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    Clinical Trial Results:
    A Phase IIb Multicenter, Randomized, Double-blind Study of ALX-0061 Administered Subcutaneously as Monotherapy, in Subjects with Moderate to Severe Rheumatoid Arthritis who are Intolerant to Methotrexate or for whom Continued Methotrexate Treatment is Inappropriate

    Summary
    EudraCT number
    		 2014-003012-36
    Trial protocol
    		 BE   DE   HU   CZ   ES   BG  
    Global end of trial date
    19 Jul 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jul 2017
    First version publication date
    20 Jul 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ALX0061-C202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02287922
    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
    14 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jul 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 monotherapy administered subcutaneously (s.c.) to subjects with active rheumatoid arthritis (RA). Subjects randomized to one of the 3 ALX-0061 treatment groups who completed the 12-week assessment period 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 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 adhered to throughout the study.
    Background therapy
    		 -
    Evidence for comparator
    		 Tocilizumab (TCZ). The open-label treatment with TCZ s.c. was not intended to be an active comparator but to provide parallel efficacy and safety data for TCZ in the same RA population.
    Actual start date of recruitment
    18 Mar 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
    Poland: 36
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Bulgaria: 20
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 19
    Country: Number of subjects enrolled
    Moldova, Republic of: 29
    Country: Number of subjects enrolled
    Serbia: 16
    Country: Number of subjects enrolled
    Georgia: 46
    Country: Number of subjects enrolled
    Mexico: 36
    Country: Number of subjects enrolled
    United States: 16
    Worldwide total number of subjects
    251
    EEA total number of subjects
    89
    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)
    218
    From 65 to 84 years
    33
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 251 subjects were recruited at 58 sites located in Europe (42 sites; 199 subjects), Latin America (6 sites; 36 subjects) and North America (10 sites; 16 subjects). Consent was obtained from the first subject on 18 Mar 2015; the last subject completed the final visit in on 19 Jul 2016.

    Pre-assignment
    Screening details
    		 Of the 599 subjects screened, 348 were screen failures and 251 subjects were randomly assigned to treatment (Intent-to-treat population). All subjects enrolled received study medication and were included in the safety population. All subjects who received at least one dose of ALX-0061were 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 150 mg q4w
    Arm description
    		 ALX-0061 150 mg every 4 weeks from baseline through Week 12 + placebo every 2 weeks from baseline through Week 12. The last injection with study drug was administered at the Week 10 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
    Arm description
    		 ALX-0061 150 mg every 2 weeks from baseline through Week 12 + placebo every 2 weeks from baseline through Week 12. The last injection with study drug was administered at the Week 10 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
    Arm description
    		 ALX-0061 225 mg every 2 weeks from baseline through Week 12. The last injection with study drug was administered at the Week 10 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
    		 TCZ 162 mg q1w or q2w
    Arm description
    		 Open-label TCZ. Injections were to be performed q1w or q2w depending on the approved label per region (last injection was administered at Week 10 or Week 11, depending on the dose regimen).
    Arm type
    		 collection of parallel efficacy and safety data

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Actemra, RoActemra
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    subcutaneous injections (162 mg of TCZ [RoActemra – Actemra]) in the lower part of the abdomen below the navel (belly button).

    Number of subjects in period 1
    		ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Started
    62
    62
    63
    64
    Completed
    59
    60
    56
    57
    Not completed
    3
    2
    7
    7
         Sponsor's decision
    -
    -
    -
    1
         Consent withdrawn by subject
    1
    1
    1
    2
         Adverse event, non-fatal
    1
    1
    3
    4
         Other
    1
    -
    2
    -
         Lost to follow-up
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ALX-0061 150 mg q4w
    Reporting group description
    		 ALX-0061 150 mg every 4 weeks from baseline through Week 12 + placebo every 2 weeks from baseline through Week 12. The last injection with study drug was administered at the Week 10 visit.

    Reporting group title
    ALX-0061 150 mg q2w
    Reporting group description
    		 ALX-0061 150 mg every 2 weeks from baseline through Week 12 + placebo every 2 weeks from baseline through Week 12. The last injection with study drug was administered at the Week 10 visit.

