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    Clinical Trial Results:
    An international, double-blind, randomised, placebo-controlled phase IIb trial to assess the efficacy, safety, and pharmacokinetics of GNbAC1 in patients with relapsing remitting multiple sclerosis

    Summary
    EudraCT number
    		 2015-004059-29
    Trial protocol
    		 HU   CZ   DE   ES   EE   PL   BG   HR   IT  
    Global end of trial date
    21 Dec 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jan 2019
    First version publication date
    05 Jan 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GNC-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02782858
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GeNeuro SA
    Sponsor organisation address
    Chemin du Pré-Fleuri 3, Plan-les-Ouates, Switzerland, CH-1228
    Public contact
    Clinical Trials Information, GeNeuro SA, 0041 22 552 48 00, contact@geneuro.com
    Scientific contact
    Clinical Trials Information, GeNeuro SA, 0041 22 552 48 00, contact@geneuro.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
    21 Dec 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jun 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of repeated doses of GNbAC1 in patients with relapsing remitting multiple sclerosis (RRMS) based on the cumulative number of gadolinium (Gd)-enhancing T1 lesions on brain magnetic resonance imaging (MRI) scans at Weeks 12, 16, 20, and 24 versus placebo.
    Protection of trial subjects
    Patients remained under observation for 2 hours following the end of the infusion for the 3 first study drug administrations and 1 hour for subsequent study drug administrations. Brain MRI scans were performed at Baseline (Study Day 1) and at Weeks 12, 16, 20, 24, and 48. Glomerular filtration rate (GFR) was calculated based on the creatinine results from the previous visit and was required to be ≥ 40 mL/min prior to each MRI being performed. In case of premature discontinuation of the Investigational Medicinal Product (IMP), the patient was withdrawn from the study. Reasons for premature discontinuation of the IMP were: Adverse Events or conditions which, according to the judgement of the investigator, constituted a hazard to the patient if the treatment with the IMP continued, including lack of efficacy; major protocol deviations if they interfered to an unacceptable extent with study procedures or assessments, or if they jeopardised patient’s safety, or administration of an unauthorised concomitant treatment; start of any treatment with Multiple Sclerosis disease modifying drugs.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 May 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
    Bulgaria: 13
    Country: Number of subjects enrolled
    Croatia: 5
    Country: Number of subjects enrolled
    Czech Republic: 4
    Country: Number of subjects enrolled
    Estonia: 10
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Hungary: 5
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Poland: 62
    Country: Number of subjects enrolled
    Russian Federation: 44
    Country: Number of subjects enrolled
    Serbia: 26
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Ukraine: 96
    Worldwide total number of subjects
    270
    EEA total number of subjects
    104
    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)
    270
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects who met the inclusion criteria at the Screening visit (within 3 weeks prior to dosing) and at the Baseline visit (Study Day 1 [SD1]) were considered eligible to participate in the clinical study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GNbAC1 6 mg/kg
    Arm description
    		 GNbAC1 6 mg/kg given by IV infusion every 4 weeks for 24 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    GNbAC1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    GNbAC1 was administered by IV infusion (200 mL over 2 hours) following dilution into glucose 5% solution.

    Arm title
    		 GNbAC1 12 mg/kg
    Arm description
    		 GNbAC1 12 mg/kg given by IV infusion every 4 weeks for 24 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    GNbAC1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    GNbAC1 was administered by IV infusion (200 mL over 2 hours) following dilution into glucose 5% solution.

    Arm title
    		 GNbAC1 18 mg/kg
    Arm description
    		 GNbAC1 18 mg/kg given by IV infusion every 4 weeks for 24 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    GNbAC1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    GNbAC1 was administered by IV infusion (200 mL over 2 hours) following dilution into glucose 5% solution.

    Arm title
    		 Placebo
    Arm description
    		 Placebo given by IV infusion every 4 weeks for 24 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was administered by IV infusion (200 mL over 2 hours) following dilution into glucose 5% solution.

