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    Clinical Trial Results:
    A Phase IIb Multicenter, Randomized, Double-blind, Placebo-Controlled Dose-Range Finding Study of ALX-0061 Administered Subcutaneously in Combination with Methotrexate, in Subjects with Moderate to Severe Rheumatoid Arthritis Despite Methotrexate Therapy

    Summary
    EudraCT number
    		 2014-003033-26
    Trial protocol
    		 BE   HU   CZ   DE   ES   BG  
    Global end of trial date
    08 Aug 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Aug 2017
    First version publication date
    10 Aug 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ALX0061-C201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02309359
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ablynx
    Sponsor organisation address
    Technologiepark 21, Zwijnaarde, Belgium, 9052
    Public contact
    Medical Monitor, Ablynx, +32 92620000, clinicaltrials@ablynx.com
    Scientific contact
    Medical Monitor, Ablynx, +32 92620000, clinicaltrials@ablynx.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
    27 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Aug 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Aug 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy and safety of dose regimens of ALX-0061 compared to placebo administered subcutaneously (s.c.) in combination with Methotrexate (MTX) to subjects with active rheumatoid arthritis (RA) despite MTX therapy. Subjects who completed the 24-week assessment period and achieved at least 20% improvement in swollen joint count (SJC) and/or tender joint count (TJC) at Week 24 of study ALX0061-C201 were invited to participate in an open-label extension (OLE) study ALX0061-C203 (if the study was approved in their country and selection criteria were met).
    Protection of trial subjects
    Only subjects who met all the study inclusion criteria and none of the exclusion criteria were to be randomized to study treatment. All subjects were free to withdraw from the clinical study at any time for any reason. Close monitoring of all subjects was to be adhered to throughout the study.
    Background therapy
    		 Minimum treatment duration with MTX of 4 months prior to screening and stable dose and route of administration of MTX (12.5-25.0 mg weekly) maintained during the 6 consecutive weeks before screening and for the duration of the study. Commercially available MTX (not provided by the Sponsor) was used in this study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jan 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 27 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Georgia: 41
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 15
    Country: Number of subjects enrolled
    Moldova, Republic of: 7
    Country: Number of subjects enrolled
    Serbia: 24
    Country: Number of subjects enrolled
    Mexico: 59
    Country: Number of subjects enrolled
    United States: 27
    Country: Number of subjects enrolled
    Poland: 93
    Country: Number of subjects enrolled
    Romania: 3
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Bulgaria: 26
    Country: Number of subjects enrolled
    Czech Republic: 7
    Country: Number of subjects enrolled
    Hungary: 29
    Worldwide total number of subjects
    345
    EEA total number of subjects
    172
    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)
    285
    From 65 to 84 years
    60
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 345 subjects were recruited at 63 sites located in Europe (46 sites; 259 subjects), Latin America (7 sites; 59 subjects) and North America (10 sites; 27 subjects). Consent was obtained from the first subject on 30 Jan 2015; the last subject completed the final visit on 8 Aug 2016.

    Pre-assignment
    Screening details
    		 Of the 712 subjects screened, 367 were screen failures and 345 were randomly assigned to treatment (Intent-to-treat population). All subjects enrolled received study drug and were included in the safety population. All subjects who received at least one dose of ALX-0061 (i.e., 276 subjects) were included in the pharmacokinetic (PK) population.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ALX-0061 75 mg q4w + MTX
    Arm description
    		 ALX-0061 75 mg every 4 weeks + placebo every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24. The last study drug administration was at the Week 22 visit.
    Arm type
    		 Experimental

    Investigational medicinal product name
    vobarilizumab
    Investigational medicinal product code
    ALX-0061
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dosage of 75 mg every 4 weeks administered via a subcutaneous injection in the abdominal region.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    ALX-0061 Placebo
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo every 2 weeks administered via a subcutaneous injection in the abdominal region.

    Arm title
    		 ALX-0061 150 mg q4w + MTX
    Arm description
    		 ALX-0061 150 mg every 4 weeks + placebo every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24. The last study drug administration was at the Week 22 visit.
    Arm type
    		 Experimental

    Investigational medicinal product name
    vobarilizumab
    Investigational medicinal product code
    ALX-0061
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dosage of 150 mg every 4 weeks administered via a subcutaneous injection in the abdominal region.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    ALX-0061 Placebo
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo every 2 weeks administered via a subcutaneous injection in the abdominal region.

