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    Clinical Trial Results:
    A randomized, double-blind, double-dummy, parallel-group study comparing the efficacy and safety of ofatumumab versus teriflunomide in patients with relapsing multiple sclerosis

    Summary
    EudraCT number
    		 2015-005418-31
    Trial protocol
    		 BE   DE   HU   GB   SE   DK   CZ   SK   ES   NL   EE   BG   GR   PL   HR   FR   IT  
    Global end of trial date
    20 Jul 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Aug 2021
    First version publication date
    05 Aug 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    COMB157G2301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02792218
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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
    20 Jul 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective was to demonstrate that ofatumumab 20 mg subcutaneous injection once every 4 weeks was superior to teriflunomide 14 mg given orally, once daily, in reducing the frequency of confirmed relapses as evaluated by the annualized relapse rate (ARR) in patients with relapsing multiple sclerosis.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Sep 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 18
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Bulgaria: 15
    Country: Number of subjects enrolled
    Canada: 15
    Country: Number of subjects enrolled
    Croatia: 16
    Country: Number of subjects enrolled
    Czechia: 36
    Country: Number of subjects enrolled
    Denmark: 17
    Country: Number of subjects enrolled
    Estonia: 18
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 31
    Country: Number of subjects enrolled
    Greece: 9
    Country: Number of subjects enrolled
    Hungary: 18
    Country: Number of subjects enrolled
    India: 29
    Country: Number of subjects enrolled
    Israel: 11
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Mexico: 8
    Country: Number of subjects enrolled
    Netherlands: 15
    Country: Number of subjects enrolled
    Poland: 197
    Country: Number of subjects enrolled
    Russian Federation: 153
    Country: Number of subjects enrolled
    Slovakia: 12
    Country: Number of subjects enrolled
    Spain: 54
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    Thailand: 1
    Country: Number of subjects enrolled
    Turkey: 13
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    United States: 193
    Worldwide total number of subjects
    927
    EEA total number of subjects
    475
    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)
    927
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 1277 patients were screened, of whom 927 patients were randomized into the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 OMB 20 mg
    Arm description
    		 Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ofatumumab
    Investigational medicinal product code
    OMB157
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Ofatumumab 20 mg pre-filled syringes for subcutaneous injection on days 1 ,7 ,14,Week 4 and every 4 weeks thereafter

    Investigational medicinal product name
    Teriflunomide-matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo (teriflunomide 0 mg) capsule orally once daily

    Arm title
    		 TER 14 mg
    Arm description
    		 Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ofatumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo (OMB 0 mg) pre-filled syringes for subcutaneous injection on days 1 ,7 ,14,Week 4 and every 4 weeks thereafter

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Teriflunomide 14 mg capsule orally once daily

    Number of subjects in period 1
    		OMB 20 mg TER 14 mg
    Started
    465
    462
    Completed
    416
    381
    Not completed
    49
    81
         Physician decision
    4
    4
         Adverse event, non-fatal
    15
    14
         Protocol deviation
    3
    2
         Non-compliance with study treatment
    -
    1
         Pregnancy
    1
    -
         Patient/guardian decision
    15
    42
         Lost to follow-up
    10
    5
         New therapy for study indication
    -
    1
         Lack of efficacy
    1
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    OMB 20 mg
    Reporting group description
    		 Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)

    Reporting group title
    TER 14 mg
    Reporting group description
    		 Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)

    Reporting group values
    		 OMB 20 mg TER 14 mg Total
    Number of subjects
    		 465 462 927
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 465 462 927
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 38.9 ( 8.77 ) 37.8 ( 8.95 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 318 317 635
        Male
    		 147 145 292
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 15 16 31
        Black or African American
    		 15 20 35
        White
    		 411 412 823
        Other
    		 22 14 36
        Unknown
    		 2 0 2
    Number of relapses in the past 12 months prior to screening
    Reported numbers are from investigator records
    Units: Number of relapses
        arithmetic mean (standard deviation)
    		 1.2 ( 0.63 ) 1.3 ( 0.69 ) -
    Expanded Disability Status Scale (EDSS)
    Units: Score on a scale
        arithmetic mean (standard deviation)
    		 2.97 ( 1.357 ) 2.94 ( 1.355 ) -
    Number of Gd-enhancing T1 lesions
    Magnetic Resonance Imaging (MRI) scans of the brain were were read by the central MRI reading center. The central reading center was blinded with no access to information on treatment assignments
    Units: T1 lesions
        arithmetic mean (standard deviation)
    		 1.7 ( 4.93 ) 1.2 ( 2.58 ) -