    Number of subjects in period 1
    		GNbAC1 6 mg/kg GNbAC1 12 mg/kg GNbAC1 18 mg/kg Placebo
    Started
    67
    67
    67
    69
    Completed
    60
    60
    62
    65
    Not completed
    7
    7
    5
    4
         Consent withdrawn by subject
    4
    3
    1
    -
         Withdrawn from the analysis
    -
    -
    2
    2
         Adverse event, non-fatal
    2
    1
    2
    -
         Pregnancy
    -
    -
    -
    2
         Lack of efficacy
    1
    1
    -
    -
         Protocol deviation
    -
    2
    -
    -
    Period 2
    Period 2 title
    Treatment Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    The study was double-blind during the first 24 weeks (Period 1) and was dose-blind during Period 2. Neither the investigators, nor the raters, nor the patients, nor the local project managers, nor the monitors (apart from the site unblinded Pharmacist, unblinded clinical research associates, or designee) were informed of patient treatment assignment for the 24-week double-blind Treatment Period 1 or during the dose-blind 24-week Treatment Period 2 before the database lock for the whole study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GNbAC1 6 mg/kg
    Arm description
    		 GNbAC1 6 mg/kg given by IV infusion every 4 weeks for 24 weeks in Treatment Period 2. Patients who received GNbAC1 6 mg/kg in Period 1 continued with the same dose in Period 2. Patients randomised to the placebo group in Period 1 were re-randomised to GNbAC1 6, 12, or 18 mg kg (1:1:1) in Period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GNbAC1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    GNbAC1 was administered by IV infusion (200 mL over 2 hours) following dilution into glucose 5% solution.

    Arm title
    		 GNbAC1 12 mg/kg
    Arm description
    		 GNbAC1 12 mg/kg given by IV infusion every 4 weeks for 24 weeks in Treatment Period 2. Patients who received GNbAC1 12 mg/kg in Period 1 continued with the same dose in Period 2. Patients randomised to the placebo group in Period 1 were re-randomised to GNbAC1 6, 12, or 18 mg kg (1:1:1) in Period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GNbAC1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    GNbAC1 was administered by IV infusion (200 mL over 2 hours) following dilution into glucose 5% solution.

    Arm title
    		 GNbAC1 18 mg/kg
    Arm description
    		 GNbAC1 18 mg/kg given by IV infusion every 4 weeks for 24 weeks in Treatment Period 2. Patients who received GNbAC1 18 mg/kg in Period 1 continued with the same dose in Period 2. Patients randomised to the placebo group in Period 1 were re-randomised to GNbAC1 6, 12, or 18 mg kg (1:1:1) in Period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GNbAC1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    GNbAC1 was administered by IV infusion (200 mL over 2 hours) following dilution into glucose 5% solution.

    Number of subjects in period 2
    		GNbAC1 6 mg/kg GNbAC1 12 mg/kg GNbAC1 18 mg/kg
    Started
    81
    82
    84
    Completed
    79
    73
    80
    Not completed
    2
    9
    4
         Consent withdrawn by subject
    1
    2
    1
         Adverse event, non-fatal
    -
    1
    -
         Other
    -
    2
    -
         Lost to follow-up
    1
    -
    -
         Lack of efficacy
    -
    4
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GNbAC1 6 mg/kg
    Reporting group description
    		 GNbAC1 6 mg/kg given by IV infusion every 4 weeks for 24 weeks

    Reporting group title
    GNbAC1 12 mg/kg
    Reporting group description
    		 GNbAC1 12 mg/kg given by IV infusion every 4 weeks for 24 weeks

    Reporting group title
    GNbAC1 18 mg/kg
    Reporting group description
    		 GNbAC1 18 mg/kg given by IV infusion every 4 weeks for 24 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo given by IV infusion every 4 weeks for 24 weeks

    Reporting group values
    		 GNbAC1 6 mg/kg GNbAC1 12 mg/kg GNbAC1 18 mg/kg Placebo Total
    Number of subjects
    		 67 67 67 69 270
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 67 67 67 69 270
        From 65-84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38.1 ( 9.69 ) 38.9 ( 9.18 ) 37.9 ( 8.53 ) 36.2 ( 9.66 ) -
    Gender categorical
    Units: Subjects
        Female
    		 43 47 34 50 174
        Male
    		 24 20 33 19 96

    End points

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    End points reporting groups
    Reporting group title
    GNbAC1 6 mg/kg
    Reporting group description
    		 GNbAC1 6 mg/kg given by IV infusion every 4 weeks for 24 weeks

    Reporting group title
    GNbAC1 12 mg/kg
    Reporting group description
    		 GNbAC1 12 mg/kg given by IV infusion every 4 weeks for 24 weeks

    Reporting group title
    GNbAC1 18 mg/kg
    Reporting group description
    		 GNbAC1 18 mg/kg given by IV infusion every 4 weeks for 24 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo given by IV infusion every 4 weeks for 24 weeks
    Reporting group title
    GNbAC1 6 mg/kg
    Reporting group description
    		 GNbAC1 6 mg/kg given by IV infusion every 4 weeks for 24 weeks in Treatment Period 2. Patients who received GNbAC1 6 mg/kg in Period 1 continued with the same dose in Period 2. Patients randomised to the placebo group in Period 1 were re-randomised to GNbAC1 6, 12, or 18 mg kg (1:1:1) in Period 2.

