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    Clinical Trial Results:
    A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Multicenter Phase III Study of the Efficacy and Safety of Olokizumab in Subjects with Moderately to Severely Active Rheumatoid Arthritis Inadequately Controlled by Tumor Necrosis Factor Alpha (TNF-α) Inhibitor Therapy

    Summary
    EudraCT number
    		 2015-005308-27
    Trial protocol
    		 CZ   HU   DE  
    Global end of trial date
    01 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Dec 2020
    First version publication date
    31 Dec 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CL04041025
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02760433
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND No: 104933
    Sponsors
    Sponsor organisation name
    R-Pharm International
    Sponsor organisation address
    19 1, Berzarina Street, Moscow, Russian Federation, 123154
    Public contact
    Medical Department, R-Pharm International, +7 495 956 7937,
    Scientific contact
    Medical Department, R-Pharm International, +7 495 956 7937,
    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
    01 Oct 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of Olokizumab (OKZ) 64 milligram (mg) administered subcutaneously (SC) once every 2 weeks (q2w) or once every 4 weeks (q4w) relative to placebo in subjects with moderately to severely active rheumatoid arthritis (RA) inadequately controlled by tumor necrosis factor alpha (TNF-α) therapy.
    Protection of trial subjects
    The study was conducted in accordance with the protocol, the ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, applicable International Council for Harmonisation Good Clinical Practice Guidelines, and applicable laws and regulations.
    Background therapy
    		 Stable methotrexate (MTX) dose was continued during the study. Folic acid ≥5 mg per week or equivalent was required during the study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Jan 2017
    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
    Argentina: 28
    Country: Number of subjects enrolled
    Brazil: 24
    Country: Number of subjects enrolled
    Colombia: 13
    Country: Number of subjects enrolled
    Czechia: 36
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 24
    Country: Number of subjects enrolled
    Korea, Republic of: 4
    Country: Number of subjects enrolled
    Mexico: 73
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    Russian Federation: 21
    Country: Number of subjects enrolled
    United States: 128
    Worldwide total number of subjects
    368
    EEA total number of subjects
    77
    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)
    300
    From 65 to 84 years
    68
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This was a randomized, double-blind, parallel-group, placebo-controlled, multicenter Phase III study conducted at 123 study centers in 11 countries between 25 January 2017 and 01 October 2019. A total of 718 subjects were screened, of which 350 subjects were screen failures and 368 subjects were randomized in the study.

    Pre-assignment
    Screening details
    		 Subjects with moderately to severely active RA with an inadequate response to TNF-α inhibitor therapy for at least 12 weeks prior to Screening with ≥1 licensed TNF-α inhibitor were assessed for eligibility. Eligible subjects were randomized in 2:2:1 ratio to receive OKZ 64 mg q4w, OKZ 64 mg q2w, or placebo in 24-week double-blind Treatment Period.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Assessor, Subject
    Blinding implementation details
    Since the study treatments were distinguishable, they were prepared by the unblinded pharmacist (or their unblinded designee) out of sight of the subject and any blinded study team members. The study treatments were provided to blinded site staff in blinded syringes that were identical in appearance.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 OKZ 64 mg q4w
    Arm description
    		 Subjects received an SC injection of OKZ 64 mg q4w alternating with SC injections of placebo q4w to maintain blinding and stable dose of MTX. The last dose of study treatment was at Week 20 of the Treatment Period from Week 0 to Week 24. After completion of the double-blind Treatment Period at Week 24, subjects were offered the opportunity to enter the optional open-label extension (OLE) study. Subjects who did not consent to participate in the OLE study attended the End of Treatment (EoT) Visit at Week 24. After the EoT Visit, these subjects were scheduled for 3 Safety Follow-Up Visits up to Week 44.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olokizumab
    Investigational medicinal product code
    Other name
    OKZ, CDP6038, L04041
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 64 mg q4w OKZ by SC injection in either abdomen or thigh, prepared in blinded syringes of 0.4 milliliter (mL).

