    3.06 ± 2.97
    3.45 ± 2.85
        Tingling, Weeks 5-8 combined; n=71, 70, 70
    2.03 ± 2.41
    2.07 ± 2.5
    2.79 ± 2.56
        Tingling, Weeks 9-12 combined; n=68, 65, 65
    1.71 ± 2.17
    1.78 ± 2.43
    2.54 ± 2.69
        Itching, Weeks 5-8 combined; n=71, 70, 70
    1.92 ± 2.35
    2.17 ± 2.32
    2.64 ± 2.59
        Itching, Weeks 9-12 combined; n=68, 65, 65
    1.51 ± 2.04
    1.69 ± 2.15
    2.17 ± 2.52
    No statistical analyses for this end point

    Secondary: Duration of Flushing Episodes During Weeks 1-4, 5-8 and 9-12 of the Study, as Assessed by MGFSS

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    End point title
    Duration of Flushing Episodes During Weeks 1-4, 5-8 and 9-12 of the Study, as Assessed by MGFSS
    End point description
    Duration of subject-reported flushing events during weeks 1-4, 5-8 and 9-12 of the study recorded on the eDiary as assessed by MGFSS. The MGFSS measures the side effects related to flushing during the past 24 hours. Flushing means redness, warmth, tingling or itching of the skin. Each question is rated on a scale from 0 (no flushing side effects) to 10 (extreme flushing side effects).
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 12
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    0 [4]
    0 [5]
    0 [6]
    Units: hours
        number (not applicable)
    Notes
    [4] - Could not be calculated; specific flushing events with start/end times were not captured in MGFSS.
    [5] - Could not be calculated; specific flushing events with start/end times were not captured in MGFSS.
    [6] - Could not be calculated; specific flushing events with start/end times were not captured in MGFSS.
    No statistical analyses for this end point

    Secondary: Duration of Flushing Episodes During Weeks 1-4, 5-8 and 9-12 of the Study, as Assessed by MFSS

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    End point title
    Duration of Flushing Episodes During Weeks 1-4, 5-8 and 9-12 of the Study, as Assessed by MFSS
    End point description
    Duration of subject-reported flushing events during weeks 1-4, 5-8 and 9-12 of the study recorded on the eDiary as assessed by MFSS. MFSS questionnaire measures the side effects related to flushing following drug administration. Flushing means redness, warmth, tingling or itching of the skin. This questionnaire relates only to the period of time since the investigational drug was administered and was to be completed within 10 hours of taking the study drug (2 times/day). Each question is rated on a scale from 0 (no flushing side effects) to 10 (extreme flushing side effects). For subjects with more than 1 flushing event during a visit interval, the average duration for the visit interval was used.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 12
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    81
    80
    80
    Units: hours
    arithmetic mean (standard deviation)
        Weeks 1-4 combined; n=73, 75, 77
    0.69 ± 0.44
    0.8 ± 0.59
    1.11 ± 1.16
        Weeks 5-8 combined; n=57, 58, 59
    1.06 ± 2.12
    0.73 ± 0.52
    1.08 ± 1.18
        Weeks 9-12 combined; n=45, 45, 51
    0.66 ± 0.52
    0.69 ± 0.59
    0.79 ± 0.94
    Attachments
    Untitled (Filename: Table 58_ Statistical Analyses for Endpoint 10.pdf)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Self-Reported Flushing Events During Weeks 13 to 48

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    End point title
    Number of Subjects With Self-Reported Flushing Events During Weeks 13 to 48
    End point description
    Subject-reported flushing events (which include redness, warmth, tingling, and/or itching of the skin) during Weeks 13 to 48 of treatment were recorded in the CRF.
    End point type
    Secondary
    End point timeframe
    Week 13 to Week 48
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    81
    80
    80
    Units: subjects
        number (not applicable)
    36
    35
    42
    No statistical analyses for this end point

    Secondary: Number of Subjects Experiencing Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs in the First 12 Weeks

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    End point title
    Number of Subjects Experiencing Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs in the First 12 Weeks
    End point description
    AE: any untoward medical occurrence that does not necessarily have a causal relationship with treatment. SAE: any untoward medical occurrence that at any dose: results in death; in the view of the Investigator, places the subject at immediate risk of death (a life-threatening event); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity, or; results in a congenital anomaly/birth defect. An SAE may also be any other medically important event that, in the opinion of the Investigator, may jeopardize the subject or may require intervention to prevent one of the other outcomes listed above. A treatment-emergent AE is defined as any AE that occurs after the first administration of DMF or ASA/Placebo drug.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 12
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    81
    80
    80
    Units: subjects
    number (not applicable)
        Any event
    66
    68
    63
        Moderate or severe event
    24
    38
    26
        Severe event
    3
    5
    8
        Related event
    35
    38
    40
        Serious event
    1
    1
    2
        Discontinued treatment due to event
    5
    9
    12
        Discontinued study due to event
    5
    9
    13
    No statistical analyses for this end point

