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    Clinical Trial Results:
    A Multicenter, Open-Label, Extension Study to Evaluate the Long-Term Safety and Efficacy of BIIB019, Daclizumab High Yield Process (DAC HYP), Monotherapy in Subjects With Multiple Sclerosis Who Have Completed Study 205MS301

    Summary
    EudraCT number
    2012-003176-39
    Trial protocol
    DE   IT   CZ   HU   PL   SE   ES   IE   GB   FI   GR   FR   DK  
    Global end of trial date
    24 Sep 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    27 Nov 2019
    First version publication date
    10 Oct 2019
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    The EudraCT record is being updated to align with the updates made on ClinicalTrials.gov as a result of PRS Review comments.

    Trial information

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    Trial identification
    Sponsor protocol code
    205MS303
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01797965
    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
    24 Sep 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Sep 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to assess the safety and tolerability of long-term treatment with BIIB019 (Daclizumab High Yield Process; DAC HYP) monotherapy in subjects with relapsing remitting multiple sclerosis (RRMS) who completed Study 205MS301 (NCT01064401), Study 205MS203 (NCT01051349) or Study 205MS302 (NCT01462318). Secondary objectives of this study in this study population are as follows: To describe MS-related outcomes, including MS relapse, disability progression, MS lesion formation, and subject-reported impact of MS, following long-term treatment with DAC HYP To assess the long-term immunogenicity of DAC HYP administered by prefilled syringe (PFS) To assess the safety, tolerability, and efficacy of switching to DAC HYP in subjects previously on long-term treatment with interferon β-1a (Avonex) in Study 205MS301(NCT01064401).
    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
    15 Feb 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    6 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 413
    Country: Number of subjects enrolled
    Russian Federation: 175
    Country: Number of subjects enrolled
    United States: 114
    Country: Number of subjects enrolled
    Ukraine: 133
    Country: Number of subjects enrolled
    Serbia: 86
    Country: Number of subjects enrolled
    Czech Republic: 132
    Country: Number of subjects enrolled
    Italy: 57
    Country: Number of subjects enrolled
    United Kingdom: 61
    Country: Number of subjects enrolled
    France: 35
    Country: Number of subjects enrolled
    Germany: 30
    Country: Number of subjects enrolled
    Hungary: 67
    Country: Number of subjects enrolled
    Romania: 26
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    Brazil: 19
    Country: Number of subjects enrolled
    India: 21
    Country: Number of subjects enrolled
    Argentina: 16
    Country: Number of subjects enrolled
    Greece: 13
    Country: Number of subjects enrolled
    Sweden: 16
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    Moldova, Republic of: 12
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Ireland: 7
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Mexico: 8
    Country: Number of subjects enrolled
    Georgia: 3
    Country: Number of subjects enrolled
    Switzerland: 3
    Worldwide total number of subjects
    1501
    EEA total number of subjects
    889
    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)
    1501
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were enrolled in the study at 226 investigative sites in 28 countries (United States, Canada, Western European countries, Australia, Israel, Eastern European countries, Argentina, Brazil, India, and Mexico) from 15 February 2013 to 24 September 2018.

    Pre-assignment
    Screening details
    Subjects who completed studies: 205MS301 (NCT01064401), 205MS203 (NCT01051349), 205MS302 (NCT01462318) were eligible to enroll in this long-term extension study.

    Pre-assignment period milestones
    Number of subjects started
    1501
    Number of subjects completed
    1500

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Adverse event, non-fatal: 1
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)
    Arm description
    Daclizumab High Yield Process (DAC HYP) 150 mg SC injection every 4 weeks for up to 4.6 years in this long-term extension study 303; includes subjects who previously received interferon beta-1a (IFN β-1a) 30 µg intramuscular (IM) injection once weekly in study 301 every 4 weeks for up to 144 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    DAC HYP 150 mg SC injection every 4 weeks
    Investigational medicinal product code
    Daclizumab High Yield Process
    Other name
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Daclizumab High Yield Process 150 mg subcutaneous (SC) injection every 4 weeks.

    Arm title
    DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Arm description
    DAC HYP 150 mg subcutaneous (SC) injection every 4 weeks for up to 4.6 years in this long-term extension study 205MS303 (303); includes subjects who previously received DAC HYP 150 mg SC injection in Study 205MS301 (301) every 4 weeks for up to 144 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    DAC HYP 150 mg SC injection every 4 weeks
    Investigational medicinal product code
    Daclizumab High Yield Process
    Other name
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Daclizumab High Yield Process 150 mg subcutaneous (SC) injection every 4 weeks.

    Arm title
    DAC HYP 150 mg (302) /DAC HYP 150 mg (303)
    Arm description
    DAC HYP 150 mg SC injection every 4 weeks for up to 93.7 weeks in this long-term extension study 303 (subjects started at Week 144 of the study); includes subjects who previously received DAC HYP 150 mg SC injection in study 205MS302 (302) every 4 weeks for up to 24 weeks followed by a 20-week washout period then continued treatment for up to an additional 3 years.
    Arm type
    Experimental

    Investigational medicinal product name
    DAC HYP 150 mg SC injection every 4 weeks
    Investigational medicinal product code
    Daclizumab High Yield Process
    Other name
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Daclizumab High Yield Process 150 mg subcutaneous (SC) injection every 4 weeks.

    Arm title
    DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Arm description
    DAC HYP 150 mg SC injection every 4 weeks for up to 94. 1 weeks in this long-term extension study 303 (subjects started at Week 144 of the study); includes subjects who previously received DAC HYP 150 mg SC injection in study 205MS203 (203) every 4 weeks for up to 288 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    DAC HYP 150 mg SC injection every 4 weeks
    Investigational medicinal product code
    Daclizumab High Yield Process
    Other name
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Daclizumab High Yield Process 150 mg subcutaneous (SC) injection every 4 weeks.

    Number of subjects in period 1 [1]
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Started
    597
    606
    70
    227
    Completed
    48
    38
    62
    154
    Not completed
    549
    568
    8
    73
         Investigator decision
    21
    15
    -
    -
         Death
    2
    4
    -
    -
         Consent withdrawn
    130
    117
    3
    35
         Reason Not Specified
    280
    295
    -
    15
         Disease progression, defined by protocol
    3
    1
    -
    -
         Adverse event, non-fatal
    104
    128
    4
    21
         Lost to follow-up
    9
    8
    1
    2
    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: One subject who had an adverse event and did not receive study drug is not included.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)
    Reporting group description
    Daclizumab High Yield Process (DAC HYP) 150 mg SC injection every 4 weeks for up to 4.6 years in this long-term extension study 303; includes subjects who previously received interferon beta-1a (IFN β-1a) 30 µg intramuscular (IM) injection once weekly in study 301 every 4 weeks for up to 144 weeks.

    Reporting group title
    DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Reporting group description
    DAC HYP 150 mg subcutaneous (SC) injection every 4 weeks for up to 4.6 years in this long-term extension study 205MS303 (303); includes subjects who previously received DAC HYP 150 mg SC injection in Study 205MS301 (301) every 4 weeks for up to 144 weeks.

    Reporting group title
    DAC HYP 150 mg (302) /DAC HYP 150 mg (303)
    Reporting group description
    DAC HYP 150 mg SC injection every 4 weeks for up to 93.7 weeks in this long-term extension study 303 (subjects started at Week 144 of the study); includes subjects who previously received DAC HYP 150 mg SC injection in study 205MS302 (302) every 4 weeks for up to 24 weeks followed by a 20-week washout period then continued treatment for up to an additional 3 years.

    Reporting group title
    DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Reporting group description
    DAC HYP 150 mg SC injection every 4 weeks for up to 94. 1 weeks in this long-term extension study 303 (subjects started at Week 144 of the study); includes subjects who previously received DAC HYP 150 mg SC injection in study 205MS203 (203) every 4 weeks for up to 288 weeks.

    Reporting group values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303) Total
    Number of subjects
    597 606 70 227 1500
    Age, Customized
    Units: Subjects
        Adults (18-64 years)
    597 606 70 227 1500
    Sex: Female, Male
    Units: Subjects
        Female
    394 400 42 130 966
        Male
    203 206 28 97 534
    Race/Ethnicity, Customized
    Units: Subjects
        White|
    546 559 2 223 1330
        Black or African American|
    5 5 3 0 13
        Asian|
    11 10 0 4 25
        Other|
    18 14 1 0 33
        Not Reported|
    17 18 64 0 99
    Age
    Units: Subjects
        adullt
    597 606 70 227 1500
    Subject analysis sets

    Subject analysis set title
    DAC HYP 150 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received DAC HYP 150 mg SC injection in study 205MS303.

    Subject analysis sets values
    DAC HYP 150 mg
    Number of subjects
    1500
    Age, Customized
    Units: Subjects
        Adults (18-64 years)
    1500
    Age continuous
    Units:
        
    ±
    Sex: Female, Male
    Units: Subjects
        Female
        Male
    Race/Ethnicity, Customized
    Units: Subjects
        White|
        Black or African American|
        Asian|
        Other|
        Not Reported|
    Age
    Units: Subjects
        adullt

    End points

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    End points reporting groups
    Reporting group title
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)
    Reporting group description
    Daclizumab High Yield Process (DAC HYP) 150 mg SC injection every 4 weeks for up to 4.6 years in this long-term extension study 303; includes subjects who previously received interferon beta-1a (IFN β-1a) 30 µg intramuscular (IM) injection once weekly in study 301 every 4 weeks for up to 144 weeks.

    Reporting group title
    DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Reporting group description
    DAC HYP 150 mg subcutaneous (SC) injection every 4 weeks for up to 4.6 years in this long-term extension study 205MS303 (303); includes subjects who previously received DAC HYP 150 mg SC injection in Study 205MS301 (301) every 4 weeks for up to 144 weeks.

    Reporting group title
    DAC HYP 150 mg (302) /DAC HYP 150 mg (303)
    Reporting group description
    DAC HYP 150 mg SC injection every 4 weeks for up to 93.7 weeks in this long-term extension study 303 (subjects started at Week 144 of the study); includes subjects who previously received DAC HYP 150 mg SC injection in study 205MS302 (302) every 4 weeks for up to 24 weeks followed by a 20-week washout period then continued treatment for up to an additional 3 years.

    Reporting group title
    DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Reporting group description
    DAC HYP 150 mg SC injection every 4 weeks for up to 94. 1 weeks in this long-term extension study 303 (subjects started at Week 144 of the study); includes subjects who previously received DAC HYP 150 mg SC injection in study 205MS203 (203) every 4 weeks for up to 288 weeks.

    Subject analysis set title
    DAC HYP 150 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received DAC HYP 150 mg SC injection in study 205MS303.

    Primary: Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs) [1]
    End point description
    An AE is defined as any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product; it does not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product. An SAE is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria. Safety Population consisted of all subjects who completed Study 301, 203 or 302 and had at least 1 dose of DAC HYP during Study 303.
    End point type
    Primary
    End point timeframe
    First dose of study drug in Study 303 to within 180 days of last dose (up to approximately 5.5 years)
    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: No statistical analyses are reported for this endpoint.
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    70
    227
    Units: subjects
        Subjects with AEs
    541
    560
    53
    172
        Subjects with SAEs
    157
    190
    15
    38
    No statistical analyses for this end point

    Secondary: Annualized Relapse Rate (ARR) in the 205MS303 Treatment Period

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    End point title
    Annualized Relapse Rate (ARR) in the 205MS303 Treatment Period
    End point description
    Relapses are defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Study Neurologist. The unadjusted ARR was calculated by tabulating the total number of relapses experienced in the group divided by the number of days up to the end of study, and the ratio then multiplied by 365.25. Relapses that occurred after subjects received alternative multiple sclerosis (MS) medications were excluded from the analyses. ARR was adjusted for relapse rate, IFN beta use, Expanded Disability Status Scale (EDSS) (<=2.5 vs >2.5) and age (<=35 vs >35) prior to start of study treatment in 205MS301, calculated using the negative binomial model. Intent-to-treat (ITT) Population consisted of all subjects who completed Study 301, 203 or 302 and received at least 1 dose of DAC HYP during Study 303.
    End point type
    Secondary
    End point timeframe
    Up to 4.6 years in the 303 study
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    70
    227
    Units: relapses per year
        arithmetic mean (confidence interval 95%)
    0.158 (0.134 to 0.188)
    0.163 (0.138 to 0.193)
    0.167 (0.097 to 0.288)
    0.080 (0.047 to 0.136)
    No statistical analyses for this end point

    Secondary: ARR in the 205MS301-303 Combined Study Period and 205MS301 Treatment Period