    Arm title
    		 ALX-0061 150 mg q2w + MTX
    Arm description
    		 ALX-0061 150 mg every 2 weeks + placebo every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24. The last study drug administration was at the Week 22 visit.
    Arm type
    		 Experimental

    Investigational medicinal product name
    vobarilizumab
    Investigational medicinal product code
    ALX-0061
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dosage of 150 mg every 2 weeks administered via a subcutaneous injection in the abdominal region.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    ALX-0061 Placebo
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo every 2 weeks administered via a subcutaneous injection in the abdominal region.

    Arm title
    		 ALX-0061 225 mg q2w + MTX
    Arm description
    		 ALX-0061 225 mg every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24. The last study drug administration was at the Week 22 visit.
    Arm type
    		 Experimental

    Investigational medicinal product name
    vobarilizumab
    Investigational medicinal product code
    ALX-0061
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dosage of 225 mg every 2 weeks administered via a subcutaneous injection in the abdominal region.

    Arm title
    		 Placebo q2w + MTX
    Arm description
    		 placebo every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24. The last study drug administration was at the Week 22 visit.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo every 2 weeks administered via a subcutaneous injection in the abdominal region.

    Number of subjects in period 1
    		ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Started
    69
    70
    68
    69
    69
    Completed
    57
    62
    57
    57
    60
    Not completed
    12
    8
    11
    12
    9
         Adverse event, serious fatal
    1
    -
    -
    -
    -
         Consent withdrawn by subject
    2
    2
    4
    4
    -
         Adverse event, non-fatal
    4
    5
    5
    4
    4
         Other
    2
    -
    2
    3
    2
         Lost to follow-up
    -
    -
    -
    1
    -
         Lack of efficacy
    3
    1
    -
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ALX-0061 75 mg q4w + MTX
    Reporting group description
    		 ALX-0061 75 mg every 4 weeks + placebo every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24. The last study drug administration was at the Week 22 visit.

    Reporting group title
    ALX-0061 150 mg q4w + MTX
    Reporting group description
    		 ALX-0061 150 mg every 4 weeks + placebo every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24. The last study drug administration was at the Week 22 visit.

    Reporting group title
    ALX-0061 150 mg q2w + MTX
    Reporting group description
    		 ALX-0061 150 mg every 2 weeks + placebo every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24. The last study drug administration was at the Week 22 visit.

    Reporting group title
    ALX-0061 225 mg q2w + MTX
    Reporting group description
    		 ALX-0061 225 mg every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24. The last study drug administration was at the Week 22 visit.

    Reporting group title
    Placebo q2w + MTX
    Reporting group description
    		 placebo every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24. The last study drug administration was at the Week 22 visit.

    Reporting group values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX Total
    Number of subjects
    		 69 70 68 69 69 345
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 59 59 56 55 56 285
        From 65-84 years
    		 10 11 12 14 13 60
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.3 ± 10.35 52 ± 13.16 51.9 ± 11.93 52.3 ± 13.36 52.8 ± 11.92 -
    Gender categorical
    Units: Subjects
        Female
    		 58 62 59 55 55 289
        Male
    		 11 8 9 14 14 56
    Subject analysis sets

    Subject analysis set title
    ALX-0061 total
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects randomized to the ALX0061 75 mg q4w, ALX-0061 150 q4w, ALX-0061 150 mg q2w and ALX-0061 225 mg q2w groups

    Subject analysis sets values
    		 ALX-0061 total
    Number of subjects
    276
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    229
        From 65-84 years
    47
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    52.4 ± 12.21
    Gender categorical
    Units: Subjects
        Female
    234
        Male
    42

    End points

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    End points reporting groups
    Reporting group title
    ALX-0061 75 mg q4w + MTX
    Reporting group description
    		 ALX-0061 75 mg every 4 weeks + placebo every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24. The last study drug administration was at the Week 22 visit.

    Reporting group title
    ALX-0061 150 mg q4w + MTX
    Reporting group description
    		 ALX-0061 150 mg every 4 weeks + placebo every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24. The last study drug administration was at the Week 22 visit.

    Reporting group title
    ALX-0061 150 mg q2w + MTX
    Reporting group description
    		 ALX-0061 150 mg every 2 weeks + placebo every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24. The last study drug administration was at the Week 22 visit.