    Reporting group title
    GNbAC1 12 mg/kg
    Reporting group description
    		 GNbAC1 12 mg/kg given by IV infusion every 4 weeks for 24 weeks in Treatment Period 2. Patients who received GNbAC1 12 mg/kg in Period 1 continued with the same dose in Period 2. Patients randomised to the placebo group in Period 1 were re-randomised to GNbAC1 6, 12, or 18 mg kg (1:1:1) in Period 2.

    Reporting group title
    GNbAC1 18 mg/kg
    Reporting group description
    		 GNbAC1 18 mg/kg given by IV infusion every 4 weeks for 24 weeks in Treatment Period 2. Patients who received GNbAC1 18 mg/kg in Period 1 continued with the same dose in Period 2. Patients randomised to the placebo group in Period 1 were re-randomised to GNbAC1 6, 12, or 18 mg kg (1:1:1) in Period 2.

    Subject analysis set title
    Per Protocol Set-like
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set-like (PPS-like) included all randomised patients who had an assessable MRI at both Baseline (SD1) and Week 24, and did not miss 2 consecutive post-Baseline MRIs between Week 12 and 24. The PPS-like was used for all MRI based endpoints. Patients in the PPS-like were analysed as randomised; only those patients who received the treatment to which they were randomised were included.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) included all patients who took at least 1 dose of IMP following randomisation and had at least 1 of the following post-Baseline efficacy assessments: MRI brain scan, EDSS, MSFC or answer to the question “Did the patient meet the protocol defined MS Relapse criteria since the last visit?” The FAS was used for all clinical endpoints (excluding MRI-based endpoints) and for a sensitivity analysis for the primary and key secondary endpoints. Patients in the FAS were analysed as randomised.

    Subject analysis set title
    Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Set included all patients having taken at least 1 dose of IMP. Patients in the Safety Set were analysed as treated.

    Subject analysis set title
    Full Analysis Set Entering Period 2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set Entering Period 2 (FAS Entering Period 2) included all patients in the FAS who received a dose in Period 2.

    Subject analysis set title
    Alternative grouping: GNbAC1 6 mg/kg / GNbAC1 6 mg/kg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Alternative treatment grouping used for the Week 48 analyses of efficacy in order to evaluate the comparison of each Active group versus Placebo/GNbAC1 (6, 12 or 18 mg/kg).

    Subject analysis set title
    Alternative grouping: GNbAC1 12 mg/kg / GNbAC1 12 mg/kg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Alternative treatment grouping used for the Week 48 analyses of efficacy in order to evaluate the comparison of each Active group versus Placebo/GNbAC1 (6, 12 or 18 mg/kg).

    Subject analysis set title
    Alternative grouping: GNbAC1 18 mg/kg / GNbAC1 18 mg/kg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Alternative treatment grouping used for the Week 48 analyses of efficacy in order to evaluate the comparison of each Active group versus Placebo/GNbAC1 (6, 12 or 18 mg/kg).

    Subject analysis set title
    Alternative grouping: Placebo / GNbAC1 (6, 12 or 18 mg/kg)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Alternative treatment grouping used for the Week 48 analyses of efficacy in order to evaluate the comparison of each Active group versus Placebo/GNbAC1 (6, 12 or 18 mg/kg).

