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    Clinical Trial Results:
    Effect of MD1003 in progressive multiple sclerosis: a randomized double-blind placebo-controlled study.

    Summary
    EudraCT number
    		 2016-000700-29
    Trial protocol
    		 CZ   SE   DE   ES   HU   BE   PL   IT  
    Global end of trial date
    23 Apr 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Oct 2020
    First version publication date
    07 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MD1003CT2016-01MS-SPI2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02936037
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ClinicalTrials.gov: NCT02936037
    Sponsors
    Sponsor organisation name
    Medday Pharmaceuticals
    Sponsor organisation address
    24-26 rue de la pépinière, Paris, France, 75008
    Public contact
    clinical trials information desk, Medday Pharmaceuticals, +33 1 80 40 14 40, frederic.sedel@medday-pharma.com
    Scientific contact
    clinical trials information desk, Medday Pharmaceuticals, +33 1 80 40 14 40, frederic.sedel@medday-pharma.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
    15 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Nov 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Apr 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To demonstrate the superiority of MD1003, 300 mg/day, over placebo to clinically improve patients with not active progressive multiple sclerosis (MS).
    Protection of trial subjects
    This protocol complied with the principal laid down by the 18th World Medical Assembly (Helsinki, 1964 an following amendments) and all applicable amendments laid down by the World Medical Assemblies, as well as the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. The trial complied with the laws and regulations of the country in which the study was performed, and any applicable guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Nov 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 25
    Country: Number of subjects enrolled
    Spain: 63
    Country: Number of subjects enrolled
    Sweden: 20
    Country: Number of subjects enrolled
    United Kingdom: 81
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Czech Republic: 60
    Country: Number of subjects enrolled
    Germany: 103
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Australia: 16
    Country: Number of subjects enrolled
    Canada: 82
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    Turkey: 6
    Country: Number of subjects enrolled
    United States: 285
    Worldwide total number of subjects
    766
    EEA total number of subjects
    377
    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)
    745
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 766 subjects were screened and 642 were randomized into the study, of which 642 received at least one dose of placebo or biotin.

    Period 1
    Period 1 title
    Double-Blind Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects with progressive multiple sclerosis received placebo matched to MD1003 (biotin) TID
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matching MD1003 100 mg capsule TID

    Arm title
    		 MD1003
    Arm description
    		 Subjects with progressive multiple sclerosis received MD1003 (100mg caps TID).
    Arm type
    		 Experimental

    Investigational medicinal product name
    MD1003
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received MD1003 100 mg capsule TID.

    Number of subjects in period 1 [1]
    		Placebo MD1003
    Started
    316
    326
    Completed
    267
    261
    Not completed
    49
    65
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    31
    28
         Suicidal risk
    -
    1
         Adverse event, non-fatal
    11
    11
         Other
    2
    7
         Lost to follow-up
    -
    1
         Lack of efficacy
    4
    12
         Protocol deviation
    1
    4
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: For the worldwide number we included patients that were screened without taking account if they were randomized or screen failure (766 patients). For the baseline period, we included only randomized patients (642 patients).
    Period 2
    Period 2 title
    Open label extension
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 MD1003
    Arm description
    		 Subjects with progressive multiple sclerosis received MD1003 (100mg caps TID).
    Arm type
    		 Experimental

    Investigational medicinal product name
    MD1003
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received MD1003 100 mg capsule TID

    Number of subjects in period 2
    		MD1003
    Started
    528
    Completed
    518
    Not completed
    10
         Consent withdrawn by subject
    4
         Adverse event, non-fatal
    3
         not specified
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with progressive multiple sclerosis received placebo matched to MD1003 (biotin) TID

    Reporting group title
    MD1003
    Reporting group description
    		 Subjects with progressive multiple sclerosis received MD1003 (100mg caps TID).

    Reporting group values
    		 Placebo MD1003 Total
    Number of subjects
    		 316 326 642
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.8 ( 7.60 ) 52.6 ( 7.79 ) -
    Gender categorical
    Units: Subjects
        Female
    		 170 175 345
        Male
    		 146 151 297

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with progressive multiple sclerosis received placebo matched to MD1003 (biotin) TID

    Reporting group title
    MD1003
    Reporting group description
    		 Subjects with progressive multiple sclerosis received MD1003 (100mg caps TID).
    Reporting group title
    MD1003
    Reporting group description
    		 Subjects with progressive multiple sclerosis received MD1003 (100mg caps TID).