    Reporting group title
    ALX-0061 225 mg q2w + MTX
    Reporting group description
    		 ALX-0061 225 mg every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24. The last study drug administration was at the Week 22 visit.

    Reporting group title
    Placebo q2w + MTX
    Reporting group description
    		 placebo every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24. The last study drug administration was at the Week 22 visit.

    Subject analysis set title
    ALX-0061 total
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects randomized to the ALX0061 75 mg q4w, ALX-0061 150 q4w, ALX-0061 150 mg q2w and ALX-0061 225 mg q2w groups

    Primary: Proportion of subjects achieving American College of Rheumatology (ACR) 20 response at Week 12

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    End point title
    		 Proportion of subjects achieving American College of Rheumatology (ACR) 20 response at Week 12
    End point description
    The primary endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing ACR20 response at Week 12 were treated as non responders.
    End point type
    Primary
    End point timeframe
    at Week 12 visit
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    69 [1]
    70 [2]
    68 [3]
    69 [4]
    69 [5]
    Units: percent responders
    75
    81
    78
    72
    62
    Notes
    [1] - Intent-to-treat population
    [2] - Intent-to-treat population
    [3] - Intent-to-treat population
    [4] - Intent-to-treat population
    [5] - Intent-to-treat population
    Statistical analysis title
    		 Cochran Armitage Test for Trend
    Statistical analysis description
    Under the assumption of monotonicity, a Cochran-Armitage trend test was performed as the primary efficacy analysis. Data were analyzed according to the ITT principle; thus, subjects were analyzed according to the treatment to which they were assigned. Subjects with missing ACR20 response at Week 12 were treated as non responders (non responder imputation approach).
    Comparison groups
    ALX-0061 75 mg q4w + MTX v ALX-0061 150 mg q4w + MTX v ALX-0061 150 mg q2w + MTX v ALX-0061 225 mg q2w + MTX v Placebo q2w + MTX
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.172
    Method
    		 Cochran-Armitage trend test
    Confidence interval
    Notes
    [6] - The null hypothesis of this test was that there is no difference in the percentage of subjects achieving ACR20 response between the treatment groups and the alternative hypothesis was that the percentage of subjects achieving ACR20 response increases with increasing dose level.

    Secondary: Proportion of subjects with ACR20 response at Week 24

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    End point title
    		 Proportion of subjects with ACR20 response at Week 24
    End point description
    This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at Week 24 were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 24 visit
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    69 [7]
    70 [8]
    68 [9]
    69 [10]
    69 [11]
    Units: percent responders
    74
    79
    72
    75
    74
    Notes
    [7] - Intent-to-treat population
    [8] - Intent-to-treat population
    [9] - Intent-to-treat population
    [10] - Intent-to-treat population
    [11] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Proportion of subjects with ACR50 response at Weeks 12 and 24

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    End point title
    		 Proportion of subjects with ACR50 response at Weeks 12 and 24
    End point description
    This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at the concerned visit were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 and Week 24 visits
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    69 [12]
    70 [13]
    68 [14]
    69 [15]
    69 [16]
    Units: percent responders
        Week 12
    29
    44
    41
    45
    28
        Week 24
    48
    56
    54
    61
    39
    Notes
    [12] - Intent-to-treat population
    [13] - Intent-to-treat population
    [14] - Intent-to-treat population
    [15] - Intent-to-treat population
    [16] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Proportion of subjects with ACR70 response at Weeks 12 and 24

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    End point title
    		 Proportion of subjects with ACR70 response at Weeks 12 and 24
    End point description
    This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at the concerned visit were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 and Week 24 visit
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    69 [17]
    70 [18]
    68 [19]
    69 [20]
    69 [21]
    Units: percent responders
        Week 12
    14
    21
    19
    17
    9
        Week 24
    23
    33
    22
    45
    17
    Notes
    [17] - Intent-to-treat population
    [18] - Intent-to-treat population
    [19] - Intent-to-treat population
    [20] - Intent-to-treat population
    [21] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Proportion of subjects with Low Disease Activity (LDA) using Disease Activity Score 28 (DAS28) using C-reactive protein (CRP)