    Secondary: Number of Subjects Experiencing Treatment-Emergent AEs, SAEs, and Discontinuations Due to AEs in Weeks 13 to 48

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    End point title
    Number of Subjects Experiencing Treatment-Emergent AEs, SAEs, and Discontinuations Due to AEs in Weeks 13 to 48
    End point description
    AE: any untoward medical occurrence that does not necessarily have a causal relationship with treatment. SAE: any untoward medical occurrence that at any dose: results in death; in the view of the Investigator, places the subject at immediate risk of death (a life-threatening event); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity, or; results in a congenital anomaly/birth defect. An SAE may also be any other medically important event that, in the opinion of the Investigator, may jeopardize the subject or may require intervention to prevent one of the other outcomes listed above. A treatment-emergent AE is defined as any AE that occurs after the first administration of DMF or ASA/Placebo drug.
    End point type
    Secondary
    End point timeframe
    Week 13 to Week 48
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    81
    80
    80
    Units: subjects
    number (not applicable)
        Any event
    66
    68
    66
        Moderate or severe event
    40
    50
    51
        Severe event
    5
    12
    12
        Related event
    45
    42
    49
        Serious event
    3
    7
    3
        Discontinued treatment due to event
    9
    6
    10
        Discontinued study due to event
    9
    6
    10
    No statistical analyses for this end point

    Secondary: Number of Subjects Discontinuing Treatment and Discontinuing the Study Due to Treatment-emergent Flushing AEs in the First 12 Weeks

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    End point title
    Number of Subjects Discontinuing Treatment and Discontinuing the Study Due to Treatment-emergent Flushing AEs in the First 12 Weeks
    End point description
    A treatment-emergent AE is defined as any AE that occurs after the first administration of DMF or ASA/Placebo drug. Flushing AEs include redness, warmth, tingling, and/or itching of the skin.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 12
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    81
    80
    80
    Units: subjects
    number (not applicable)
        Discontinuing treatment
    0
    0
    2
        Discontinuing study
    0
    0
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects Discontinuing Treatment and Discontinuing the Study Due to Treatment-Emergent Flushing AEs in Weeks 13 to 48

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    End point title
    Number of Subjects Discontinuing Treatment and Discontinuing the Study Due to Treatment-Emergent Flushing AEs in Weeks 13 to 48
    End point description
    A treatment-emergent AE is defined as any AE that occurs after the first administration of DMF or ASA/Placebo drug. Flushing AEs include redness, warmth, tingling, and/or itching of the skin.
    End point type
    Secondary
    End point timeframe
    Week 13 to Week 48
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    81
    80
    80
    Units: subjects
    number (not applicable)
        Discontinuing treatment
    2
    0
    0
        Discontinuing study
    2
    0
    0
    No statistical analyses for this end point

    Secondary: Change from Baseline at Weeks 24 and 48 in Quality of Life Measurements as Assessed by Short Form-36 (SF-36) Questionnaire: Physical Component Summary (PCS)

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    End point title
    Change from Baseline at Weeks 24 and 48 in Quality of Life Measurements as Assessed by Short Form-36 (SF-36) Questionnaire: Physical Component Summary (PCS)
    End point description
    SF-36 is a self-administered, generic health status questionnaire consisting of 36 questions that measure 8 health concepts: physical functioning, role limitations due to physical problems, bodily pain, general health perception, vitality, social functioning, role limitations due to emotional problems and mental health. The score for a domain is an average of the individual question scores, which are scaled 0 (worst health-related quality of life) to 100 (best health-related quality of life). Score from physical function, role physical, bodily pain, and general health domains were averaged to calculate PCS. Total score range for PCS was 0 (lowest level of physical functioning) to 100 (highest level of physical functioning).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, Week 48 or early termination (ET)
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    81
    80
    80
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline; n=81, 80, 80
    44.627 ± 10.822
    41.99 ± 10.966
    43.16 ± 11.438
        Change at Week 24; n=68, 63, 61
    -0.014 ± 9.154
    0.551 ± 8.473
    -1.471 ± 7.754
        Change at Week 48/ET; n=68, 65, 64
    -1.008 ± 10.31
    -1.449 ± 10.964
    -2.989 ± 14.22
    No statistical analyses for this end point

    Secondary: Change from Baseline at Weeks 24 and 48 in Quality of Life Measurements as Assessed by SF-36 Questionnaire: Mental Component Summary (MCS)