    Primary: Cumulative Number of Gadolinium-enhancing T1 Lesions Measured Using Repeated Magnetic Resonance Imaging Assessments from Weeks 12 to 24, Per Protocol Set-like

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    End point title
    		 Cumulative Number of Gadolinium-enhancing T1 Lesions Measured Using Repeated Magnetic Resonance Imaging Assessments from Weeks 12 to 24, Per Protocol Set-like
    End point description
    The primary endpoint was the cumulative number of Gd-enhancing T1 lesions measured using repeated MRI assessments from Weeks 12 to 24 (ie, the sum of Gd-enhancing T1 lesions assessed by 4 MRI scans from Weeks 12 to 24).
    End point type
    Primary
    End point timeframe
    Week 12 to 24
    End point values
    		 GNbAC1 6 mg/kg GNbAC1 12 mg/kg GNbAC1 18 mg/kg Placebo
    Number of subjects analysed
    60
    60
    63
    65
    Units: Total number of lesions
    506
    410
    335
    568
    Statistical analysis title
    		 GNbAC1 (18 mg/kg) versus Placebo
    Statistical analysis description
    Each dose of GNbAC1 was compared to placebo in the PPS-like population using a Negative Binomial Generalised Linear Model (NBGLM) studying treatment effect and adjusted for the absence or presence of Baseline (SD1) Gd-enhancing T1 lesions. The estimate of treatment effect, its standard error (SE) and 95% confidence interval (CI), as well as the associated P-value were provided.
    Comparison groups
    GNbAC1 18 mg/kg v Placebo
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.721
    Method
    		 Negative Binomial GLM
    Parameter type
    		 Treatment Comparison Ratio
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 1.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.28
    Statistical analysis title
    		 GNbAC1 (12 mg/kg) versus Placebo
    Statistical analysis description
    Each dose of GNbAC1 was compared to placebo in the PPS-like population using a Negative Binomial Generalised Linear Model (NBGLM) studying treatment effect and adjusted for the absence or presence of Baseline (SD1) Gd-enhancing T1 lesions. The estimate of treatment effect, its standard error (SE) and 95% confidence interval (CI), as well as the associated P-value were provided.
    Comparison groups
    GNbAC1 12 mg/kg v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.998
    Method
    		 Negative Binomial GLM
    Parameter type
    		 Treatment Comparison Ratio
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1.84
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.31
    Statistical analysis title
    		 GNbAC1 (6 mg/kg) versus Placebo
    Statistical analysis description
    Each dose of GNbAC1 was compared to placebo in the PPS-like population using a Negative Binomial Generalised Linear Model (NBGLM) studying treatment effect and adjusted for the absence or presence of Baseline (SD1) Gd-enhancing T1 lesions. The estimate of treatment effect, its standard error (SE) and 95% confidence interval (CI), as well as the associated P-value were provided.
    Comparison groups
    GNbAC1 6 mg/kg v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.814
    Method
    		 Negative Binomial GLM
    Parameter type
    		 Treatment Comparison Ratio
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.69
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.28

    Secondary: Number of Qualifying New T1-hypointense lesions at Week 48 - Treatment Grouping 3, Full Analysis Set Entering Period 2

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    End point title
    		 Number of Qualifying New T1-hypointense lesions at Week 48 - Treatment Grouping 3, Full Analysis Set Entering Period 2
    End point description
    Alternative treatment groupings were predefined by the Sponsor to further explore treatment effects between the placebo-like and Active groups for the Week 48 analyses. Treatment Grouping 3 included all patients originally randomized to placebo in Treatment Period 1, pooling all re-randomized, Period 2, placebo/active GNbAC1 groups (thus preserving the original treatment groups from Treatment Period 1).
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 Alternative grouping: GNbAC1 6 mg/kg / GNbAC1 6 mg/kg Alternative grouping: GNbAC1 12 mg/kg / GNbAC1 12 mg/kg Alternative grouping: GNbAC1 18 mg/kg / GNbAC1 18 mg/kg Alternative grouping: Placebo / GNbAC1 (6, 12 or 18 mg/kg)
    Number of subjects analysed
    60
    60
    62
    65
    Units: Total number of lesions
    42
    46
    18
    60
    Statistical analysis title
    		 GNbAC1 18 mg/kg versus Comparator group
    Statistical analysis description
    GNbAC1 (18 mg/kg)/GNbAC1 (18 mg/kg) versus Placebo/GNbAC1 (6, 12 or 18 mg/kg)
    Comparison groups
    Alternative grouping: GNbAC1 18 mg/kg / GNbAC1 18 mg/kg v Alternative grouping: Placebo / GNbAC1 (6, 12 or 18 mg/kg)
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.014
    Method
    		 Negative Binomial GLM
    Parameter type
    		 Treatment Comparison Ratio
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 0.82
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.15

    Secondary: Percentage Change in Brain Volume from Baseline to Week 48 in Whole Brain - Treatment Grouping 3, Full Analysis Set Entering Period 2

