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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo controlled, Parallel-Group, Dose-Ranging Study to Investigate the MRI Efficacy and Safety of Six Months administration of Ofatumumab in Subjects with Relapsing-Remitting Multiple Sclerosis (RRMS)

    Summary
    EudraCT number
    		 2011-002333-19
    Trial protocol
    		 DE   ES   NL   DK   CZ   IT  
    Global end of trial date
    10 Jun 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    19 Mar 2017
    First version publication date
    15 Apr 2016
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Changes required.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    OMS112831
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    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
    16 Sep 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether ofatumumab 3, 30 or 60 milligrams (mg) given subcutaneously (SQ), reduces the cumulative number of new T1 GdE brain lesions over a period of 12 weeks, as compared with placebo, in subjects with RRMS
    Protection of trial subjects
    Only the first 12 weeks of the study were placebo-controlled, shortening the duration of the placebo-control period in this Phase II trial, lowering the potential risks associated with exposure to placebo. All participants received pre-medication, before each subcutaneous injection of Investigational product (IP), to minimise effects of B-cell lysis. This study did not restrict the use of rescue medications (e.g. glucocorticoids) to manage the occurrence of a relapse. However, due to the potential interference with the Magnetic resonance imaging (MRI), if a relapse requiring management with glucocorticoids occurred around the time of a scheduled MRI, the MRI was to be rescheduled to ensure that the subject has a minimum of a 1 week washout period following completion of treatment with glucocorticoids. An Independent Data Monitoring Committee (IDMC) evaluated risks relative to benefits through review of safety and efficacy information on an ongoing basis during the study. A PML Adjudication Committee reviewed all cases of Progressive Multifocal Leukoencephalopathy(PML) and suspected PML, on an ongoing basis during the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Nov 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Russian Federation: 66
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    United States: 49
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Spain: 30
    Country: Number of subjects enrolled
    Bulgaria: 16
    Country: Number of subjects enrolled
    Czech Republic: 22
    Country: Number of subjects enrolled
    Denmark: 10
    Country: Number of subjects enrolled
    Germany: 24
    Country: Number of subjects enrolled
    Italy: 3
    Worldwide total number of subjects
    232
    EEA total number of subjects
    111
    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)
    232
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 A participant (par.) completes the study if he/she completes all assessments up to and including the 24 Week Follow-up Phase (Week 48) without prematurely discontinuing.

    Pre-assignment
    Screening details
    		 A total of 324 participants with Relapsing-Remitting Multiple Sclerosis (RRMS) were screened and 232 par. were randomized to the 24 Week Treatment Phase (weeks 0-12 were placebo controlled) of the study. A total of 231 par. received at least one dose of double-blind Investigational Product (IP) and were included in the Safety Population (pop.).

    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, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo/Ofatumumab 3 mg
    Arm description
    		 Participants received ofatumumab matching placebo subcutaneous (SC) injection every 4 weeks (q4w) from Week 0 to Week 20, except on Week 12 participants received 3 milligrams (mg) ofatumumab SC injection. Participants also received pre-medication of acetaminophen 1 gram (g) and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 ml Placebo doses to match the active doses using normal saline (sterile, pyrogen-free 0.9% Sodium Chloride [NaCl]) subcutaneous injection

    Arm title
    		 Ofatumumab 3 mg q12w
    Arm description
    		 Participants received ofatumumab 3 mg SC injection every 12th week (q12w) on Week 1 and Week 12. Participants received matching placebo on Weeks 0, 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ofatumumab 3 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.03 milliliter (mL) Ofatumumab 100 milligrams (mg)/mL and 0.97mL sterile, pyrogen-free 0.9% NaCl subcutaneous injection

    Arm title
    		 Ofatumumab 30 mg q12w
    Arm description
    		 Participants received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 30 mg SC injection every 12th week (q12w) on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ofatumumab 30 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.3mL Ofatumumab 100mg/mL and 0.7mL sterile, pyrogen-free 0.9% NaCl subcutaneous injection

    Arm title
    		 Ofatumumab 60 mg q12w
    Arm description
    		 Participants received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection every 12th week (q12w) on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ofatumumab 60 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.6mL Ofatumumab 100mg/mL and 0.4mL sterile, pyrogen-free 0.9% NaCl subcutaneous injection

    Arm title
    		 Ofatumumab 60mg q4w
    Arm description
    		 Participants received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection every 4th week (q4w) from Week 1 to Week 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ofatumumab 60 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.6mL Ofatumumab 100mg/mL and 0.4mL sterile, pyrogen-free 0.9% NaCl subcutaneous injection