    Reporting group title
    ALX-0061 225 mg q2w
    Reporting group description
    		 ALX-0061 225 mg every 2 weeks from baseline through Week 12. The last injection with study drug was administered at the Week 10 visit.

    Reporting group title
    TCZ 162 mg q1w or q2w
    Reporting group description
    		 Open-label TCZ. Injections were to be performed q1w or q2w depending on the approved label per region (last injection was administered at Week 10 or Week 11, depending on the dose regimen).

    Reporting group values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w Total
    Number of subjects
    		 62 62 63 64 251
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 50 54 56 58 218
        From 65-84 years
    		 12 8 7 6 33
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53 ( 12.25 ) 51.2 ( 12.05 ) 51.3 ( 11.81 ) 50 ( 12.26 ) -
    Gender categorical
    Units: Subjects
        Female
    		 49 53 54 56 212
        Male
    		 13 9 9 8 39
    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 150 q4w, ALX-0061 150 mg q2w and ALX-0061 225 mg q2w groups

    Subject analysis sets values
    		 ALX-0061 total
    Number of subjects
    187
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    160
        From 65-84 years
    27
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    51.8 ( 12 )
    Gender categorical
    Units: Subjects
        Female
    156
        Male
    31

    End points

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    End points reporting groups
    Reporting group title
    ALX-0061 150 mg q4w
    Reporting group description
    		 ALX-0061 150 mg every 4 weeks from baseline through Week 12 + placebo every 2 weeks from baseline through Week 12. The last injection with study drug was administered at the Week 10 visit.

    Reporting group title
    ALX-0061 150 mg q2w
    Reporting group description
    		 ALX-0061 150 mg every 2 weeks from baseline through Week 12 + placebo every 2 weeks from baseline through Week 12. The last injection with study drug was administered at the Week 10 visit.

    Reporting group title
    ALX-0061 225 mg q2w
    Reporting group description
    		 ALX-0061 225 mg every 2 weeks from baseline through Week 12. The last injection with study drug was administered at the Week 10 visit.

    Reporting group title
    TCZ 162 mg q1w or q2w
    Reporting group description
    		 Open-label TCZ. Injections were to be performed q1w or q2w depending on the approved label per region (last injection was administered at Week 10 or Week 11, depending on the dose regimen).

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

    Primary: Percentage of subjects with American College of Rheumatology 20 (ACR20) response at Week 12

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    End point title
    		 Percentage of subjects with American College of Rheumatology 20 (ACR20) response at Week 12 [1]
    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
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The primary endpoint was analyzed using descriptive statistics (frequency, percentage) which were presented by treatment group on the intent-to-treat population. Subjects with missing ACR20 response at Week 12 were treated as non responders (non-responder imputation [NRI] approach).
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Number of subjects analysed
    62 [2]
    62 [3]
    63 [4]
    64 [5]
    Units: percent responders
    73
    77
    81
    78
    Notes
    [2] - Intent-to-treat population
    [3] - Intent-to-treat population
    [4] - Intent-to-treat population
    [5] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Proportion of subjects with ACR50 response at Week 12

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    End point title
    		 Proportion of subjects with ACR50 response at Week 12
    End point description
    This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at Week 12 were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 visit
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Number of subjects analysed
    62 [6]
    62 [7]
    63 [8]
    64 [9]
    Units: percent responders
    44
    37
    49
    45
    Notes
    [6] - Intent-to-treat population
    [7] - Intent-to-treat population
    [8] - Intent-to-treat population
    [9] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Proportion of subjects with ACR70 response at Week 12

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    End point title
    		 Proportion of subjects with ACR70 response at Week 12
    End point description
    This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at Week 12 were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 visit
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Number of subjects analysed
    62 [10]
    62 [11]
    63 [12]
    64 [13]
    Units: percent responders
    16
    24
    21
    23
    Notes
    [10] - Intent-to-treat population
    [11] - Intent-to-treat population
    [12] - Intent-to-treat population
    [13] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Proportion of subjects with Low Disease Activity (LDA) using Disease Activity Score using 28 joint counts (DAS28) using C-reactive protein (CRP) at Week 12