    End points

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    End points reporting groups
    Reporting group title
    OMB 20 mg
    Reporting group description
    		 Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily)

    Reporting group title
    TER 14 mg
    Reporting group description
    		 Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter)

    Primary: Annualized relapse rate (ARR)

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    End point title
    		 Annualized relapse rate (ARR)
    End point description
    ARR was the number of confirmed relapses in a year, calculated as the total number of relapses for all participants in the treatment group divided by the total participant-years of time in study. A confirmed MS relapse was defined as one accompanied by a clinically-relevant change in the EDSS performed by the Independent EDSS rater, i.e. an increase of at least 0.5 points on the EDSS score, or an increase of 1 point on two functional scores or 2 points on one functional score (excluding changes involving bowel/bladder or cerebral functional system). Comparisons were made to the previous rating (the last EDSS rating that did not occur during a relapse).
    End point type
    Primary
    End point timeframe
    Baseline up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    454
    451
    Units: number of relapses in a year
        arithmetic mean (confidence interval 95%)
    0.11 (0.09 to 0.14)
    0.22 (0.18 to 0.26)
    Statistical analysis title
    		 ARR
    Statistical analysis description
    Obtained from fitting a negative binomial regression model with log-link to the number of relapses, adjusted for treatment and region as factors, number of relapses in previous year, baseline EDSS, baseline number of Gd-enhancing lesions and the patient’s age at baseline as covariates. The natural log of the time-in-study was used as offset to annualize the relapse rate.
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    905
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 negative binomial regression model
    Parameter type
    		 rate ratio
    Point estimate
    0.495
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.375
         upper limit
    		 0.655

    Secondary: 3-month confirmed disability worsening (3mCDW) based on EDSS

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    End point title
    		 3-month confirmed disability worsening (3mCDW) based on EDSS
    End point description
    A 3-month confirmed disability worsening (3mCDW) was defined as an increase from baseline in Expanded Disability Status Scale (EDSS) score sustained for at least 3 months. For patients with a baseline EDSS of 0, the criterion for disability worsening was an increase in EDSS of ≥1.5, for patients with a baseline EDSS of 1 to 5 or ≥5.5, the criterion for disability worsening was an increase in EDSS of ≥1 or ≥0.5, respectively. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2302 to address this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    465
    459
    Units: percentage of participants
    number (confidence interval 95%)
        Month 18 - from Kaplan Meier estimates
    9.4 (7.0 to 12.6)
    13.9 (10.9 to 17.5)
        Month 24 - from Kaplan Meier estimates
    11.3 (8.4 to 15.1)
    15.4 (12.1 to 19.4)
    Statistical analysis title
    		 3mCDW
    Statistical analysis description
    This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2302 to address this endpoint.
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    924
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.029
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.652
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.445
         upper limit
    		 0.956

    Secondary: 6-month confirmed disability worsening (6mCDW) based on EDSS

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    End point title
    		 6-month confirmed disability worsening (6mCDW) based on EDSS
    End point description
    A 6-month confirmed disability worsening (6mCDW) was defined as an increase from baseline in Expanded Disability Status Scale (EDSS) score sustained for at least 6 months. For patients with a baseline EDSS of 0, the criterion for disability worsening was an increase in EDSS of ≥1.5, for patients with a baseline EDSS of 1 to 5 or ≥5.5, the criterion for disability worsening was an increase in EDSS of ≥1 or ≥0.5, respectively. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2302 to address this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    465
    459
    Units: percentage of participants
    number (confidence interval 95%)
        Month 18- from Kaplan Meier estimates
    7.5 (5.4 to 10.4)
    11.5 (8.9 to 14.9)
        Month 24 - from Kaplan Meier estimates
    8.2 (6.0 to 11.3)
    13.0 (10.0 to 16.9)
    Statistical analysis title
    		 6mCDW
    Statistical analysis description
    This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2302 to address this endpoint.
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    924
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.022
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.607
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.396
         upper limit
    		 0.93