    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
    Subjects received placebo (sodium chloride 0.9%) q4w by SC injection in either abdomen or thigh, prepared in blinded syringes of 0.4 mL.

    Arm title
    		 OKZ 64 mg q2w
    Arm description
    		 Subjects received an SC injection of OKZ 64 mg q2w and stable dose of MTX. The last dose of study treatment was at Week 22 of the Treatment Period from Week 0 to Week 24. After completion of the double-blind Treatment Period at Week 24, subjects were offered the opportunity to enter the optional OLE study. Subjects who did not consent to participate in the OLE study attended the EoT Visit at Week 24. After the EoT Visit, these subjects were scheduled for 3 Safety Follow-Up Visits up to Week 44.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olokizumab
    Investigational medicinal product code
    Other name
    OKZ, CDP6038, L04041
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 64 mg q2w OKZ by SC injection in either abdomen or thigh, prepared in blinded syringes of 0.4 mL.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received an SC injection of Placebo q2w and stable dose of MTX. The last dose of placebo was at Week 14 of the Treatment Period from Week 0 to Week 24. Subjects were re-randomized in a blinded fashion to receive either OKZ 64 mg q4w alternating with placebo q4w or OKZ 64 mg q2w starting at Week 16 and continuing for the remainder of the double-blind Treatment Period. After completion of the double-blind Treatment Period at Week 24, subjects were offered the opportunity to enter the optional OLE study. Subjects who did not consent to participate in the OLE study attended the EoT Visit at Week 24. After the EoT Visit, these subjects were scheduled for 3 Safety Follow-Up Visits up to Week 44.
    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
    Subjects received placebo (sodium chloride 0.9%) q2w or q4w by SC injection in either abdomen or thigh, prepared in blinded syringes of 0.4 mL.

    Investigational medicinal product name
    Olokizumab
    Investigational medicinal product code
    Other name
    OKZ, CDP6038, L04041
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 64 mg q4w or q2w OKZ by SC injection in either abdomen or thigh, prepared in blinded syringes of 0.4 mL.

    Number of subjects in period 1
    		OKZ 64 mg q4w OKZ 64 mg q2w Placebo
    Started
    161
    138
    69
    Received Treatment
    161
    138
    69
    Completed Week 16
    139
    129
    58
    Completed Treatment Period
    136
    127 [1]
    57
    Continued into Safety Follow-Up Period
    14 [2]
    9 [3]
    8 [4]
    Enrolled in OLE
    127 [5]
    124 [6]
    51 [7]
    Completed
    134
    128
    56
    Not completed
    27
    10
    13
         Consent withdrawn by subject
    23
    9
    11
         Other
    3
    1
    1
         Lost to follow-up
    1
    -
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The subjects who discontinued treatment early and entered the safety follow-up period were considered completers for the whole study if they performed all 3 follow-up visits. Therefore, the number of subjects who completed study can be higher than number of treatment completers.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The subjects who discontinued treatment early had to enter the safety follow-up period as well as subjects who completed treatment period; therefore, the numbers subjects enrolled in OLE and continued to the safety follow-up period are higher than those who completed treatment period.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The subjects who discontinued treatment early had to enter the safety follow-up period as well as subjects who completed treatment period; therefore, the numbers subjects enrolled in OLE and continued to the safety follow-up period are higher than those who completed treatment period.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The subjects who discontinued treatment early had to enter the safety follow-up period as well as subjects who completed treatment period; therefore, the numbers subjects enrolled in OLE and continued to the safety follow-up period are higher than those who completed treatment period.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The subjects who discontinued treatment early had to enter the safety follow-up period as well as subjects who completed treatment period; therefore, the numbers subjects enrolled in OLE and continued to the safety follow-up period are higher than those who completed treatment period.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The subjects who discontinued treatment early had to enter the safety follow-up period as well as subjects who completed treatment period; therefore, the numbers subjects enrolled in OLE and continued to the safety follow-up period are higher than those who completed treatment period.
    [7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The subjects who discontinued treatment early had to enter the safety follow-up period as well as subjects who completed treatment period; therefore, the numbers subjects enrolled in OLE and continued to the safety follow-up period are higher than those who completed treatment period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    OKZ 64 mg q4w
    Reporting group description
    		 Subjects received an SC injection of OKZ 64 mg q4w alternating with SC injections of placebo q4w to maintain blinding and stable dose of MTX. The last dose of study treatment was at Week 20 of the Treatment Period from Week 0 to Week 24. After completion of the double-blind Treatment Period at Week 24, subjects were offered the opportunity to enter the optional open-label extension (OLE) study. Subjects who did not consent to participate in the OLE study attended the End of Treatment (EoT) Visit at Week 24. After the EoT Visit, these subjects were scheduled for 3 Safety Follow-Up Visits up to Week 44.