    Subject analysis set title
    ITT analysis set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized subjects

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who received at least one dose of study medication. Patients are summarised according to their randomized treatment group, except for the Safety Analysis Set, where subjects are summarised according to the actual treatment received

    Primary: Decreased EDSS or improved TW25 at M12 confirmed at M15

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    End point title
    		 Decreased EDSS or improved TW25 at M12 confirmed at M15
    End point description
    The primary endpoint is a composite criterion which can be met in one of two ways: either through confirmed improvement in the EDSS score or in TW25. The composite criterion includes either • a decreased EDSS at M12 confirmed at M15 (decrease of at least 1 point if baseline EDSS is from 3.5 to 5.5 and of at least 0.5 point if baseline EDSS is from 6 to 6.5) compared to baseline EDSS or • an improved TW25 of at least 20% at M12 confirmed at M15 compared to baseline TW25. The baseline score for EDSS will be the lowest (best) value obtained during either the inclusion or randomization visits. For the TW25, the baseline value will be the best mean of the 2 values obtained at either the inclusion or randomization visits (the lowest mean value between these 2 visits). The TW25 value at visit M12 is defined as the mean of the two TW25 attempts at visit M12. The TW25 value at visit M15 is defined as the mean of the two TW25 attempts at visit M15.
    End point type
    Primary
    End point timeframe
    The primary efficacy measure is the comparison of the proportion of patients achieving either composite criterion at M12 confirmed at M15 across treatment groups.
    End point values
    		 Placebo MD1003 ITT analysis set
    Number of subjects analysed
    316
    326
    642
    Units: percent
        number (not applicable)
    9.2
    12.0
    10.6
    Statistical analysis title
    		 Improved EDSS or TW25 at M12 confirmed at M15
    Statistical analysis description
    A logistic regression will be fitted to estimate the treatment effect (odd-ratio of improved patients) using treatment, disease history (SPMS/PPMS) and geographical region as fixed factors (referred as the main logistic model in the following parts). The main logistic model will then be used for each component of the composite outcome (EDSS and TW25 responses), to complement the analysis of the main endpoint.
    Comparison groups
    Placebo v MD1003
    Number of subjects included in analysis
    642
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1537
    Method
    		 t-test, 1-sided
    Confidence interval

    Secondary: Time to 12-weeks confirmed EDSS progression

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    End point title
    		 Time to 12-weeks confirmed EDSS progression
    End point description
    12-weeks EDSS progression is defined as an increase of at least 1 point for baseline EDSS up to 5.5 and of at least 0.5 point for baseline EDSS 6 to 6.5 with respective confirmation 12 weeks later
    End point type
    Secondary
    End point timeframe
    time to increase of baseline EDSS confirmed 12 weeks later
    End point values
    		 Placebo MD1003 ITT analysis set
    Number of subjects analysed
    316
    326
    642
    Units: weeks
        median (confidence interval 95%)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 Time to 12-weeks confirmed EDSS progression
    Statistical analysis description
    Timeto12-weeksconfirmedEDSSprogressionwillbecalculatedasdateof12-weeksconfirmedEDSSprogression(orcensoring)minusdateofrandomizationplus1;itwillbeexpressedinweeks.
    Comparison groups
    Placebo v MD1003
    Number of subjects included in analysis
    642
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4348
    Method
    		 Regression, Logistic
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.385

    Secondary: Clinical Global Impression of Improvement (CGI-I) at Visit M15

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    End point title
    		 Clinical Global Impression of Improvement (CGI-I) at Visit M15
    End point description
    End point type
    Secondary
    End point timeframe
    Mean difference between treatment arms in clinician global impression at M15
    End point values
    		 Placebo MD1003 ITT analysis set
    Number of subjects analysed
    316
    326
    642
    Units: percentage
    number (not applicable)
        Very much improved
    0
    0
    0
        Much improved
    1.4
    3.2
    2.3
        Minimally improved
    14.3
    12.9
    13.6
        No change
    48.0
    48.6
    48.3
        Minimally worse
    25.8
    26.1
    25.9
        Much worse
    9.7
    8.6
    9.1
        Very much worse
    0.7
    0.7
    0.7
    Statistical analysis title
    		 Clinical Global Impression of Improvement (CGI-I)
    Statistical analysis description
    One-sided Van Elteren test stratified for disease history (SPMS/PPMS) and geographical region (North America-Australia/Europe) comparing the two study treatment groups
    Comparison groups
    Placebo v MD1003
    Number of subjects included in analysis
    642
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5796
    Method
    		 Van Elteren
    Confidence interval

