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    Clinical Trial Results:
    A Phase II Multicenter, Open-Label Extension Study Assessing the Long-Term Efficacy and Safety of Subcutaneous ALX-0061 in Subjects with Moderate to Severe Rheumatoid Arthritis who Have Completed One of the Preceding Phase IIb Studies with ALX-0061

    Summary
    EudraCT number
    		 2014-003034-42
    Trial protocol
    		 HU   DE   ES   BG   BE  
    Global end of trial date
    23 Aug 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 May 2019
    First version publication date
    01 May 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ALX0061-C203
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02518620
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ablynx NV
    Sponsor organisation address
    Technologiepark 21, Zwijnaarde, Belgium, 9052
    Public contact
    Medical Monitor, Ablynx, +32 (0)9 262 00 00, clinicaltrials@ablynx.com
    Scientific contact
    Medical Monitor, Ablynx, +32 (0)9 262 00 00, 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
    09 Oct 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the long-term efficacy and safety of ALX-0061 administered subcutaneously (s.c.) to subjects with active Rheumatoid Arthritis (RA).
    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
    		 Eligible subjects from the preceding Phase IIb study ALX0061-C201 (combination therapy study with ALX-0061 and MTX) continued their MTX treatment throughout this study.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    13 Jul 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 105
    Country: Number of subjects enrolled
    Romania: 3
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Belgium: 16
    Country: Number of subjects enrolled
    Bulgaria: 38
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Hungary: 26
    Country: Number of subjects enrolled
    Georgia: 65
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 21
    Country: Number of subjects enrolled
    Mexico: 73
    Country: Number of subjects enrolled
    Moldova, Republic of: 22
    Country: Number of subjects enrolled
    Serbia: 32
    Worldwide total number of subjects
    406
    EEA total number of subjects
    193
    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)
    341
    From 65 to 84 years
    65
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 406 subjects was enrolled at 56 sites located in Europe (48 sites, 333 subjects) and Latin America (8 sites, 73 subjects). Consent was obtained from the first subject on 13 July 2015; the last subject completed the final visit on 23 August 2018.

    Pre-assignment
    Screening details
    		 A total of 472 subjects completed the entire treatment and assessment period of the preceding Phase IIb studies (placebo and ALX-0061 treatment arms only). Of these, 406 subjects were enrolled in this study. All screened subjects were included in the Intent-to-observe (ITO) Population. Overall, 405 subjects were included in the Safety Population.

    Period 1
    Period 1 title
    Overall Study Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    As this was an open-label extension study, blinding was not required.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ALX-0061 150 mg q2w + MTX (C201 All Subjects)
    Arm description
    		 ALX-0061 150 mg s.c. q2w + MTX
    Arm type
    		 Experimental

    Investigational medicinal product name
    ALX-0061
    Investigational medicinal product code
    ALX-0061
    Other name
    Vobarilizumab
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received ALX-0061 150 mg s.c. injections, beginning at Week 0 and q2w thereafter, up to and including Week 102. Subjects from the preceding study ALX0061-C201 also continued their MTX treatment.

    Arm title
    		 ALX-0061 150 mg q2w (C202 All Subjects)
    Arm description
    		 ALX-0061 150 mg s.c. q2w
    Arm type
    		 Experimental

    Investigational medicinal product name
    ALX-0061
    Investigational medicinal product code
    ALX-0061
    Other name
    Vobarilizumab
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received ALX-0061 150 mg s.c. injections, beginning at Week 0 and q2w thereafter, up to and including Week 102.

    Number of subjects in period 1
    		ALX-0061 150 mg q2w + MTX (C201 All Subjects) ALX-0061 150 mg q2w (C202 All Subjects)
    Started
    257
    149
    Completed
    205
    123
    Not completed
    52
    26
         Adverse event, serious fatal
    1
    -
         Relocation
    2
    1
         Sponsor's decision
    -
    3
         Physician decision
    1
    1
         Consent withdrawn by subject
    17
    9
         Adverse event, non-fatal
    23
    11
         Pregnancy
    1
    -
         Non-compliance with study drug
    1
    -
         Lost to follow-up
    1
    1
         Pregnancy wish
    3
    -
         Lack of efficacy
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ALX-0061 150 mg q2w + MTX (C201 All Subjects)
    Reporting group description
    		 ALX-0061 150 mg s.c. q2w + MTX