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    End point title
    Change from Baseline at Weeks 24 and 48 in Quality of Life Measurements as Assessed by SF-36 Questionnaire: Mental Component Summary (MCS)
    End point description
    SF-36 is a self-administered, generic health status questionnaire consisting of 36 questions that measure 8 health concepts: physical functioning, role limitations due to physical problems, bodily pain, general health perception, vitality, social functioning, role limitations due to emotional problems and mental health. The score for a domain is an average of the individual question scores, which are scaled 0 (worst health-related quality of life) to 100 (best health-related quality of life). Score from mental health, role emotional, social functioning, and vitality domains were averaged to calculate MCS. Total score range for MCS was 0 (lowest level of physical functioning) to 100 (highest level of physical functioning).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, Week 48 or ET
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    81
    80
    80
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline; n=81, 80, 80
    47.413 ± 8.772
    45.048 ± 10.531
    46.496 ± 10.812
        Change at Week 24; n=68, 63, 61
    -0.139 ± 11.66
    -0.893 ± 10.059
    -0.312 ± 12.251
        Change at Week 48/ET; n=68, 65, 64
    -0.976 ± 13.759
    -2.081 ± 13.733
    -2.82 ± 15.465
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 24 and Week 48 in Quality of Life Measurements as Assessed by the European Quality of Life 5-Dimensions Questionnaire (EQ-5D-5L) Questionnaire: Mobility

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    End point title
    Change from Baseline to Week 24 and Week 48 in Quality of Life Measurements as Assessed by the European Quality of Life 5-Dimensions Questionnaire (EQ-5D-5L) Questionnaire: Mobility
    End point description
    EQ-5D-5L is a standardized, subject-rated instrument for use as a measure of health outcomes. The EQ 5D-5L includes 2 components: the EQ-5D-5L descriptive system and the EQ-VAS. The EQ-5D-5L descriptive system provides a profile of the subject’s health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each dimension, the subject is instructed to indicate whether he or she has “no problems” (1), “some problems” (2), or “severe problems” (3). A negative change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, Week 48 or ET
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    81
    80
    80
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline; n=81, 79, 80
    1.877 ± 0.967
    1.785 ± 0.887
    1.888 ± 0.928
        Change at Week 24; n=67, 63, 60
    -0.104 ± 0.606
    0.095 ± 1.214
    -0.05 ± 0.467
        Change at Week 48/ET; n=67, 63, 63
    0.03 ± 0.627
    0.079 ± 1.021
    0.095 ± 0.56
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 24 and Week 48 in Quality of Life Measurements as Assessed by the EQ-5D-5L Questionnaire: Self-Care

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    End point title
    Change from Baseline to Week 24 and Week 48 in Quality of Life Measurements as Assessed by the EQ-5D-5L Questionnaire: Self-Care
    End point description
    EQ-5D-5L is a standardized, subject-rated instrument for use as a measure of health outcomes. The EQ 5D-5L includes 2 components: the EQ-5D-5L descriptive system and the EQ-VAS. The EQ-5D-5L descriptive system provides a profile of the subject’s health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each dimension, the subject is instructed to indicate whether he or she has “no problems” (1), “some problems” (2), or “severe problems” (3). A negative change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, Week 48 or ET
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    81
    80
    80
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline; n=81, 79, 80
    1.321 ± 0.668
    1.38 ± 0.722
    1.363 ± 0.621
        Change at Week 24; n=67, 63, 60
    -0.045 ± 0.442
    -0.079 ± 1.182
    0.017 ± 0.567
        Change at Week 48/ET; n=67, 64, 63
    -0.045 ± 0.367
    -0.109 ± 1.143
    0.079 ± 0.604
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 24 and Week 48 in Quality of Life Measurements as Assessed by the EQ-5D-5L Questionnaire: Usual Activities

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    End point title
    Change from Baseline to Week 24 and Week 48 in Quality of Life Measurements as Assessed by the EQ-5D-5L Questionnaire: Usual Activities
    End point description
    EQ-5D-5L is a standardized, subject-rated instrument for use as a measure of health outcomes. The EQ 5D-5L includes 2 components: the EQ-5D-5L descriptive system and the EQ-VAS. The EQ-5D-5L descriptive system provides a profile of the subject’s health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each dimension, the subject is instructed to indicate whether he or she has “no problems” (1), “some problems” (2), or “severe problems” (3). A negative change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, Week 48 or ET
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    81
    80
    80
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline; n=81, 79, 80
    1.827 ± 0.891
    1.975 ± 0.947
    2.025 ± 0.993
        Change at Week 24; n=67, 63, 60
    -0.06 ± 0.694
    0 ± 1.244
    -0.017 ± 0.725
        Change at Week 48/ET; n=67, 64, 63
    0.149 ± 0.783
    -0.016 ± 1.105
    0.063 ± 0.896
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 24 and Week 48 in Quality of Life Measurements as Assessed by the EQ-5D-5L Questionnaire: Pain/Discomfort