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    End point title
    ARR in the 205MS301-303 Combined Study Period and 205MS301 Treatment Period [2]
    End point description
    Relapses are defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Study Neurologist. The unadjusted ARR was calculated by tabulating the total number of relapses experienced in the group divided by the number of days up to the end of study, and the ratio then multiplied by 365.25. Relapses that occurred after subjects received alternative MS medications were excluded from the analyses. ARR was adjusted for relapse rate, IFN beta use, EDSS (<=2.5 vs >2.5) and age (<=35 vs >35) prior to start of study treatment in 301, calculated using the negative binomial model. 301-303 ITT Population consisted of all subjects who completed Study 301 and received at least 1 dose of DAC HYP during Study 303.
    End point type
    Secondary
    End point timeframe
    Up to 5.6 years combining 303 with the initial Study 301; Up to 1 year in the 301 study
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the baseline period are applicable to this endpoint.
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    Units: relapses per year
    arithmetic mean (confidence interval 95%)
        301-303 Combined Study Period
    0.247 (0.220 to 0.279)
    0.175 (0.154 to 0.199)
        301 Treatment Period
    0.317 (0.280 to 0.360)
    0.195 (0.169 to 0.225)
    No statistical analyses for this end point

    Secondary: Number of Subjects with Relapse in the 205MS303 Treatment Period

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    End point title
    Number of Subjects with Relapse in the 205MS303 Treatment Period
    End point description
    Relapses are defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Study Neurologist. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and had at least 1 dose of DAC HYP during Study 303.
    End point type
    Secondary
    End point timeframe
    Up to 4.6 years in the 303 study
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    70
    227
    Units: subjects
    184
    172
    16
    35
    No statistical analyses for this end point

    Secondary: Number of Subjects with Relapse in the 205MS301-303 Combined Study Period

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    End point title
    Number of Subjects with Relapse in the 205MS301-303 Combined Study Period [3]
    End point description
    Relapses are defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Study Neurologist. 301-303 ITT Population consisted of all subjects who completed Study 301 and had at least 1 dose of DAC HYP during Study 303.
    End point type
    Secondary
    End point timeframe
    Up to 5.6 years combining 303 with the initial Study 301
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the baseline period are applicable to this endpoint.
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    Units: subjects
    339
    261
    No statistical analyses for this end point

    Secondary: Number of Subjects with Sustained Disability Progression in the 205MS303 Treatment Period

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    End point title
    Number of Subjects with Sustained Disability Progression in the 205MS303 Treatment Period
    End point description
    Sustained disability progression is defined as at least a 1.0-point increase on the Expanded Disability Status Scale (EDSS) from 303 baseline EDSS ≥1.0 that is sustained for 24 weeks, or at least a 1.5-point increase on the EDSS from 303 baseline EDSS of 0, that is sustained for 24 weeks. The EDSS measures the disability status of people with multiple sclerosis on a scale that ranges from 0 to 10. The range of main categories include (0) =normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS. Higher scores indicate more disability. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and had at least 1 dose of DAC HYP during Study 303.
    End point type
    Secondary
    End point timeframe
    Up to 4.6 years in Study 303
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    70
    227
    Units: subjects
    95
    97
    2
    8
    No statistical analyses for this end point

    Secondary: Number of Subjects with Sustained Disability Progression in the 205MS301-303 Combined Study Period

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    End point title
    Number of Subjects with Sustained Disability Progression in the 205MS301-303 Combined Study Period [4]
    End point description
    Sustained disability progression is defined as at least a 1.0-point increase on the Expanded Disability Status Scale (EDSS) from 303 baseline EDSS ≥1.0 that is sustained for 24 weeks, or at least a 1.5-point increase on the EDSS from 303 baseline EDSS of 0, that is sustained for 24 weeks. The EDSS measures the disability status of people with multiple sclerosis on a scale that ranges from 0 to 10. The range of main categories include (0) =normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS. Higher scores indicate more disability. 301-303 ITT Population consisted of all subjects who completed Study 301 and had at least 1 dose of DAC HYP during Study 303.
    End point type
    Secondary
    End point timeframe
    Up to 5.6 years combining 303 with the initial Study 301
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the baseline period are applicable to this endpoint.
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    Units: subjects
    144
    130
    No statistical analyses for this end point

    Secondary: Number of Subjects with New or Newly Enlarging T2 Hyperintense Lesions in the 205MS303 Treatment Period

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    End point title
    Number of Subjects with New or Newly Enlarging T2 Hyperintense Lesions in the 205MS303 Treatment Period [5]
    End point description
    T2 Hyperintense Lesions were assessed by magnetic resonance imaging (MRI) and were analysed by a central MRI reader. The number of subjects with New or Newly Enlarging T2 Hyperintense Lesions relative to the 303 Baseline in the 303 Treatment Period is reported. 301-303 ITT population consisted of all subjects who completed Study 301 and received at least 1 dose of DAC HYP during Study 303. No data was collected for subjects from the 203 and 302 studies. 'n' is the number of subjects with data available at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline 303, Weeks 48, 96, 144, 192, 240 in Study 303
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the baseline period are applicable to this endpoint.
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    Units: subjects
        Week 48 (n= 530, 499)
    270
    144
        Week 96 (n= 376, 345)
    213
    130
        Week 144 (n= 375, 370)
    223
    157
        Week 192 (n= 261, 267)
    173
    126
        Week 240 (n= 37, 45)
    20
    22
    No statistical analyses for this end point

    Secondary: Number of Subjects with New or Newly Enlarging T2 Hyperintense Lesions in the 205MS301 Treatment Period

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    End point title
    Number of Subjects with New or Newly Enlarging T2 Hyperintense Lesions in the 205MS301 Treatment Period [6]
    End point description
    T2 Hyperintense Lesions were assessed by MRI and were analysed by a central MRI reader. The number of subjects with New or Newly Enlarging T2 Hyperintense Lesions relative to the 301 Baseline in the 301 Treatment Period is reported. 301-303 ITT population consisted of all subjects who completed Study 301 and received at least 1 dose of DAC HYP during Study 303. 'n' is the number of subjects with data available at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline 301, Weeks 24, 96, 144 in Study 301
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the baseline period are applicable to this endpoint.
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    Units: subjects
        Week 24 (n= 586, 595)
    347
    314
        Week 96 (n= 587, 590)
    435
    368
        Week 144 (n= 167, 165)
    126
    113
    No statistical analyses for this end point

    Secondary: Number of Subjects with Gadolinium-enhancing (Gd+) Lesions in the 205MS303 Treatment Period

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    End point title
    Number of Subjects with Gadolinium-enhancing (Gd+) Lesions in the 205MS303 Treatment Period
    End point description
    Gd+ lesions were evaluated by MRI and were analysed by a central MRI reader. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAY HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no subjects were analysed.
    End point type
    Secondary
    End point timeframe
    301-303: Baseline 303, Weeks 48, 96, 144, 192, 240; 203-303 and 302-303: Week 96
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    70
    227
    Units: subjects
        Baseline 303 (n= 591, 590, 0, 0)
    180
    77
    999999
    999999
        Week 48 (n= 533, 510, 0, 0)
    89
    46
    999999
    999999
        Week 96 (n= 375, 353, 147, 52)
    43
    23
    2
    8
        Week 144 (n= 375, 374, 0, 0)
    43
    42
    999999
    999999
        Week 192 (n= 261, 272, 0, 0)
    25
    29
    999999
    999999
        Week 240 (n= 37, 44, 0, 0)
    1
    7
    999999
    999999
    No statistical analyses for this end point

    Secondary: Number of Subjects with Gadolinium-enhancing (Gd+) Lesions in the 205MS301 Treatment Period

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    End point title
    Number of Subjects with Gadolinium-enhancing (Gd+) Lesions in the 205MS301 Treatment Period [7]
    End point description
    Gd+ lesions were evaluated by MRI and were analysed by a central MRI reader. 301-303 ITT Population consisted of all subjects who completed Study 301 and received at least one dose of DAY HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline 301, Weeks 24, 96 and 144
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the baseline period are applicable to this endpoint.
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    Units: subjects
        Baseline 301 (n= 591, 595)
    263
    265
        Week 24 (n= 593, 604)
    153
    119
        Week 96 (n= 593, 598)
    172
    66
        Week 144 (n= 168, 167)
    49
    20
    No statistical analyses for this end point

    Secondary: Number of Subjects with New T1 Hypointense Lesions in the 205MS303 Treatment Period

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    End point title
    Number of Subjects with New T1 Hypointense Lesions in the 205MS303 Treatment Period [8]
    End point description
    T1 hypointense lesions were evaluated by MRI and were analysed by a central MRI reader. The number of subjects with New T1 Hyperintense Lesions relative to the 303 Baseline in the 303 Treatment Period is reported. 301-303 ITT Population consisted of all subjects who completed Study 303 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline 303, Weeks 48, 96, 144, 192, 240 in Study 303
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the baseline period are applicable to this endpoint.
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    Units: subjects
        Week 48 (n= 531, 510)
    200
    96
        Week 96 (n= 376, 352)
    168
    91
        Week 144 (n= 375, 374)
    184
    116
        Week 192 (n= 261, 272)
    152
    94
        Week 240 (n= 37, 44)
    16
    18
    No statistical analyses for this end point

    Secondary: Number of Subjects with New T1 Hypointense Lesions in the 205MS301 Treatment Period

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    End point title
    Number of Subjects with New T1 Hypointense Lesions in the 205MS301 Treatment Period [9]
    End point description
    T1 hypointense lesions were evaluated by MRI and were analysed by a central MRI reader. The number of subjects with New T1 Hyperintense Lesions relative to the 301 Baseline in the 301 Treatment Period is reported. 301-303 ITT Population consisted of all subjects who completed Study 301 and received at least 1 dose of DAC HYP during Study 303. 'n' is the number of subjects with data available at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline 301, Weeks 24, 96, 144 in Study 301
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the baseline period are applicable to this endpoint.
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    Units: subjects
        Week 24 (n= 585, 594)
    276
    244
        Week 96 (n= 584, 588)
    375
    300
        Week 144 (n= 166, 164)
    111
    87
    No statistical analyses for this end point

    Secondary: Percent Change in Brain Volume from the 205MS303 Baseline

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    End point title
    Percent Change in Brain Volume from the 205MS303 Baseline [10]
    End point description
    To assess brain atrophy, total brain volume was measured by MRI and was analysed by a central MRI reader. A negative percent change from baseline indicates improvement. 301-303 ITT Population consisted of all subjects who completed Study 303 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. No data was collected for subjects from the 203 and 302 studies.
    End point type
    Secondary
    End point timeframe
    Baseline 303, Weeks 48, 96, 144, 192, 240 in Study 303
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the baseline period are applicable to this endpoint.
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    Units: percent change
    arithmetic mean (standard deviation)
        Week 48 (n= 400, 360)
    -0.451 ± 0.5917
    -0.355 ± 0.5100
        Week 96 (n= 293, 280)
    -0.713 ± 0.7288
    -0.549 ± 0.6126
        Week 144 (n= 290, 287)
    -1.050 ± 0.8566
    -0.801 ± 0.7145
        Week 192 (n= 216, 222)
    -1.225 ± 1.0139
    -0.967 ± 0.8772
        Week 240 (n= 30, 41)
    -1.261 ± 1.0382
    -0.852 ± 0.9890
    No statistical analyses for this end point

    Secondary: Percent Change in Brain Volume from 205MS301 Baseline

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    End point title
    Percent Change in Brain Volume from 205MS301 Baseline [11]
    End point description
    To assess brain atrophy, total brain volume was measured by MRI and was analysed by a central MRI reader. A negative percent change from baseline indicates improvement. 301-303 ITT Population consisted of all subjects who completed Study 303 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline 301, Weeks 48, 96, 144, 192, 240 in Study 303
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the baseline period are applicable to this endpoint.
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    Units: percent change
    arithmetic mean (standard deviation)
        Week 48 (n= 462, 427)
    -1.535 ± 1.1975
    -1.409 ± 1.1538
        Week 96 (n= 338, 315)
    -1.871 ± 1.3720
    -1.595 ± 1.0736
        Week 144 (n= 333, 333)
    -2.165 ± 1.4596
    -1.812 ± 1.2044
        Week 192 (n= 258, 261)
    -2.403 ± 1.6088
    -1.970 ± 1.3439
        Week 240 (n= 36, 44)
    -2.415 ± 1.6005
    -1.922 ± 1.2258
    No statistical analyses for this end point

    Secondary: Total Volume of T2 Hyperintense Lesions in the 205MS303 Treatment Period