    Reporting group title
    ALX-0061 150 mg q2w (C202 All Subjects)
    Reporting group description
    		 ALX-0061 150 mg s.c. q2w

    Reporting group values
    		 ALX-0061 150 mg q2w + MTX (C201 All Subjects) ALX-0061 150 mg q2w (C202 All Subjects) Total
    Number of subjects
    		 257 149 406
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 213 128 341
        From 65-84 years
    		 44 21 65
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.7 ± 12.26 51.1 ± 12.01 -
    Gender categorical
    Units: Subjects
        Female
    		 217 124 341
        Male
    		 40 25 65

    End points

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    End points reporting groups
    Reporting group title
    ALX-0061 150 mg q2w + MTX (C201 All Subjects)
    Reporting group description
    		 ALX-0061 150 mg s.c. q2w + MTX

    Reporting group title
    ALX-0061 150 mg q2w (C202 All Subjects)
    Reporting group description
    		 ALX-0061 150 mg s.c. q2w

    Subject analysis set title
    ALX-0061 150 mg q2w (C203 All Subjects)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received ALX-0061 150 mg s.c. injections, beginning at Week 0 and q2w thereafter, up to and including Week 102. Subjects from the preceding study ALX0061-C201 also continued their MTX.

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

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    End point title
    		 Percentage of subjects with American College of Rheumatology 20 (ACR20) response [1]
    End point description
    ACR20 response is defined as: • 20% improvement in tender/painful joint count (68 joints) relative to baseline AND • 20% improvement in swollen joint count (66 joints) relative to baseline AND • 20% improvement in 3 of the following 5 areas relative to baseline: - Patient's Assessment of Pain (100 mm-VAS), - Patient's Global Assessment of Disease Activity (100 mm-VASPA), - Physician's Global Assessment of Disease Activity (100 mm-VASPHA), - Patient's assessment of physical function as measured by HAQ-DI, - C-reactive protein (CRP) level ACR20 responses were measured at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, and 104.
    End point type
    Primary
    End point timeframe
    At Weeks 0, 12, 48, and 104.
    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: This study was an open label extension study. No inferential statistical analyses were performed. All statistical analyses are descriptive.
    End point values
    		 ALX-0061 150 mg q2w + MTX (C201 All Subjects) ALX-0061 150 mg q2w (C202 All Subjects) ALX-0061 150 mg q2w (C203 All Subjects)
    Number of subjects analysed
    257 [2]
    149 [3]
    406 [4]
    Units: Percent
        Week 0
    89
    85
    88
        Week 12
    90
    92
    91
        Week 48
    94
    94
    94
        Week 104
    97
    95
    96
    Notes
    [2] - ITO Population Number of subjects evaluated at: W0: n=251 W12: n=246 W48: n=223 W104: n=199
    [3] - ITO Population Number of subjects evaluated at: W0: n=149 W12: n=141 W48: n=134 W104: n=123
    [4] - Number of subjects evaluated at: W0: n=400 W12: n=387 W48: n=357 W104: n=322
    No statistical analyses for this end point