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    End point title
    Change from Baseline to Week 24 and Week 48 in Quality of Life Measurements as Assessed by the EQ-5D-5L Questionnaire: Pain/Discomfort
    End point description
    EQ-5D-5L is a standardized, subject-rated instrument for use as a measure of health outcomes. The EQ 5D-5L includes 2 components: the EQ-5D-5L descriptive system and the EQ-VAS. The EQ-5D-5L descriptive system provides a profile of the subject’s health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each dimension, the subject is instructed to indicate whether he or she has “no problems” (1), “some problems” (2), or “severe problems” (3). A negative change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, Week 48 or ET
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    81
    80
    80
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline; n=81, 79, 80
    2 ± 0.88
    2.038 ± 0.869
    1.975 ± 0.941
        Change at Week 24; n=67, 63, 60
    -0.104 ± 0.699
    0 ± 1.032
    0.1 ± 0.573
        Change at Week 48/ET; n=67, 64, 63
    -0.09 ± 0.712
    0.078 ± 1.117
    -0.127 ± 0.707
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 24 and Week 48 in Quality of Life Measurements as Assessed by the EQ-5D-5L Questionnaire: Anxiety/Depression

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    End point title
    Change from Baseline to Week 24 and Week 48 in Quality of Life Measurements as Assessed by the EQ-5D-5L Questionnaire: Anxiety/Depression
    End point description
    EQ-5D-5L is a standardized, subject-rated instrument for use as a measure of health outcomes. The EQ 5D-5L includes 2 components: the EQ-5D-5L descriptive system and the EQ-VAS. The EQ-5D-5L descriptive system provides a profile of the subject’s health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each dimension, the subject is instructed to indicate whether he or she has “no problems” (1), “some problems” (2), or “severe problems” (3). A negative change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, Week 48 or ET
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    81
    80
    80
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline; n=81, 79, 80
    1.642 ± 0.763
    1.848 ± 0.893
    1.763 ± 0.917
        Change at Week 24; n=67, 63, 60
    -0.06 ± 0.903
    -0.19 ± 1.293
    0 ± 0.803
        Change at Week 48/ET; n=67, 63, 63
    0.03 ± 0.953
    -0.127 ± 1.184
    -0.032 ± 0.842
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 24 and Week 48 in Quality of Life Measurements as Assessed by the EQ-VAS

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    End point title
    Change from Baseline to Week 24 and Week 48 in Quality of Life Measurements as Assessed by the EQ-VAS
    End point description
    For the EQ-VAS, the subject was instructed to draw a line on a 20-cm vertical scale at the point that best describes his or her own health, where 0 represents the “worst imaginable health state” and 100 represents the “best imaginable health state.”
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, Week 48 or ET
    End point values
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Number of subjects analysed
    81
    80
    80
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline; n=80, 80, 80
    78.288 ± 16.442
    69.6 ± 19.535
    73.438 ± 16.38
        Change at Week 24; n=66, 63, 60
    -2.318 ± 12.579
    -0.587 ± 17.24
    -2.95 ± 16.326
        Change at Week 48/ET; n=66, 64, 63
    -3.061 ± 18.053
    -0.438 ± 17.834
    -1.476 ± 13.201
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening through Week 48
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    DMF + ASA-Placebo BID
    Reporting group description
    DMF 120 mg taken BID for the first 7 days and 240 mg BID from Week 2 through Week 48. ASA-Placebo taken BID from Day 1 through Week 4. (Between Weeks 5 and 8, ASA was prohibited; between Weeks 9 and 48, ASA was allowed as needed.)

    Reporting group title
    DMF + ASA 75 mg QAM
    Reporting group description
    DMF 120 mg BID for the first 7 days and 240 mg BID from Week 2 through Week 48. ASA 75 mg QAM and ASA-Placebo in the evening from Day 1 through Week 4. (Between Weeks 5 and 8, ASA was prohibited; between Weeks 9 and 48, ASA was allowed as needed.)

    Reporting group title
    DMF + ASA 150 mg BID
    Reporting group description
    DMF 120 mg BID for the first 7 days and 240 mg BID from Week 2 through Week 48. ASA 150 mg BID from Day 1 through Week 4. (Between Weeks 5 and 8, ASA was prohibited; between Weeks 9 and 48, ASA was allowed as needed.)