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    End point title
    		 Proportion of subjects with Low Disease Activity (LDA) using Disease Activity Score using 28 joint counts (DAS28) using C-reactive protein (CRP) at Week 12
    End point description
    This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at Week 12 were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 visit
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Number of subjects analysed
    62 [14]
    62 [15]
    63 [16]
    64 [17]
    Units: percent
    42
    56
    60
    44
    Notes
    [14] - Intent-to-treat population
    [15] - Intent-to-treat population
    [16] - Intent-to-treat population
    [17] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Proportion of subjects with LDA using DAS28 using Erythrocyte Sedimentation Rate (ESR) at Week 12

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    End point title
    		 Proportion of subjects with LDA using DAS28 using Erythrocyte Sedimentation Rate (ESR) at Week 12
    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 Week 12 were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 visit
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Number of subjects analysed
    62 [18]
    62 [19]
    63 [20]
    64 [21]
    Units: percent
    42
    52
    54
    31
    Notes
    [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 LDA using Simplified Disease Activity Index (SDAI) at Week 12

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    End point title
    		 Proportion of subjects with LDA using Simplified Disease Activity Index (SDAI) at Week 12
    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 Week 12 were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 visit
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Number of subjects analysed
    62 [22]
    62 [23]
    63 [24]
    64 [25]
    Units: percent
    37
    44
    52
    34
    Notes
    [22] - Intent-to-treat population
    [23] - Intent-to-treat population
    [24] - Intent-to-treat population
    [25] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Proportion of subjects with LDA using Clinical Disease Activity Index (CDAI) at Week 12

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    End point title
    		 Proportion of subjects with LDA using Clinical Disease Activity Index (CDAI) at Week 12
    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 Week 12 were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 visit
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Number of subjects analysed
    62 [26]
    62 [27]
    63 [28]
    64 [29]
    Units: percent
    37
    34
    51
    33
    Notes
    [26] - Intent-to-treat population
    [27] - Intent-to-treat population
    [28] - Intent-to-treat population
    [29] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Proportion of subjects with European League Against Rheumatism (EULAR) (CRP) good response at Week 12

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    End point title
    		 Proportion of subjects with European League Against Rheumatism (EULAR) (CRP) good response at Week 12
    End point description
    This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at Week 12 were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 visit
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Number of subjects analysed
    62 [30]
    62 [31]
    63 [32]
    64 [33]
    Units: percent responders
    40
    55
    60
    44
    Notes
    [30] - Intent-to-treat population
    [31] - Intent-to-treat population
    [32] - Intent-to-treat population
    [33] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Proportion of subjects in remission using DAS28 (ESR) at Week 12

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    End point title
    		 Proportion of subjects in remission using DAS28 (ESR) at Week 12
    End point description
    This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at Week 12 were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 visit
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Number of subjects analysed
    62 [34]
    62 [35]
    63 [36]
    64 [37]
    Units: percent
    34
    21
    40
    25
    Notes
    [34] - Intent-to-treat population
    [35] - Intent-to-treat population
    [36] - Intent-to-treat population
    [37] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Proportion of subjects in remission using SDAI at Week 12

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    End point title
    		 Proportion of subjects in remission using SDAI at Week 12
    End point description
    This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at Week 12 were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 visit
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Number of subjects analysed
    62 [38]
    62 [39]
    63 [40]
    64 [41]
    Units: percent
    8
    5
    8
    11
    Notes
    [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 in remission using CDAI at Week 12

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    End point title
    		 Proportion of subjects in remission using CDAI at Week 12
    End point description
    This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at Week 12 were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 visit
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Number of subjects analysed
    62 [42]
    62 [43]
    63 [44]
    64 [45]
    Units: percent
    10
    5
    6
    9
    Notes
    [42] - Intent-to-treat population
    [43] - Intent-to-treat population
    [44] - Intent-to-treat population
    [45] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Proportion of subjects in remission using Boolean defined remission criteria at Week 12