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    End point title
    Total Volume of T2 Hyperintense Lesions in the 205MS303 Treatment Period
    End point description
    Volume of T2 hyperintense Lesions was evaluated by MRI and was analysed by a central MRI reader. ITT Population included all subjects who completed Study 301, 203 or 302 and received at least 1 dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no subjects were analysed.
    End point type
    Secondary
    End point timeframe
    Baseline 303, Weeks 48, 96, 144, 192, 240 in Study 303; 203-303 and 302-303: Week 96
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    70
    227
    Units: millimeters cubed (mm^3)
    arithmetic mean (standard deviation)
        Baseline 303 (n= 593, 592, 0, 0)
    10357.54 ± 11977.864
    9323.33 ± 10777.863
    999999 ± 999999
    999999 ± 999999
        Week 48 (n= 530, 499, 0, 0)
    10738.32 ± 12358.857
    9524.23 ± 10822.502
    999999 ± 999999
    999999 ± 999999
        Week 96 (n= 376, 345, 147, 53)
    11498.94 ± 12769.813
    10018.09 ± 11432.768
    12627.51 ± 14777.178
    16116.01 ± 16791.388
        Week 144 (n= 375, 370, 0, 0)
    11242.79 ± 12838.060
    10265.04 ± 11324.227
    999999 ± 999999
    999999 ± 9999999
        Week 192 (n= 261, 267, 0, 0)
    12453.96 ± 13643.373
    10662.66 ± 11815.075
    999999 ± 999999
    999999 ± 999999
        Week 240 (n= 37, 45, 0, 0)
    9368.05 ± 12428.209
    9230.78 ± 11395.493
    99999 ± 999999
    999999 ± 999999
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Multiple Sclerosis Functional Composite (MSFC) Score in the 205MS303 Treatment Period

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    End point title
    Change from Baseline in the Multiple Sclerosis Functional Composite (MSFC) Score in the 205MS303 Treatment Period [12]
    End point description
    MSFC is a three-part, standardised, quantitative, assessment instrument consisting of (Timed 25-Foot Walk, Nine-Hole Peg Test (9HPT) and Paced Auditory Serial Addition Test (PASAT-3”). 2 timed 25-foot walk scores are averaged. 4 trials of the Peg Test (2 for each hand) are converted to the reciprocals and averaged. The number correct of the PASAT-3 is used. The composite Z-score is calculated by: Z(25-foot walk) + Z (HPT) + Z(PASAT)/3. A positive change from baseline indicates improvement. 301-303 ITT Population consisted of all subjects who completed Study 301 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. No data was collected from subjects from the 203 and 302 studies.
    End point type
    Secondary
    End point timeframe
    Baseline 303, Weeks 12, 24 and 48 in Study 303
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the baseline period are applicable to this endpoint.
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    Units: z-score
    median (full range (min-max))
        Baseline 303 (n= 596, 606)
    0.24958 (-5.5818 to 1.2110)
    0.30019 (-6.1660 to 1.5643)
        Change to Week 12 (n= 584, 583)
    0.00010 (-3.3934 to 1.6147)
    -0.01021 (-4.5948 to 0.9577)
        Change to Week 24 (n= 564, 554)
    -0.00599 (-2.7855 to 1.6913)
    -0.00010 (-3.4062 to 1.3673)
        Change to Week 48 (n= 529, 507)
    -0.01026 (-3.7220 to 1.7775)
    -0.01897 (-3.5941 to 1.4111)
    Statistical analysis title
    Analysis 1
    Statistical analysis description
    Change to Week 12
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5937
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 3
    Statistical analysis description
    Change to Week 48
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1884
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 2
    Statistical analysis description
    Change to Week 24
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6233
    Method
    ANCOVA
    Confidence interval

    Secondary: Change from 205MS301 Baseline in the MSFC Score in the 205MS301-303 Combined Study Period

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    End point title
    Change from 205MS301 Baseline in the MSFC Score in the 205MS301-303 Combined Study Period [13]
    End point description
    MSFC is a three-part, standardised, quantitative, assessment instrument consisting of (Timed 25-Foot Walk, Nine-Hole Peg Test (9HPT) and Paced Auditory Serial Addition Test (PASAT-3”). 2 timed 25-foot walk scores are averaged. 4 trials of the Peg Test (2 for each hand) are converted to the reciprocals and averaged. The number correct of the PASAT-3 is used. The composite Z-score is calculated by: Z(25-foot walk) + Z (HPT) + Z(PASAT)/3. A positive change from baseline indicates improvement. 301-303 ITT Population consisted of all subjects who completed Study 301 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline 301, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156 in the 301 study, Baseline 303, Weeks 12, 24, 48 in the 303 study
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the baseline period are applicable to this endpoint.
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    Units: z-score
    median (full range (min-max))
        Baseline (BL) 301 (n= 596, 605)
    0.14629 (-6.4963 to 1.3731)
    0.14298 (-2.9163 to 1.3865)
        Change from BL 301 to Week 12 for 301 (n=592, 603)
    -0.00133 (-1.8674 to 6.4516)
    0.02593 (-1.7953 to 2.3905)
        Change from BL 301 to Week 24 for 301 (n=594, 599)
    0.02377 (-1.9966 to 6.2712)
    0.04728 (-4.3661 to 2.1389)
        Change from BL 301 to Week 36 for 301 (n=593, 597)
    0.04764 (-3.0131 to 6.2565)
    0.05771 (-11.0047 to 2.1389)
        Change from BL 301 to Week 48 for 301 (n=592, 601)
    0.06491 (-1.6103 to 6.5816)
    0.07793 (-1.3713 to 2.1024)
        Change from BL 301 to Week 60 for 301 (n=589, 598)
    0.06893 (-4.4756 to 6.6543)
    0.08973 (-1.3564 to 1.9165)
        Change from BL 301 to Week 72 for 301 (n=592, 600)
    0.08645 (-3.7849 to 6.7127)
    0.08690 (-5.6579 to 2.0135)
        Change from BL 301 to Week 84 for 301 (n=591, 597)
    0.05704 (-4.3418 to 6.6940)
    0.10283 (-5.4012 to 2.0493)
        Change from BL 301 to Week 96 for 301 (n=593, 600)
    0.06731 (-4.1506 to 6.8296)
    0.11283 (-5.8373 to 2.2536)
        Change from BL 301 to Week 108 for 301(n=489, 500)
    0.08020 (-4.8814 to 6.8182)
    0.09868 (-5.0171 to 2.4199)
        Change from BL 301 to Week 120 for 301(n=397, 395)
    0.08406 (-4.4964 to 6.8441)
    0.10367 (-3.4544 to 1.2502)
        Change from BL 301 to Week 132 for 301(n=273, 289)
    0.07712 (-4.6292 to 3.6137)
    0.08682 (-3.9359 to 3.2500)
        Change from BL 301 to Week 144 for 301(n=210, 203)
    0.09674 (-2.1875 to 4.0089)
    0.12943 (-0.8767 to 1.2626)
        Change from BL 301 to Week 156 for 301 (n= 0, 1)
    999999 (999999 to 999999)
    -0.0272 (-0.0272 to -0.0272)
        Change from BL 301 to BL 303 (n= 595, 603)
    0.06638 (-1.9364 to 6.8441)
    0.11003 (-5.0171 to 3.3811)
        Change from BL 301 to Week 12 for 303 (n=582, 579)
    0.06449 (-2.8537 to 6.9351)
    0.09616 (-5.3094 to 3.3600)
        Change from BL 301 to Week 24 for 303 (n=562, 550)
    0.07140 (-2.7241 to 6.7870)
    0.12955 (-5.0936 to 3.2141)
        Change from BL 301 to Week 48 for 303 (n=527, 503)
    0.05533 (-2.8215 to 7.0425)
    0.09332 (-5.3475 to 3.3180)
    Statistical analysis title
    Analysis 1
    Statistical analysis description
    Change from Baseline 301 to Week 12 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0204
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 2
    Statistical analysis description
    Change from Baseline 301 to Week 24 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0805
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 3
    Statistical analysis description
    Change from Baseline 301 to Week 36 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2535
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 4
    Statistical analysis description
    Change from Baseline 301 to Week 48 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4738
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 5
    Statistical analysis description
    Change from Baseline 301 to Week 60 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2302
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 6
    Statistical analysis description
    Change from Baseline 301 to Week 72 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8522
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 7
    Statistical analysis description
    Change from Baseline 301 to Week 84 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0431
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 8
    Statistical analysis description
    Change from Baseline 301 to Week 96 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0339
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 9
    Statistical analysis description
    Change from Baseline 301 to Week 108 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3195
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 10
    Statistical analysis description
    Change from Baseline 301 to Week 120 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2119
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 11
    Statistical analysis description
    Change from Baseline 301 to Week 132 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3619
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 12
    Statistical analysis description
    Change from Baseline 301 to Week 144 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.017
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 13
    Statistical analysis description
    Change from Baseline 301 to Baseline 303
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.017
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 14
    Statistical analysis description
    Change from Baseline 301 to Week 12 for 303
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0849
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 15
    Statistical analysis description
    Change from Baseline 301 to Week 24 for 303
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0057
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 16
    Statistical analysis description
    Change from Baseline 301 to Week 48 for 303
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.396
    Method
    ANCOVA
    Confidence interval

    Secondary: Change from Baseline in the Expanded Disability Status Scale (EDSS) Score in the 205MS303 Treatment Period

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    End point title
    Change from Baseline in the Expanded Disability Status Scale (EDSS) Score in the 205MS303 Treatment Period
    End point description
    The EDSS measures the disability status of people with multiple sclerosis as assessed by the Study Neurologist based on 8 functional systems that ranges from 0=normal neurologic exam; to 5=ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to 10=death due to MS. Higher scores indicate more disability. A negative change from Baseline indicates improvement. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no subjects were analysed.
    End point type
    Secondary
    End point timeframe
    301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 260; 203-303 and 302-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 116 in Study 303
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    70
    227
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline 303 (n= 595, 605, 226, 70)
    2.50 ± 1.468
    2.44 ± 1.409
    2.56 ± 1.395
    2.86 ± 1.500
        Change at Week 12 (n= 586, 592, 7, 2)
    0.04 ± 0.464
    0.02 ± 0.467
    0.00 ± 0.000
    0.14 ± 0.244
        Change at Week 24 (n= 585, 581, 223, 70)
    0.06 ± 0.570
    0.03 ± 0.480
    -0.06 ± 0.325
    0.02 ± 0.237
        Change at Week 48 (n= 551, 541, 215, 69)
    0.09 ± 0.614
    0.06 ± 0.495
    -0.05 ± 0.455
    0.00 ± 0.349
        Change at Week 72 (n= 520, 495, 204, 64)
    0.11 ± 0.670
    0.10 ± 0.548
    0.00 ± 0.542
    0.04 ± 0.378
        Change at Week 96 (n= 492, 469, 193, 55)
    0.13 ± 0.729
    0.13 ± 0.602
    0.01 ± 0.486
    0.04 ± 0.400
        Change at Week 116 (n= 0, 0, 150, 54)
    999999 ± 999999
    999999 ± 999999
    0.11 ± 0.572
    0.05 ± 0.353
        Change at Week 120 (n= 453, 441, 0, 0)
    0.17 ± 0.768
    0.11 ± 0.578
    999999 ± 99999
    999999 ± 999999
        Change at Week 144 (n= 426, 417, 0, 0)
    0.16 ± 0.742
    0.17 ± 0.701
    999999 ± 999999
    999999 ± 999999
        Change at Week 168 (n= 393, 381, 0, 0)
    0.22 ± 0.798
    0.19 ± 0.765
    999999 ± 999999
    999999 ± 999999
        Change at Week 192 (n= 344, 348, 0, 0)
    0.22 ± 0.756
    0.22 ± 0.777
    999999 ± 999999
    999999 ± 999999
        Change at Week 216 (n= 307, 315, 0, 0)
    0.22 ± 0.775
    0.22 ± 0.762
    999999 ± 999999
    999999 ± 999999
        Change at Week 240 (n= 224, 223, 0, 0)
    0.19 ± 0.789
    0.26 ± 0.829
    999999 ± 999999
    999999 ± 999999
        Change at Week 260 (n= 18, 12, 0, 0)
    0.53 ± 1.007
    -0.17 ± 0.718
    999999 ± 999999
    999999 ± 999999
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Are Free from Disease Activity in the 205MS303 Treatment Period

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    End point title
    Number of Subjects Who Are Free from Disease Activity in the 205MS303 Treatment Period [14]
    End point description
    Subjects without clinical or radiological activity are defined as disease-free. Clinical activity includes assessment of relapses and of disease progression. Radiological activity includes assessments of Gd+ lesions and new or enlarging T2 lesions. 301-303 ITT Population consisted of all subjects who completed Study 301 and received at least 1 dose of DAC HYP during Study 303. No data was collected for subjects from the 203 and 302 studies.
    End point type
    Secondary
    End point timeframe
    Up to 4.6 years in Study 303
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the baseline period are applicable to this endpoint.
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    Units: subjects
    9
    7
    Statistical analysis title
    Analysis 1
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.8417
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.902
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.329
         upper limit
    2.473

    Secondary: Change from Baseline in the Multiple Sclerosis Impact Scale 29 (MSIS 29) Physical and Psychological Scores in the 205MS303 Treatment Period