    Secondary: 6-month confirmed disability improvement (6mCDI ) based on EDSS

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    End point title
    		 6-month confirmed disability improvement (6mCDI ) based on EDSS
    End point description
    A 6-month confirmed disability improvement (6mCDI) was defined as a decrease from baseline EDSS sustained for at least 6 months. For patients with a baseline EDSS of 0 to 1.5, no disability improvement was possible based on the protocol definition of an improvement; for patients with a baseline EDSS of ≥2 to 6 or ≥6.5 to 9.5, the criterion for disability improvement was a decrease in EDSS of ≤1 or ≤0.5, respectively. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2302 to address this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    375
    363
    Units: percentage of participants
    arithmetic mean (confidence interval 95%)
        Month 18 - from Kaplan Meier estimates
    9.1 (6.5 to 12.7)
    7.1 (4.8 to 10.3)
        Month 24 - from Kaplan Meier estimates
    9.7 (7.0 to 13.5)
    8.2 (5.6 to 11.9)
    Statistical analysis title
    		 6mCDI
    Statistical analysis description
    This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2302 to address this endpoint.
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    738
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.516
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.186
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.709
         upper limit
    		 1.983

    Secondary: Number of Gd-enhancing T1 lesions per MRI scan

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    End point title
    		 Number of Gd-enhancing T1 lesions per MRI scan
    End point description
    Total number of Gd-enhancing T1 lesions across all scans per patient adjusted for different number of scans due to variable follow-up time in study.
    End point type
    Secondary
    End point timeframe
    Baseline, yearly up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    432
    420
    Units: lesions per scan
        arithmetic mean (confidence interval 95%)
    0.0115 (0.006 to 0.022)
    0.4555 (0.358 to 0.579)
    Statistical analysis title
    		 T1 lesions
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 negative binomial regression model
    Parameter type
    		 rate ratio
    Point estimate
    0.025
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.013
         upper limit
    		 0.049

    Secondary: Number of new or enlarging T2 lesions on MRI per year (annualized lesion rate)

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    End point title
    		 Number of new or enlarging T2 lesions on MRI per year (annualized lesion rate)
    End point description
    Number of new/enlarging T2 lesions on last available MRI scan compared to baseline adjusted for different time of scans versus baseline due to variable follow up time in study
    End point type
    Secondary
    End point timeframe
    Baseline, yearly up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    440
    431
    Units: T2 lesions per year
    arithmetic mean (confidence interval 95%)
        Month 12 n=420,407
    1.13 (0.95 to 1.33)
    4.30 (3.71 to 4.98)
        Month 24 n=103,93
    0.72 (0.53 to 0.98)
    3.21 (2.42 to 4.24)
        EOS n=440,431
    0.72 (0.61 to 0.85)
    4.00 (3.47 to 4.61)
    Statistical analysis title
    		 T2 lesions
    Statistical analysis description
    Month 12
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    871
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 negative binomial regression model
    Parameter type
    		 rate ratio
    Point estimate
    0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.21
         upper limit
    		 0.33
    Statistical analysis title
    		 T2 lesions
    Statistical analysis description
    Month 24
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    871
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 negative binomial regression model
    Parameter type
    		 rate ratio
    Point estimate
    0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 0.34
    Statistical analysis title
    		 T2 lesions
    Statistical analysis description
    End of Study
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    871
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 negative binomial regression model
    Parameter type
    		 rate ratio
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 0.22

    Secondary: Neurofilament light chain (NfL) concentration in serum

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    End point title
    		 Neurofilament light chain (NfL) concentration in serum
    End point description
    The NfL concentration (geometric mean concentration) was estimated by treatment and time point with using a repeated measures model on the basis of all evaluable log-transformed NfL values.
    End point type
    Secondary
    End point timeframe
    Month 3, 12 and 24
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    430
    403
    Units: pg/mL
    geometric mean (confidence interval 95%)
        Month 3 n=430,403
    8.80 (8.48 to 9.13)
    9.41 (9.06 to 9.77)
        Month 12 n=414,398
    7.02 (6.73 to 7.32)
    9.63 (9.23 to 10.06)
        Month 24 n=371,349
    6.90 (6.57 to 7.24)
    8.99 (8.56 to 9.45)
    Statistical analysis title
    		 NfL
    Statistical analysis description
    Month 3
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    833
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.011
    Method
    		 Mixed models analysis
    Parameter type
    		 Geo-mean ratio
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 0.98
    Statistical analysis title
    		 NfL
    Statistical analysis description
    Month 12
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    833
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Geo-mean ratio
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 0.77
    Statistical analysis title
    		 NfL
    Statistical analysis description
    Month 24
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    833
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Geo-mean ratio
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 0.82

    Secondary: Annualized rate of brain volume loss based on assessments of percent brain volume change from baseline