    Serious adverse events
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 81 (4.94%)
    8 / 80 (10.00%)
    5 / 80 (6.25%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 80 (2.50%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Drug intolerance
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abasia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 80 (2.50%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    DMF + ASA-Placebo BID DMF + ASA 75 mg QAM DMF + ASA 150 mg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    77 / 81 (95.06%)
    76 / 80 (95.00%)
    76 / 80 (95.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    42 / 81 (51.85%)
    36 / 80 (45.00%)
    45 / 80 (56.25%)
         occurrences all number
    59
    62
    83
    Hypertension
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Peripheral coldness
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Hot flush
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bowen's disease
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 80 (1.25%)
    1 / 80 (1.25%)
         occurrences all number
    1
    1
    1
    Food allergy
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    1 / 80 (1.25%)
         occurrences all number
    0
    1
    2
    Seasonal allergy
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    9 / 81 (11.11%)
    11 / 80 (13.75%)
    7 / 80 (8.75%)
         occurrences all number
    10
    12
    8
    Influenza like illness
         subjects affected / exposed
    2 / 81 (2.47%)
    2 / 80 (2.50%)
    4 / 80 (5.00%)
         occurrences all number
    3
    3
    4
    Asthenia
         subjects affected / exposed
    2 / 81 (2.47%)
    0 / 80 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    2
    0
    2
    Chest discomfort
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 80 (2.50%)
    2 / 80 (2.50%)
         occurrences all number
    0
    2
    2
    Pain
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 80 (2.50%)
    1 / 80 (1.25%)
         occurrences all number
    0
    2
    1
    Chills
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    0
    0
    3
    Feeling abnormal
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    3
    Malaise
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 81 (1.23%)
    2 / 80 (2.50%)
    0 / 80 (0.00%)
         occurrences all number
    1
    2
    0
    Chest pain
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 80 (1.25%)
    1 / 80 (1.25%)
         occurrences all number
    1
    1
    1
    Gait disturbance
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    3 / 80 (3.75%)
         occurrences all number
    0
    0
    4
    Adverse drug reaction
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    1
    1
    0
    Device failure
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Feeling hot
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    1 / 81 (1.23%)
    3 / 80 (3.75%)
    2 / 80 (2.50%)
         occurrences all number
    1
    3
    2
    Anxiety
         subjects affected / exposed
    1 / 81 (1.23%)
    2 / 80 (2.50%)
    2 / 80 (2.50%)
         occurrences all number
    1
    2
    2
    Depression
         subjects affected / exposed
    5 / 81 (6.17%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    5
    1
    0
    Irritability
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    1
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Anger
         subjects affected / exposed
    2 / 81 (2.47%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    2
    0
    0
    Libido decreased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Mental disorder
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Sleep disorder
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Panic attack
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    1
    1
    0
    Disturbance in attention
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    3 / 81 (3.70%)
    0 / 80 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    3
    0
    4
    Dysmenorrhoea
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 80 (2.50%)
    0 / 80 (0.00%)
         occurrences all number
    0
    2
    0
    Menorrhagia
         subjects affected / exposed
    2 / 81 (2.47%)
    1 / 80 (1.25%)
    1 / 80 (1.25%)
         occurrences all number
    2
    1
    1
    Breast cyst
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Breast mass
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    1 / 80 (1.25%)
         occurrences all number
    0
    1
    1
    Vulvovaginal pain
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Metrorrhagia
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    2
    0
    1
    Anisomastia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Nipple pain
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Menstruation irregular
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Pruritus genital
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Testicular cyst
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Testicular pain
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    5 / 81 (6.17%)
    2 / 80 (2.50%)
    6 / 80 (7.50%)
         occurrences all number
    6
    3
    8
    Contusion
         subjects affected / exposed
    1 / 81 (1.23%)
    3 / 80 (3.75%)
    1 / 80 (1.25%)
         occurrences all number
    1
    4
    1
    Accidental overdose
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Arthropod bite
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Epicondylitis
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Vaccination complication
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Tooth fracture
         subjects affected / exposed
    2 / 81 (2.47%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    2
    0
    0
    Ligament sprain
         subjects affected / exposed
    2 / 81 (2.47%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    2
    1
    0
    Muscle strain
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    1 / 80 (1.25%)
         occurrences all number
    0
    1
    1
    Ankle fracture
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Head injury
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Limb injury
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Laceration
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle rupture
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Patella fracture