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    End point title
    Change from Baseline in the Multiple Sclerosis Impact Scale 29 (MSIS 29) Physical and Psychological Scores in the 205MS303 Treatment Period [15]
    End point description
    The 29-item MSIS-29 is a disease specific subject-reported outcome measure that has been developed and validated to examine the physical (coordination and mobility) and psychological (mental) impact of MS from a subject's perspective; it measures 20 physical items and 9 psychological items. The results for each of the physical and psychological scores are transformed to a score of 0 to 100 (worse state of health). A negative change from Baseline indicates improvement. 301-303 ITT Population consisted of all subjects who completed Study 301 and received at least 1 dose of DAC HYP during Study 303. 'n' is the number of subjects with data available at the given timepoint. No data was collected for subjects from the 203 and 302 studies.
    End point type
    Secondary
    End point timeframe
    Baseline 303, Weeks 12, 24, 48, 96, 120 and 144
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the baseline period are applicable to this endpoint.
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    Units: score on a scale
    arithmetic mean (standard deviation)
        Physical Scores: Baseline 303
    20.61 ± 20.134
    19.19 ± 19.390
        Physical Scores: Change to Week 12 (n= 596, 600)
    0.22 ± 11.114
    -0.28 ± 9.217
        Physical Scores: Change to Week 24 (n= 581, 574)
    -0.46 ± 10.313
    -0.88 ± 9.147
        Physical Scores: Change to Week 48 (n=554, 531)
    0.12 ± 11.178
    0.13 ± 9.779
        Physical Scores: Change to Week 96 (n= 173, 165)
    2.23 ± 12.713
    0.48 ± 10.617
        Physical Scores: Change to Week 120 (n= 27, 26)
    0.51 ± 9.062
    1.44 ± 10.504
        Physical Scores: Change to Week 144 (n= 1, 1)
    -1.25 ± 0
    -5.00 ± 0
        Psychological (Psy) Scores: Baseline 303
    23.46 ± 21.310
    22.37 ± 20.816
        Psy Scores: Change to Week 12 (n= 596, 600)
    -1.06 ± 12.501
    -0.34 ± 11.226
        Psy Scores: Change to Week 24 (n= 581, 574)
    -1.14 ± 14.154
    -1.69 ± 11.576
        Psy Scores: Change to Week 48 (n= 554, 531)
    -0.46 ± 14.865
    0.10 ± 13.648
        Psy Scores: Change to Week 96 (n= 173, 165)
    -0.16 ± 13.923
    -0.89 ± 14.411
        Psy Scores: Change to Week 120 (n= 27, 26)
    -2.26 ± 10.105
    0.00 ± 8.642
        Psy Scores: Change to Week 144 (n= 1, 1)
    8.33 ± 0
    -13.89 ± 0
    No statistical analyses for this end point

    Secondary: Change from Baseline in Quality of Life as Assessed by the European Quality of Life, 5 Dimensions (EQ 5D) Health Scores in the 205MS303 Treatment Period

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    End point title
    Change from Baseline in Quality of Life as Assessed by the European Quality of Life, 5 Dimensions (EQ 5D) Health Scores in the 205MS303 Treatment Period
    End point description
    The EQ-5D is a self-administered questionnaire consisting of 5 domains pertaining to specific health state profile: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The subjects recorded their level of current health for each domain where: 1=no problems, 2=some problem and 3=severe problems. The health score is derived from the individual scores for each of the 5 domains transformed to a score of 0=worst health state to 1=perfect health state. A positive change from Baseline indicates improvement. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no data was collected.
    End point type
    Secondary
    End point timeframe
    301-303: Baseline 303, Weeks 12, 24, 48, 96, 120, 144, 192, 240; 203-303 and 302-303: Baseline 303, Weeks 48 and 96 in Study 303
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    70
    227
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline 303
    0.77 ± 0.233
    0.79 ± 0.201
    0.77 ± 0.213
    0.71 ± 0.242
        Change to Week 12 (n= 596, 600, 0, 0)
    0.01 ± 0.168
    -0.01 ± 0.137
    999999 ± 999999
    999999 ± 999999
        Change to Week 24 (n= 581, 574, 0, 0)
    0.01 ± 0.171
    0.00 ± 0.144
    999999 ± 999999
    999999 ± 999999
        Change to Week 48 (n= 553, 531, 225, 70)
    -0.01 ± 0.185
    -0.01 ± 0.152
    0.00 ± 0.174
    0.00 ± 0.164
        Change to Week 96 (n= 497, 472, 194, 56)
    0.00 ± 0.168
    -0.02 ± 0.170
    0.00 ± 0.184
    -0.01 ± 0.162
        Change to Week 120 (n= 448, 431, 0, 0)
    0.01 ± 0.166
    -0.01 ± 0.175
    999999 ± 999999
    999999 ± 999999
        Change to Week 144 (n= 416, 409, 0, 0)
    0.01 ± 0.187
    -0.02 ± 0.172
    999999 ± 999999
    999999 ± 999999
        Change to Week 192 (n= 332, 338, 0, 0)
    0.00 ± 0.187
    -0.03 ± 0.174
    999999 ± 999999
    999999 ± 999999
        Change to Week 240 (n= 103, 105, 0, 0)
    -0.01 ± 0.154
    -0.06 ± 0.187
    999999 ± 999999
    999999 ± 999999
    No statistical analyses for this end point

    Secondary: Change from Baseline in Quality of Life as Assessed by the European Quality of Life, Visual Analog Scale (EQ VAS) in the 205MS303 Treatment Period

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    End point title
    Change from Baseline in Quality of Life as Assessed by the European Quality of Life, Visual Analog Scale (EQ VAS) in the 205MS303 Treatment Period
    End point description
    The subject rated their current health state using the EQ VAS 20-centimeter horizontal line from 0 (worst imaginable health state) to 100 (best imaginable health state). A positive change from baseline indicates improvement. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no data was collected.
    End point type
    Secondary
    End point timeframe
    301-303: Baseline 303, Weeks 12, 24, 48, 96, 120, 44, 192, 240; 203-303 and 302-303: Baseline 303, Weeks 48 and 96 in Study 303
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    70
    227
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline 303
    76.19 ± 19.534
    77.74 ± 19.144
    76.97 ± 19.225
    72.13 ± 21.154
        Change at Week 12 (n= 595, 598, 0, 0)
    1.42 ± 12.753
    0.25 ± 12.358
    999999 ± 999999
    999999 ± 999999
        Change at Week 24 (n= 581, 574, 0, 0)
    1.20 ± 12.135
    0.74 ± 11.400
    999999 ± 999999
    999999 ± 999999
        Change at Week 48 (n= 554, 531, 222, 70)
    0.66 ± 12.966
    -0.35 ± 13.543
    -0.64 ± 13.440
    -1.50 ± 13.604
        Change at Week 96 (n= 497, 472, 190, 56)
    -0.54 ± 14.963
    0.56 ± 12.054
    -0.95 ± 11.222
    0.45 ± 11.724
        Change at Week 120 (n= 448, 430, 0, 0)
    0.80 ± 13.406
    1.52 ± 13.492
    999999 ± 999999
    999999 ± 999999
        Change at Week 144 (n= 416, 409, 0, 0)
    0.36 ± 14.263
    1.64 ± 13.648
    999999 ± 999999
    999999 ± 999999
        Change at Week 192 (n= 332, 338, 0, 0)
    0.45 ± 15.058
    0.66 ± 14.921
    999999 ± 999999
    999999 ± 999999
        Change at Week 240 (n= 103, 105, 0, 0)
    -0.64 ± 11.318
    -1.53 ± 13.082
    999999 ± 999999
    999999 ± 999999
    No statistical analyses for this end point

    Secondary: Direct Health Resource Utilisation (HRU): Number of Unscheduled Site Visits in the 205MS303 Treatment Period

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    End point title
    Direct Health Resource Utilisation (HRU): Number of Unscheduled Site Visits in the 205MS303 Treatment Period
    End point description
    Heath resource utilisation was assessed by the number of hospitalisations, emergency room visits, and unscheduled neurologist visits for MS-related and non-MS-related visits. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no data was collected.
    End point type
    Secondary
    End point timeframe
    301-303: Baseline 303, Weeks 24, 48, 96, 144, 192, 240; 203-303 and 302-303: Baseline 303, Weeks 48, 96 in 303
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    70
    227
    Units: site visits
        MS-related: Baseline 303 (n= 557, 549, 201, 67)
    141
    102
    11
    27
        MS-related: Week 24 (n= 491, 492, 0, 0)
    80
    48
    999999
    999999
        MS-related: Week 48 (n= 491, 464, 191, 54)
    100
    70
    6
    15
        MS-related: Week 96 (n= 441, 420, 174, 55)
    46
    71
    3
    20
        MS-related: Week 144 (n= 396, 378, 0, 0)
    37
    36
    999999
    999999
        MS-related: Week 192 (n= 321, 319, 0, 0)
    26
    26
    999999
    999999
        MS-related: Week 240 (n= 119, 128, 0, 0)
    6
    16
    999999
    999999
        Non-MS related: Baseline 303 (n=557, 549, 201, 67)
    90
    97
    2
    15
        Non-MS related: Week 24 (n= 491, 492, 0, 0)
    81
    56
    999999
    999999
        Non-MS related: Week 48 (n= 491, 464, 191, 54)
    111
    41
    5
    16
        Non-MS related: Week 96 (n= 441, 420, 174, 55)
    90
    93
    10
    23
        Non-MS related: Week 144 (n= 396, 378, 0, 0)
    52
    42
    999999
    999999
        Non-MS related: Week 192 (n= 321, 319, 0, 0)
    42
    39
    999999
    999999
        Non-MS related: Week 240 (n= 119, 128, 0, 0)
    10
    12
    999999
    999999
    No statistical analyses for this end point

    Secondary: Direct Health Resource Utilisation (HRU): Number of Unscheduled Site Visits in the 205MS301 Treatment Period

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    End point title
    Direct Health Resource Utilisation (HRU): Number of Unscheduled Site Visits in the 205MS301 Treatment Period [16]
    End point description
    Heath resource utilisation was assessed by the number of hospitalisations, emergency room visits, and unscheduled neurologist visits for MS-related and non-MS-related visits. 301-303 ITT Population consisted of all subjects who completed Study 301 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline 301, Weeks 24, 48, 72, 96, 120 and 144 in 301
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the baseline period are applicable to this endpoint.
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    Units: site visits
        MS-related: Baseline 301 (n= 446, 440)
    277
    349
        MS-related: Week 24 (n= 410, 408)
    76
    78
        MS-related: Week 48 (n= 412, 417)
    77
    49
        MS-related: Week 72 (n= 411, 413)
    60
    49
        MS-related: Week 96 (n= 434, 425)
    88
    53
        MS-related: Week 120 (n= 347, 336)
    55
    18
        MS-related: Week 144 (n= 184, 186)
    13
    24
        Non MS-related: Baseline 301 (n= 446, 440)
    93
    93
        Non MS-related: Week 24 (n= 410, 408)
    50
    45
        Non MS-related: Week 48 (n= 412, 417)
    65
    51
        Non MS-related: Week 72 (n= 411, 413)
    54
    69
        Non MS-relate: Week 96 (n= 434, 425)
    44
    52
        Non MS-related: Week 120 (n= 347, 336)
    43
    41
        Non MS-related: Week 144 (n= 184, 186)
    24
    32
    No statistical analyses for this end point

    Secondary: Treatment Satisfaction as Assessed by the Subject in the 205MS303 Treatment Period

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    End point title
    Treatment Satisfaction as Assessed by the Subject in the 205MS303 Treatment Period [17]
    End point description
    Subjects answered the question: “How satisfied or dissatisfied are you with the ability of the medication to prevent or treat the condition?” using the following scale: Dissatisfied (Extremely dissatisfied, Very dissatisfied, Dissatisfied) or Satisfied (Somewhat satisfied, Satisfied, Very Satisfied and Extremely satisfied). The number of subjects in the Dissatisfied and Satisfied categories is reported. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. No data was collected for subjects from the 203 and 302 studies.
    End point type
    Secondary
    End point timeframe
    Baseline 303, Weeks 12, 24, 48, 72, 96, 120 in Study 303
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the baseline period are applicable to this endpoint.
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    Units: subjects
        Dissatisfied: Baseline 303 (n= 578, 592)
    49
    31
        Dissatisfied: Week 12 (n= 586, 584)
    46
    41
        Dissatisfied: Week 24 (n= 569, 559)
    44
    27
        Dissatisfied: Week 48 (n= 530, 507)
    32
    35
        Dissatisfied: Week 72 (n= 503, 472)
    27
    22
        Dissatisfied: Week 96 (n= 152, 145)
    19
    9
        Dissatisfied: Week 120 (n= 27, 24)
    2
    1
        Satisfied: Baseline 303 (n= 578, 592)
    529
    561
        Satisfied: Week 12 (n= 586, 584)
    540
    543
        Satisfied: Week 24 (n= 569, 559)
    525
    532
        Satisfied: Week 48 (n= 530, 507)
    498
    472
        Satisfied: Week 72 (n= 503, 472)
    476
    450
        Satisfied: Week 96 (n= 152, 145)
    133
    136
        Satisfied: Week 120 (n= 27, 24)
    25
    23
    No statistical analyses for this end point