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    End point title
    		 Annualized rate of brain volume loss based on assessments of percent brain volume change from baseline
    End point description
    Percent change from baseline in brain volume loss (BVL) on all MRI scans adjusted for different time of scan versus baseline due to variable follow up time in study
    End point type
    Secondary
    End point timeframe
    Baseline, months 12 and 24
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    418
    408
    Units: percentage of brain volume loss
        arithmetic mean (confidence interval 95%)
    -0.28 (-0.34 to 0.22)
    -0.35 (-0.41 to 0.29)
    Statistical analysis title
    		 Brain volume
    Comparison groups
    OMB 20 mg v TER 14 mg
    Number of subjects included in analysis
    826
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.118
    Method
    		 random coefficient model
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.15

    Secondary: Time to first confirmed relapse

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    End point title
    		 Time to first confirmed relapse
    End point description
    A confirmed MS relapse was defined as one accompanied by a clinically-relevant change in the EDSS performed by the Independent EDSS rater, i.e. an increase of at least 0.5 points on the EDSS score, or an increase of 1 point on two functional scores or 2 points on one functional score (excluding changes involving bowel/bladder or cerebral functional system).
    End point type
    Secondary
    End point timeframe
    Baseline up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    454
    451
    Units: percentage of participants
        number (confidence interval 95%)
    18.82 (15.27 to 23.09)
    32.73 (27.95 to 38.09)
    No statistical analyses for this end point

    Secondary: Annualized relapse rate (ARR) >8 weeks after onset of treatment

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    End point title
    		 Annualized relapse rate (ARR) >8 weeks after onset of treatment
    End point description
    ARR was the number of confirmed relapses in a year, calculated as the total number of relapses for all participants in the treatment group divided by the total participant-years of time in study. A confirmed MS relapse was defined as one accompanied by a clinically-relevant change in the EDSS performed by the Independent EDSS rater, i.e. an increase of at least 0.5 points on the EDSS score, or an increase of 1 point on two functional scores or 2 points on one functional score (excluding changes involving bowel/bladder or cerebral functional system). Comparisons were made to the previous rating (the last EDSS rating that did not occur during a relapse).
    End point type
    Secondary
    End point timeframe
    Baseline up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    453
    448
    Units: number of relapses in a year
        arithmetic mean (confidence interval 95%)
    0.096 (0.05 to 0.14)
    0.242 (0.17 to 0.31)
    No statistical analyses for this end point

    Secondary: Risk of a 3-month confirmed disability worsening (3mCDW) based on EDSS > 8 weeks after onset of treatment

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    End point title
    		 Risk of a 3-month confirmed disability worsening (3mCDW) based on EDSS > 8 weeks after onset of treatment
    End point description
    A 3-month confirmed disability worsening (3mCDW) was defined as an increase from baseline in Expanded Disability Status Scale (EDSS) score sustained for at least 3 months. For patients with a baseline EDSS of 0, the criterion for disability worsening was an increase in EDSS of ≥1.5, for patients with a baseline EDSS of 1 to 5 or ≥5.5, the criterion for disability worsening was an increase in EDSS of ≥1 or ≥0.5, respectively. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2302 to address this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    0 [1]
    0 [2]
    Units: percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [1] - Pre-specified in protocol that data for this outcome will be combined with study COMB157G2302.
    [2] - Pre-specified in protocol that data for this outcome will be combined with study COMB157G2302.
    No statistical analyses for this end point

    Secondary: Risk of a 6-month confirmed disability worsening (6mCDW) based on EDSS > 8 weeks after onset of treatment

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    End point title
    		 Risk of a 6-month confirmed disability worsening (6mCDW) based on EDSS > 8 weeks after onset of treatment
    End point description
    A 6-month confirmed disability worsening (6mCDW) was defined as an increase from baseline in Expanded Disability Status Scale (EDSS) score sustained for at least 6 months. For patients with a baseline EDSS of 0, the criterion for disability worsening was an increase in EDSS of ≥1.5, for patients with a baseline EDSS of 1 to 5 or ≥5.5, the criterion for disability worsening was an increase in EDSS of ≥1 or ≥0.5, respectively. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2302 to address this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: scores
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [3] - Pre-specified in protocol that data for this outcome will be combined with study COMB157G2302.
    [4] - Pre-specified in protocol that data for this outcome will be combined with study COMB157G2302.
    No statistical analyses for this end point