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    End point title
    		 Proportion of subjects with Low Disease Activity (LDA) using Disease Activity Score 28 (DAS28) using C-reactive protein (CRP)
    End point description
    This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at the concerned visit were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 and Week 24 visits
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    69 [22]
    70 [23]
    68 [24]
    69 [25]
    69 [26]
    Units: percent
        Week 12
    23
    53
    47
    58
    23
        Week 24
    38
    57
    60
    70
    29
    Notes
    [22] - Intent-to-treat population
    [23] - Intent-to-treat population
    [24] - Intent-to-treat population
    [25] - Intent-to-treat population
    [26] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Proportion of subjects with LDA using DAS28 using Erythrocyte Sedimentation Rate (ESR)

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    End point title
    		 Proportion of subjects with LDA using DAS28 using Erythrocyte Sedimentation Rate (ESR)
    End point description
    Subjects with low disease activity includes subjects who are in remission. This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at the concerned visit were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 and Week 24 visits
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    69 [27]
    70 [28]
    68 [29]
    69 [30]
    69 [31]
    Units: percent
        Week 12
    19
    51
    43
    48
    16
        Week 24
    35
    54
    49
    67
    19
    Notes
    [27] - Intent-to-treat population
    [28] - Intent-to-treat population
    [29] - Intent-to-treat population
    [30] - Intent-to-treat population
    [31] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Proportion of subjects with LDA using Simplified Disease Activity Index (SDAI)

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    End point title
    		 Proportion of subjects with LDA using Simplified Disease Activity Index (SDAI)
    End point description
    Subjects with low disease activity includes subjects who are in remission. This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at the concerned visit were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 and Week 24 visits
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    69 [32]
    70 [33]
    68 [34]
    69 [35]
    69 [36]
    Units: percent
        Week 12
    28
    49
    43
    36
    25
        Week 24
    42
    49
    51
    67
    32
    Notes
    [32] - Intent-to-treat population
    [33] - Intent-to-treat population
    [34] - Intent-to-treat population
    [35] - Intent-to-treat population
    [36] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Proportion of subjects with LDA using Clinical Disease Activity Index (CDAI)

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    End point title
    		 Proportion of subjects with LDA using Clinical Disease Activity Index (CDAI)
    End point description
    Subjects with low disease activity includes subjects who are in remission. This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at the concerned visit were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 and Week 24 visits
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    69 [37]
    70 [38]
    68 [39]
    69 [40]
    69 [41]
    Units: percent
        Week 12
    32
    44
    38
    33
    25
        Week 24
    42
    47
    43
    62
    33
    Notes
    [37] - Intent-to-treat population
    [38] - Intent-to-treat population
    [39] - Intent-to-treat population
    [40] - Intent-to-treat population
    [41] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Proportion of subjects with European League Against Rheumatism (EULAR) (CRP) good response

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    End point title
    		 Proportion of subjects with European League Against Rheumatism (EULAR) (CRP) good response
    End point description
    This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at the concerned visit were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 and Week 24 visits
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    69 [42]
    70 [43]
    68 [44]
    69 [45]
    69 [46]
    Units: percent
        Week 12
    22
    51
    44
    57
    22
        Week 24
    38
    56
    57
    68
    28
    Notes
    [42] - Intent-to-treat population
    [43] - Intent-to-treat population
    [44] - Intent-to-treat population
    [45] - Intent-to-treat population
    [46] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Proportion of subjects in remission using DAS28 (ESR)

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    End point title
    		 Proportion of subjects in remission using DAS28 (ESR)
    End point description
    This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at the concerned visit were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 and Week 24 visits
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    69 [47]
    70 [48]
    68 [49]
    69 [50]
    69 [51]
    Units: percent
        Week 12
    4
    37
    22
    30
    9
        Week 24
    25
    37
    34
    54
    12
    Notes
    [47] - Intent-to-treat population
    [48] - Intent-to-treat population
    [49] - Intent-to-treat population
    [50] - Intent-to-treat population
    [51] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Proportion of subjects in remission using SDAI

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    End point title
    		 Proportion of subjects in remission using SDAI
    End point description
    This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at the concerned visit were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 and Week 24 visits
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    69 [52]
    70 [53]
    68 [54]
    69 [55]
    69 [56]
    Units: percent
        Week 12
    3
    11
    9
    7
    4
        Week 24
    10
    19
    15
    20
    9
    Notes
    [52] - Intent-to-treat population
    [53] - Intent-to-treat population
    [54] - Intent-to-treat population
    [55] - Intent-to-treat population
    [56] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Proportion of subjects in remission using CDAI