    Secondary: Subject Global Impression of Improvement (SGI-I) at Visit M15

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    End point title
    		 Subject Global Impression of Improvement (SGI-I) at Visit M15
    End point description
    End point type
    Secondary
    End point timeframe
    15 months
    End point values
    		 Placebo MD1003 ITT analysis set
    Number of subjects analysed
    316
    326
    642
    Units: percent
    number (not applicable)
        Very much improved
    0
    0
    0
        Much improved
    4.0
    4.3
    4.1
        Minimally improved
    14.0
    15.6
    14.8
        No change
    34.5
    33.0
    33.8
        Minimally worse
    31.7
    36.9
    34.3
        Much worse
    14.0
    8.9
    11.4
        Very much worse
    1.8
    1.4
    1.6
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in TW25 at visit M15

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    End point title
    		 Mean Change from Baseline in TW25 at visit M15
    End point description
    End point type
    Secondary
    End point timeframe
    Mean change in TW25 score between M0 and M15
    End point values
    		 Placebo MD1003 ITT analysis set
    Number of subjects analysed
    316
    326
    0 [1]
    Units: Percentage
        arithmetic mean (confidence interval 95%)
    22.5 (-46 to 343)
    20.7 (-75 to 465)
    ( to )
    Notes
    [1] - This was only analyzed by reporting group and not as a total.
    Statistical analysis title
    		 Main analysis of percentage change from baseline
    Statistical analysis description
    Main analysis of percentage change from baseline in TW25 at M15
    Comparison groups
    Placebo v MD1003
    Number of subjects included in analysis
    642
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.524
    Method
    		 t-test, 1-sided
    Confidence interval

    Secondary: ECG at M0 and M15

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    End point title
    		 ECG at M0 and M15
    End point description
    End point type
    Secondary
    End point timeframe
    Month 0 and month 15
    End point values
    		 Placebo MD1003 Safety analysis set
    Number of subjects analysed
    316
    326
    642
    Units: percent
    number (not applicable)
        Baseline abnormal CS
    3.3
    3.1
    3.2
        M15 abnormal CS
    3.8
    3.3
    3.5
    No statistical analyses for this end point

    Secondary: Brain MRI at M15 - New or enlarging T2

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    End point title
    		 Brain MRI at M15 - New or enlarging T2
    End point description
    End point type
    Secondary
    End point timeframe
    Month 15
    End point values
    		 Placebo MD1003 Safety analysis set
    Number of subjects analysed
    316
    326
    642
    Units: percent
    number (not applicable)
        At least new
    25.5
    24.7
    25.1
    No statistical analyses for this end point

    Secondary: C-SSRS score at M15

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    End point title
    		 C-SSRS score at M15
    End point description
    End point type
    Secondary
    End point timeframe
    Month 15
    End point values
    		 Placebo MD1003 Safety analysis set
    Number of subjects analysed
    316
    326
    642
    Units: percent
    number (not applicable)
        -4 points
    0.3
    0.0
    0.2
        -2 points
    0.0
    0.3
    0.2
        -1 point
    1.0
    1.8
    1.4
        0 point
    85.2
    84.3
    84.7
        1 point
    1.6
    0.6
    1.1
        2 points
    0.3
    0.3
    0.3
        3 points
    0.6
    0.0
    0.3
        4 points
    0.0
    0.3
    0.2
    No statistical analyses for this end point