    Secondary: 6-month confirmed cognitive decline on Symbol Digit Modalities Test (SDMT)

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    End point title
    		 6-month confirmed cognitive decline on Symbol Digit Modalities Test (SDMT)
    End point description
    A 6-month confirmed cognitive decline was defined as a decrease from baseline of at least 4 points in SDMT score sustained for at least 6 months. Processing speed was measured by the Symbol Digit Modalities Test (SDMT) score. SDMT measures the time to pair abstract symbols with specific numbers. The test requires visuoperceptual processing, working memory, and psychomotor speed. The score is the number of correctly coded items in 90 seconds. (max=110, min=0). Higher scores indicate improvement. Lower scores indicate worsening. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2302 to address this endpoint
    End point type
    Secondary
    End point timeframe
    Baseline, every 6 months up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [5] - Pre-specified in protocol that data for this outcome will be combined with study COMB157G2302.
    [6] - Pre-specified in protocol that data for this outcome will be combined with study COMB157G2302.
    No statistical analyses for this end point

    Secondary: 6-month confirmed disability worsening (6mCDW) or 6-month confirmed cognitive decline (6mCCD)

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    End point title
    		 6-month confirmed disability worsening (6mCDW) or 6-month confirmed cognitive decline (6mCCD)
    End point description
    A 6-month confirmed disability worsening (6mCDW) was defined as an increase from baseline in Expanded Disability Status Scale (EDSS) score sustained for at least 6 months. For patients with a baseline EDSS of 0, the criterion for disability worsening was an increase in EDSS of ≥1.5, for patients with a baseline EDSS of 1 to 5 or ≥5.5, the criterion for disability worsening was an increase in EDSS of ≥1 or ≥0.5, respectively. A 6-month confirmed cognitive decline (6mCCD) was defined as a 4-point worsening on Symbol Digit Modalities Test (SDMT) sustained for at least 6 months. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2302 to address this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [7] - Pre-specified in protocol that data for this outcome will be combined with study COMB157G2302.
    [8] - Pre-specified in protocol that data for this outcome will be combined with study COMB157G2302.
    No statistical analyses for this end point

    Secondary: Change in cognitive performance measured by the Symbol Digit Modalities Test (SDMT)

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    End point title
    		 Change in cognitive performance measured by the Symbol Digit Modalities Test (SDMT)
    End point description
    Processing speed is being measured by the Symbol Digit Modalities Test (SDMT) score. SDMT measures the time to pair abstract symbols with specific numbers. The test requires visuoperceptual processing, working memory, and psychomotor speed. The score is the number of correctly coded items in 90 seconds. (max=110, min=0). Higher scores indicate improvement. Lower scores indicate worsening.
    End point type
    Secondary
    End point timeframe
    Baseline up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [9] - Pre-specified in protocol/SAP that data for this outcome will be combined with study COMB157G2302.
    [10] - Pre-specified in protocol/SAP that data for this outcome will be combined with study COMB157G2302.
    No statistical analyses for this end point

    Secondary: 6-month confirmed worsening of at least 20% in the Timed 25-Foot Walk (T25FW)

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    End point title
    		 6-month confirmed worsening of at least 20% in the Timed 25-Foot Walk (T25FW)
    End point description
    The patient is directed to walk 25 feet quickly and safely as possible from one marked end to the other. The time is calculated from the initiation of the patient instructed to begin, until the patient has reached the 25-foot mark. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2302 to address this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    0 [11]
    0 [12]
    Units: percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [11] - Pre-specified in protocol that data for this outcome will be combined with study COMB157G2302.
    [12] - Pre-specified in protocol that data for this outcome will be combined with study COMB157G2302.
    No statistical analyses for this end point

    Secondary: 6-month confirmed worsening of at least 20% in the 9-Hole Peg Test (9HPT)

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    End point title
    		 6-month confirmed worsening of at least 20% in the 9-Hole Peg Test (9HPT)
    End point description
    9 Hole Peg Test is a test of upper limb function. Participants place 9 pegs on pegboard and remove pegs and this is timed for each hand. Time recorded in seconds. Longer time indicates poorer upper limb function. 20% improvement is defined as 20% shorter time in seconds. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2302 to address this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, every 6 months up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    0 [13]
    0 [14]
    Units: percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [13] - Pre-specified in protocol that data for this outcome will be combined with study COMB157G2302.
    [14] - Pre-specified in protocol that data for this outcome will be combined with study COMB157G2302.
    No statistical analyses for this end point