    Secondary: Health Related Productivity Questionnaire (HRPQ): Scheduled Work Hours in the 205MS303 Treatment Period

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    End point title
    Health Related Productivity Questionnaire (HRPQ): Scheduled Work Hours in the 205MS303 Treatment Period
    End point description
    The HRPQ was used by the subject to assess the impact of MS or its treatments on employment. The subject recorded their scheduled work hours. Data is reported by part time or full time employment. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicated that no data was collected.
    End point type
    Secondary
    End point timeframe
    301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    70
    227
    Units: hours
    arithmetic mean (standard deviation)
        Part Time: Baseline 303 (n= 71, 71, 27, 9)
    20.4 ± 10.60
    19.5 ± 11.45
    20.2 ± 6.06
    23.6 ± 9.46
        Part Time: Week 12 (n= 71, 69, 0, 0)
    21.4 ± 10.30
    22.4 ± 13.62
    999999 ± 999999
    999999 ± 999999
        Part Time: Week 24 (n= 70, 67, 28, 11)
    21.2 ± 12.80
    20.6 ± 13.47
    24.5 ± 5.22
    23.5 ± 9.37
        Part Time: Week 48 (n= 67, 68, 24, 11)
    22.3 ± 11.12
    21.9 ± 11.28
    27.7 ± 13.79
    22.7 ± 11.23
        Part Time: Week 72 (n= 71, 59, 26, 9)
    21.6 ± 12.44
    23.0 ± 11.64
    25.2 ± 6.08
    22.8 ± 11.60
        Part Time: Week 96 (n= 67, 58, 25, 8)
    25.7 ± 17.40
    19.9 ± 11.79
    23.5 ± 7.98
    24.8 ± 10.13
        Part Time: Week 120 (n= 54, 49, 0, 0)
    27.0 ± 16.13
    20.8 ± 13.15
    999999 ± 999999
    999999 ± 999999
        Part Time: Week 144 (n= 43, 48, 0, 0)
    22.9 ± 14.79
    21.4 ± 12.90
    999999 ± 999999
    999999 ± 999999
        Part Time: Week 168 (n= 36, 40, 0, 0)
    21.0 ± 12.06
    20.3 ± 11.93
    999999 ± 999999
    999999 ± 999999
        Part Time: Week 192 (n= 35, 36, 0, 0)
    23.2 ± 12.07
    23.2 ± 16.37
    999999 ± 999999
    999999 ± 999999
        Part Time: Week 216 (n= 26, 35, 0, 0)
    24.9 ± 13.18
    25.3 ± 11.79
    999999 ± 999999
    999999 ± 999999
        Part Time: Week 240 (n= 4, 0, 0, 0)
    21.3 ± 8.54
    999999 ± 999999
    999999 ± 999999
    999999 ± 999999
        Full Time: Baseline 303 (n= 288, 301, 114, 41)
    36.8 ± 14.23
    37.4 ± 12.71
    40.1 ± 10.44
    39.3 ± 12.23
        Full Time: Week 12 (n= 287, 306, 0, 0)
    37.3 ± 14.23
    38.5 ± 18.79
    999999 ± 999999
    999999 ± 999999
        Full Time: Week 24 (n= 278, 287, 115, 39)
    35.0 ± 15.43
    36.4 ± 17.43
    42.0 ± 7.34
    37.2 ± 14.19
        Full Time: Week 48 ( n= 270, 277, 103, 40)
    36.0 ± 13.47
    38.2 ± 20.63
    41.1 ± 8.50
    38.6 ± 10.90
        Full Time: Week 72 (n= 255, 244, 97, 33)
    36.9 ± 12.90
    38.5 ± 12.21
    42.0 ± 5.24
    38.4 ± 9.91
        Full Time: Week 96 (n= 235, 232, 92, 33)
    36.0 ± 13.42
    37.6 ± 12.35
    41.5 ± 5.05
    36.4 ± 14.36
        Full Time: Week 120 (n= 224, 234, 0, 0)
    37.7 ± 11.04
    39.2 ± 22.80
    999999 ± 999999
    999999 ± 999999
        Full Time: Week 144 (n= 219, 210, 0, 0)
    37.3 ± 12.79
    39.7 ± 12.68
    999999 ± 999999
    999999 ± 999999
        Full Time: Week 168 (n= 180, 178, 0, 0)
    37.3 ± 12.35
    39.4 ± 10.36
    999999 ± 999999
    999999 ± 999999
        Full Time: Week 192 (n= 168, 166, 0, 0)
    37.7 ± 10.31
    40.4 ± 9.00
    999999 ± 999999
    999999 ± 999999
        Full Time: Week 216 (n= 155, 152, 0, 0)
    37.7 ± 12.44
    38.8 ± 11.68
    999999 ± 999999
    999999 ± 999999
        Full Time: Week 240 (n= 19, 18, 0, 0)
    39.8 ± 4.16
    39.3 ± 12.33
    999999 ± 999999
    999999 ± 999999
    No statistical analyses for this end point

    Secondary: HRPQ: Number of Subjects where MS or Its Treatments Resulted in Missed Work in the 205MS303 Treatment Period

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    End point title
    HRPQ: Number of Subjects where MS or Its Treatments Resulted in Missed Work in the 205MS303 Treatment Period
    End point description
    The HRPQ was used by the subject to assess the impact of MS or its treatments on employment. The subject recorded whether their MS or its treatments caused them to miss work. Data is reported by part time or full time employment. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no data was collected.
    End point type
    Secondary
    End point timeframe
    301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    70
    227
    Units: subjects
        Part Time: Baseline 303 (n= 71, 73, 27, 9)
    11
    7
    1
    1
        Part Time: Week 12 (n= 73, 69, 0, 0)
    10
    8
    999999
    999999
        Part Time: Week 24 (n= 70, 67, 28, 11)
    12
    7
    2
    3
        Part Time: Week 48 (n= 68, 68, 24, 11)
    9
    7
    1
    2
        Part Time: Week 72 (n= 72, 59, 27, 9)
    7
    4
    2
    2
        Part Time: Week 96 (n= 68, 58, 25, 8)
    6
    5
    2
    2
        Part Time: Week 120 (n= 54, 49, 0, 0)
    11
    6
    999999
    999999
        Part Time: Week 144 (n= 43, 49, 0, 0)
    4
    6
    999999
    999999
        Part Time: Week 168 (n= 36, 40, 0, 0)
    5
    6
    999999
    999999
        Part Time: Week 192 (n= 35, 38, 0, 0)
    5
    3
    999999
    999999
        Part Time: Week 216 (n= 26, 35, 0, 0)
    1
    4
    999999
    999999
        Part Time: Week 240 (n= 4, 0, 0, 0)
    1
    999999
    999999
    999999
        Full Time: Baseline 303 (n= 305, 291, 112, 41)
    28
    30
    3
    11
        Full Time: Week 12 (n= 291, 305, 0, 0)
    19
    26
    999999
    999999
        Full Time: Week 24 (n= 279, 288, 111, 39)
    11
    21
    3
    8
        Full Time: Week 48 (n= 271, 277, 104, 40)
    20
    24
    3
    6
        Full Time: Week 72 (n= 255, 245, 97, 33)
    13
    10
    3
    6
        Full Time: Week 96 (n= 236, 232, 90, 33)
    10
    16
    1
    3
        Full Time: Week 120 (n= 224, 235, 0, 0)
    8
    18
    999999
    999999
        Full Time: Week 144 (n= 219, 210, 0, 0)
    16
    16
    999999
    999999
        Full Time: Week 168 (n= 182, 178, 0, 0)
    10
    17
    999999
    999999
        Full Time: Week 192 (n= 170, 166, 0, 0)
    10
    13
    999999
    999999
        Full Time: Week 216 (n= 155, 152, 0, 0)
    6
    10
    999999
    999999
        Full Time: Week 240 (n= 19, 18, 0, 0)
    0
    2
    999999
    999999
    No statistical analyses for this end point

    Secondary: HRPQ: Hours of Work Missed Due to MS or Its Treatment in the 205MS303 Treatment Period

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    End point title
    HRPQ: Hours of Work Missed Due to MS or Its Treatment in the 205MS303 Treatment Period
    End point description
    The HRPQ was used by the subject to assess the impact of MS or its treatments on employment. The subject recorded the hours they missed work due to MS or its treatments. Data is reported by part time or full time employment. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects who missed work with data available at the given timepoint. '999999' indicates that no data was collected.
    End point type
    Secondary
    End point timeframe
    301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    70
    227
    Units: hours
    arithmetic mean (standard deviation)
        Part Time: Baseline 303 (n= 11, 7, 1, 1)
    8.5 ± 5.82
    5.6 ± 4.93
    20.0 ± 0
    12.0 ± 0
        Part Time: Week 12 (n= 12, 8, 0, 0)
    8.7 ± 8.43
    8.4 ± 8.11
    999999 ± 999999
    999999 ± 999999
        Part Time: Week 24 (n= 13, 7, 3, 2)
    15.2 ± 19.31
    10.1 ± 3.63
    3.0 ± 1.41
    8.3 ± 6.51
        Part Time: Week 48 (n= 9, 7, 2, 1)
    8.6 ± 4.85
    12.3 ± 12.83
    15.0 ± 0
    4.5 ± 3.54
        Part Time: Week 72 (n= 6, 4, 2, 2)
    7.5 ± 7.01
    10.1 ± 13.05
    7.0 ± 4.24
    16.0 ± 19.80
        Part Time: Week 96 (n= 6, 5, 2, 2)
    22.2 ± 38.48
    8.7 ± 12.02
    22.5 ± 3.54
    5.0 ± 0.00
        Part Time: Week 120 (n= 11, 6, 0, 0)
    9.5 ± 5.92
    7.3 ± 8.21
    999999 ± 999999
    999999 ± 999999
        Part Time: Week 144 (n= 4, 7, 0, 0)
    3.3 ± 2.22
    10.3 ± 7.18
    999999 ± 999999
    999999 ± 999999
        Part Time: Week 168 (n= 5, 6, 0, 0)
    7.3 ± 7.90
    5.3 ± 5.16
    999999 ± 999999
    999999 ± 999999
        Part Time: Week 192 (n= 5, 2, 0, 0)
    3.6 ± 1.14
    9.0 ± 4.24
    999999 ± 999999
    999999 ± 999999
        Part Time: Week 216 (n= 1, 5, 0, 0)
    3.0 ± 0
    16.4 ± 15.71
    999999 ± 999999
    999999 ± 999999
        Part Time: Week 240 (n= 1, 0, 0, 0)
    5.0 ± 0
    999999 ± 999999
    999999 ± 999999
    999999 ± 999999
        Full Time: Baseline 303 (n= 26, 30, 11, 3)
    11.0 ± 11.42
    15.0 ± 13.58
    8.0 ± 0.00
    8.8 ± 11.39
        Full Time: Week 12 (n= 19, 27, 0, 0)
    8.5 ± 10.13
    7.9 ± 8.06
    999999 ± 999999
    999999 ± 999999
        Full Time: Week 24 (n= 13, 23, 8, 3)
    11.2 ± 13.80
    12.4 ± 13.31
    7.3 ± 1.15
    14.1 ± 16.27
        Full Time: Week 48 (n= 21, 26, 5, 3)
    15.7 ± 15.50
    11.7 ± 11.11
    6.7 ± 3.06
    12.7 ± 15.57
        Full Time: Week 72 (n= 15, 11, 6, 3)
    13.8 ± 11.51
    7.6 ± 6.00
    8.7 ± 3.06
    15.0 ± 17.54
        Full Time: Week 96 (n= 11, 17, 3, 1)
    14.2 ± 13.19
    16.1 ± 15.14
    3.0 ± 0
    6.7 ± 2.89
        Full Time: Week 120 (n= 10, 20, 0, 0)
    12.4 ± 13.88
    10.7 ± 11.19
    999999 ± 999999
    999999 ± 999999
        Full Time: Week 144 (n= 17, 16, 0, 0)
    16.0 ± 14.32
    13.1 ± 15.44
    999999 ± 999999
    999999 ± 999999
        Full Time: Week 168 (n= 10, 17, 0, 0)
    7.3 ± 4.45
    16.9 ± 15.73
    999999 ± 999999
    999999 ± 999999
        Full Time: Week 192 (n= 10, 13, 0, 0)
    15.9 ± 11.94
    10.0 ± 11.53
    999999 ± 999999
    999999 ± 999999
        Full Time: Week 216 (n= 10, 13, 0, 0)
    10.3 ± 13.98
    11.2 ± 14.00
    999999 ± 999999
    999999 ± 999999
        Full Time: Week 240 (n= 0, 2, 0, 0)
    999999 ± 999999
    14.5 ± 4.95
    999999 ± 999999
    999999 ± 999999
    No statistical analyses for this end point