    Reporting group title
    OKZ 64 mg q2w
    Reporting group description
    		 Subjects received an SC injection of OKZ 64 mg q2w and stable dose of MTX. The last dose of study treatment was at Week 22 of the Treatment Period from Week 0 to Week 24. After completion of the double-blind Treatment Period at Week 24, subjects were offered the opportunity to enter the optional OLE study. Subjects who did not consent to participate in the OLE study attended the EoT Visit at Week 24. After the EoT Visit, these subjects were scheduled for 3 Safety Follow-Up Visits up to Week 44.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received an SC injection of Placebo q2w and stable dose of MTX. The last dose of placebo was at Week 14 of the Treatment Period from Week 0 to Week 24. Subjects were re-randomized in a blinded fashion to receive either OKZ 64 mg q4w alternating with placebo q4w or OKZ 64 mg q2w starting at Week 16 and continuing for the remainder of the double-blind Treatment Period. After completion of the double-blind Treatment Period at Week 24, subjects were offered the opportunity to enter the optional OLE study. Subjects who did not consent to participate in the OLE study attended the EoT Visit at Week 24. After the EoT Visit, these subjects were scheduled for 3 Safety Follow-Up Visits up to Week 44.

    Reporting group values
    		 OKZ 64 mg q4w OKZ 64 mg q2w Placebo Total
    Number of subjects
    		 161 138 69 368
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 132 114 54 300
        From 65-84 years
    		 29 24 15 68
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.9 ± 11.68 53.4 ± 12.68 53.0 ± 13.70 -
    Gender categorical
    Units: Subjects
        Female
    		 130 122 55 307
        Male
    		 31 16 14 61
    Race
    Units: Subjects
        Asian
    		 3 6 2 11
        Black or African American
    		 11 11 1 23
        White
    		 139 110 53 302
        Other / Mixed
    		 8 11 13 32
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 77 64 42 183
        Not Hispanic or Latino
    		 84 74 27 185

    End points

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    End points reporting groups
    Reporting group title
    OKZ 64 mg q4w
    Reporting group description
    		 Subjects received an SC injection of OKZ 64 mg q4w alternating with SC injections of placebo q4w to maintain blinding and stable dose of MTX. The last dose of study treatment was at Week 20 of the Treatment Period from Week 0 to Week 24. After completion of the double-blind Treatment Period at Week 24, subjects were offered the opportunity to enter the optional open-label extension (OLE) study. Subjects who did not consent to participate in the OLE study attended the End of Treatment (EoT) Visit at Week 24. After the EoT Visit, these subjects were scheduled for 3 Safety Follow-Up Visits up to Week 44.

    Reporting group title
    OKZ 64 mg q2w
    Reporting group description
    		 Subjects received an SC injection of OKZ 64 mg q2w and stable dose of MTX. The last dose of study treatment was at Week 22 of the Treatment Period from Week 0 to Week 24. After completion of the double-blind Treatment Period at Week 24, subjects were offered the opportunity to enter the optional OLE study. Subjects who did not consent to participate in the OLE study attended the EoT Visit at Week 24. After the EoT Visit, these subjects were scheduled for 3 Safety Follow-Up Visits up to Week 44.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received an SC injection of Placebo q2w and stable dose of MTX. The last dose of placebo was at Week 14 of the Treatment Period from Week 0 to Week 24. Subjects were re-randomized in a blinded fashion to receive either OKZ 64 mg q4w alternating with placebo q4w or OKZ 64 mg q2w starting at Week 16 and continuing for the remainder of the double-blind Treatment Period. After completion of the double-blind Treatment Period at Week 24, subjects were offered the opportunity to enter the optional OLE study. Subjects who did not consent to participate in the OLE study attended the EoT Visit at Week 24. After the EoT Visit, these subjects were scheduled for 3 Safety Follow-Up Visits up to Week 44.