    Secondary: 6-month confirmed disability improvement (6mCDI) sustained until End of Study (EOS) as measured by EDSS

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    End point title
    		 6-month confirmed disability improvement (6mCDI) sustained until End of Study (EOS) as measured by EDSS
    End point description
    A 6-month confirmed disability improvement (6mCDI) sustained until EOS was defined as a decrease from baseline EDSS sustained until EOS. For patients with a baseline EDSS of 0 to 1.5, no disability improvement was possible based on the protocol definition of an improvement; for patients with a baseline EDSS of ≥2 to 6 or ≥6.5 to 9.5, the criterion for disability improvement was a decrease in EDSS of ≤1 or ≤0.5, respectively. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2302 to address this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 months up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    0 [15]
    0 [16]
    Units: percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [15] - Pre-specified in protocol that data for this outcome will be combined with study COMB157G2302.
    [16] - Pre-specified in protocol that data for this outcome will be combined with study COMB157G2302.
    No statistical analyses for this end point

    Secondary: Number of new or enlarging T2 lesions on MRI per year from Month 12 until End of Study (EOS)

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    End point title
    		 Number of new or enlarging T2 lesions on MRI per year from Month 12 until End of Study (EOS)
    End point description
    Number of new/enlarging T2 lesions on the last available MRI scan compared to Month 12 adjusted for different time of scans versus Month 12 due to variable follow up time in study.
    End point type
    Secondary
    End point timeframe
    Month 12 up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    356
    344
    Units: T2 lesions per year
        arithmetic mean (confidence interval 95%)
    0.05 (0.03 to 0.09)
    3.73 (3.12 to 4.46)
    No statistical analyses for this end point

    Secondary: Percent change in T2 lesion volume relative to baseline

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    End point title
    		 Percent change in T2 lesion volume relative to baseline
    End point description
    Percent change from baseline in total T2 lesion volume
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    436
    430
    Units: percentage change in lesion volume
    arithmetic mean (standard deviation)
        Month 12 n=436,430
    -1.4 ( 14.07 )
    9.7 ( 28.83 )
        Month 24 n=332,324
    -2.6 ( 10.48 )
    13.5 ( 34.71 )
    No statistical analyses for this end point

    Secondary: No evidence of disease activity (NEDA-4)

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    End point title
    		 No evidence of disease activity (NEDA-4)
    End point description
    NEDA-4 was defined as no 3-month confirmed disability worsening, no confirmed MS relapse, no new or enlarging T2 lesions compared to baseline, and the annualized rate of brain atrophy >-0.04%.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    428
    413
    Units: percentage of participants
    number (confidence interval 95%)
        Month 12 n=428,413
    23.4 (19.4 to 27.4)
    14.8 (11.3 to 18.2)
        Month 24 n=104,95
    14.4 (7.7 to 21.2)
    3.2 (0.0 to 6.7)
    No statistical analyses for this end point

    Secondary: Multiple Sclerosis Impact Scale (MSIS-29) physical impact score change from baseline

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    End point title
    		 Multiple Sclerosis Impact Scale (MSIS-29) physical impact score change from baseline
    End point description
    MSIS-29 is a 29-item, self-administered questionnaire that includes 2 domains, physical and psychological. Responses are captured on a 4-point scale ranging from “not at all” (1) to “extremely” (4), where higher scores reflect greater impact on day to day life.
    End point type
    Secondary
    End point timeframe
    Baseline, every 6 months up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    455
    451
    Units: scores on a scale
    arithmetic mean (standard error)
        Month 6 n=455,451
    -2.75 ( 0.687 )
    -0.44 ( 0.690 )
        Month 12 n=438,428
    -2.43 ( 0.704 )
    0.17 ( 0.710 )
        Month 18 n=428,406
    -2.37 ( 0.768 )
    0.67 ( 0.780 )
        Month 24 n=262,233
    -2.60 ( 0.842 )
    0.59 ( 0.874 )
        Month 30 n=86,65
    -3.16 ( 1.130 )
    0.57 ( 1.262 )
    No statistical analyses for this end point

    Secondary: Multiple Sclerosis Impact Scale (MSIS-29) psychological impact score change from baseline