    Number of subjects in period 1 [1]
    		Placebo/Ofatumumab 3 mg Ofatumumab 3 mg q12w Ofatumumab 30 mg q12w Ofatumumab 60 mg q12w Ofatumumab 60mg q4w
    Started
    67
    34
    32
    34
    64
    Completed to Week 12
    65
    31
    30
    33
    60
    Completed to Week 24
    64
    29
    30
    33
    58
    Completed to Week 48
    63
    30
    30
    32
    57
    Completed to Week IFU
    11 [2]
    14 [3]
    12 [4]
    15 [5]
    36 [6]
    Completed
    61
    28
    28
    32
    56
    Not completed
    6
    6
    4
    2
    8
         Physician decision
    1
    -
    1
    -
    1
         Consent withdrawn by subject
    2
    1
    -
    1
    3
         Adverse event, non-fatal
    -
    4
    2
    -
    2
         Protocol-defined Stopping Criteria
    1
    1
    -
    -
    2
         Lost to follow-up
    -
    -
    -
    1
    -
         Lack of efficacy
    1
    -
    -
    -
    -
         Protocol deviation
    1
    -
    1
    -
    -
    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: A total of 324 participants with Relapsing-Remitting Multiple Sclerosis (RRMS) were screened and 232 par. were randomized to the 24 Week Treatment Phase (weeks 0-12 were placebo controlled) of the study. A total of 231 par. received at least one dose of double-blind Investigational Product (IP) and were included in the Safety Population.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: A participant (par.) completes the study if he/she completes all assessments up to and including the 24 Week Follow-up Phase (Week 48) without prematurely discontinuing. The # of participants completing each milestone is also presented.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: A participant (par.) completes the study if he/she completes all assessments up to and including the 24 Week Follow-up Phase (Week 48) without prematurely discontinuing. The # of participants completing each milestone is also presented.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: A participant (par.) completes the study if he/she completes all assessments up to and including the 24 Week Follow-up Phase (Week 48) without prematurely discontinuing. The # of participants completing each milestone is also presented.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: A participant (par.) completes the study if he/she completes all assessments up to and including the 24 Week Follow-up Phase (Week 48) without prematurely discontinuing. The # of participants completing each milestone is also presented.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: A participant (par.) completes the study if he/she completes all assessments up to and including the 24 Week Follow-up Phase (Week 48) without prematurely discontinuing. The # of participants completing each milestone is also presented.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo/Ofatumumab 3 mg
    Reporting group description
    		 Participants received ofatumumab matching placebo subcutaneous (SC) injection every 4 weeks (q4w) from Week 0 to Week 20, except on Week 12 participants received 3 milligrams (mg) ofatumumab SC injection. Participants also received pre-medication of acetaminophen 1 gram (g) and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.

    Reporting group title
    Ofatumumab 3 mg q12w
    Reporting group description
    		 Participants received ofatumumab 3 mg SC injection every 12th week (q12w) on Week 1 and Week 12. Participants received matching placebo on Weeks 0, 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.

    Reporting group title
    Ofatumumab 30 mg q12w
    Reporting group description
    		 Participants received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 30 mg SC injection every 12th week (q12w) on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.

    Reporting group title
    Ofatumumab 60 mg q12w
    Reporting group description
    		 Participants received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection every 12th week (q12w) on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.

    Reporting group title
    Ofatumumab 60mg q4w
    Reporting group description
    		 Participants received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection every 4th week (q4w) from Week 1 to Week 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.

    Reporting group values
    		 Placebo/Ofatumumab 3 mg Ofatumumab 3 mg q12w Ofatumumab 30 mg q12w Ofatumumab 60 mg q12w Ofatumumab 60mg q4w Total
    Number of subjects
    		 67 34 32 34 64 231
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.7 ± 9.38 38.1 ± 8.29 37.2 ± 10.04 37.3 ± 9.67 36.2 ± 9.57 -
    Gender categorical
    Units: Subjects
        Female
    		 46 22 24 22 41 155
        Male
    		 21 12 8 12 23 76
    Race, Customized
    Units: Subjects
        African American/African Heritage
    		 1 0 0 0 1 2
        Asian - East Asian Heritage
    		 0 0 1 0 0 1
        White - White/Caucasian/European Heritage
    		 65 34 31 34 61 225
        Mixed Race
    		 1 0 0 0 2 3

    End points

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    End points reporting groups
    Reporting group title
    Placebo/Ofatumumab 3 mg
    Reporting group description
    		 Participants received ofatumumab matching placebo subcutaneous (SC) injection every 4 weeks (q4w) from Week 0 to Week 20, except on Week 12 participants received 3 milligrams (mg) ofatumumab SC injection. Participants also received pre-medication of acetaminophen 1 gram (g) and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.

    Reporting group title
    Ofatumumab 3 mg q12w
    Reporting group description
    		 Participants received ofatumumab 3 mg SC injection every 12th week (q12w) on Week 1 and Week 12. Participants received matching placebo on Weeks 0, 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.

    Reporting group title
    Ofatumumab 30 mg q12w
    Reporting group description
    		 Participants received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 30 mg SC injection every 12th week (q12w) on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.

    Reporting group title
    Ofatumumab 60 mg q12w
    Reporting group description
    		 Participants received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection every 12th week (q12w) on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.

    Reporting group title
    Ofatumumab 60mg q4w
    Reporting group description
    		 Participants received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection every 4th week (q4w) from Week 1 to Week 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.