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    End point title
    		 Proportion of subjects in remission using CDAI
    End point description
    This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at the concerned visit were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 and Week 24 visits
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    69 [57]
    70 [58]
    68 [59]
    69 [60]
    69 [61]
    Units: percent
        Week 12
    4
    10
    6
    7
    4
        Week 24
    14
    19
    12
    19
    10
    Notes
    [57] - Intent-to-treat population
    [58] - Intent-to-treat population
    [59] - Intent-to-treat population
    [60] - Intent-to-treat population
    [61] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Proportion of subjects in remission using Boolean defined remission criteria

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    End point title
    		 Proportion of subjects in remission using Boolean defined remission criteria
    End point description
    This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at the concerned visit were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 and Week 24 visits
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    69 [62]
    70 [63]
    68 [64]
    69 [65]
    69 [66]
    Units: percent
        Week 12
    0
    7
    3
    6
    4
        Week 24
    9
    13
    9
    19
    9
    Notes
    [62] - Intent-to-treat population
    [63] - Intent-to-treat population
    [64] - Intent-to-treat population
    [65] - Intent-to-treat population
    [66] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI)

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    End point title
    		 Change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI)
    End point description
    Missing values were imputed with the last non-missing observation (i.e., LOCF imputation).
    End point type
    Secondary
    End point timeframe
    From baseline till Week 24
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    69 [67]
    68 [68]
    64 [69]
    67 [70]
    67 [71]
    Units: not applicable
    arithmetic mean (standard error)
        Week 12
    -0.696 ± 0.0857
    -0.619 ± 0.0657
    -0.771 ± 0.0763
    -0.615 ± 0.0858
    -0.613 ± 0.0718
        Week 24
    -0.82 ± 0.0913
    -0.665 ± 0.0682
    -0.876 ± 0.0802
    -0.772 ± 0.0926
    -0.662 ± 0.0798
    Notes
    [67] - Intent-to-treat population, number of subjects with data available
    [68] - Intent-to-treat population, number of subjects with data available
    [69] - Intent-to-treat population, number of subjects with data available
    [70] - Intent-to-treat population, number of subjects with data available
    [71] - Intent-to-treat population, number of subjects with data available
    No statistical analyses for this end point

    Secondary: Change from baseline in physical component score of Short Form Health Survey (SF-36)

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    End point title
    		 Change from baseline in physical component score of Short Form Health Survey (SF-36)
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline till Week 24
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    61 [72]
    66 [73]
    58 [74]
    60 [75]
    59 [76]
    Units: not applicable
    arithmetic mean (standard error)
        Week 12
    7.372 ± 0.9136
    7.1 ± 0.7477
    6.534 ± 0.8878
    7.778 ± 0.994
    5.413 ± 0.7813
        Week 24
    10.412 ± 1.0642
    8.725 ± 0.9194
    8.835 ± 1.009
    10.762 ± 1.1497
    7.255 ± 0.9483
    Notes
    [72] - Intent-to-treat population, number of subjects with data available (N=61 at Week 12; N=58 at Week24)
    [73] - Intent-to-treat population, number of subjects with data available (N=66 at Week 12; N=62 at Week24)
    [74] - Intent-to-treat population, number of subjects with data available (N=58 at Weeks 12 and 24)
    [75] - Intent-to-treat population, number of subjects with data available (N=60 at Week 12; N=58 at Week24)
    [76] - Intent-to-treat population, number of subjects with data available (N=59 at Weeks 12 and 24)
    No statistical analyses for this end point

    Secondary: Change from baseline in mental component score of Short Form Health Survey (SF-36)

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    End point title
    		 Change from baseline in mental component score of Short Form Health Survey (SF-36)
    End point description
    End point type
    Secondary
    End point timeframe
    from Baseline till Week 24
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    61 [77]
    66 [78]
    58 [79]
    60 [80]
    60 [81]
    Units: not applicable
    arithmetic mean (standard error)
        Week 12
    9.096 ± 1.4966
    7.249 ± 1.1237
    9.749 ± 1.4177
    5.686 ± 1.6485
    5.569 ± 1.6467
        Week 24
    9.857 ± 1.5326
    7.962 ± 1.3932
    11.739 ± 1.4159
    8.981 ± 1.6876
    6.198 ± 1.696
    Notes
    [77] - Intent-to-treat population, number of subjects with data available (N=61 at Week 12; N=58 at Week24)
    [78] - Intent-to-treat population, number of subjects with data available (N=66 at Week 12; N=62 at Week24)
    [79] - Intent-to-treat population, number of subjects with data available (N=58 at Weeks 12 and 24)
    [80] - Intent-to-treat population, number of subjects with data available (N=60 at Week 12; N=58 at Week24)
    [81] - Intent-to-treat population, number of subjects with data available (N=60 at Weeks 12 and 24)
    No statistical analyses for this end point