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    End point title
    		 Multiple Sclerosis Impact Scale (MSIS-29) psychological impact score change from baseline
    End point description
    MSIS-29 is a 29-item, self-administered questionnaire that includes 2 domains, physical and psychological. Responses are captured on a 4-point scale ranging from “not at all” (1) to “extremely” (4), where higher scores reflect greater impact on day to day life.
    End point type
    Secondary
    End point timeframe
    Baseline, every 6 months up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    455
    451
    Units: scores on a scale
    arithmetic mean (standard error)
        Month 6 n=454,449
    -5.20 ( 0.835 )
    -3.07 ( 0.839 )
        Month 12 n=438,427
    -5.22 ( 0.902 )
    -2.57 ( 0.910 )
        Month 18 n=428,406
    -5.72 ( 0.919 )
    -3.94 ( 0.937 )
        Month 24 n=262,232
    -6.14 ( 0.972 )
    -3.93 ( 1.013 )
        Month 30 n=86,65
    -7.78 ( 1.509 )
    -0.85 ( 1.698 )
    No statistical analyses for this end point

    Secondary: Annualized relapse rates (ARR) by NfL high-low subgroups

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    End point title
    		 Annualized relapse rates (ARR) by NfL high-low subgroups
    End point description
    ARR was the number of confirmed relapses in a year, calculated as the total number of relapses for all participants in the treatment group divided by the total participant-years of time in study. A confirmed MS relapse was defined as one accompanied by a clinically-relevant change in the EDSS performed by the Independent EDSS rater, i.e. an increase of at least 0.5 points on the EDSS score, or an increase of 1 point on two functional scores or 2 points on one functional score (excluding changes involving bowel/bladder or cerebral functional system).
    End point type
    Secondary
    End point timeframe
    Baseline up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    0 [17]
    0 [18]
    Units: number of relapses in a year
        arithmetic mean (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [17] - Supportive sub-group analysis based on estimations from pooled data from this study and COMB157G2302
    [18] - Supportive sub-group analysis based on estimations from pooled data from this study and COMB157G2302
    No statistical analyses for this end point

    Secondary: Number of new or enlarging T2 lesions per year by NfL high-low subgroups

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    End point title
    		 Number of new or enlarging T2 lesions per year by NfL high-low subgroups
    End point description
    Number of new or enlarging T2 lesions on MRI per year (annualized lesion rate).
    End point type
    Secondary
    End point timeframe
    Baseline, yearly up to 2.5 years
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    0 [19]
    0 [20]
    Units: T2 lesions per year
        arithmetic mean (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [19] - Supportive sub-group analysis based on estimations from pooled data from this study and COMB157G2302
    [20] - Supportive sub-group analysis based on estimations from pooled data from this study and COMB157G2302
    No statistical analyses for this end point

    Secondary: Brain volume loss by NfL high-low subgroups

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    End point title
    		 Brain volume loss by NfL high-low subgroups
    End point description
    Percent change from baseline in brain volume loss (BVL) on all MRI scans adjusted for different time of scan versus baseline due to variable follow up time in study.
    End point type
    Secondary
    End point timeframe
    Baseline, months 12 and 24
    End point values
    		 OMB 20 mg TER 14 mg
    Number of subjects analysed
    0 [21]
    0 [22]
    Units: percentage of brain volume loss
        arithmetic mean (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [21] - Supportive sub-group analysis based on estimations from pooled data from this study and COMB157G2302
    [22] - Supportive sub-group analysis based on estimations from pooled data from this study and COMB157G2302
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) concentrations of ofatumumab

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    End point title
    		 Pharmacokinetic (PK) concentrations of ofatumumab [23]
    End point description
    Summary statistics of pharmacokinetic (PK) concentrations from trough samples collected within a 7-day window prior or at day of dosing.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 12, 24, 48, 96
    Notes
    [23] - 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: No analysis was done
    End point values
    		 OMB 20 mg
    Number of subjects analysed
    465
    Units: ug/mL
    arithmetic mean (standard deviation)
        Baseline n=304
    0.00267 ( 0.033819 )
        Week 4 n=347
    1.25746 ( 0.985148 )
        Week 12 n=323
    0.22645 ( 0.339619 )
        Week 24 n=304
    0.36991 ( 0.437480 )
        Week 48 n=270
    0.51280 ( 0.463758 )
        Week 96 n=336
    1.05314 ( 0.992612 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from first dose of study treatment until end of study treatment plus 100 days post treatment, up to a maximum duration of 2.7 years.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    OMB 20mg
    Reporting group description
    		 OMB 20mg

    Reporting group title
    TER 14mg
    Reporting group description
    		 TER 14mg