    Primary: Cumulative number of new gadolinium-enhancing T1 lesions at Week 12

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    End point title
    		 Cumulative number of new gadolinium-enhancing T1 lesions at Week 12
    End point description
    The cumulative number of new gadolinium-enhancing (GdE) T1 lesion at Wk 12 were analyzed from screen based on magnetic resonance imaging (MRI) brain scans at Weeks 4, 8, 12. The endpoint was analyzed using an Emax model adjusting for the presence/absence of GdE lesions on the Screening MRI and assuming the number of new lesions followed a negative binomial distribution. Dose was fitted as a continuous variable. The number of scans contributing to the cumulative number of lesions was fitted as an offset. Estimates of the rate of cumulative number of new gadolinium-enhancing lesions per scan at Wk 12 were determined from the model. The all evaluable scans (AES) dataset was used which included all evaluable on-treatment MRI scans for each par. analysed. Intent-to-Treat (ITT) Population: all randomized par. who received at least one dose of investigational product and who had at least one post screen MRI assessment. See notes about ITT pop. in statistical analyses and caveats sections.
    End point type
    Primary
    End point timeframe
    Week (Wk) 12
    End point values
    		 Placebo/Ofatumumab 3 mg Ofatumumab 3 mg q12w Ofatumumab 30 mg q12w Ofatumumab 60 mg q12w Ofatumumab 60mg q4w
    Number of subjects analysed
    67 [1]
    33 [2]
    30 [3]
    33 [4]
    63 [5]
    Units: Cumulative number of lesions
        arithmetic mean (standard deviation)
    4.2 ± 7.57
    1.7 ± 3.29
    2.2 ± 3.41
    2.2 ± 3.7
    1.2 ± 2.83
    Notes
    [1] - ITT Population. Only those participants available at the specified time points were analyzed.
    [2] - ITT Population. Only those participants available at the specified time points were analyzed.
    [3] - ITT Population. Only those participants available at the specified time points were analyzed.
    [4] - ITT Population. Only those participants available at the specified time points were analyzed.
    [5] - ITT Population. Only those participants available at the specified time points were analyzed.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Note: There is a discrepancy in the number of par. in ITT populations at Wk 24 and Wk 48: 228 and 229 respectively. This resulted from a data issue: one par was incorrectly excluded from ITT pop. at Wk 24, but correctly included in Wk 48. This error affects all source tables, analyses relating to ITT and per protocol populations, primary endpoint and secondary MRI endpoints reported at Wk 24. This discrepancy affects all statistical analyses, but not summary statistics.
    Comparison groups
    Placebo/Ofatumumab 3 mg v Ofatumumab 3 mg q12w
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.001
    Method
    		 Non-Linear Emax Model
    Parameter type
    		 Ratio
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.221
         upper limit
    		 0.548
    Notes
    [6] - The incorrect exclusion of one par. from ITT pop. at Wk 24 was not considered to impact overall interpretation of data: no updates were made to source tables/analyses. This par. had withdrawn early, having never received a dose of active study drug.
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Placebo/Ofatumumab 3 mg v Ofatumumab 30 mg q12w
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Non-Linear Emax Model
    Parameter type
    		 Ratio
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.221
         upper limit
    		 0.548
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Placebo/Ofatumumab 3 mg v Ofatumumab 60 mg q12w
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Non-Linear Emax Model
    Parameter type
    		 Ratio
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.221
         upper limit
    		 0.548
    Statistical analysis title
    		 Statistical analysis 4
    Comparison groups
    Placebo/Ofatumumab 3 mg v Ofatumumab 60mg q4w
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Non-Linear Emax Model
    Parameter type
    		 Ratio
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.221
         upper limit
    		 0.548

    Secondary: Cumulative number of new gadolinium-enhancing T1 lesions at Week 24

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    End point title
    		 Cumulative number of new gadolinium-enhancing T1 lesions at Week 24
    End point description
    The cumulative number of new GdE T1 lesion at Week 24 were analyzed from screen based on MRI brain scans at Weeks 4, 8, 12, 16, 20 and 24. The endpoint was analyzed using a generalized linear model assuming an underlying negative binomial distribution with a log-link function, adjusted for treatment and presence/absence of GdE lesions on the Screening MRI. Treatment group was fitted as a categorical variable. The number of scans contributing to the cumulative number of lesions was fitted as an offset. Estimates of the rate of cumulative number of new GdE T1 lesions per scan at Week 24 were determined from the model. The AES dataset was used which included all evaluable on-treatment MRI scans for each participant analyzed. Pairwise comparisons were conducted for each group compared to placebo.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Placebo/Ofatumumab 3 mg Ofatumumab 3 mg q12w Ofatumumab 30 mg q12w Ofatumumab 60 mg q12w Ofatumumab 60mg q4w
    Number of subjects analysed
    67 [7]
    33 [8]
    30 [9]
    33 [10]
    63 [11]
    Units: Cumulative number of lesions
        arithmetic mean (standard deviation)
    5.6 ± 9.34
    2.2 ± 3.8
    2.5 ± 3.88
    2.2 ± 3.83
    1.4 ± 3.04
    Notes
    [7] - ITT Population. Only those participants available at the specified time points were analyzed.
    [8] - ITT Population. Only those participants available at the specified time points were analyzed.
    [9] - ITT Population. Only those participants available at the specified time points were analyzed.
    [10] - ITT Population. Only those participants available at the specified time points were analyzed.
    [11] - ITT Population. Only those participants available at the specified time points were analyzed.
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo/Ofatumumab 3 mg v Ofatumumab 3 mg q12w
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 General Linear Model
    Parameter type
    		 Ratio
    Point estimate
    0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.72
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Placebo/Ofatumumab 3 mg v Ofatumumab 30 mg q12w
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 General Linear Model
    Parameter type
    		 Ratio
    Point estimate
    0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.72
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Placebo/Ofatumumab 3 mg v Ofatumumab 60 mg q12w
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 General Linear Model
    Parameter type
    		 Ratio
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 0.65
    Statistical analysis title
    		 Statistical analysis 4
    Comparison groups
    Placebo/Ofatumumab 3 mg v Ofatumumab 60mg q4w
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 General Linear Model
    Parameter type
    		 Ratio
    Point estimate
    0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.13
         upper limit
    		 0.39