    Secondary: HRPQ: Percent Impact on Employment in the 205MS303 Treatment Period

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    End point title
    HRPQ: Percent Impact on Employment in the 205MS303 Treatment Period
    End point description
    The HRPQ was used by the subject to assess the impact of MS or its treatments on employment. The subjects assessed the percent impact of MS and its treatments on their work output using a VAS where 0= MS or its treatments had no impact on how much I accomplished to 100=MS or its treatments kept me from accomplishing anything. Data is reported by part time or full time employment. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no data was collected.
    End point type
    Secondary
    End point timeframe
    301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    70
    227
    Units: percent impact
    arithmetic mean (standard deviation)
        Part Time: Baseline 303 (n= 69, 68, 27, 9)
    18.4 ± 24.18
    21.1 ± 26.16
    32.2 ± 34.65
    19.0 ± 24.78
        Part Time: Week 12 (n= 69, 66, 0, 0)
    18.8 ± 24.06
    16.0 ± 22.87
    999999 ± 999999
    999999 ± 999999
        Part Time: Week 24 (n= 63, 61, 28, 11)
    17.5 ± 24.30
    16.8 ± 22.84
    14.4 ± 14.42
    26.5 ± 33.85
        Part Time: Week 48 (n= 66, 66, 24, 11)
    16.0 ± 23.54
    14.0 ± 23.03
    19.1 ± 24.17
    18.8 ± 25.03
        Part Time: Week 72 (n= 70, 58, 27, 9)
    20.8 ± 27.63
    18.8 ± 27.93
    11.1 ± 10.83
    23.3 ± 29.50
        Part Time: Week 96 (n= 64, 57, 25, 8)
    18.4 ± 24.01
    16.8 ± 23.90
    22.3 ± 33.41
    19.1 ± 23.80
        Part Time: Week 120 (n= 54, 47, 0, 0)
    19.6 ± 26.58
    22.4 ± 30.15
    999999 ± 999999
    999999 ± 999999
        Part Time: Week 144 (n= 41, 49, 0, 0)
    17.4 ± 23.16
    15.3 ± 24.07
    999999 ± 999999
    999999 ± 999999
        Part Time: Week 168 (n= 35, 39, 0, 0)
    35.7 ± 33.82
    15.3 ± 22.93
    999999 ± 999999
    999999 ± 999999
        Part Time: Week 192 (n= 34, 35, 0, 0)
    30.9 ± 33.29
    21.4 ± 25.03
    999999 ± 999999
    999999 ± 999999
        Part Time: Week 216 (n= 26, 35, 0, 0)
    23.6 ± 27.73
    20.3 ± 28.78
    999999 ± 999999
    999999 ± 999999
        Part Time: Week 240 (n= 4, 0, 0, 0)
    7.5 ± 15.00
    999999 ± 999999
    999999 ± 999999
    999999 ± 999999
        Full Time: Baseline 303 (n= 282, 298, 112, 41)
    10.0 ± 19.52
    11.8 ± 24.02
    6.7 ± 16.33
    13.9 ± 25.56
        Full Time: Week 12 (n= 288, 301, 0, 0)
    8.0 ± 17.72
    10.3 ± 21.17
    999999 ± 999999
    999999 ± 999999
        Full Time: Week 24 (n= 269, 276, 111, 39)
    9.1 ± 20.13
    8.3 ± 18.54
    11.2 ± 25.20
    12.7 ± 25.79
        Full Time: Week 48 (n= 258, 271, 103, 40)
    8.2 ± 19.37
    9.6 ± 21.75
    9.9 ± 24.25
    12.2 ± 23.87
        Full Time: Week 72 (n= 251, 238, 97, 33)
    9.7 ± 21.40
    7.8 ± 18.39
    11.3 ± 22.72
    14.0 ± 23.47
        Full Time: Week 96 (n= 228, 227, 89, 33)
    7.3 ± 18.29
    8.4 ± 18.59
    10.2 ± 24.63
    11.1 ± 23.76
        Full Time: Week 120 (n= 223, 230, 0, 0)
    6.4 ± 13.87
    8.6 ± 19.19
    999999 ± 999999
    999999 ± 999999
        Full Time: Week 144 (n= 216, 205, 0, 0)
    8.2 ± 18.36
    7.8 ± 17.91
    999999 ± 999999
    999999 ± 999999
        Full Time: Week 168 (n= 180, 178, 0, 0)
    8.8 ± 18.53
    10.1 ± 22.45
    999999 ± 999999
    999999 ± 999999
        Full Time: Week 192 (n= 167, 166, 0, 0)
    9.0 ± 19.23
    7.5 ± 17.59
    999999 ± 999999
    999999 ± 999999
        Full Time: Week 216 (n= 152, 148, 0, 0)
    10.0 ± 22.36
    9.3 ± 20.91
    999999 ± 999999
    999999 ± 999999
        Full Time: Week 240 (n= 19, 18, 0, 0)
    13.1 ± 23.33
    7.5 ± 18.01
    999999 ± 999999
    999999 ± 999999
    No statistical analyses for this end point

    Secondary: HRPQ: Hours of Household Chores Planned to Perform in the 205MS303 Treatment Period

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    End point title
    HRPQ: Hours of Household Chores Planned to Perform in the 205MS303 Treatment Period
    End point description
    The HRPQ was used by the subject to assess the impact of MS or its treatments on performing household chores. The subject recorded their planned hours for household chores. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no data was collected.
    End point type
    Secondary
    End point timeframe
    301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    70
    227
    Units: hours
    arithmetic mean (standard deviation)
        Baseline 303 (n= 585, 597, 219, 70)
    10.1 ± 10.87
    10.0 ± 10.85
    11.5 ± 7.94
    15.8 ± 13.68
        Week 12 (n= 589, 596, 0, 0)
    11.8 ± 11.38
    12.2 ± 12.33
    999999 ± 999999
    999999 ± 999999
        Week 24 (n= 568, 561, 227, 70)
    12.0 ± 11.75
    12.6 ± 11.24
    11.1 ± 7.72
    14.4 ± 13.66
        Week 48 (n= 552, 538, 213, 69)
    11.6 ± 11.43
    12.6 ± 11.39
    11.6 ± 8.37
    15.7 ± 14.74
        Week 72 (n= 514, 486, 199, 59)
    13.3 ± 12.10
    13.9 ± 12.87
    12.3 ± 8.94
    15.0 ± 13.55
        Week 96 (n= 486, 461, 191, 57)
    11.9 ± 10.70
    13.5 ± 12.10
    12.6 ± 9.17
    14.8 ± 12.20
        Week 120 (n= 451, 438, 0, 0)
    12.6 ± 12.09
    13.1 ± 12.09
    999999 ± 999999
    999999 ± 999999
        Week 144 (n= 426, 412, 0, 0)
    13.0 ± 12.89
    13.4 ± 11.99
    999999 ± 999999
    999999 ± 999999
        Week 168 (n= 358, 361, 0, 0)
    12.9 ± 12.35
    13.7 ± 12.58
    999999 ± 999999
    999999 ± 999999
        Week 192 (n= 332, 330, 0, 0)
    13.4 ± 11.78
    13.9 ± 12.43
    999999 ± 999999
    999999 ± 999999
        Week 216 (n= 292, 299, 0, 0)
    14.2 ± 13.01
    14.0 ± 11.46
    999999 ± 999999
    999999 ± 999999
        Week 240 (n= 42, 30, 0, 0)
    13.6 ± 11.49
    10.1 ± 7.89
    999999 ± 999999
    999999 ± 999999
    No statistical analyses for this end point

    Secondary: HRPQ: Number of Subjects where MS or Its Treatments Kept the Subject from Completing Chores in the 205MS303 Treatment Period

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    End point title
    HRPQ: Number of Subjects where MS or Its Treatments Kept the Subject from Completing Chores in the 205MS303 Treatment Period
    End point description
    The HRPQ was used by the subject to assess the impact of MS or its treatments on performing household chores. The subject recorded whether MS or its treatments kept them from completing household chores. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no data was collected.
    End point type
    Secondary
    End point timeframe
    301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    70
    227
    Units: subjects
        Baseline 303 (n= 591, 600, 220, 70)
    112
    104
    15
    58
        Week 12 (n= 593, 600, 0, 0)
    110
    111
    999999
    999999
        Week 24 (n= 572, 565, 227, 70)
    125
    110
    12
    68
        Week 48 (n= 553, 541, 213, 69)
    113
    93
    19
    66
        Week 72 (n= 515, 489, 199, 59)
    111
    93
    15
    58
        Week 96 (n= 487, 464, 191, 57)
    94
    79
    16
    53
        Week 120 (n= 452, 439, 0, 0)
    93
    84
    999999
    999999
        Week 144 (n= 427, 413, 0, 0)
    91
    87
    999999
    999999
        Week 168 (n= 359, 362, 0, 0)
    82
    81
    999999
    999999
        Week 192 (n= 333, 331, 0, 0)
    71
    65
    999999
    999999
        Week 216 (n= 293, 299, 0, 0)
    65
    65
    999999
    999999
        Week 240 (n= 42, 30, 0, 0)
    2
    7
    999999
    999999
    No statistical analyses for this end point

    Secondary: HRPQ: Hours not Performing Household Chores due to MS or Its Treatment in 205MS303 Treatment Period

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    End point title
    HRPQ: Hours not Performing Household Chores due to MS or Its Treatment in 205MS303 Treatment Period
    End point description
    The HRPQ was used by the subject to assess the impact of MS or its treatments on performing household chores. The subject recorded the hours where they were not able to perform household chores due to MS or its treatments. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects unable to complete chores with data available at the given timepoint. '999999' indicates that no data was collected.
    End point type
    Secondary
    End point timeframe
    301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    70
    227
    Units: hours
    arithmetic mean (standard deviation)
        Baseline 303 (n= 107, 104, 58, 15)
    6.4 ± 7.82
    5.1 ± 5.08
    5.2 ± 4.06
    5.4 ± 6.25
        Week 12 (n= 111, 113, 0, 0)
    7.0 ± 9.35
    5.9 ± 7.63
    999999 ± 999999
    999999 ± 999999
        Week 24 (n= 124, 109, 67, 12)
    6.3 ± 7.56
    5.2 ± 4.59
    5.0 ± 3.57
    5.7 ± 7.75
        Week 48 (n= 111, 89, 66, 19)
    7.3 ± 11.41
    4.7 ± 3.53
    4.7 ± 4.21
    7.9 ± 9.19
        Week 72 (n= 110, 94, 59, 15)
    7.2 ± 7.16
    6.6 ± 10.32
    5.8 ± 4.46
    6.8 ± 8.03
        Week 96 (n= 95, 77, 53, 17)
    5.2 ± 3.93
    5.1 ± 4.67
    3.8 ± 3.81
    8.1 ± 9.35
        Week 120 (n= 92, 84, 0, 0)
    6.0 ± 8.23
    5.9 ± 11.13
    999999 ± 999999
    999999 ± 999999
        Week 144 (n= 93, 87, 0, 0)
    5.7 ± 4.95
    6.3 ± 6.10
    999999 ± 999999
    999999 ± 999999
        Week 168 (n= 82, 83, 0, 0)
    5.8 ± 5.19
    5.5 ± 5.16
    999999 ± 999999
    999999 ± 999999
        Week 192 (n= 72, 65, 0, 0)
    6.9 ± 9.01
    5.7 ± 5.96
    999999 ± 999999
    999999 ± 999999
        Week 216 (n= 66, 70, 0, 0)
    6.9 ± 7.09
    7.3 ± 10.97
    999999 ± 999999
    999999 ± 999999
        Week 240 (n= 2, 8, 0, 0)
    5.5 ± 6.36
    9.8 ± 13.04
    999999 ± 999999
    999999 ± 999999
    No statistical analyses for this end point

    Secondary: HRPQ: Percent Impact on Performing Household chores in the 205MS303 Treatment Period