    Serious adverse events
    		 OMB 20mg TER 14mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    51 / 465 (10.97%)
    39 / 462 (8.44%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cervix carcinoma
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibrosarcoma
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive breast carcinoma
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma recurrent
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Thrombophlebitis
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adnexa uteri cyst
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    1 / 465 (0.22%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 465 (0.00%)
    2 / 462 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sarcoidosis
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression suicidal
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somatic symptom disorder
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    2 / 465 (0.43%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Liver function test increased
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric evaluation
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fibula fracture
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection related reaction
         subjects affected / exposed
    2 / 465 (0.43%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post-traumatic pain
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebellar ischaemia
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiplegic migraine
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbosacral radiculopathy
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    1 / 465 (0.22%)
    4 / 462 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness neurosensory
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    2 / 465 (0.43%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 465 (0.00%)
    2 / 462 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal polyp
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis migration
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 465 (0.00%)
    2 / 462 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 465 (0.43%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoroacetabular impingement
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaw cyst
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Morphoea
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess sweat gland
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    3 / 465 (0.65%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter infection
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 465 (0.43%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salpingo-oophoritis
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tick-borne viral encephalitis
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 465 (0.22%)
    0 / 462 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 465 (0.00%)
    1 / 462 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 OMB 20mg TER 14mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    282 / 465 (60.65%)
    308 / 462 (66.67%)
    Investigations
    Blood immunoglobulin M decreased
         subjects affected / exposed
    26 / 465 (5.59%)
    13 / 462 (2.81%)
         occurrences all number
    51
    22
    Injury, poisoning and procedural complications
    Injection related reaction
         subjects affected / exposed
    74 / 465 (15.91%)
    77 / 462 (16.67%)
         occurrences all number
    200
    176
    Vascular disorders
    Hypertension
         subjects affected / exposed
    15 / 465 (3.23%)
    24 / 462 (5.19%)
         occurrences all number
    15
    26
    Nervous system disorders
    Headache
         subjects affected / exposed
    59 / 465 (12.69%)
    53 / 462 (11.47%)
         occurrences all number
    77
    78
    Paraesthesia
         subjects affected / exposed
    17 / 465 (3.66%)
    30 / 462 (6.49%)
         occurrences all number
    19
    40
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    46 / 465 (9.89%)
    39 / 462 (8.44%)
         occurrences all number
    52
    42
    Injection site reaction
         subjects affected / exposed
    41 / 465 (8.82%)
    26 / 462 (5.63%)
         occurrences all number
    109
    39
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    24 / 465 (5.16%)
    64 / 462 (13.85%)
         occurrences all number
    25
    89
    Nausea
         subjects affected / exposed
    33 / 465 (7.10%)
    33 / 462 (7.14%)
         occurrences all number
    34
    40
    Abdominal pain
         subjects affected / exposed
    23 / 465 (4.95%)
    24 / 462 (5.19%)
         occurrences all number
    23
    29
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    27 / 465 (5.81%)
    65 / 462 (14.07%)
         occurrences all number
    28
    66
    Psychiatric disorders
    Depression
         subjects affected / exposed
    20 / 465 (4.30%)
    26 / 462 (5.63%)
         occurrences all number
    21
    26
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    30 / 465 (6.45%)
    31 / 462 (6.71%)
         occurrences all number
    35
    36
    Back pain
         subjects affected / exposed
    35 / 465 (7.53%)
    34 / 462 (7.36%)
         occurrences all number
    45
    36
    Pain in extremity
         subjects affected / exposed
    23 / 465 (4.95%)
    36 / 462 (7.79%)
         occurrences all number
    23
    39
    Infections and infestations
    Influenza
         subjects affected / exposed
    31 / 465 (6.67%)
    28 / 462 (6.06%)
         occurrences all number
    35
    33
    Nasopharyngitis
         subjects affected / exposed
    82 / 465 (17.63%)
    69 / 462 (14.94%)
         occurrences all number
    136
    109
    Upper respiratory tract infection
         subjects affected / exposed
    47 / 465 (10.11%)
    73 / 462 (15.80%)
         occurrences all number
    65
    108
    Urinary tract infection
         subjects affected / exposed
    41 / 465 (8.82%)
    41 / 462 (8.87%)
         occurrences all number
    71
    68

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    This study was not powered for the analysis of some secondary endpoints as a stand-alone study. It was pre-specified in the study protocol to combine the data with study COMB157G2302 to address these endpoints.
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