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    End point title
    		 Percentage Change in Brain Volume from Baseline to Week 48 in Whole Brain - Treatment Grouping 3, Full Analysis Set Entering Period 2
    End point description
    Alternative treatment groupings were predefined by the Sponsor to further explore treatment effects between the placebo-like and Active groups for the Week 48 analyses. Treatment Grouping 3 included all patients originally randomized to placebo in Treatment Period 1, pooling all re-randomized, Period 2, placebo/active GNbAC1 groups (thus preserving the original treatment groups from Treatment Period 1).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 Alternative grouping: GNbAC1 6 mg/kg / GNbAC1 6 mg/kg Alternative grouping: GNbAC1 12 mg/kg / GNbAC1 12 mg/kg Alternative grouping: GNbAC1 18 mg/kg / GNbAC1 18 mg/kg Alternative grouping: Placebo / GNbAC1 (6, 12 or 18 mg/kg)
    Number of subjects analysed
    54
    50
    58
    63
    Units: Percentage change in whole brain volume
        least squares mean (standard error)
    -0.65 ( 0.11 )
    -0.57 ( 0.11 )
    -0.57 ( 0.10 )
    -0.72 ( 0.10 )
    Statistical analysis title
    		 GNbAC1 18 mg/kg versus Comparator group
    Statistical analysis description
    GNbAC1 (18 mg/kg)/GNbAC1 (18 mg/kg) versus Placebo/GNbAC1 (6, 12 or 18 mg/kg)
    Comparison groups
    Alternative grouping: GNbAC1 18 mg/kg / GNbAC1 18 mg/kg v Alternative grouping: Placebo / GNbAC1 (6, 12 or 18 mg/kg)
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.288
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.43

    Secondary: Percentage Change in Brain Volume from Baseline to Week 48 in Cerebral Cortex - Treatment Grouping 3, Full Analysis Set Entering Period 2

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    End point title
    		 Percentage Change in Brain Volume from Baseline to Week 48 in Cerebral Cortex - Treatment Grouping 3, Full Analysis Set Entering Period 2
    End point description
    Alternative treatment groupings were predefined by the Sponsor to further explore treatment effects between the placebo-like and Active groups for the Week 48 analyses. Treatment Grouping 3 included all patients originally randomized to placebo in Treatment Period 1, pooling all re-randomized, Period 2, placebo/active GNbAC1 groups (thus preserving the original treatment groups from Treatment Period 1).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 Alternative grouping: GNbAC1 6 mg/kg / GNbAC1 6 mg/kg Alternative grouping: GNbAC1 12 mg/kg / GNbAC1 12 mg/kg Alternative grouping: GNbAC1 18 mg/kg / GNbAC1 18 mg/kg Alternative grouping: Placebo / GNbAC1 (6, 12 or 18 mg/kg)
    Number of subjects analysed
    54
    50
    58
    63
    Units: Percentage change in cerebral cortex vol
        least squares mean (standard error)
    -0.55 ( 0.13 )
    -0.51 ( 0.14 )
    -0.36 ( 0.13 )
    -0.63 ( 0.12 )
    Statistical analysis title
    		 GNbAC1 18 mg/kg versus Comparator group
    Statistical analysis description
    GNbAC1 (18 mg/kg)/GNbAC1 (18 mg/kg) versus Placebo/GNbAC1 (6, 12 or 18 mg/kg)
    Comparison groups
    Alternative grouping: GNbAC1 18 mg/kg / GNbAC1 18 mg/kg v Alternative grouping: Placebo / GNbAC1 (6, 12 or 18 mg/kg)
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.134
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.61

    Secondary: Percentage Change in Brain Volume from Baseline to Week 48 in Thalamus - Treatment Grouping 3, Full Analysis Set Entering Period 2