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    End point title
    		 Proportion of subjects in remission using Boolean defined remission criteria at Week 12
    End point description
    This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at Week 12 were treated as non responders.
    End point type
    Secondary
    End point timeframe
    at Week 12 visit
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Number of subjects analysed
    62 [46]
    62 [47]
    63 [48]
    64 [49]
    Units: percent
    3
    5
    6
    6
    Notes
    [46] - Intent-to-treat population
    [47] - Intent-to-treat population
    [48] - Intent-to-treat population
    [49] - Intent-to-treat population
    No statistical analyses for this end point

    Secondary: Change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12

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    End point title
    		 Change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12
    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 12
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Number of subjects analysed
    61 [50]
    60 [51]
    59 [52]
    64 [53]
    Units: not applicable
        arithmetic mean (standard error)
    -0.541 ( 0.0809 )
    -0.746 ( 0.0935 )
    -0.817 ( 0.0802 )
    -0.689 ( 0.0811 )
    Notes
    [50] - Intent-to-treat population, number of subjects with data available
    [51] - Intent-to-treat population, number of subjects with data available
    [52] - Intent-to-treat population, number of subjects with data available
    [53] - 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) at Week 12

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    End point title
    		 Change from baseline in physical component score of Short Form Health Survey (SF-36) at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline till Week 12
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Number of subjects analysed
    58 [54]
    60 [55]
    56 [56]
    54 [57]
    Units: not applicable
        arithmetic mean (standard error)
    7.808 ( 0.8533 )
    7.979 ( 1.1895 )
    8.861 ( 1.0818 )
    7.611 ( 0.9562 )
    Notes
    [54] - Intent-to-treat population, number of subjects with data available
    [55] - Intent-to-treat population, number of subjects with data available
    [56] - Intent-to-treat population, number of subjects with data available
    [57] - Intent-to-treat population, number of subjects with data available
    No statistical analyses for this end point

    Secondary: Change from baseline in mental component score of Short Form Health Survey (SF-36) at Week 12

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    End point title
    		 Change from baseline in mental component score of Short Form Health Survey (SF-36) at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline till Week 12
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Number of subjects analysed
    58 [58]
    60 [59]
    56 [60]
    55 [61]
    Units: not applicable
        arithmetic mean (standard error)
    5.49 ( 1.221 )
    8.836 ( 1.5243 )
    8.913 ( 1.3903 )
    6.156 ( 1.3192 )
    Notes
    [58] - Intent-to-treat population, number of subjects with data available
    [59] - Intent-to-treat population, number of subjects with data available
    [60] - Intent-to-treat population, number of subjects with data available
    [61] - Intent-to-treat population, number of subjects with data available
    No statistical analyses for this end point

    Secondary: Change from baseline in Functional assessment of Chronic Illness Therapy - fatigue (FACIT-F) subscale at Week 12

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    End point title
    		 Change from baseline in Functional assessment of Chronic Illness Therapy - fatigue (FACIT-F) subscale at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline till Week 12
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Number of subjects analysed
    58 [62]
    60 [63]
    56 [64]
    57 [65]
    Units: not applicable
        arithmetic mean (standard error)
    7.832 ( 1.3438 )
    11.41 ( 1.53 )
    12.996 ( 1.3702 )
    8.971 ( 1.4461 )
    Notes
    [62] - Intent-to-treat population, number of subjects with data available
    [63] - Intent-to-treat population, number of subjects with data available
    [64] - Intent-to-treat population, number of subjects with data available
    [65] - Intent-to-treat population, number of subjects with data available
    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 12
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Number of subjects analysed
    62 [66]
    62 [67]
    63 [68]
    64 [69]
    Units: ng/mL
    arithmetic mean (standard error)
        Baseline
    33 ( 4.65 )
    42.3 ( 8.71 )
    30.9 ( 3.72 )
    31 ( 2.54 )
        Week 12
    376 ( 21.6 )
    460 ( 19.9 )
    459 ( 18.8 )
    269 ( 11.1 )
    Notes
    [66] - Safety population
    [67] - Safety population
    [68] - Safety population
    [69] - Safety population
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: ALX-0061 concentration in serum over time