    Primary: Percentage of subjects with ACR50 response

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    End point title
    		 Percentage of subjects with ACR50 response [5]
    End point description
    ACR50 responses are defined as: • 50% improvement in tender/painful joint count (68 joints) relative to baseline AND • 50% improvement in swollen joint count (66 joints) relative to baseline AND • 50% improvement in 3 of the following 5 areas relative to baseline: - Patient's Assessment of Pain (100 mm-VAS), - Patient's Global Assessment of Disease Activity (100 mm-VASPA), - Physician's Global Assessment of Disease Activity (100 mm-VASPHA), - Patient's assessment of physical function as measured by HAQ-DI, - CRP level ACR50 responses were measured at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, and 104.
    End point type
    Primary
    End point timeframe
    At Weeks 0, 12, 48, and 104
    Notes
    [5] - 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: This study was an open label extension study. No inferential statistical analyses were performed. All statistical analyses are descriptive.
    End point values
    		 ALX-0061 150 mg q2w + MTX (C201 All Subjects) ALX-0061 150 mg q2w (C202 All Subjects) ALX-0061 150 mg q2w (C203 All Subjects)
    Number of subjects analysed
    257 [6]
    149 [7]
    406 [8]
    Units: Percent
        Week 0
    62
    47
    56
        Week 12
    71
    62
    68
        Week 48
    77
    81
    78
        Week 104
    84
    85
    84
    Notes
    [6] - ITO Population Number of subjects evaluated at: W0:n=246 W12:n=244 W48:n=222 W104:n=198
    [7] - ITO Population Number of subjects evaluated at: W0:n=148 W12:n=141 W48:n=134 W104:n=123
    [8] - Number of subjects evaluated at: W0: n=394 W12: n=385 W48: n=356 W104: n=321
    No statistical analyses for this end point

    Primary: Percentage of subjects with ACR70 response

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    End point title
    		 Percentage of subjects with ACR70 response [9]
    End point description
    ACR70 responses are defined as: • 70% improvement in tender/painful joint count (68 joints) relative to baseline AND • 70% improvement in swollen joint count (66 joints) relative to baseline AND • 70% improvement in 3 of the following 5 areas relative to baseline: - Patient's Assessment of Pain (100 mm-VAS), - Patient's Global Assessment of Disease Activity (100 mm-VASPA), - Physician's Global Assessment of Disease Activity (100 mm-VASPHA), - Patient's assessment of physical function as measured by HAQ-DI, - CRP level ACR70 responses were measured at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, and 104.
    End point type
    Primary
    End point timeframe
    At weeks 0, 12, 48, and 104
    Notes
    [9] - 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: This study was an open label extension study. No inferential statistical analyses were performed. All statistical analyses are descriptive.
    End point values
    		 ALX-0061 150 mg q2w + MTX (C201 All Subjects) ALX-0061 150 mg q2w (C202 All Subjects) ALX-0061 150 mg q2w (C203 All Subjects)
    Number of subjects analysed
    257 [10]
    149 [11]
    406 [12]
    Units: Percent
        Week 0
    34
    22
    30
        Week 12
    44
    36
    41
        Week 48
    61
    50
    57
        Week 104
    69
    72
    70
    Notes
    [10] - ITO Population Number of subjects evaluated at: W0:n=249 W12:n=243 W48:n=221 W104:n=197
    [11] - ITO Population Number of subjects evaluated at: W0:n=147 W12:n=141 W48:n=133 W104:n=123
    [12] - Number of subjects evaluated at: W0: n=396 W12: n=384 W48: n=354 W104: n=320
    No statistical analyses for this end point

    Primary: ACR-N Index of Improvement

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    End point title
    		 ACR-N Index of Improvement [13]
    End point description
    The ACR-N Index of Improvement is defined as the minimum of the following 3 criteria: • The percent improvement from Week 0 in TJCs • The percent improvement from Week 0 in SJCs • The median percent improvement from Week 0 for the following 5 assessments: - Subject's assessment of pain (VAS) - Subject's global assessment of disease activity (VASPHA) - Physician's global assessment of disease activity (VASPHA) - Subject's assessment of physical function as measured by the HAQ-DI - CRP level ACR-N Index of Improvement was measured at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, and 104.
    End point type
    Primary
    End point timeframe
    At Weeks 0, 12, 48, and 104
    Notes
    [13] - 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: This study was an open label extension study. No inferential statistical analyses were performed. All statistical analyses are descriptive.
    End point values
    		 ALX-0061 150 mg q2w + MTX (C201 All Subjects) ALX-0061 150 mg q2w (C202 All Subjects) ALX-0061 150 mg q2w (C203 All Subjects)
    Number of subjects analysed
    257 [14]
    149 [15]
    406 [16]
    Units: No unit
    arithmetic mean (standard error)
        Week 0
    55.77 ± 1.703
    48.18 ± 2.171
    52.98 ± 1.351
        Week 12
    61.51 ± 1.643
    57.07 ± 2.181
    59.91 ± 1.315
        Week 48
    67.73 ± 1.691
    66.49 ± 2.048
    67.27 ± 1.306
        Week 104
    74.83 ± 1.554
    73.82 ± 2.171
    74.45 ± 1.265
    Notes
    [14] - ITO Population Number of subjects evaluated at: W0:n=256 W12:n=252 W48:n=228 W104:n=205
    [15] - ITO Population Number of subjects evaluated at: W0:n=149 W12:n=142 W48:n=135 W104:n=123
    [16] - Number of subjects evaluated at: W0: n=405 W12: n=394 W48: n=363 W104: n=328
    No statistical analyses for this end point