    Secondary: Change from Baseline in brain volume at Week 24 and Week 48

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    End point title
    		 Change from Baseline in brain volume at Week 24 and Week 48
    End point description
    Brain volume is a measure of brain size determined by a MRI scan. Baseline is defined as the participant’s last available assessment prior to initiation of IP (i.e. Screening). Change from Baseline was calculated by subtracting the Baseline value from the post-Baseline value. These are summary statistics only and no statistical analysis was performed on this endpoint. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and Week 48
    End point values
    		 Placebo/Ofatumumab 3 mg Ofatumumab 3 mg q12w Ofatumumab 30 mg q12w Ofatumumab 60 mg q12w Ofatumumab 60mg q4w
    Number of subjects analysed
    67 [12]
    33 [13]
    32 [14]
    33 [15]
    63 [16]
    Units: Cubic centimeters
    arithmetic mean (standard deviation)
        Week 24, n=25, 12, 16, 12, 22
    -13.5 ± 26.96
    -7.2 ± 22.26
    -8.4 ± 26.62
    -13.3 ± 34.02
    -1.4 ± 56.42
        Week 48, n=28, 12, 16, 11, 19
    -22 ± 38.22
    -12.9 ± 14.55
    -5 ± 28.84
    -7.3 ± 29.16
    -11.8 ± 55.3
    Notes
    [12] - ITT Population
    [13] - ITT Population
    [14] - ITT Population
    [15] - ITT Population
    [16] - ITT Population
    No statistical analyses for this end point

    Secondary: Cumulative number of persistent gadolinium-enhancing brain lesions on T1-weighted MRI at Week 12

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    End point title
    		 Cumulative number of persistent gadolinium-enhancing brain lesions on T1-weighted MRI at Week 12
    End point description
    The cumulative number of persistent GdE T1 lesions at Week 12 were analyzed from screen based on MRI scans at Weeks 4, 8, and 12. These are summary statistics only and no statistical analysis was performed on this endpoint. The AES dataset was used which included all evaluable on-treatment MRI scans for each participant analyzed.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo/Ofatumumab 3 mg Ofatumumab 3 mg q12w Ofatumumab 30 mg q12w Ofatumumab 60 mg q12w Ofatumumab 60mg q4w
    Number of subjects analysed
    67 [17]
    34 [18]
    30 [19]
    33 [20]
    63 [21]
    Units: Number of lesions per scan
        arithmetic mean (standard deviation)
    3.2 ± 7.41
    1.2 ± 1.94
    2.3 ± 3.94
    1.8 ± 3.31
    1.8 ± 4.81
    Notes
    [17] - ITT Population. Only those participants available at the specified time points were analyzed.
    [18] - ITT Population. Only those participants available at the specified time points were analyzed.
    [19] - ITT Population. Only those participants available at the specified time points were analyzed.
    [20] - ITT Population. Only those participants available at the specified time points were analyzed.
    [21] - ITT Population. Only those participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Cumulative number of all (new plus persistent) gadolinium-enhancing brain lesions on T1-weighted MRI at Week 12

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    End point title
    		 Cumulative number of all (new plus persistent) gadolinium-enhancing brain lesions on T1-weighted MRI at Week 12
    End point description
    The cumulative number of all (new plus persistent) GdE T1 lesion at Week 12 were analyzed from screen based on MRI brain scans at Weeks 4, 8 and 12. The endpoint was analyzed using a generalized linear model assuming an underlying negative binomial distribution with a log-link function, adjusted for treatment and presence/absence of GdE lesions on the Screening MRI. Treatment group was fitted as a categorical variable. The number of scans contributing to the cumulative number of lesions was fitted as an offset. Estimates of the rate of cumulative number of all (new plus persistent) GdE T1 lesions per scan at Week 12 were determined from the model. The AES dataset was used which included all evaluable on-treatment MRI scans for each participant analyzed. Pairwise comparisons were conducted for each group compared to placebo.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo/Ofatumumab 3 mg Ofatumumab 3 mg q12w Ofatumumab 30 mg q12w Ofatumumab 60 mg q12w Ofatumumab 60mg q4w
    Number of subjects analysed
    67 [22]
    33 [23]
    30 [24]
    33 [25]
    63 [26]
    Units: Cumulative number of lesions
        arithmetic mean (standard deviation)
    7.4 ± 13.9
    2.9 ± 4.62
    4.5 ± 7.09
    4 ± 6.7
    3.1 ± 6.82
    Notes
    [22] - ITT Population. Only those participants available at the specified time points were analyzed.
    [23] - ITT Population. Only those participants available at the specified time points were analyzed.
    [24] - ITT Population. Only those participants available at the specified time points were analyzed.
    [25] - ITT Population. Only those participants available at the specified time points were analyzed.
    [26] - ITT Population. Only those participants available at the specified time points were analyzed.
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo/Ofatumumab 3 mg v Ofatumumab 3 mg q12w
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 General Linear Model
    Parameter type
    		 Ratio
    Point estimate
    0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 0.6
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Placebo/Ofatumumab 3 mg v Ofatumumab 30 mg q12w
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.075
    Method
    		 General Linear Model
    Parameter type
    		 Ratio
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 1.06
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Placebo/Ofatumumab 3 mg v Ofatumumab 60 mg q12w
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.035
    Method
    		 General Linear Model
    Parameter type
    		 Ratio
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 0.95
    Statistical analysis title
    		 Statistical analysis 4
    Comparison groups
    Placebo/Ofatumumab 3 mg v Ofatumumab 60mg q4w
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 General Linear Model
    Parameter type
    		 Ratio
    Point estimate
    0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 0.55