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    End point title
    HRPQ: Percent Impact on Performing Household chores in the 205MS303 Treatment Period
    End point description
    The HRPQ was used by the subject to assess the impact of MS or its treatments on performing household chores. The subject assessed the percent impact of MS and its treatments on how much they accomplished using a VAS where 0= MS or its treatments had no impact on how much I accomplished to 100=MS or its treatments kept me from accomplishing anything. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no data was collected.
    End point type
    Secondary
    End point timeframe
    301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    70
    227
    Units: percent impact
    arithmetic mean (standard deviation)
        Baseline 303 (n= 519, 515, 219, 69)
    16.0 ± 23.16
    17.5 ± 25.31
    18.9 ± 24.41
    25.3 ± 29.42
        Week 12 (n= 578, 587, 0, 0)
    16.7 ± 24.40
    17.5 ± 25.38
    999999 ± 999999
    999999 ± 999999
        Week 24 (n= 557, 552, 226, 68)
    17.0 ± 25.23
    16.7 ± 24.71
    24.8 ± 30.25
    25.5 ± 28.81
        Week 48 (n= 541, 531, 210, 69)
    16.9 ± 25.48
    17.1 ± 26.23
    21.0 ± 27.62
    23.8 ± 28.52
        Week 72 (n= 507, 485, 199, 59)
    19.9 ± 26.83
    17.8 ± 26.13
    19.6 ± 23.37
    25.4 ± 27.88
        Week 96 (n= 482, 455, 187, 57)
    16.4 ± 25.39
    17.7 ± 26.18
    21.4 ± 27.23
    23.8 ± 29.07
        Week 120 (n= 449, 435, 0, 0)
    17.4 ± 25.10
    16.9 ± 25.00
    999999 ± 999999
    999999 ± 999999
        Week 144 (n= 421, 411, 0, 0)
    16.5 ± 24.40
    17.4 ± 25.25
    999999 ± 999999
    999999 ± 999999
        Week 168 (n= 356, 358, 0, 0)
    19.1 ± 26.03
    18.2 ± 26.37
    999999 ± 999999
    999999 ± 999999
        Week 192 (n= 330, 330, 0, 0)
    18.5 ± 26.55
    17.3 ± 25.07
    999999 ± 999999
    999999 ± 999999
        Week 216 (n= 291, 298, 0, 0)
    18.8 ± 26.11
    18.3 ± 26.18
    999999 ± 999999
    999999 ± 999999
        Week 240 (n= 42, 30, 0, 0)
    9.6 ± 14.95
    16.0 ± 26.06
    999999 ± 999999
    999999 ± 999999
    No statistical analyses for this end point

    Secondary: Number of Subjects with Clinically Significant Changes from Baseline in Clinical Laboratory Assessments in the 205MS303 Treatment Period

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    End point title
    Number of Subjects with Clinically Significant Changes from Baseline in Clinical Laboratory Assessments in the 205MS303 Treatment Period
    End point description
    Clinical Laboratory assessments included tests of hematology, blood chemistry, renal function, and thyroid function. The investigator determined if the results were clinically significant. Safety Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303.
    End point type
    Secondary
    End point timeframe
    Up to 4.6 years Study 303
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    70
    227
    Units: subjects
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Local Tolerability as assessed by Subject-reported Injection Site Pain VAS

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    End point title
    Local Tolerability as assessed by Subject-reported Injection Site Pain VAS
    End point description
    The VAS is a 10 cm-long horizontal line labeled with 2 extremes of pain at either end: 0 =no pain on the left and 100=very painful on the right. The subject rates their perceived pain of each injection by placing a vertical mark on the line to indicate the level of pain. Safety Population included all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects in this study who received DAC HYP with data available for analysis. Local tolerability of the DAC HYP injection was assessed for all subjects who received DAC HYP in Study 303 and is independent of the treatment previously received.
    End point type
    Secondary
    End point timeframe
    After the first and fourth injections in 303, approximately Week 0 and Week 12
    End point values
    DAC HYP 150 mg
    Number of subjects analysed
    1500
    Units: score on scale
    arithmetic mean (standard deviation)
        First Injection, Post-dose (n= 97)
    1.7 ± 2.46
        Fourth Injection, Post-dose (n=87)
    1.6 ± 2.34
    No statistical analyses for this end point

    Secondary: Number of Subjects in Local Tolerability Clinician Injection Site Assessment Categories

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    End point title
    Number of Subjects in Local Tolerability Clinician Injection Site Assessment Categories
    End point description
    The investigator assessed the injection site after the first dose and before the fourth dose for the presence of erythema (None, Mild, Moderate, Severe), pigmentation (None, Hypo, Hyper), Induration (None, Mild, Moderate, Severe), Tenderness (None, Mild, Moderate, Severe) and Temperature (Normal, Warm, Hot). The number of subjects in each grade is reported. Safety Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. This outcome measure was assessed for all subjects who received at least one dose of DAC HYP combined. 'n' is the number of subjects with data available at the given timepoint. Local tolerability of the DAC HYP injection was assessed for all subjects who received DAC HYP in Study 303 and is independent of the treatment previously received.
    End point type
    Secondary
    End point timeframe
    After the first and fourth injections in 303, approximately Week 0 and Week 12
    End point values
    DAC HYP 150 mg
    Number of subjects analysed
    1500
    Units: subjects
        First Injection Post-dose, Erythema: None (n= 97)
    87
        First Injection Post-dose, Erythema: Mild (n= 97)
    8
        First Injection Post-dose,Erythema:Moderate (n=97)
    2
        First Injection Post-dose, Erythema: Severe (n=97)
    0
        Fourth Injection Pre-dose, Erythema: None (n= 87)
    87
        Fourth Injection Pre-dose, Erythema: Mild (n= 87)
    0
        Fourth Injection Pre-dose,Erythema:Moderate (n=87)
    0
        Fourth Injection Pre-dose, Erythema: Severe (n=87)
    0
        First Injection Post-dose,Pigmentation:None (n=97)
    90
        First Injection Post-dose,Pigmentation:Hypo (n=97)
    7
        First Injection Post-dose,Pigmentation:Hyper(n=97)
    0
        Fourth Injection Pre-dose,Pigmentation:None (n=87)
    87
        Fourth Injection Pre-dose,Pigmentation:Hypo (n=87)
    0
        Fourth Injection Pre-dose,Pigmentation:Hyper(n=87)
    0
        First Injection Post-dose, Induration: None (n=93)
    89
        First Injection Post-dose, Induration: Mild (n=93)
    4
        First Injection Postdose,Induration:Moderate(n=93)
    0
        First Injection Post-dose,Induration:Severe (n=93)
    0
        Fourth Injection Pre-dose, Induration: None (n=87)
    87
        Fourth Injection Pre-dose, Induration: Mild (n=87)
    0
        Fourth Injection Predose,Induration:Moderate(n=87)
    0
        Fourth Injection Pre-dose,Induration:Severe (n=87)
    0
        First Injection Post-dose, Tenderness: None (n=97)
    94
        First Injection Post-dose, Tenderness: Mild (n=97)
    3
        First Injection Postdose,Tenderness:Moderate(n=97)
    0
        First Injection Post-dose,Tenderness:Severe (n=97)
    0
        Fourth Injection Pre-dose, Tenderness: None (n=87)
    87
        Fourth Injection Pre-dose, Tenderness: Mild (n=87)
    0
        Fourth Injection Predose,Tenderness:Moderate(n=87)
    0
        Fourth Injection Pre-dose,Tenderness:Severe (n=87)
    0
        First Injection Postdose,Temperature:Normal (n=97)
    97
        First Injection Post-dose,Temperature:Warm (n=97)
    0
        First Injection Post-dose,Temperature: Hot (n= 97)
    0
        Fourth Injection Pre-dose,Temperature:Normal(n=87)
    87
        Fourth Injection Pre-dose,Temperature:Warm (n=87)
    0
        Fourth Injection Pre-dose, Temperature: Hot (n=87)
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Anti-BIIB019 Binding Antibodies (ADAbs) in the 205MS303 Treatment Period

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    End point title
    Number of Subjects with Anti-BIIB019 Binding Antibodies (ADAbs) in the 205MS303 Treatment Period
    End point description
    Blood samples were collected for ADAbs and were analysed using a laboratory test. The number of subjects ADAb positive at any post-baseline timepoint is reported. Safety Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. Number of subjects analyzed is the number of subjects with evaluable data for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Up to 4.6 years in the 303 Treatment Period
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    603
    35
    68
    Units: subjects
    113
    48
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Anti-BIIB019 Neutralizing Antibodies (Nabs) in the 205MS303 Treatment Period

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    End point title
    Number of Subjects with Anti-BIIB019 Neutralizing Antibodies (Nabs) in the 205MS303 Treatment Period
    End point description
    Blood samples were collected for NAbs and were analysed using a laboratory test. The number of subjects NAb positive at any post-baseline timepoint is reported. Safety Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. Number of subjects analyzed is the number of subjects with evaluable data for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Up to 4.6 years in the 303 Treatment Period
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    35
    67
    Units: subjects
    45
    21
    0
    0
    No statistical analyses for this end point

    Secondary: Change from 205MS303 Baseline in the Symbol Digit Modalities Test (SDMT) Score in the 205MS303 Treatment Period

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    End point title
    Change from 205MS303 Baseline in the Symbol Digit Modalities Test (SDMT) Score in the 205MS303 Treatment Period [18]
    End point description
    SDMT is a screening test for cognitive impairment. Subjects are given 90 seconds in which to pair specific numbers with given geometric figures using a key. Scores range from 0 to 110 (best). A positive change from baseline indicates improvement. 301-303 ITT Population consisted of all subjects who completed Study 301 and received at least 1 dose of DAC HYP during Study 303. 'n' is the number of subjects with data available at the given timepoint. No data is collected for subjects from 203 and 302 studies.
    End point type
    Secondary
    End point timeframe
    Baseline 303, Weeks 144, 168, 192, 240 in 303
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the baseline period are applicable to this endpoint.
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects analysed
    408
    400
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline 303
    52.0 ± 15.13
    52.4 ± 16.08
        Change at Week 144 (n= 321, 315)
    -3.0 ± 11.38
    -3.5 ± 11.91
        Change at Week 168 (n= 327, 340)
    -1.9 ± 11.59
    -3.7 ± 13.10
        Change at Week 192 (n= 314, 318)
    -2.5 ± 12.02
    -2.8 ± 12.92
        Change at Week 240 (n= 24, 16)
    2.0 ± 10.78
    -2.0 ± 15.38
    No statistical analyses for this end point

    Secondary: Change from 205MS301 Baseline in the SDMT Score in the 205MS301-303 Combined Study Period

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    End point title
    Change from 205MS301 Baseline in the SDMT Score in the 205MS301-303 Combined Study Period [19]
    End point description
    SDMT is a screening test for cognitive impairment. Subjects are given 90 seconds in which to pair specific numbers with given geometric figures using a key. Scores range from 0 to 110 (best). A positive change from baseline indicates improvement. 301-303 ITT Population consisted of all subjects who completed Study 301 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline 301, Weeks 24, 48, 72, 96, 120, 144 in 301; Weeks 144, 168, 192, 216, 240 in 303
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the baseline period are applicable to this endpoint.
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects analysed
    577
    584
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (BL) 301
    47.8 ± 16.18
    48.4 ± 16.32
        Change from BL 301 at Week 24 for 301 (n=572, 575)
    1.3 ± 11.20
    1.1 ± 12.42
        Change from BL 301 at Week 48 for 301 (n=568, 577)
    2.7 ± 12.31
    2.2 ± 12.01
        Change from BL 301 at Week 72 for 301 (n=568, 573)
    3.0 ± 13.12
    3.6 ± 12.98
        Change from BL 301 at Week 96 for 301 (n=574, 579)
    3.0 ± 13.04
    4.1 ± 13.09
        Change from BL 301 at Week 120 for 301(n=416, 437)
    3.5 ± 13.53
    5.4 ± 12.75
        Change from BL 301 at Week 144 for 301(n=237, 238)
    3.2 ± 13.38
    6.6 ± 13.15
        Change from BL 301 at Week 144 for 303(n=308, 297)
    0.7 ± 14.95
    1.3 ± 13.92
        Change from BL 301 at Week 168 for 303(n=315, 321)
    2.0 ± 14.78
    1.6 ± 14.86
        Change from BL 301 at Week 192 for 303(n=300, 302)
    1.7 ± 15.81
    2.1 ± 15.35
        Change from BL 301 at Week 216 for 303(n=255, 265)
    4.7 ± 15.91
    4.5 ± 14.59
        Change from BL 301 at Week 240 for 303(n=24, 16)
    3.8 ± 11.41
    8.8 ± 9.42
    No statistical analyses for this end point

    Secondary: Change from Baseline in 3-Second Paced Auditory Serial Addition Test (PASAT 3) Score in the 205MS303 Treatment Period