    Primary: Percentage of subjects in remission based on Disease Activity Score using 28 joint counts (DAS28) using estimated sedimentation rate (ESR)

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    End point title
    		 Percentage of subjects in remission based on Disease Activity Score using 28 joint counts (DAS28) using estimated sedimentation rate (ESR) [17]
    End point description
    DAS28(ESR) = (0.56 × √TJC28) + (0.28 × √SJC28) + (0.70 × ln[ESR]) + (0.014 × VASPA) Remission = DAS28(ESR) < 2.6 Disease activity based on DAS28(ESR) was measured at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, and 104.
    End point type
    Primary
    End point timeframe
    At Weeks 0, 12, 48, and 104.
    Notes
    [17] - 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: This study was an open label extension study. No inferential statistical analyses were performed. All statistical analyses are descriptive.
    End point values
    		 ALX-0061 150 mg q2w + MTX (C201 All Subjects) ALX-0061 150 mg q2w (C202 All Subjects) ALX-0061 150 mg q2w (C203 All Subjects)
    Number of subjects analysed
    257 [18]
    149 [19]
    406 [20]
    Units: Percent
        Week 0
    40
    34
    38
        Week 12
    57
    49
    54
        Week 48
    63
    53
    59
        Week 104
    74
    69
    72
    Notes
    [18] - ITO Population Number of subjects evaluated at: W0: n=253 W12: n=248 W48: n=220 W104: n=198
    [19] - ITO Population Number of subjects evaluated at: W0: n=148 W12: n=138 W48: n=132 W104: n=121
    [20] - Number of subjects evaluated at: W0: n=401 W12: n=386 W48: n=352 W104: n=319
    No statistical analyses for this end point

    Primary: Percentage of subjects with low disease activity based on DAS28(ESR)

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    End point title
    		 Percentage of subjects with low disease activity based on DAS28(ESR) [21]
    End point description
    DAS28(ESR) = (0.56 × √TJC28) + (0.28 × √SJC28) + (0.70 × ln[ESR]) + (0.014 × VASPA) Low disease activity = 2.6 ≤ DAS28 ≤ 3.2 Disease activity based on DAS28(ESR) was measured at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, and 104.
    End point type
    Primary
    End point timeframe
    At Weeks 0, 12, 48, and 104.
    Notes
    [21] - 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: This study was an open label extension study. No inferential statistical analyses were performed. All statistical analyses are descriptive.
    End point values
    		 ALX-0061 150 mg q2w + MTX (C201 All Subjects) ALX-0061 150 mg q2w (C202 All Subjects) ALX-0061 150 mg q2w (C203 All Subjects)
    Number of subjects analysed
    257 [22]
    149 [23]
    406 [24]
    Units: Percent
        Week 0
    15
    18
    16
        Week 12
    15
    14
    15
        Week 48
    14
    20
    16
        Week 104
    14
    10
    13
    Notes
    [22] - ITO Population Number of subjects evaluated at: W0: n=253 W12: n=248 W48: n=220 W104: n=198
    [23] - ITO Population Number of subjects evaluated at: W0: n=148 W12: n=138 W48: n=132 W104: n=121
    [24] - Number of subjects evaluated at: W0: n=401 W12: n=386 W48: n=352 W104: n=319
    No statistical analyses for this end point