    Secondary: Total volume of new gadolinium-enhancing brain lesions on T1-weighted MRI at Week 12

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    End point title
    		 Total volume of new gadolinium-enhancing brain lesions on T1-weighted MRI at Week 12
    End point description
    Lesion volume is a measure of lesion size determined by a MRI brain scan. The cumulative volume of new GdE T1 lesions at Week 12 were analyzed from screen based on MRI brain scans at Weeks 4, 8 and 12. The endpoint was analyzed using a generalized linear model assuming an underlying negative binomial distribution with a log-link function, adjusted for treatment and presence/absence of GdE lesions on the Screening MRI. Treatment group was fitted as a categorical variable. The number of scans contributing to the cumulative volume of lesions was fitted as an offset. Estimates of the rate of cumulative volume of new GdE T1 lesions per scan at Week 12 were determined from the model. The AES dataset was used which included all evaluable on-treatment MRI scans for each participant analyzed. Pairwise comparisons were conducted for each group compared to placebo.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo/Ofatumumab 3 mg Ofatumumab 3 mg q12w Ofatumumab 30 mg q12w Ofatumumab 60 mg q12w Ofatumumab 60mg q4w
    Number of subjects analysed
    67 [27]
    34 [28]
    30 [29]
    33 [30]
    63 [31]
    Units: Cubic millimeter (mm^3)
        arithmetic mean (standard deviation)
    607.5 ± 1090.89
    226.5 ± 449.37
    452.9 ± 682.33
    248.6 ± 457.62
    146.6 ± 304.89
    Notes
    [27] - ITT Population. Only those participants available at the specified time points were analyzed.
    [28] - ITT Population. Only those participants available at the specified time points were analyzed.
    [29] - ITT Population. Only those participants available at the specified time points were analyzed.
    [30] - ITT Population. Only those participants available at the specified time points were analyzed.
    [31] - ITT Population. Only those participants available at the specified time points were analyzed.
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Ofatumumab 3 mg q12w v Placebo/Ofatumumab 3 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.026
    Method
    		 General Linear Model
    Parameter type
    		 Ratio
    Point estimate
    0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.06
         upper limit
    		 0.84
    Statistical analysis title
    		 Statstical analysis 2
    Comparison groups
    Placebo/Ofatumumab 3 mg v Ofatumumab 30 mg q12w
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.296
    Method
    		 General Linear Model
    Parameter type
    		 Ratio
    Point estimate
    0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.13
         upper limit
    		 1.86
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Placebo/Ofatumumab 3 mg v Ofatumumab 60 mg q12w
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.285
    Method
    		 General Linear Model
    Parameter type
    		 Ratio
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 1.78
    Statistical analysis title
    		 Statistical analysis 4
    Comparison groups
    Placebo/Ofatumumab 3 mg v Ofatumumab 60mg q4w
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.009
    Method
    		 Non-Linear Emax Model
    Parameter type
    		 Ratio
    Point estimate
    0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 0.71

    Secondary: Total volume of all (new and persistent) gadolinium-enhancing brain lesions on T1-weighted MRI at Week 12