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Wrist fracture
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Sunburn
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Alanine aminotransferase abnormal
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 80 (1.25%)
    3 / 80 (3.75%)
         occurrences all number
    1
    1
    4
    Aspartate aminotransferase abnormal
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Liver function test abnormal
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 80 (2.50%)
    1 / 80 (1.25%)
         occurrences all number
    0
    2
    1
    Serum ferritin decreased
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    1
    1
    0
    Smear cervix abnormal
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Weight increased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    5 / 81 (6.17%)
    5 / 80 (6.25%)
    5 / 80 (6.25%)
         occurrences all number
    5
    5
    5
    Platelet count decreased
         subjects affected / exposed
    2 / 81 (2.47%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    2
    1
    0
    Blood iron decreased
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    1
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Lymphocyte count abnormal
         subjects affected / exposed
    2 / 81 (2.47%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    2
    0
    0
    Weight decreased
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    1
    0
    1
    Blood folate decreased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Vitamin B12 decreased
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    White blood cells urine positive
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    1
    1
    0
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 80 (1.25%)
    1 / 80 (1.25%)
         occurrences all number
    1
    1
    1
    Lymphadenopathy
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    1
    1
    0
    Anaemia
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 81 (11.11%)
    3 / 80 (3.75%)
    5 / 80 (6.25%)
         occurrences all number
    10
    3
    5
    Dyspnoea
         subjects affected / exposed
    3 / 81 (3.70%)
    3 / 80 (3.75%)
    2 / 80 (2.50%)
         occurrences all number
    3
    3
    2
    Rhinorrhea
         subjects affected / exposed
    3 / 81 (3.70%)
    2 / 80 (2.50%)
    3 / 80 (3.75%)
         occurrences all number
    3
    2
    3
    Oropharyngeal pain
         subjects affected / exposed
    3 / 81 (3.70%)
    4 / 80 (5.00%)
    6 / 80 (7.50%)
         occurrences all number
    4
    4
    6
    Asthma
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Dry throat
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 80 (2.50%)
    0 / 80 (0.00%)
         occurrences all number
    0
    3
    0
    Nasal congestion
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Nasal dryness
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Wheezing
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Throat tightness
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 81 (19.75%)
    14 / 80 (17.50%)
    18 / 80 (22.50%)
         occurrences all number
    27
    15
    26
    Multiple sclerosis relapse
         subjects affected / exposed
    5 / 81 (6.17%)
    12 / 80 (15.00%)
    5 / 80 (6.25%)
         occurrences all number
    5
    12
    6
    Paraesthesia
         subjects affected / exposed
    5 / 81 (6.17%)
    7 / 80 (8.75%)
    5 / 80 (6.25%)
         occurrences all number
    6
    11
    8
    Hypoaesthesia
         subjects affected / exposed
    4 / 81 (4.94%)
    8 / 80 (10.00%)
    4 / 80 (5.00%)
         occurrences all number
    4
    9
    7
    Migraine
         subjects affected / exposed
    2 / 81 (2.47%)
    2 / 80 (2.50%)
    1 / 80 (1.25%)
         occurrences all number
    4
    4
    1
    Balance disorder
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    3 / 80 (3.75%)
         occurrences all number
    1
    0
    3
    Dizziness
         subjects affected / exposed
    3 / 81 (3.70%)
    2 / 80 (2.50%)
    4 / 80 (5.00%)
         occurrences all number
    3
    3
    4
    Amnesia
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Memory impairment
         subjects affected / exposed
    1 / 81 (1.23%)
    2 / 80 (2.50%)
    1 / 80 (1.25%)
         occurrences all number
    1
    2
    1
    Dysgeusia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Dystonia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Optic neuritis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    3 / 80 (3.75%)
         occurrences all number
    1
    0
    3
    Syncope
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 80 (1.25%)
    1 / 80 (1.25%)
         occurrences all number
    1
    1
    1
    Tremor
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    1
    0
    1
    Uhthoff's phenomenon
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 80 (2.50%)
    0 / 80 (0.00%)
         occurrences all number
    0
    2
    0
    Visual field defect
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Neuralgia
         subjects affected / exposed
    1 / 81 (1.23%)
    2 / 80 (2.50%)
    0 / 80 (0.00%)
         occurrences all number
    1
    2
    0
    Sensory disturbance
         subjects affected / exposed
    2 / 81 (2.47%)
    2 / 80 (2.50%)
    0 / 80 (0.00%)
         occurrences all number
    2
    2
    0
    Aphasia
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Aphonia
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Coordination abnormal
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Dysarthria
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Hyperaesthesia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Hemiparesis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Lethargy
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Motor dysfunction
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Nerve compression
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Peroneal nerve palsy
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Burning sensation
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    2 / 81 (2.47%)
    2 / 80 (2.50%)
    2 / 80 (2.50%)
         occurrences all number
    2
    2
    2
    Ocular hyperaemia
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    1
    1
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Eye irritation
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Eye pain