    Secondary: Brain MRI at M0 and M15 - Gd+ lesion

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    End point title
    		 Brain MRI at M0 and M15 - Gd+ lesion
    End point description
    End point type
    Secondary
    End point timeframe
    Month 0 and month 15
    End point values
    		 Placebo MD1003 Safety analysis set
    Number of subjects analysed
    316
    326
    642
    Units: percent
    number (not applicable)
        Baseline Gd+
    5.8
    4.5
    5.3
        M15 Gd+
    6.3
    6.8
    5.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the whole study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    MD1003
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 MD1003 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    87 / 331 (26.28%)
    82 / 311 (26.37%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cervix carcinoma
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystadenocarcinoma ovary
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer metastatic
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenoma
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Testis cancer
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 331 (0.60%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Elective procedure
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological rehabilitation
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric banding reversal
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rehabilitation therapy
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 331 (0.60%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    2 / 331 (0.60%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 331 (0.60%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    2 / 331 (0.60%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bipolar I disorder
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breathing-related sleep disorder
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Substance-induced psychotic disorder
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device failure
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 331 (0.30%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 331 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heat stroke
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lumbar vertebral fracture
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sunburn
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Factor V Leiden mutation
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 331 (0.91%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Silent myocardial infarction
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    29 / 331 (8.76%)
    31 / 311 (9.97%)
         occurrences causally related to treatment / all
    3 / 36
    1 / 37
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    4 / 331 (1.21%)
    6 / 311 (1.93%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    1 / 331 (0.30%)
    4 / 311 (1.29%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasticity
         subjects affected / exposed
    3 / 331 (0.91%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uhthoff's phenomenon
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    2 / 331 (0.60%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sensory loss
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataplexy
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial spasm
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Narcolepsy
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Normal pressure hydrocephalus
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyramidal tract syndrome
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transverse sinus thrombosis
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye pain
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eyelid ptosis
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diaphragmatic hernia, obstructive
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal prolapse
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvi-ureteric obstruction
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric stenosis
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    4 / 331 (1.21%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint stiffness
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    2 / 331 (0.60%)
    6 / 311 (1.93%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 331 (0.91%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 331 (0.60%)
    3 / 311 (0.96%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 331 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic pneumonia
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Human anaplasmosis
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site inflammation
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lyme disease
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MD1003 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    277 / 331 (83.69%)
    264 / 311 (84.89%)
    Investigations
    Laboratory test interference
         subjects affected / exposed
    25 / 331 (7.55%)
    1 / 311 (0.32%)
         occurrences all number
    28
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    44 / 331 (13.29%)
    37 / 311 (11.90%)
         occurrences all number
    84
    60
    Contusion
         subjects affected / exposed
    13 / 331 (3.93%)
    23 / 311 (7.40%)
         occurrences all number
    20
    26
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    29 / 331 (8.76%)
    31 / 311 (9.97%)
         occurrences all number
    36
    37
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    24 / 331 (7.25%)
    26 / 311 (8.36%)
         occurrences all number
    26
    28
    Gait disturbance
         subjects affected / exposed
    22 / 331 (6.65%)
    17 / 311 (5.47%)
         occurrences all number
    28
    21
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    16 / 331 (4.83%)
    12 / 311 (3.86%)
         occurrences all number
    23
    13
    Constipation
         subjects affected / exposed
    18 / 331 (5.44%)
    16 / 311 (5.14%)
         occurrences all number
    19
    16
    Psychiatric disorders
    Depression
         subjects affected / exposed
    17 / 331 (5.14%)
    12 / 311 (3.86%)
         occurrences all number
    23
    12
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    25 / 331 (7.55%)
    26 / 311 (8.36%)
         occurrences all number
    29
    31
    Muscular weakness
         subjects affected / exposed
    20 / 331 (6.04%)
    24 / 311 (7.72%)
         occurrences all number
    27
    33
    Back pain
         subjects affected / exposed
    19 / 331 (5.74%)
    21 / 311 (6.75%)
         occurrences all number
    25
    21
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    48 / 331 (14.50%)
    50 / 311 (16.08%)
         occurrences all number
    74
    94
    Nasopharyngitis
         subjects affected / exposed
    39 / 331 (11.78%)
    58 / 311 (18.65%)
         occurrences all number
    53
    76
    Upper respiratory tract infection
         subjects affected / exposed
    25 / 331 (7.55%)
    27 / 311 (8.68%)
         occurrences all number
    33
    34

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Nov 2018
    Addition of an open-label extension for 39 additional months (up to M66). Change of the calculation method of the TW25 – part of the composite primary endpoint. Decided to take the best of the mean instead of the best value. Clarifications and minor logistic changes (i.e. Sponsor change of address, correct number of coutries and sites...). Addition of safety laboratory testings for thyroid panel testing related to laboratory interferences. Addition of Neurofilament blood level testing. Addition of the Patient Alert Card (alerting of the possibility that patient is taking biotin and it may interfere with laboratory test results).

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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