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    End point title
    		 Percentage Change in Brain Volume from Baseline to Week 48 in Thalamus - Treatment Grouping 3, Full Analysis Set Entering Period 2
    End point description
    Alternative treatment groupings were predefined by the Sponsor to further explore treatment effects between the placebo-like and Active groups for the Week 48 analyses. Treatment Grouping 3 included all patients originally randomized to placebo in Treatment Period 1, pooling all re-randomized, Period 2, placebo/active GNbAC1 groups (thus preserving the original treatment groups from Treatment Period 1).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 Alternative grouping: GNbAC1 6 mg/kg / GNbAC1 6 mg/kg Alternative grouping: GNbAC1 12 mg/kg / GNbAC1 12 mg/kg Alternative grouping: GNbAC1 18 mg/kg / GNbAC1 18 mg/kg Alternative grouping: Placebo / GNbAC1 (6, 12 or 18 mg/kg)
    Number of subjects analysed
    54
    50
    58
    63
    Units: Percentage change in thalamus volume
        least squares mean (standard error)
    -1.34 ( 0.25 )
    -0.85 ( 0.26 )
    -0.79 ( 0.24 )
    -1.40 ( 0.23 )
    Statistical analysis title
    		 GNbAC1 18 mg/kg versus Comparator group
    Statistical analysis description
    GNbAC1 (18 mg/kg)/GNbAC1 (18 mg/kg) versus Placebo/GNbAC1 (6, 12 or 18 mg/kg)
    Comparison groups
    Alternative grouping: GNbAC1 18 mg/kg / GNbAC1 18 mg/kg v Alternative grouping: Placebo / GNbAC1 (6, 12 or 18 mg/kg)
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.073
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 1.26

    Secondary: Change in Magnetization Transfer Ratio (MTR) in Normal-Appearing Periventricular White Matter Band 1 from Baseline to Week 48 - Treatment Grouping 3, Full Analysis Set Entering Period 2

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    End point title
    		 Change in Magnetization Transfer Ratio (MTR) in Normal-Appearing Periventricular White Matter Band 1 from Baseline to Week 48 - Treatment Grouping 3, Full Analysis Set Entering Period 2
    End point description
    Alternative treatment groupings were predefined by the Sponsor to further explore treatment effects between the placebo-like and Active groups for the Week 48 analyses. Treatment Grouping 3 included all patients originally randomized to placebo in Treatment Period 1, pooling all re-randomized, Period 2, placebo/active GNbAC1 groups (thus preserving the original treatment groups from Treatment Period 1).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 Alternative grouping: GNbAC1 6 mg/kg / GNbAC1 6 mg/kg Alternative grouping: GNbAC1 12 mg/kg / GNbAC1 12 mg/kg Alternative grouping: GNbAC1 18 mg/kg / GNbAC1 18 mg/kg Alternative grouping: Placebo / GNbAC1 (6, 12 or 18 mg/kg)
    Number of subjects analysed
    31
    28
    35
    42
    Units: Change in MTR
        least squares mean (standard error)
    -0.74 ( 0.54 )
    0.17 ( 0.57 )
    0.10 ( 0.51 )
    -0.73 ( 0.47 )
    Statistical analysis title
    		 GNbAC1 18 mg/kg versus Comparator group
    Comparison groups
    Alternative grouping: GNbAC1 18 mg/kg / GNbAC1 18 mg/kg v Alternative grouping: Placebo / GNbAC1 (6, 12 or 18 mg/kg)
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.237
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.55
         upper limit
    		 2.19

    Secondary: Change in Magnetization Transfer Ratio (MTR) in Cerebral Cortex Band 4 from Baseline to Week 48 - Treatment Grouping 3, Full Analysis Set Entering Period 2

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    End point title
    		 Change in Magnetization Transfer Ratio (MTR) in Cerebral Cortex Band 4 from Baseline to Week 48 - Treatment Grouping 3, Full Analysis Set Entering Period 2
    End point description
    Alternative treatment groupings were predefined by the Sponsor to further explore treatment effects between the placebo-like and Active groups for the Week 48 analyses. Treatment Grouping 3 included all patients originally randomized to placebo in Treatment Period 1, pooling all re-randomized, Period 2, placebo/active GNbAC1 groups (thus preserving the original treatment groups from Treatment Period 1).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 Alternative grouping: GNbAC1 6 mg/kg / GNbAC1 6 mg/kg Alternative grouping: GNbAC1 12 mg/kg / GNbAC1 12 mg/kg Alternative grouping: GNbAC1 18 mg/kg / GNbAC1 18 mg/kg Alternative grouping: Placebo / GNbAC1 (6, 12 or 18 mg/kg)
    Number of subjects analysed
    31
    28
    35
    42
    Units: Change in MTR
        least squares mean (standard error)
    -0.73 ( 0.51 )
    -0.21 ( 0.54 )
    0.17 ( 0.48 )
    -0.65 ( 0.44 )
    Statistical analysis title
    		 GNbAC1 18 mg/kg versus Comparator group
    Comparison groups
    Alternative grouping: GNbAC1 18 mg/kg / GNbAC1 18 mg/kg v Alternative grouping: Placebo / GNbAC1 (6, 12 or 18 mg/kg)
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.215
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 2.11