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    End point title
    		 Total volume of all (new and persistent) gadolinium-enhancing brain lesions on T1-weighted MRI at Week 12
    End point description
    Lesion volume is a measure of lesion size determined by a MRI brain scan. The cumulative volume of all (new and persistent) GdE T1 lesions at Week 12 were analyzed from screen based on MRI brain scans at Weeks 4, 8 and 12. The endpoint was analyzed using a generalized linear model assuming an underlying negative binomial distribution with a log-link function, adjusted for treatment and presence/absence of GdE lesions on the Screening MRI. Treatment group was fitted as a categorical variable. The number of scans contributing to the cumulative volume of lesions was fitted as an offset. Estimates of the rate of cumulative volume of all (new and persistent) GdE T1 lesions per scan at Week 12 were determined from the model. The AES dataset was used which included all evaluable on-treatment MRI scans for each participant analyzed. Pairwise comparisons were conducted for each group compared to placebo.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo/Ofatumumab 3 mg Ofatumumab 3 mg q12w Ofatumumab 30 mg q12w Ofatumumab 60 mg q12w Ofatumumab 60mg q4w
    Number of subjects analysed
    67 [32]
    33 [33]
    30 [34]
    33 [35]
    63 [36]
    Units: mm^3
        arithmetic mean (standard deviation)
    1039.6 ± 1809.97
    386.2 ± 628.41
    886.2 ± 1637.47
    426.5 ± 679.44
    344.4 ± 735.57
    Notes
    [32] - ITT Population. Only those participants available at the specified time points were analyzed.
    [33] - ITT Population. Only those participants available at the specified time points were analyzed.
    [34] - ITT Population. Only those participants available at the specified time points were analyzed.
    [35] - ITT Population. Only those participants available at the specified time points were analyzed.
    [36] - ITT Population. Only those participants available at the specified time points were analyzed.
    Statistical analysis title
    		 Statistical analysis
    Comparison groups
    Placebo/Ofatumumab 3 mg v Ofatumumab 3 mg q12w
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 General Linear Model
    Parameter type
    		 Ratio
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 0.58
    Statistical analysis title
    		 Statistical analysis
    Comparison groups
    Placebo/Ofatumumab 3 mg v Ofatumumab 30 mg q12w
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.248
    Method
    		 General Linear Model
    Parameter type
    		 Ratio
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 1.63
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Placebo/Ofatumumab 3 mg v Ofatumumab 60 mg q12w
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.181
    Method
    		 General Linear Model
    Parameter type
    		 Ratio
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 1.43
    Statistical analysis title
    		 Statistical analysis 4
    Comparison groups
    Ofatumumab 60mg q4w v Placebo/Ofatumumab 3 mg
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 General Linear Model
    Parameter type
    		 Ratio
    Point estimate
    0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 0.62

    Secondary: Cumulative number of new and newly enlarging gadolinium-enhancing T2 lesions at Week 12

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    End point title
    		 Cumulative number of new and newly enlarging gadolinium-enhancing T2 lesions at Week 12
    End point description
    The cumulative number of new and newly enlarging GdE T2 lesions (NET2L) at Week 12 were analyzed from screen based on MRI brain scans at Weeks 4, 8 and 12. The endpoint was analyzed using a generalized linear model assuming an underlying negative binomial distribution with a log-link function, adjusted for treatment and presence/absence of GdE lesions on the Screening MRI. Treatment group was fitted as a categorical variable. The number of scans contributing to the cumulative number of lesions was fitted as an offset. Estimates of the rate of cumulative number of NET2L per scan at Week 12 were determined from the model. The AES dataset was used which included all evaluable on-treatment MRI scans for each participant analyzed. Pairwise comparisons were conducted for each group compared to placebo
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo/Ofatumumab 3 mg Ofatumumab 3 mg q12w Ofatumumab 30 mg q12w Ofatumumab 60 mg q12w Ofatumumab 60mg q4w
    Number of subjects analysed
    67 [37]
    33 [38]
    30 [39]
    33 [40]
    63 [41]
    Units: Cumulative number of lesions
        arithmetic mean (standard deviation)
    3.7 ± 6.72
    1.2 ± 2.38
    1.6 ± 2.79
    1.7 ± 2.67
    0.8 ± 1.55
    Notes
    [37] - ITT Population. Only those participants available at the specified time points were analyzed.
    [38] - ITT Population. Only those participants available at the specified time points were analyzed.
    [39] - ITT Population. Only those participants available at the specified time points were analyzed.
    [40] - ITT Population. Only those participants available at the specified time points were analyzed.
    [41] - ITT Population. Only those participants available at the specified time points were analyzed.
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Ofatumumab 3 mg q12w v Placebo/Ofatumumab 3 mg
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 General Linear Model
    Parameter type
    		 Ratio
    Point estimate
    0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 0.58
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Placebo/Ofatumumab 3 mg v Ofatumumab 30 mg q12w
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 General Linear Model
    Parameter type
    		 Ratio
    Point estimate
    0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 0.68
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Placebo/Ofatumumab 3 mg v Ofatumumab 60 mg q12w
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 General Linear Model
    Parameter type
    		 Ratio
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.21
         upper limit
    		 0.77
    Statistical analysis title
    		 Statistical analysis 4
    Comparison groups
    Placebo/Ofatumumab 3 mg v Ofatumumab 60mg q4w
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 General Linear Model
    Parameter type
    		 Ratio
    Point estimate
    0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.11
         upper limit
    		 0.35

    Secondary: Total volume of new and/or newly enlarging T2 lesions at Week 12

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    End point title
    		 Total volume of new and/or newly enlarging T2 lesions at Week 12
    End point description
    Lesion volume is a measure of lesion size determined by a MRI brain scan. T2 lesions, are indicative of brain myelin content.The cumulative volume of new and/or newly enlarging T2 lesions at Week 12 were analyzed from screen based on MRI brain scans at Weeks 4, 8, and 12. The AES dataset was used which included all evaluable on-treatment MRI scans for each participant.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo/Ofatumumab 3 mg Ofatumumab 3 mg q12w Ofatumumab 30 mg q12w Ofatumumab 60 mg q12w Ofatumumab 60mg q4w
    Number of subjects analysed
    67 [42]
    34 [43]
    30 [44]
    33 [45]
    63 [46]
    Units: mm^3
        arithmetic mean (standard deviation)
    1204.5 ± 3426.79
    279.9 ± 695.75
    611.3 ± 1042.06
    293.8 ± 576.35
    167.9 ± 450.65
    Notes
    [42] - ITT Population. Only those participants available at the specified time points were analyzed.
    [43] - ITT Population. Only those participants available at the specified time points were analyzed.
    [44] - ITT Population. Only those participants available at the specified time points were analyzed.
    [45] - ITT Population. Only those participants available at the specified time points were analyzed.
    [46] - ITT Population. Only those participants available at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Cumulative number of new T1 hypointense lesions at Week 24 and Week 48