    Secondary: Change from baseline in Functional assessment of Chronic Illness Therapy - fatigue (FACIT-F) subscale

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    End point title
    		 Change from baseline in Functional assessment of Chronic Illness Therapy - fatigue (FACIT-F) subscale
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline till Week 24
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    61 [82]
    65 [83]
    58 [84]
    61 [85]
    62 [86]
    Units: not applicable
    arithmetic mean (standard error)
        Week 12
    11.014 ± 1.3593
    8.63 ± 1.0465
    10.884 ± 1.5424
    9.389 ± 1.3706
    6.381 ± 1.2026
        Week 24
    12.446 ± 1.5687
    10.439 ± 1.2157
    13.374 ± 1.5621
    12.381 ± 1.5193
    6.712 ± 1.4651
    Notes
    [82] - Intent-to-treat population, number of subjects with data available (N=61 at Week 12; N=58 at Week24)
    [83] - Intent-to-treat population, number of subjects with data available (N=65 at Week 12; N=62 at Week24)
    [84] - Intent-to-treat population, number of subjects with data available (N=58 at Weeks 12 and 24)
    [85] - Intent-to-treat population, number of subjects with data available (N=61 at Weeks 12 and 24)
    [86] - Intent-to-treat population, number of subjects with data available (N=60 at Week 12; N=62 at Week24)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: ALX-0061 concentration in serum

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    End point title
    		 Pharmacokinetics: ALX-0061 concentration in serum [87]
    End point description
    End point type
    Secondary
    End point timeframe
    at Week 12 and Week 24 visits
    Notes
    [87] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: ALX-0061 concentrations were only measured in samples of subjects randomized to any of the ALX-0061 treatment arms.
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX
    Number of subjects analysed
    69 [88]
    70 [89]
    68 [90]
    69 [91]
    Units: microgram(s)/millilitre
    geometric mean (geometric coefficient of variation)
        Week 12
    0.163 ± 3.7
    1.79 ± 3.08
    19.9 ± 1.56
    32.1 ± 1.43
        Week 24
    0.122 ± 2.56
    1.64 ± 3.11
    20.9 ± 1.5
    35.2 ± 1.37
    Notes
    [88] - PK population
    [89] - PK population
    [90] - PK population
    [91] - PK population
    No statistical analyses for this end point

    Secondary: Pharmacodynamics: Concentrations of soluble interleukin-6 receptor (sIL-6R)

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    End point title
    		 Pharmacodynamics: Concentrations of soluble interleukin-6 receptor (sIL-6R)
    End point description
    Values below the limit of quantification are imputed with the lower limit of quantification (LLOQ).
    End point type
    Secondary
    End point timeframe
    from baseline till Week 24
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    69 [92]
    70 [93]
    68 [94]
    69 [95]
    69 [96]
    Units: ng/mL
    arithmetic mean (standard error)
        Baseline
    26.9 ± 0.995
    29.2 ± 1.04
    27.7 ± 0.78
    28.9 ± 1.05
    28.9 ± 1.1
        Week 12
    166 ± 16.7
    420 ± 21
    519 ± 16.8
    488 ± 16.8
    52.9 ± 14.1
        Week 24
    150 ± 12.9
    422 ± 17.8
    484 ± 16.3
    487 ± 14.3
    35.4 ± 6.6
    Notes
    [92] - Safety population
    [93] - Safety population
    [94] - Safety population
    [95] - Safety population
    [96] - Safety population
    No statistical analyses for this end point

    Secondary: Number of subjects with development of a treatment-emergent anti-drug antibody response

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    End point title
    		 Number of subjects with development of a treatment-emergent anti-drug antibody response
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline till follow-up
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX ALX-0061 total
    Number of subjects analysed
    69 [97]
    70 [98]
    68 [99]
    69 [100]
    69 [101]
    276 [102]
    Units: subjects
    9
    16
    31
    33
    13
    89
    Notes
    [97] - Safety population
    [98] - Safety population
    [99] - Safety population
    [100] - Safety population
    [101] - Safety population
    [102] - Safety population
    No statistical analyses for this end point