    Primary: Percentage of subjects with DAS28 using C-reactive protein (CRP) < 2.6

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    End point title
    		 Percentage of subjects with DAS28 using C-reactive protein (CRP) < 2.6 [25]
    End point description
    DAS28(CRP) = (0.56 × √TJC28) + (0.28 × √SJC28) + (0.36 × ln[CRP+1]) + (0.014 × VASPA) + 0.96 DAS28(CRP) < 2.6 Disease activity based on DAS28(CRP) was measured at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, and 104.
    End point type
    Primary
    End point timeframe
    At Weeks 0, 12, 48, and 104.
    Notes
    [25] - 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: This study was an open label extension study. No inferential statistical analyses were performed. All statistical analyses are descriptive.
    End point values
    		 ALX-0061 150 mg q2w + MTX (C201 All Subjects) ALX-0061 150 mg q2w (C202 All Subjects) ALX-0061 150 mg q2w (C203 All Subjects)
    Number of subjects analysed
    257 [26]
    149 [27]
    406 [28]
    Units: Percent
        Week 0
    39
    33
    37
        Week 12
    60
    51
    57
        Week 48
    67
    58
    64
        Week 104
    78
    75
    77
    Notes
    [26] - ITO Population Number of subjects evaluated at: W0: n=256 W12: n=249 W48: n=228 W104: n=204
    [27] - ITO Population Number of subjects evaluated at: W0: n=149 W12: n=142 W48: n=134 W104: n=123
    [28] - Number of subjects evaluated at: W0: n=405 W12: n=391 W48: n=362 W104: n=327
    No statistical analyses for this end point

    Primary: Percentage of subjects with low disease activity based on DAS28(CRP)

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    End point title
    		 Percentage of subjects with low disease activity based on DAS28(CRP) [29]
    End point description
    DAS28(CRP) = (0.56 × √TJC28) + (0.28 × √SJC28) + (0.36 × ln[CRP+1]) + (0.014 × VASPA) + 0.96 Low disease activity = 2.6 ≤ DAS28 ≤ 3.2 Disease activity based on DAS28(CRP) was measured at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, and 104.
    End point type
    Primary
    End point timeframe
    At Weeks 0, 12, 48, and 104.
    Notes
    [29] - 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: This study was an open label extension study. No inferential statistical analyses were performed. All statistical analyses are descriptive.
    End point values
    		 ALX-0061 150 mg q2w + MTX (C201 All Subjects) ALX-0061 150 mg q2w (C202 All Subjects) ALX-0061 150 mg q2w (C203 All Subjects)
    Number of subjects analysed
    257 [30]
    149 [31]
    406 [32]
    Units: Percent
        Week 0
    21
    23
    21
        Week 12
    16
    16
    16
        Week 48
    18
    19
    18
        Week 104
    14
    16
    15
    Notes
    [30] - ITO Population Number of subjects evaluated at: W0: n=256 W12: n=249 W48: n=228 W104: n=204
    [31] - ITO Population Number of subjects evaluated at: W0: n=149 W12: n=142 W48: n=134 W104: n=123
    [32] - Number of subjects evaluated at: W0: n=405 W12: n=391 W48: n=362 W104: n=327
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From time of first study drug administration in study ALX0061-C203 until the subject's study completion/discontinuation date.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    ALX-0061 150 mg q2w + MTX (C201 All Subjects)
    Reporting group description
    		 ALX-0061 150 mg s.c. q2w + MTX

    Reporting group title
    ALX-0061 150 mg q2w (C202 All Subjects)
    Reporting group description
    		 ALX-0061 150 mg s.c. q2w

    Reporting group title
    ALX-0061 150 mg q2w (C203 All Subjects)
    Reporting group description
    		 Subjects received ALX-0061 150 mg s.c. injections, beginning at Week 0 and q2w thereafter, up to and including Week 102. Subjects from the preceding study ALX0061-C201 also continued their MTX treatment.