    Primary: Percentage of Subjects Meeting the American College of Rheumatology 20% Response Criteria (ACR20) at Week 12

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    End point title
    		 Percentage of Subjects Meeting the American College of Rheumatology 20% Response Criteria (ACR20) at Week 12
    End point description
    To meet ACR20 response criteria at Week 12, a subject must have had at least 20% improvement from baseline in the following ACR Core Set values: • Tender joint count (TJC) (68 joint count) • Swollen joint count (SJC) (66 joint count) An improvement of at least 20% from baseline in at least 3 of the following 5 components: 1) Patient Global Assessment of Disease Activity (Visual Analog Scale [VAS]); 2) Subject Assessment of Pain (VAS); 3) Health Assessment Questionnaire - Disability Index (HAQ-DI); 4) Physician Global Assessment (VAS); 5) Level of acute phase reactant (C-reactive protein [CRP]). A responder was a subject meeting the ACR20 criteria and remaining on randomized treatment and in the study at Week 12. Analysis was performed on the intent-to-treat (ITT) population, which included all randomized subjects.
    End point type
    Primary
    End point timeframe
    From Baseline to Week 12
    End point values
    		 OKZ 64 mg q4w OKZ 64 mg q2w Placebo
    Number of subjects analysed
    161
    138
    69
    Units: Percentage of subjects
        number (not applicable)
    59.6
    60.9
    40.6
    Statistical analysis title
    		 Comparison of OKZ 64 mg q4w Vs Placebo
    Comparison groups
    OKZ 64 mg q4w v Placebo
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004 [1]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.19
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 0.337
    Notes
    [1] - P-values are 1-sided p-values from 2x2 chi-square test, assessed for statistical significance at the alfa level of 0.0125. Confidence interval was calculated using Newcombe hybrid score method.
    Statistical analysis title
    		 Comparison of OKZ 64 mg q2w Vs Placebo
    Comparison groups
    OKZ 64 mg q2w v Placebo
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0029 [2]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.203
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.038
         upper limit
    		 0.353
    Notes
    [2] - P-values are 1-sided p-values from 2x2 chi-square test, assessed for statistical significance at the alfa level of 0.0125. Confidence interval was calculated using Newcombe hybrid score method.

    Secondary: Percentage of Subjects Achieving Low Disease Activity, Defined as Disease Activity Score 28-Joint Count CRP (DAS 28 [CRP]) <3.2 at Week 12