    Secondary: Number of subjects with treatment-emergent adverse event(s) by severity

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    End point title
    		 Number of subjects with treatment-emergent adverse event(s) by severity
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline till Week 24 or Early Termination Visit
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    69 [103]
    70 [104]
    68 [105]
    69 [106]
    69 [107]
    Units: subjects
        mild
    21
    28
    23
    20
    20
        moderate
    15
    12
    19
    20
    14
        severe
    6
    4
    2
    4
    2
    Notes
    [103] - Safety population
    [104] - Safety population
    [105] - Safety population
    [106] - Safety population
    [107] - Safety population
    No statistical analyses for this end point

    Secondary: Number of treatment-emergent adverse events by severity

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    End point title
    		 Number of treatment-emergent adverse events by severity
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline till Week 24 or the Early Termination visit
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    69 [108]
    70 [109]
    68 [110]
    69 [111]
    69 [112]
    Units: Events
        mild
    66
    78
    66
    56
    49
        moderate
    34
    24
    26
    40
    22
        severe
    6
    5
    4
    5
    2
    Notes
    [108] - Safety population
    [109] - Safety population
    [110] - Safety population
    [111] - Safety population
    [112] - Safety population
    No statistical analyses for this end point

    Secondary: Number of subjects with treatment-related treatment-emergent adverse event(s)

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    End point title
    		 Number of subjects with treatment-related treatment-emergent adverse event(s)
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline till Week 24 or the Ealy termination visit
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    69 [113]
    70 [114]
    68 [115]
    69 [116]
    69 [117]
    Units: subjects
    26
    25
    26
    25
    18
    Notes
    [113] - Safety population
    [114] - Safety population
    [115] - Safety population
    [116] - Safety population
    [117] - Safety population
    No statistical analyses for this end point

    Secondary: Number of treatment-related treatment-emergent adverse events

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    End point title
    		 Number of treatment-related treatment-emergent adverse events
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline till Week 24 or early termination visit
    End point values
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Number of subjects analysed
    69 [118]
    70 [119]
    68 [120]
    69 [121]
    69 [122]
    Units: events
    55
    52
    46
    47
    21
    Notes
    [118] - Safety population
    [119] - Safety population
    [120] - Safety population
    [121] - Safety population
    [122] - Safety population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first study drug intake until the Week 24 or Early Termination visit. Only safety data through Week 24 is reported as 256 of the 293 subjects who completed the 24-week treatment period rolled-over to the OLE Study and did not perform the FU visit.
    Adverse event reporting additional description
    4 subjects had SAEs during the FU period, ie, 2 subjects in the 150 mg q4w group (pharyngitis [possibly related] and pneumonia [not related] in 1 subject each) and 2 subjects in the 225 mg q2w group (one with staphylococcal sepsis and staphylococcal intervertebral discitis [both possibly related] and one with large intestine perforation [related]).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    ALX-0061 75 mg q4w + MTX
    Reporting group description
    		 ALX-0061 75 mg every 4 weeks + MTX (at a stable dose and route) from baseline through Week 24

    Reporting group title
    ALX-0061 150 mg q4w + MTX
    Reporting group description
    		 ALX-0061 150 mg every 4 weeks + MTX (at a stable dose and route) from baseline through Week 24

    Reporting group title
    ALX-0061 150 mg q2w + MTX
    Reporting group description
    		 ALX-0061 150 mg every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24

    Reporting group title
    ALX-0061 225 mg q2w + MTX
    Reporting group description
    		 ALX-0061 225 mg every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24

    Reporting group title
    Placebo q2w + MTX
    Reporting group description
    		 placebo every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24