    Secondary: Proportion of Patients Free of Qualifying Gd-enhancing T1 Lesions Over 48 Weeks - Treatment Grouping 3, Full Analysis Set Entering Period 2

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    End point title
    		 Proportion of Patients Free of Qualifying Gd-enhancing T1 Lesions Over 48 Weeks - Treatment Grouping 3, Full Analysis Set Entering Period 2
    End point description
    Alternative treatment groupings were predefined by the Sponsor to further explore treatment effects between the placebo-like and Active groups for the Week 48 analyses. Treatment Grouping 3 included all patients originally randomized to placebo in Treatment Period 1, pooling all re-randomized, Period 2, placebo/active GNbAC1 groups (thus preserving the original treatment groups from Treatment Period 1).
    End point type
    Secondary
    End point timeframe
    Weeks 12 to 48
    End point values
    		 Alternative grouping: GNbAC1 6 mg/kg / GNbAC1 6 mg/kg Alternative grouping: GNbAC1 12 mg/kg / GNbAC1 12 mg/kg Alternative grouping: GNbAC1 18 mg/kg / GNbAC1 18 mg/kg Alternative grouping: Placebo / GNbAC1 (6, 12 or 18 mg/kg)
    Number of subjects analysed
    60
    60
    62
    65
    Units: Number of patients free of lesions
    15
    24
    29
    17
    Statistical analysis title
    		 GNbAC1 18 mg/kg versus Comparator group
    Statistical analysis description
    GNbAC1 (18 mg/kg)/GNbAC1 (18 mg/kg) versus Placebo/GNbAC1 (6, 12 or 18 mg/kg)
    Comparison groups
    Alternative grouping: GNbAC1 18 mg/kg / GNbAC1 18 mg/kg v Alternative grouping: Placebo / GNbAC1 (6, 12 or 18 mg/kg)
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.017
    Method
    		 Fisher exact
    Parameter type
    		 Difference
    Point estimate
    0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 0.37

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from the signing of informed consent onwards until the patient's last study visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    GNbAC1 6 mg/kg
    Reporting group description
    		 In Period 1, patients received GNbAC1 6 mg/kg or placebo given by IV infusion every 4 weeks for 24 weeks. In Period 2, patients received GNbAC1 6 mg/kg given by IV infusion every 4 weeks for 24 weeks. Only events reported during the Period where the patient received GNbAC1 therapy are included.

    Reporting group title
    GNbAC1 12 mg/kg
    Reporting group description
    		 In Period 1, patients received GNbAC1 12 mg/kg or placebo given by IV infusion every 4 weeks for 24 weeks. In Period 2, patients received GNbAC1 12 mg/kg given by IV infusion every 4 weeks for 24 weeks. Only events reported during the Period where the patient received GNbAC1 therapy are included.

    Reporting group title
    GNbAC1 18 mg/kg
    Reporting group description
    		 In Period 1, patients received GNbAC1 18 mg/kg or placebo given by IV infusion every 4 weeks for 24 weeks. In Period 2, patients received GNbAC1 18 mg/kg given by IV infusion every 4 weeks for 24 weeks. Only events reported during the Period where the patient received GNbAC1 therapy are included.