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    End point title
    Change from Baseline in 3-Second Paced Auditory Serial Addition Test (PASAT 3) Score in the 205MS303 Treatment Period [20]
    End point description
    The PASAT 3 assesses auditory information processing speed. A random series of numbers from 1 to 9, inclusive, are presented and the subject is instructed to consecutively add pairs of numbers so that each number is added to the one that immediately preceded it. In the 3- second PASAT, numbers are presented at a rate of 1 every 3 seconds. The total possible score is the number of correct responses from 0 to 60 (best). A positive change from baseline indicates improvement. 301-303 ITT Population consisted of all subjects who completed Study 301 and received at least 1 dose of DAC HYP during Study 303. 'n' is the number of subjects with data available at the given timepoint. No data was collected for subjects from the 203 and 302 studies.
    End point type
    Secondary
    End point timeframe
    Baseline 303, Weeks 12, 24, 48, 120, 144, 168, 192, 216, 240 in Study 303
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the baseline period are applicable to this endpoint.
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    Units: score on a scale
    median (full range (min-max))
        Baseline 303 (n= 595, 604)
    54.0 (0 to 60)
    54.0 (3 to 60)
        Change to Week 12 (n= 584, 584)
    0.0 (-40 to 19)
    0.0 (-23 to 25)
        Change to Week 24 (n= 564, 557)
    0.0 (-26 to 26)
    0.0 (-27 to 39)
        Change to Week 48 (n= 530, 509)
    0.0 (-41 to 21)
    0.0 (-21 to 41)
        Change to Week 120 (n= 1, 2)
    -3.0 (-3 to -3)
    -1.0 (-2 to 0)
        Change to Week 144 (n= 305, 301)
    -1.0 (-34 to 23)
    -1.0 (-31 to 35)
        Change to Week 168 (n= 327, 334)
    0.0 (-35 to 21)
    0.0 (-30 to 25)
        Change to Week 192 (n= 315, 319)
    0.0 (-33 to 26)
    0.0 (-42 to 40)
        Change to Week 216 (n= 266, 279)
    0.0 (-22 to 16)
    0.0 (-23 to 39)
        Change to Week 240 (n= 24, 16)
    0.0 (-8 to 12)
    -2.0 (-9 to 6)
    Statistical analysis title
    Analysis 1
    Statistical analysis description
    Change to Week 12
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3813
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 2
    Statistical analysis description
    Change to Week 24
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1679
    Method
    ANOVA
    Confidence interval
    Statistical analysis title
    Analysis 3
    Statistical analysis description
    Change to Week 48
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5634
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 4
    Statistical analysis description
    Change to Week 144
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7003
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 5
    Statistical analysis description
    Change to Week 168
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7812
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 6
    Statistical analysis description
    Change to Week 192
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3246
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 7
    Statistical analysis description
    Change to Week 216
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6423
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 8
    Statistical analysis description
    Change to Week 240
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0288
    Method
    ANCOVA
    Confidence interval

    Secondary: Change from Baseline in 3-Second Paced Auditory Serial Addition Test (PASAT 3) Score in the 205MS301-303 Combined Study Period

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    End point title
    Change from Baseline in 3-Second Paced Auditory Serial Addition Test (PASAT 3) Score in the 205MS301-303 Combined Study Period [21]
    End point description
    The PASAT 3 assesses auditory information processing speed. A random series of numbers from 1 to 9, inclusive, are presented and the subject is instructed to consecutively add pairs of numbers so that each number is added to the one that immediately preceded it. In the 3- second PASAT, numbers are presented at a rate of 1 every 3 seconds. The total possible score is the number of correct responses from 0 to 60 (best). A positive change from baseline indicates improvement. 301-303 ITT Population consisted of all subjects who completed study 301 and had at least 1 dose of DAC HYP during study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no data was collected.
    End point type
    Secondary
    End point timeframe
    Baseline 301, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156 in the 301 study, Baseline 303, Weeks 12, 24, 48, 120, 144,168, 192, 216, 240 in 303 study
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the baseline period are applicable to this endpoint.
    End point values
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects analysed
    597
    606
    Units: score on a scale
    median (full range (min-max))
        Baseline 301 (n= 596, 605)
    50.0 (0 to 60)
    51.0 (9 to 60)
        Change from BL 301 to Week 12 for 301 (n=593, 603)
    0.0 (-58 to 40)
    1.0 (-59 to 25)
        Change from BL 301 to Week 24 for 301 (n=594, 600)
    0.5 (-26 to 31)
    1.0 (-32 to 22)
        Change from BL 301 to Week 36 for 301 (n=594, 599)
    1.0 (-29 to 30)
    1.0 (-37 to 28)
        Change from BL 301 to Week 48 for 301 (n=592, 602)
    1.0 (-25 to 42)
    1.0 (-38 to 30)
        Change from BL 301 to Week 60 for 301 (n=589, 599)
    1.0 (-46 to 40)
    2.0 (-34 to 37)
        Change from BL 301 to Week 72 for 301 (n=592, 600)
    2.0 (-20 to 40)
    2.0 (-21 to 41)
        Change from BL 301 to Week 84 for 301 (n=591, 598)
    2.0 (-31 to 39)
    2.0 (-41 to 29)
        Change from BL 301 to Week 96 for 301 (n=594, 600)
    2.0 (-28 to 41)
    2.0 (-25 to 38)
        Change from BL 301 to Week 108 for 301(n=489, 500)
    1.0 (-27 to 43)
    2.0 (-25 to 40)
        Change from BL 301 to Week 120 for 301(n=397, 397)
    2.0 (-27 to 35)
    2.0 (-31 to 41)
        Change from BL 301 to Week 132 for 301(n=273, 289)
    2.0 (-30 to 35)
    2.0 (-19 to 38)
        Change from BL 301 to Week 144 for 301(n=210, 204)
    2.0 (-25 to 31)
    3.0 (-21 to 31)
        Change from BL 301 to Week 156 for 301(n=0, 1)
    999999 (999999 to 999999)
    -4.0 (-4 to -4)
        Change from BL 301 to BL 303 (n=595, 603)
    2.0 (-34 to 44)
    2.0 (-41 to 45)
        Change from BL 301 to Week 12 for 303 (n=582, 580)
    2.0 (-38 to 43)
    2.0 (-26 to 41)
        Change from BL 301 to Week 24 for 303 (n=562, 553)
    2.0 (-31 to 40)
    2.0 (-27 to 43)
        Change from BL 301 to Week 48 for 303 (n=528, 505)
    2.0 (-47 to 44)
    2.0 (-24 to 41)
        Change from BL 301 to Week 120 for 303(n=1, 2)
    15.0 (15 to 15)
    3.0 (1 to 5)
        Change from BL 301 to Week 144 for 303(n=303, 298)
    1.0 (-32 to 37)
    2.0 (-24 to 38)
        Change from BL 301 to Week 168 for 303(n=325, 330)
    2.0 (-36 to 42)
    2.0 (-29 to 42)
        Change from BL 301 to Week 192 for 303(n=313, 316)
    2.0 (-40 to 42)
    2.0 (-21 to 42)
        Change from BL 301 to Week 216 for 303(n=265, 277)
    2.0 (-27 to 40)
    2.0 (-30 to 41)
        Change from BL 301 to Week 240 for 303(n=24, 16)
    1.5 (-10 to 26)
    0.5 (-11 to 23)
    Statistical analysis title
    Analysis 1
    Statistical analysis description
    Change from Baseline 301 to Week 12 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2567
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 2
    Statistical analysis description
    Change from Baseline 301 to Week 24 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6152
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 3
    Statistical analysis description
    Change from Baseline 301 to Week 36 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2024
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 4
    Statistical analysis description
    Change from Baseline 301 to Week 48 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9988
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 5
    Statistical analysis description
    Change from Baseline 301 to Week 60 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7962
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 6
    Statistical analysis description
    Change from Baseline 301 to Week 72 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8486
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 7
    Statistical analysis description
    Change from Baseline 301 to Week 84 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4478
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 8
    Statistical analysis description
    Change from Baseline 301 to Week 96 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.325
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 9
    Statistical analysis description
    Change from Baseline 301 to Week 108 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.129
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 10
    Statistical analysis description
    Change from Baseline 301 to Week 120 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7295
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 11
    Statistical analysis description
    Change from Baseline 301 to Week 132 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8647
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 12
    Statistical analysis description
    Change from Baseline 301 to Week 144 for 301
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2183
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 13
    Statistical analysis description
    Change from Baseline 301 to Baseline 303
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3945
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 14
    Statistical analysis description
    Change from Baseline 301 to Week 12 for 303
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5068
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 15
    Statistical analysis description
    Change from Baseline 301 to Week 24 for 303
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1669
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 16
    Statistical analysis description
    Change from Baseline 301 to Week 48 for 303
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5038
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 17
    Statistical analysis description
    Change from Baseline 301 to Week 144 for 303
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6001
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 18
    Statistical analysis description
    Change from Baseline 301 to Week 168 for 303
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8617
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 19
    Statistical analysis description
    Change from Baseline 301 to Week 192 for 303
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.259
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 20
    Statistical analysis description
    Change from Baseline 301 to Week 216 for 303
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5159
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Analysis 21
    Statistical analysis description
    Change from Baseline 301 to Week 240 for 303
    Comparison groups
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6123
    Method
    ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study drug in study 205MS303 to within 180 days of last dose (up to approximately 5.5 years)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)
    Reporting group description
    DAC HYP 150 mg SC injection every 4 weeks for up to 4.6 years in this long-term extension study 303; includes subjects who previously received interferon beta-1a (IFN β-1a) 30 µg intramuscular (IM) injection once weekly in study 301 every 4 weeks for up to 144 weeks.

    Reporting group title
    DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
    Reporting group description
    DAC HYP 150 mg subcutaneous (SC) injection every 4 weeks for up to 4.6 years in this long-term extension study 205MS303 (303); includes subjects who previously received DAC HYP 150 mg SC injection in Study 205MS301 (301) every 4 weeks for up to 144 weeks.

    Reporting group title
    DAC HYP 150 mg (302) /DAC HYP 150 mg (303)
    Reporting group description
    DAC HYP 150 mg SC injection every 4 weeks for up to 93.7 weeks in this long-term extension study 303 (subjects started at Week 144 of the study); includes subjects who previously received DAC HYP 150 mg SC injection in study 205MS302 (302) every 4 weeks for up to 24 weeks followed by a 20-week washout period then continued treatment for up to an additional 3 years.

    Reporting group title
    DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Reporting group description
    DAC HYP 150 mg SC injection every 4 weeks for up to 94. 1 weeks in this long-term extension study 303 (subjects started at Week 144 of the study); includes subjects who previously received DAC HYP 150 mg SC injection in study 205MS203 (203) every 4 weeks for up to 288 weeks.

    Serious adverse events
    IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) DAC HYP 150 mg (301) /DAC HYP 150 mg (303) DAC HYP 150 mg (302) /DAC HYP 150 mg (303) DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    157 / 597 (26.30%)
    190 / 606 (31.35%)
    15 / 70 (21.43%)
    38 / 227 (16.74%)
         number of deaths (all causes)
    2
    4
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Granulomatosis with polyangiitis
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 606 (0.00%)
    1 / 70 (1.43%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kawasaki's disease
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abdominoplasty
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Female sterilisation
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hospitalisation
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immunosuppressant drug therapy
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mastectomy
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anorectal human papilloma virus infection
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign neoplasm of thyroid gland
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    3 / 597 (0.50%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibroadenoma of breast
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metaplastic breast carcinoma
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian fibroma
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parathyroid tumour benign
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Testicular neoplasm
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 597 (0.00%)
    4 / 606 (0.66%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyosarcoma
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 606 (0.00%)
    1 / 70 (1.43%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Serum sickness
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blighted ovum
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foetal growth restriction
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Premature delivery
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    1 / 70 (1.43%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multi-organ disorder
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 597 (0.17%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 597 (0.50%)
    3 / 606 (0.50%)
    0 / 70 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Psychiatric disorders
    Acute stress disorder
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bipolar i disorder
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Personality disorder
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somatoform disorder
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    2 / 597 (0.34%)
    3 / 606 (0.50%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adnexal torsion
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysfunctional uterine bleeding
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian adhesion
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst ruptured
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic prolapse
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 597 (0.17%)
    7 / 606 (1.16%)
    1 / 70 (1.43%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 597 (0.00%)
    2 / 606 (0.33%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 597 (0.00%)
    2 / 606 (0.33%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament injury
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 597 (0.00%)
    2 / 606 (0.33%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Snake bite
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 597 (0.17%)
    2 / 606 (0.33%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 597 (0.17%)
    2 / 606 (0.33%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diagnostic procedure
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Protein urine present
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 597 (0.00%)
    2 / 606 (0.33%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular hypertrophy
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 606 (0.00%)
    1 / 70 (1.43%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Choking
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal necrosis
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    1 / 70 (1.43%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sarcoidosis
         subjects affected / exposed
    0 / 597 (0.00%)
    3 / 606 (0.50%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 606 (0.17%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheal fistula
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 606 (0.00%)
    0 / 70 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    1 / 597 (0.17%)