    Serious adverse events
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 69 (7.25%)
    4 / 70 (5.71%)
    0 / 68 (0.00%)
    1 / 69 (1.45%)
    4 / 69 (5.80%)
         number of deaths (all causes)
    1
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Ovarian adenoma
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 70 (0.00%)
    0 / 68 (0.00%)
    0 / 69 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Tendon rupture
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 70 (0.00%)
    0 / 68 (0.00%)
    0 / 69 (0.00%)
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 70 (0.00%)
    0 / 68 (0.00%)
    0 / 69 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Cytopenia
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
    0 / 69 (0.00%)
    0 / 69 (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
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 70 (0.00%)
    0 / 68 (0.00%)
    0 / 69 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         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
    1 / 69 (1.45%)
    0 / 70 (0.00%)
    0 / 68 (0.00%)
    0 / 69 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
    0 / 69 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis bacterial
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 70 (0.00%)
    0 / 68 (0.00%)
    1 / 69 (1.45%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
    0 / 69 (0.00%)
    0 / 69 (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
    Ear infection
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 70 (0.00%)
    0 / 68 (0.00%)
    0 / 69 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 70 (0.00%)
    0 / 68 (0.00%)
    0 / 69 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
    0 / 69 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 70 (1.43%)
    0 / 68 (0.00%)
    0 / 69 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         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
    		 ALX-0061 75 mg q4w + MTX ALX-0061 150 mg q4w + MTX ALX-0061 150 mg q2w + MTX ALX-0061 225 mg q2w + MTX Placebo q2w + MTX
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 69 (60.87%)
    43 / 70 (61.43%)
    44 / 68 (64.71%)
    44 / 69 (63.77%)
    34 / 69 (49.28%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 69 (2.90%)
    2 / 70 (2.86%)
    2 / 68 (2.94%)
    6 / 69 (8.70%)
    0 / 69 (0.00%)
         occurrences all number
    3
    2
    2
    7
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 69 (2.90%)
    2 / 70 (2.86%)
    1 / 68 (1.47%)
    5 / 69 (7.25%)
    0 / 69 (0.00%)
         occurrences all number
    2
    2
    1
    6
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 69 (4.35%)
    2 / 70 (2.86%)
    3 / 68 (4.41%)
    4 / 69 (5.80%)
    1 / 69 (1.45%)
         occurrences all number
    3
    2
    3
    5
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    4 / 69 (5.80%)
    2 / 70 (2.86%)
    0 / 68 (0.00%)
    0 / 69 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    7
    2
    0
    0
    0
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    4 / 69 (5.80%)
    5 / 70 (7.14%)
    7 / 68 (10.29%)
    3 / 69 (4.35%)
    0 / 69 (0.00%)
         occurrences all number
    5
    7
    8
    3
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    6 / 69 (8.70%)
    2 / 70 (2.86%)
    3 / 68 (4.41%)
    3 / 69 (4.35%)
    3 / 69 (4.35%)
         occurrences all number
    7
    2
    3
    3
    3
    Nasopharyngitis
         subjects affected / exposed
    4 / 69 (5.80%)
    5 / 70 (7.14%)
    2 / 68 (2.94%)
    4 / 69 (5.80%)
    6 / 69 (8.70%)
         occurrences all number
    4
    5
    2
    4
    6
    Pharyngitis
         subjects affected / exposed
    2 / 69 (2.90%)
    6 / 70 (8.57%)
    3 / 68 (4.41%)
    1 / 69 (1.45%)
    0 / 69 (0.00%)
         occurrences all number
    2
    6
    4
    1
    0
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    2 / 69 (2.90%)
    7 / 70 (10.00%)
    4 / 68 (5.88%)
    5 / 69 (7.25%)
    4 / 69 (5.80%)
         occurrences all number
    2
    7
    6
    6
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jul 2015
    • Assessment of C-telopeptide pyridinoline crosslinks of Type I collagen (ICTP) was removed, as the commercially available Enzyme-linked immunosorbent assay (ELISAs) for ICTP were not adequate. • Inclusion criterion on active RA was updated to allow inclusion of subjects with C-reactive protein (CRP) > 1.0 × upper limit of normal (ULN) at screening. • Exclusion criterion on previously received approved or investigational biological or targeted synthetic Disease-modifying antirheumatic drug (DMARD) therapies for RA was updated with details about subjects who previously received rituximab. • Pregnancy testing was clarified to confirm that it applied only to women of childbearing potential. • CRP or fibrinogen results were specified for unblinding in case of an alert and at screening (because these results are required at screening to assess subjects’ eligibility). • Inclusion criterion 8 was updated with details about the inclusion of subjects with latent tuberculosis who have a positive Interferon-gamma release assay (IGRA) test and have completed appropriate treatment. • High-potency opioid analgesics were specified as prohibited medication during subjects’ participation in the study. • The Investigator was directed to refer to the CTCAE v4.0 criteria to assess the severity of adverse events (AEs) related to laboratory abnormalities.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    none reported
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