         subjects affected / exposed
    2 / 81 (2.47%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    2
    0
    1
    Diplopia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Colour blindness acquired
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Scleritis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    1
    1
    0
    Hearing impaired
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Hypoacusis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Tinnitus
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Vertigo
         subjects affected / exposed
    2 / 81 (2.47%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    2
    0
    1
    Ear pain
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    2
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    17 / 81 (20.99%)
    21 / 80 (26.25%)
    19 / 80 (23.75%)
         occurrences all number
    21
    24
    23
    Nausea
         subjects affected / exposed
    12 / 81 (14.81%)
    16 / 80 (20.00%)
    23 / 80 (28.75%)
         occurrences all number
    12
    18
    29
    Vomiting
         subjects affected / exposed
    14 / 81 (17.28%)
    14 / 80 (17.50%)
    14 / 80 (17.50%)
         occurrences all number
    18
    16
    18
    Abdominal pain
         subjects affected / exposed
    8 / 81 (9.88%)
    5 / 80 (6.25%)
    10 / 80 (12.50%)
         occurrences all number
    10
    8
    12
    Abdominal pain upper
         subjects affected / exposed
    9 / 81 (11.11%)
    10 / 80 (12.50%)
    7 / 80 (8.75%)
         occurrences all number
    13
    10
    7
    Constipation
         subjects affected / exposed
    3 / 81 (3.70%)
    7 / 80 (8.75%)
    5 / 80 (6.25%)
         occurrences all number
    5
    8
    6
    Abdominal distension
         subjects affected / exposed
    6 / 81 (7.41%)
    0 / 80 (0.00%)
    5 / 80 (6.25%)
         occurrences all number
    7
    0
    8
    Dyspepsia
         subjects affected / exposed
    2 / 81 (2.47%)
    3 / 80 (3.75%)
    4 / 80 (5.00%)
         occurrences all number
    2
    3
    5
    Abdominal discomfort
         subjects affected / exposed
    3 / 81 (3.70%)
    1 / 80 (1.25%)
    2 / 80 (2.50%)
         occurrences all number
    3
    1
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 81 (0.00%)
    3 / 80 (3.75%)
    4 / 80 (5.00%)
         occurrences all number
    0
    3
    4
    Abdominal pain lower
         subjects affected / exposed
    1 / 81 (1.23%)
    2 / 80 (2.50%)
    2 / 80 (2.50%)
         occurrences all number
    1
    4
    2
    Dry mouth
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 80 (2.50%)
    0 / 80 (0.00%)
         occurrences all number
    0
    2
    0
    Eructation
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    1 / 80 (1.25%)
         occurrences all number
    0
    1
    1
    Flatulence
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    1
    0
    2
    Gastritis
         subjects affected / exposed
    2 / 81 (2.47%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    2
    0
    0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    1
    0
    1
    Abdominal mass
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Dysphagia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Faeces discoloured
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Faeces soft
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Gingival bleeding
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    2
    Haematemesis
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Toothache
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 80 (1.25%)
    2 / 80 (2.50%)
         occurrences all number
    1
    1
    2
    Fecal incontinence
         subjects affected / exposed
    2 / 81 (2.47%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    2
    1
    0
    Anorectal discomfort
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Food poisoning
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Gingival swelling
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Hemorrhoids
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Oesophagitis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Stomach ulcer
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Cholecystitis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Micturition urgency
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Dysuria
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Haematuria
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Pollakiuria
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Renal pain
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    5 / 81 (6.17%)
    11 / 80 (13.75%)
    4 / 80 (5.00%)
         occurrences all number
    6
    12
    4
    Rash
         subjects affected / exposed
    2 / 81 (2.47%)
    2 / 80 (2.50%)
    4 / 80 (5.00%)
         occurrences all number
    2
    3
    4
    Alopecia
         subjects affected / exposed
    3 / 81 (3.70%)
    1 / 80 (1.25%)
    2 / 80 (2.50%)
         occurrences all number
    3
    1
    2
    Rash generalised
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 80 (1.25%)
    2 / 80 (2.50%)
         occurrences all number
    1
    1
    2
    Rash pruritic
         subjects affected / exposed
    2 / 81 (2.47%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    3
    1
    0
    Acne
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Erythema
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Urticaria
         subjects affected / exposed
    2 / 81 (2.47%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    3
    0
    1
    Xanthelasma
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Dermal cyst
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Night sweats
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    3
    0
    0
    Pruritis generalised
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Nail hypertrophy
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Psoriasis
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Rash papular
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Skin discolouration
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Rosacea
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    2
    0
    0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    6 / 81 (7.41%)
    4 / 80 (5.00%)
    2 / 80 (2.50%)
         occurrences all number
    6
    4
    2
    Pain in extremity
         subjects affected / exposed
    5 / 81 (6.17%)