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    End point title
    		 Pharmacokinetics: ALX-0061 concentration in serum over time [70]
    End point description
    End point type
    Secondary
    End point timeframe
    at Week 12 visit
    Notes
    [70] - 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 analyzed in samples from subjects randomized to one of the ALX-0061 treatment groups.
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w
    Number of subjects analysed
    62 [71]
    62 [72]
    63 [73]
    Units: microgram(s)/millilitre
    geometric mean (geometric coefficient of variation)
        Week 12
    1.4 ( 3.61 )
    18.4 ( 2.95 )
    27.9 ( 2.53 )
    Notes
    [71] - PK population
    [72] - PK population
    [73] - PK 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 [74]
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline till follow-up (FU)
    Notes
    [74] - 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: Anti-drug antibody repsonses were only analyzed in samples from subjects randomized to one of the ALX-0061 treatment groups.
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w ALX-0061 total
    Number of subjects analysed
    62 [75]
    62 [76]
    63 [77]
    187 [78]
    Units: subjects
    7
    25
    26
    58
    Notes
    [75] - Safety population
    [76] - Safety population
    [77] - Safety population
    [78] - Safety population
    No statistical analyses for this end point

    Secondary: Number of subjects categorized as NAb positive on treatment

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    End point title
    		 Number of subjects categorized as NAb positive on treatment [79]
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline till FU
    Notes
    [79] - 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: Neutralizing antibody repsonses were only analyzed in samples from subjects randomized to one of the ALX-0061 treatment groups.
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w ALX-0061 total
    Number of subjects analysed
    62 [80]
    62 [81]
    63 [82]
    187 [83]
    Units: subjects
    4
    3
    4
    11
    Notes
    [80] - Safety population
    [81] - Safety population
    [82] - Safety population
    [83] - Safety population
    No statistical analyses for this end point

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

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    End point title
    		 Number of subjects with treatment-emergent adverse event by severity
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline till Week 12
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Number of subjects analysed
    62 [84]
    62 [85]
    63 [86]
    64 [87]
    Units: subjects
        mild
    22
    18
    21
    19
        moderate
    12
    13
    9
    10
        severe
    0
    2
    1
    2
    Notes
    [84] - Safety population
    [85] - Safety population
    [86] - Safety population
    [87] - Safety population
    No statistical analyses for this end point

    Secondary: Number of treatment-emergent adverse event by severity

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    End point title
    		 Number of treatment-emergent adverse event by severity
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline till Week 12
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Number of subjects analysed
    62 [88]
    62 [89]
    63 [90]
    64 [91]
    Units: treatment-emergent adverse events
        mild
    46
    75
    84
    47
        moderate
    18
    22
    15
    15
        severe
    0
    2
    3
    2
    Notes
    [88] - Safety population
    [89] - Safety population
    [90] - Safety population
    [91] - Safety population
    No statistical analyses for this end point

    Secondary: Number of subjects with a treatment-related treatment-emergent adverse event

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    End point title
    		 Number of subjects with a treatment-related treatment-emergent adverse event
    End point description
    treatment related = considered at least possibly related to study drug by the Investigator
    End point type
    Secondary
    End point timeframe
    from baseline till Week 12
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Number of subjects analysed
    62 [92]
    62 [93]
    63 [94]
    64 [95]
    Units: subjects
    21
    20
    21
    20
    Notes
    [92] - Safety population
    [93] - Safety population
    [94] - Safety population
    [95] - Safety population
    No statistical analyses for this end point