    Serious adverse events
    		 GNbAC1 6 mg/kg GNbAC1 12 mg/kg GNbAC1 18 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 88 (3.41%)
    4 / 90 (4.44%)
    1 / 89 (1.12%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 90 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 90 (1.11%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 90 (1.11%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 90 (1.11%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 90 (1.11%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2.5%
    Non-serious adverse events
    		 GNbAC1 6 mg/kg GNbAC1 12 mg/kg GNbAC1 18 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    51 / 88 (57.95%)
    51 / 90 (56.67%)
    51 / 89 (57.30%)
    Investigations
    Activated partial thomboplastin time prolonged
         subjects affected / exposed
    3 / 88 (3.41%)
    2 / 90 (2.22%)
    1 / 89 (1.12%)
         occurrences all number
    3
    7
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 88 (5.68%)
    2 / 90 (2.22%)
    7 / 89 (7.87%)
         occurrences all number
    5
    2
    8
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 88 (3.41%)
    1 / 90 (1.11%)
    5 / 89 (5.62%)
         occurrences all number
    3
    1
    5
    Blood alkaline phosphatase increased
         subjects affected / exposed
    4 / 88 (4.55%)
    1 / 90 (1.11%)
    0 / 89 (0.00%)
         occurrences all number
    4
    3
    0
    C-reactive protein increased
         subjects affected / exposed
    1 / 88 (1.14%)
    3 / 90 (3.33%)
    2 / 89 (2.25%)
         occurrences all number
    1
    3
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    5 / 88 (5.68%)
    4 / 90 (4.44%)
    2 / 89 (2.25%)
         occurrences all number
    7
    4
    2
    White blood cell count increased
         subjects affected / exposed
    0 / 88 (0.00%)
    3 / 90 (3.33%)
    0 / 89 (0.00%)
         occurrences all number
    0
    3
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 88 (4.55%)
    5 / 90 (5.56%)
    6 / 89 (6.74%)
         occurrences all number
    10
    7
    9
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 88 (3.41%)
    0 / 90 (0.00%)
    1 / 89 (1.12%)
         occurrences all number
    3
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 88 (1.14%)
    3 / 90 (3.33%)
    0 / 89 (0.00%)
         occurrences all number
    1
    5
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 88 (4.55%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    9
    0
    0
    Nausea
         subjects affected / exposed
    3 / 88 (3.41%)
    1 / 90 (1.11%)
    0 / 89 (0.00%)
         occurrences all number
    3
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    3 / 88 (3.41%)
    1 / 90 (1.11%)
    1 / 89 (1.12%)
         occurrences all number
    4
    1
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 88 (3.41%)
    1 / 90 (1.11%)
    2 / 89 (2.25%)
         occurrences all number
    3
    1
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 88 (2.27%)
    1 / 90 (1.11%)
    3 / 89 (3.37%)
         occurrences all number
    2
    1
    4
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 88 (1.14%)
    3 / 90 (3.33%)
    2 / 89 (2.25%)
         occurrences all number
    1
    3
    3
    Nasopharyngitis
         subjects affected / exposed
    12 / 88 (13.64%)
    7 / 90 (7.78%)
    8 / 89 (8.99%)
         occurrences all number
    16
    12
    8
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 88 (1.14%)
    3 / 90 (3.33%)
    3 / 89 (3.37%)
         occurrences all number
    1
    4
    3
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 88 (1.14%)
    4 / 90 (4.44%)
    5 / 89 (5.62%)
         occurrences all number
    1
    5
    6
    Metabolism and nutrition disorders
    Hypernatraemia
         subjects affected / exposed
    2 / 88 (2.27%)
    3 / 90 (3.33%)
    0 / 89 (0.00%)
         occurrences all number
    4
    3
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 88 (1.14%)
    3 / 90 (3.33%)
    1 / 89 (1.12%)
         occurrences all number
    3
    11
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jun 2016
    The protocol was amended to comply with some requests from Competent Authorities or commitments made by the Sponsor during the review of clinical trial applications. In particular, additional monitoring of patients after study drug administration was added. Additional changes included the removal of the MRI brain scan at Week 36, the clarification of renal function assessment timing details, the addition of MSFC/EDSS assessments at Weeks 12 and 36, the addition of one selection criterion (clinical stability for 30 days prior to selection) and the addition of some non selection criteria. The lack of efficacy in the judgement of the investigator was added as a reason for premature discontinuation of the IMP. Some wording was added to ensure documented discussion with the investigator in case a patient experienced a confirmed relapse or confirmed EDSS progression in the absence of a relapse. The IMP dose recalculation rules during the study and the criteria for a definite relapse on study were clarified.
    22 Mar 2017
    The protocol was amended to add change in magnetisation transfer ratio (MTR) within regions of interest, defined by new gadolinium-enhancing T1 and T2 lesions and within pre-specified regions of interest, located in periventricular normal-appearing white matter (NAWM) and cerebral cortex, as secondary endpoints. The opportunity was taken to prioritise annualised relapse rate as the first secondary endpoint, correct certain inconsistencies, revise wording and update study dates.

    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.
    Quality Control implemented by the Central MRI Reading Center from Week 24 to Week 48 resulted in exclusion of approximately 30% of scans for Week 48 analyses of Magnetisation Transfer Ratio, limiting the power for reliable comparisons across groups
    For support, Contact us.
    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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