    Serious adverse events
    		 ALX-0061 150 mg q2w + MTX (C201 All Subjects) ALX-0061 150 mg q2w (C202 All Subjects) ALX-0061 150 mg q2w (C203 All Subjects)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 257 (9.73%)
    9 / 148 (6.08%)
    34 / 405 (8.40%)
         number of deaths (all causes)
    2
    0
    2
         number of deaths resulting from adverse events
    2
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 148 (0.68%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Testicular seminoma (pure)
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 148 (0.68%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Extremity necrosis
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 148 (0.68%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 148 (0.68%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 257 (0.39%)
    1 / 148 (0.68%)
    2 / 405 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 257 (0.78%)
    0 / 148 (0.00%)
    2 / 405 (0.49%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 148 (0.68%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 148 (0.68%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 257 (0.39%)
    2 / 148 (1.35%)
    3 / 405 (0.74%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 257 (1.17%)
    0 / 148 (0.00%)
    3 / 405 (0.74%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess neck
         subjects affected / exposed
    0 / 257 (0.00%)
    1 / 148 (0.68%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal abscess
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    Septic shock
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 257 (0.39%)
    0 / 148 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ALX-0061 150 mg q2w + MTX (C201 All Subjects) ALX-0061 150 mg q2w (C202 All Subjects) ALX-0061 150 mg q2w (C203 All Subjects)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    175 / 257 (68.09%)
    100 / 148 (67.57%)
    275 / 405 (67.90%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 257 (3.50%)
    8 / 148 (5.41%)
    17 / 405 (4.20%)
         occurrences all number
    9
    8
    17
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 257 (1.56%)
    9 / 148 (6.08%)
    13 / 405 (3.21%)
         occurrences all number
    5
    13
    18
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    14 / 257 (5.45%)
    11 / 148 (7.43%)
    25 / 405 (6.17%)
         occurrences all number
    28
    23
    51
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    12 / 257 (4.67%)
    8 / 148 (5.41%)
    20 / 405 (4.94%)
         occurrences all number
    12
    8
    20
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    23 / 257 (8.95%)
    12 / 148 (8.11%)
    35 / 405 (8.64%)
         occurrences all number
    31
    13
    44
    Nasopharyngitis
         subjects affected / exposed
    17 / 257 (6.61%)
    11 / 148 (7.43%)
    28 / 405 (6.91%)
         occurrences all number
    22
    13
    35
    Pharyngitis
         subjects affected / exposed
    15 / 257 (5.84%)
    9 / 148 (6.08%)
    24 / 405 (5.93%)
         occurrences all number
    19
    11
    30
    Urinary tract infection
         subjects affected / exposed
    14 / 257 (5.45%)
    9 / 148 (6.08%)
    23 / 405 (5.68%)
         occurrences all number
    17
    13
    30
    Influenza
         subjects affected / exposed
    8 / 257 (3.11%)
    10 / 148 (6.76%)
    18 / 405 (4.44%)
         occurrences all number
    12
    17
    29
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    6 / 257 (2.33%)
    9 / 148 (6.08%)
    15 / 405 (3.70%)
         occurrences all number
    6
    9
    15

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Dec 2015
    Main reasons for the second protocol amendment: • The exclusion criterion on laboratory abnormalities had been updated to ensure more consistency between the discontinuation criteria in the preceding Phase llb studies with ALX-0061 (ALX0061-C201 or ALX0061-C202) and the entry criteria of this open-label extension study (ALX0061-C203) and to allow unscheduled lab testing for study entry. • It had been clarified that the term baseline mentioned in the analysis endpoints was referring to the baseline value of the preceding Phase llb study with ALX-0061 (ALX0061-C201 or ALX0061-C202) the subject was enrolled in. • The use of the allowed medication non-steroidal anti-inflammatory drugs (NDAIDs) had been further clarified and the prohibited medications high-potency opioid analgesics had been specified. • It has been specified that additional pregnancy testing is allowed according to local guidelines; however, this additional pregnancy testing is not part of and cannot replace the protocol specific procedures. • Wording with regard to follow-up of adverse events (AEs) was updated to clarify that all AEs were to be followed until satisfactory outcome. • No subgroup analysis by site for efficacy were to be done as the number of patients per site was too limited. • Shift tables on vital signs variables according to their normal ranges were not be created as these were not expected to provide additional clinically useful information on top of the planned descriptive summaries on actual values and changes from baseline of the vital signs parameters; the latter being more relevant in the study population of moderate to severe RA patients. Medical assessment of the values was performed by the Investigator and during the medical review process.

    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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