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

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    End point title
    		 Number of treatment-related treatment-emergent adverse event
    End point description
    treatment related = considered at least possibly related to study drug by the Investigator
    End point type
    Secondary
    End point timeframe
    from baseline till Week 12
    End point values
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Number of subjects analysed
    62 [96]
    62 [97]
    63 [98]
    64 [99]
    Units: treatment-emergent adverse events
    46
    53
    64
    32
    Notes
    [96] - Safety population
    [97] - Safety population
    [98] - Safety population
    [99] - 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 Week 12 or ET visit. Only safety data through Week 12 is reported as 148 of the 174 subjects who completed the 12-week treatment period could roll over to OLE study ALX0061-C203 and did not perform the FU visit.
    Adverse event reporting additional description
    In the FU period (performed by 55 subjects in the TCZ group and 26 subjects in the ALX-0061 groups), 2 serious adverse events (SAEs) were reported, i.e., chronic obstructive pulmonary disease (considered not related) in 1 subject in the ALX-0061 150 mg q4w group and dehydration (considered not related) in 1 subject in the ALX-0061 225 mg q2w group.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    ALX-0061 150 mg q4w
    Reporting group description
    		 ALX-0061 150 mg every 4 weeks from baseline through Week 12 + placebo every 2 weeks from baseline through Week 12

    Reporting group title
    ALX-0061 150 mg q2w
    Reporting group description
    		 ALX-0061 150 mg every 2 weeks from baseline through Week 12 + placebo every 2 weeks from baseline through Week 12

    Reporting group title
    ALX-0061 225 mg q2w
    Reporting group description
    		 ALX-0061 225 mg every 2 weeks from baseline through Week 12

    Reporting group title
    TCZ 162 mg q1w or q2w
    Reporting group description
    		 Open-label TCZ according to the TCZ dosing regimen approved per region

    Serious adverse events
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    2 / 64 (3.13%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nail bed infection bacterial
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ALX-0061 150 mg q4w ALX-0061 150 mg q2w ALX-0061 225 mg q2w TCZ 162 mg q1w or q2w
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 62 (33.87%)
    20 / 62 (32.26%)
    20 / 63 (31.75%)
    18 / 64 (28.13%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    4 / 63 (6.35%)
    1 / 64 (1.56%)
         occurrences all number
    1
    0
    5
    1
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    4 / 62 (6.45%)
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    4
    1
    0
    2
    Neutropenia
         subjects affected / exposed
    4 / 62 (6.45%)
    3 / 62 (4.84%)
    0 / 63 (0.00%)
    5 / 64 (7.81%)
         occurrences all number
    5
    3
    0
    5
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    4 / 62 (6.45%)
    7 / 62 (11.29%)
    5 / 63 (7.94%)
    2 / 64 (3.13%)
         occurrences all number
    7
    10
    20
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 62 (0.00%)
    4 / 62 (6.45%)
    1 / 63 (1.59%)
    0 / 64 (0.00%)
         occurrences all number
    0
    4
    1
    0
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    2 / 62 (3.23%)
    5 / 62 (8.06%)
    7 / 63 (11.11%)
    2 / 64 (3.13%)
         occurrences all number
    2
    5
    7
    2

    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 1 collagen (ICTP) was removed, as the commercially available Enzyme Linked Immunosorbent Assays (ELISAs) for ICTP were not adequate. • The word “current” was deleted from the inclusion criterion on previous treatment with methotrexate (MTX) as the current MTX treatment was not feasible, because the screening period was only 3 weeks long and the protocol required a wash-out of at least 4 weeks. In addition, the inclusion criterion on active rheumatoid arthritis (RA) was updated to allow inclusion of subjects with C-reactive protein (CRP) > 1.0 × upper limit of normal (ULN) at screening. • The exclusion criterion on previous treatment with Disease Modifying Antirheumatic Drugs (DMARDs)/systemic immunosuppressives was updated to correct an error about the use of hydroxychloroquine and chloroquine. In addition, the exclusion criterion on previously received approved or investigational biological or targeted synthetic DMARD therapies for RA was updated to add details about subjects who previously received rituximab. • IWRS notification was removed from the Schedule of Assessments as this notification was a copy error from protocol ALX0061-C201. • Pregnancy testing was clarified to confirm that such testing applied only to women of childbearing potential. • CRP or fibrinogen results were specified for unblinding in case of an alert and at screening. • Inclusion criterion 9 was updated to add details about the inclusion of subjects with latent tuberculosis (TB) who have a positive Interferon-Gamma Release Assays (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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