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    End point title
    		 Cumulative number of new T1 hypointense lesions at Week 24 and Week 48
    End point description
    The cumulative number of new T1 hypointense lesions at week 24 were analyzed from screen based on MRI brain scans at Weeks 4, 8, 12, 16, 20 and 24. The AES dataset was used which included all evaluable on-treatment MRI scans for each participant. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Week 24 and Week 48
    End point values
    		 Placebo/Ofatumumab 3 mg Ofatumumab 3 mg q12w Ofatumumab 30 mg q12w Ofatumumab 60 mg q12w Ofatumumab 60mg q4w
    Number of subjects analysed
    67 [47]
    34 [48]
    32 [49]
    33 [50]
    63 [51]
    Units: Number of lesions
    arithmetic mean (standard deviation)
        Week 24, n=67, 34, 30, 33, 63
    0.4 ± 0.96
    0.4 ± 1.26
    0.5 ± 1.01
    0.5 ± 1.12
    0.3 ± 0.78
        Week 48, n=67, 34, 32, 33, 63
    0.6 ± 1.27
    0.5 ± 1.26
    0.5 ± 0.98
    0.6 ± 1.25
    0.3 ± 0.96
    Notes
    [47] - ITT Population
    [48] - ITT Population
    [49] - ITT Population
    [50] - ITT Population
    [51] - ITT Population
    No statistical analyses for this end point

    Secondary: Cumulative volume of new T1 hypointense lesions at Week 24 and Week 48

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    End point title
    		 Cumulative volume of new T1 hypointense lesions at Week 24 and Week 48
    End point description
    Lesion volume is a measure of lesion size determined by a MRI brain scan. Baseline is defined as the participant’s last available assessment prior to initiation of IP. Change from Baseline was calculated by subtracting the Baseline value from the post-Baseline value. The AES dataset was used which included all evaluable on-treatment MRI scans for each participant. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 and Week 48
    End point values
    		 Placebo/Ofatumumab 3 mg Ofatumumab 3 mg q12w Ofatumumab 30 mg q12w Ofatumumab 60 mg q12w Ofatumumab 60mg q4w
    Number of subjects analysed
    67 [52]
    34 [53]
    32 [54]
    33 [55]
    63 [56]
    Units: mm^3
    arithmetic mean (standard deviation)
        Week 24, n=67, 34, 30, 33, 63
    86.9 ± 240.4
    43.1 ± 131.96
    67.4 ± 147
    65 ± 139.14
    42.9 ± 140.93
        Week 48, n=67, 34, 32, 33, 63
    113.6 ± 270.89
    54.2 ± 137.74
    63.2 ± 143.14
    116.3 ± 370.35
    53.2 ± 173.62
    Notes
    [52] - ITT Population
    [53] - ITT Population
    [54] - ITT Population
    [55] - ITT Population
    [56] - ITT Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 24).
    Adverse event reporting additional description
    SAEs and non-serious AEs were reported for members of the safety population, comprised of all participants who were randomized to treatment, and received at least one dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Placebo/Ofatumumab 3 mg
    Reporting group description
    		 Participants received ofatumumab matching placebo subcutaneous (SC) injection every 4 weeks (q4w) from Week 0 to Week 20, except on Week 12 participants received 3 milligrams (mg) ofatumumab SC injection. Participants also received pre-medication of acetaminophen 1 gram (g) and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.

    Reporting group title
    Ofatumumab 3 mg q12w
    Reporting group description
    		 Participants received ofatumumab 3 mg SC injection every 12th week (q12w) on Week 1 and Week 12. Participants received matching placebo on Weeks 0, 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.

    Reporting group title
    Ofatumumab 30 mg q12w
    Reporting group description
    		 Participants received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 30 mg SC injection every 12th week (q12w) on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.

    Reporting group title
    Ofatumumab 60 mg q12w
    Reporting group description
    		 Participants received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection every 12th week (q12w) on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.

    Reporting group title
    Ofatumumab 60mg q4w
    Reporting group description
    		 Participants received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection every 4th week (q4w) from Week 1 to Week 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.