    2 / 80 (2.50%)
    7 / 80 (8.75%)
         occurrences all number
    6
    2
    7
    Arthralgia
         subjects affected / exposed
    3 / 81 (3.70%)
    6 / 80 (7.50%)
    3 / 80 (3.75%)
         occurrences all number
    3
    6
    3
    Muscle spasms
         subjects affected / exposed
    2 / 81 (2.47%)
    2 / 80 (2.50%)
    3 / 80 (3.75%)
         occurrences all number
    2
    2
    3
    Musculoskeletal pain
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    3 / 80 (3.75%)
         occurrences all number
    0
    1
    3
    Musculoskeletal stiffness
         subjects affected / exposed
    3 / 81 (3.70%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    3
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 80 (2.50%)
    0 / 80 (0.00%)
         occurrences all number
    0
    2
    0
    Costochondritis
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Flank pain
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    2
    0
    Limb discomfort
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Periarthritis
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    1
    1
    0
    Back pain
         subjects affected / exposed
    4 / 81 (4.94%)
    8 / 80 (10.00%)
    3 / 80 (3.75%)
         occurrences all number
    4
    8
    3
    Joint range of motion decreased
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Joint swelling
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Mastication disorder
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Pain in jaw
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    2
    Temporomandibular joint syndrome
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Gout
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    3
    Cow's milk intolerance
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Iron deficiency
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    20 / 81 (24.69%)
    15 / 80 (18.75%)
    16 / 80 (20.00%)
         occurrences all number
    24
    20
    20
    Urinary tract infection
         subjects affected / exposed
    8 / 81 (9.88%)
    9 / 80 (11.25%)
    10 / 80 (12.50%)
         occurrences all number
    11
    10
    14
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 81 (3.70%)
    10 / 80 (12.50%)
    7 / 80 (8.75%)
         occurrences all number
    3
    10
    9
    Sinusitis
         subjects affected / exposed
    2 / 81 (2.47%)
    1 / 80 (1.25%)
    5 / 80 (6.25%)
         occurrences all number
    3
    1
    6
    Candida infection
         subjects affected / exposed
    1 / 81 (1.23%)
    3 / 80 (3.75%)
    2 / 80 (2.50%)
         occurrences all number
    1
    3
    2
    Gastroenteritis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    2 / 80 (2.50%)
         occurrences all number
    0
    1
    2
    Influenza
         subjects affected / exposed
    0 / 81 (0.00%)
    3 / 80 (3.75%)
    2 / 80 (2.50%)
         occurrences all number
    0
    3
    2
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 81 (1.23%)
    2 / 80 (2.50%)
    4 / 80 (5.00%)
         occurrences all number
    1
    2
    5
    Gastroenteritis viral
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 80 (1.25%)
    1 / 80 (1.25%)
         occurrences all number
    1
    1
    1
    Oral herpes
         subjects affected / exposed
    0 / 81 (0.00%)
    3 / 80 (3.75%)
    0 / 80 (0.00%)
         occurrences all number
    0
    3
    0
    Tooth infection
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    1
    1
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    1 / 81 (1.23%)
    2 / 80 (2.50%)
    0 / 80 (0.00%)
         occurrences all number
    2
    4
    0
    Bronchitis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    1 / 80 (1.25%)
         occurrences all number
    0
    1
    1
    Cystitis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    2
    0
    0
    Gastric infection
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 80 (2.50%)
    2 / 80 (2.50%)
         occurrences all number
    0
    2
    2
    Ear infection
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    1
    1
    0
    Herpes zoster
         subjects affected / exposed
    1 / 81 (1.23%)
    2 / 80 (2.50%)
    1 / 80 (1.25%)
         occurrences all number
    1
    2
    1
    Infected dermal cyst
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    3
    Kidney infection
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    3
    0
    Laryngitis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 81 (1.23%)
    2 / 80 (2.50%)
    1 / 80 (1.25%)
         occurrences all number
    1
    2
    1
    Eye infection
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Viral pharyngitis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Impetigo
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    1
    1
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    1 / 80 (1.25%)
         occurrences all number
    0
    1
    1
    Tonsillitis
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    0
    0
    2
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Gingivitis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Herpes simplex
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Infected cyst
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Labyrinthitis
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Lower respiratory tract infection viral
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Lyme disease
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Periodontitis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Pyuria
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Tooth abscess
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    0 / 80 (0.00%)
         occurrences all number
    0
    1
    0
    Skin infection
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 80 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    0
    1
    Viral infection
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
    3 / 80 (3.75%)
         occurrences all number
    0
    1
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Apr 2014
    The primary reasons for amending the protocol were to specify that the storage temperature for aspirin should not exceed 25°C (77°F), and to clarify contraception requirements.

    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
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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