    Serious adverse events
    		 Placebo/Ofatumumab 3 mg Ofatumumab 3 mg q12w Ofatumumab 30 mg q12w Ofatumumab 60 mg q12w Ofatumumab 60mg q4w
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 34 (2.94%)
    0 / 32 (0.00%)
    1 / 34 (2.94%)
    4 / 64 (6.25%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Injection related reaction
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 34 (0.00%)
    0 / 32 (0.00%)
    0 / 34 (0.00%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 34 (0.00%)
    0 / 32 (0.00%)
    1 / 34 (2.94%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 34 (0.00%)
    0 / 32 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 34 (2.94%)
    0 / 32 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 34 (2.94%)
    0 / 32 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 34 (0.00%)
    0 / 32 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo/Ofatumumab 3 mg Ofatumumab 3 mg q12w Ofatumumab 30 mg q12w Ofatumumab 60 mg q12w Ofatumumab 60mg q4w
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 67 (61.19%)
    20 / 34 (58.82%)
    23 / 32 (71.88%)
    22 / 34 (64.71%)
    47 / 64 (73.44%)
    Investigations
    Reticulocyte count decreased
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 34 (0.00%)
    2 / 32 (6.25%)
    1 / 34 (2.94%)
    1 / 64 (1.56%)
         occurrences all number
    1
    0
    2
    1
    1
    Blood immunoglobulin G decreased
         subjects affected / exposed
    0 / 67 (0.00%)
    2 / 34 (5.88%)
    0 / 32 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    2
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 34 (0.00%)
    2 / 32 (6.25%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Injury, poisoning and procedural complications
    Injection related reaction
         subjects affected / exposed
    18 / 67 (26.87%)
    16 / 34 (47.06%)
    13 / 32 (40.63%)
    17 / 34 (50.00%)
    42 / 64 (65.63%)
         occurrences all number
    41
    49
    28
    56
    101
    Fall
         subjects affected / exposed
    0 / 67 (0.00%)
    2 / 34 (5.88%)
    1 / 32 (3.13%)
    0 / 34 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    1
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 67 (10.45%)
    2 / 34 (5.88%)
    2 / 32 (6.25%)
    2 / 34 (5.88%)
    6 / 64 (9.38%)
         occurrences all number
    11
    2
    2
    2
    7
    Dizziness
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 34 (0.00%)
    1 / 32 (3.13%)
    0 / 34 (0.00%)
    4 / 64 (6.25%)
         occurrences all number
    0
    0
    2
    0
    5
    Neuralgia
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 34 (0.00%)
    2 / 32 (6.25%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    8 / 67 (11.94%)
    0 / 34 (0.00%)
    3 / 32 (9.38%)
    2 / 34 (5.88%)
    3 / 64 (4.69%)
         occurrences all number
    9
    0
    3
    2
    4
    Pyrexia
         subjects affected / exposed
    2 / 67 (2.99%)
    2 / 34 (5.88%)
    2 / 32 (6.25%)
    1 / 34 (2.94%)
    1 / 64 (1.56%)
         occurrences all number
    2
    2
    3
    1
    1
    Injection site pain
         subjects affected / exposed
    0 / 67 (0.00%)
    2 / 34 (5.88%)
    0 / 32 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    2
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 67 (1.49%)
    2 / 34 (5.88%)
    0 / 32 (0.00%)
    1 / 34 (2.94%)
    1 / 64 (1.56%)
         occurrences all number
    1
    2
    0
    1
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    4 / 67 (5.97%)
    0 / 34 (0.00%)
    1 / 32 (3.13%)
    1 / 34 (2.94%)
    2 / 64 (3.13%)
         occurrences all number
    4
    0
    1
    1
    2
    Diarrhoea
         subjects affected / exposed
    4 / 67 (5.97%)
    0 / 34 (0.00%)
    0 / 32 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    5
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 67 (2.99%)
    2 / 34 (5.88%)
    1 / 32 (3.13%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    2
    2
    2
    0
    1
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    0 / 67 (0.00%)
    2 / 34 (5.88%)
    0 / 32 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    2
    0
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 67 (2.99%)
    1 / 34 (2.94%)
    2 / 32 (6.25%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    2
    2
    2
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    6 / 67 (8.96%)
    1 / 34 (2.94%)
    2 / 32 (6.25%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    7
    1
    2
    0
    1
    Arthralgia
         subjects affected / exposed
    2 / 67 (2.99%)
    1 / 34 (2.94%)
    2 / 32 (6.25%)
    1 / 34 (2.94%)
    0 / 64 (0.00%)
         occurrences all number
    2
    1
    2
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 67 (11.94%)
    1 / 34 (2.94%)
    4 / 32 (12.50%)
    7 / 34 (20.59%)
    7 / 64 (10.94%)
         occurrences all number
    8
    1
    5
    8
    9
    Urinary tract infection
         subjects affected / exposed
    4 / 67 (5.97%)
    3 / 34 (8.82%)
    3 / 32 (9.38%)
    2 / 34 (5.88%)
    1 / 64 (1.56%)
         occurrences all number
    4
    5
    5
    2
    1
    Respiratory tract infection
         subjects affected / exposed
    2 / 67 (2.99%)
    1 / 34 (2.94%)
    0 / 32 (0.00%)
    2 / 34 (5.88%)
    0 / 64 (0.00%)
         occurrences all number
    2
    1
    0
    2
    0

    More information

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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.
    The incorrect exclusion of one par. from ITT pop. at Wk 24 was not considered to impact overall interpretation of data: no updates were made to source tables/analyses. This par. had withdrawn early, having never received a dose of active study drug.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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