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    End point title
    		 Percentage of Subjects Achieving Low Disease Activity, Defined as Disease Activity Score 28-Joint Count CRP (DAS 28 [CRP]) <3.2 at Week 12
    End point description
    The DAS28 (CRP) was calculated using the SJC (28 joints), TJC (28 joints), CRP level (mg/mL), and the Patient Global Assessment of Disease Activity (VAS) (in millimeters) according to the formula: DAS28 (CRP) = 0.56 × √(TJC) + 0.28 × √(SJC) + 0.36 × ln (CRP + 1) + 0.014 × Patient Global Assessment of Disease Activity (VAS) + 0.96. The 28 joints evaluated for the SJC and TJC were: shoulders, elbows, wrists, interphalangeal on digit 1, proximal interphalangeals on digits 2 to 5, metacarpophalangeal on digits 1 to 5, and knees. A subject classed as having low disease activity who remained on randomized treatment and who were in the study at Week 12 and had a DAS28 (CRP) <3.2. Analysis was performed on the ITT population which included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 OKZ 64 mg q4w OKZ 64 mg q2w Placebo
    Number of subjects analysed
    161
    138
    69
    Units: Percentage of subjects
        number (not applicable)
    28.0
    39.9
    11.6
    Statistical analysis title
    		 Comparison of OKZ 64 mg q4w Vs Placebo
    Comparison groups
    OKZ 64 mg q4w v Placebo
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0035 [3]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.164
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.029
         upper limit
    		 0.268
    Notes
    [3] - P-values are 1-sided p-values from 2x2 chi-square test, assessed for statistical significance at the alfa level of 0.0125. Confidence interval was calculated using Newcombe hybrid score method.
    Statistical analysis title
    		 Comparison of OKZ 64 mg q2w Vs Placebo
    Comparison groups
    OKZ 64 mg q2w v Placebo
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.283
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.139
         upper limit
    		 0.396
    Notes
    [4] - P-values are 1-sided p-values from 2x2 chi-square test, assessed for statistical significance at the alfa level of 0.0125. Confidence interval was calculated using Newcombe hybrid score method.

    Secondary: Mean Change From Baseline to Week 12 in HAQ-DI

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    End point title
    		 Mean Change From Baseline to Week 12 in HAQ-DI
    End point description
    The HAQ-DI is a patient reported questionnaire that provided an assessment of impact of disease and its treatment on physical function. HAQ-DI assessed degree of difficulty experienced in 8 domains of daily living activities using 20 questions. For each question, level of difficulty was scored from 0 to 3 where 0= without any difficulty, 1= with some difficulty, 2= much difficulty, and 3= unable to do. Each category was scored by taking maximum score of each question. HAQ-DI was calculated by dividing sum of category scores by number of categories with at least 1 question answered. If fewer than 6 categories had responses, no disability score was calculated. A decrease from baseline indicated an improvement in physical ability. Analysis of covariance (ANCOVA) with treatment as fixed effect and baseline value as covariate was used to determine Least Square Mean (LSM) change from baseline for ITT population, which included all randomized subjects with Baseline and Week 12 HAQ-DI values.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    		 OKZ 64 mg q4w OKZ 64 mg q2w Placebo
    Number of subjects analysed
    157
    131
    68
    Units: Units on HAQ-DI scale
        least squares mean (standard error)
    -0.39 ± 0.044
    -0.49 ± 0.048
    -0.32 ± 0.068
    Statistical analysis title
    		 Comparison of OKZ 64 mg q4w Vs Placebo
    Comparison groups
    OKZ 64 mg q4w v Placebo
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.1814 [6]
    Method
    		 ANCOVA
    Parameter type
    		 LSM difference
    Point estimate
    -0.07
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 0.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.081
    Notes
    [5] - ANCOVA model included treatment as fixed effect and baseline value as a covariate. LSMs and P-value were obtained using Rubin's rule.
    [6] - P-values represent a 1-sided combined test for treatment effect from the ANCOVA model, assessed for statistical significance at the alfa level of 0.0125.
    Statistical analysis title
    		 Comparison of OKZ 64 mg q2w Vs Placebo
    Comparison groups
    OKZ 64 mg q2w v Placebo
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.0227 [8]
    Method
    		 ANCOVA
    Parameter type
    		 LSM difference
    Point estimate
    -0.17
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -0.35
         upper limit
    		 0.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.083
    Notes
    [7] - ANCOVA model included treatment as fixed effect and baseline value as a covariate. LSMs and P-value were obtained using Rubin's rule.
    [8] - P-values represent a 1-sided combined test for treatment effect from the ANCOVA model, assessed for statistical significance at the alfa level of 0.0125.

    Secondary: Percentage of Subjects Achieving American College of Rheumatology 50% Response Criteria (ACR50) at Week 12

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    End point title
    		 Percentage of Subjects Achieving American College of Rheumatology 50% Response Criteria (ACR50) at Week 12
    End point description
    To meet ACR50 response criteria at Week 12, a subject must have had at least 50% improvement from baseline in the following ACR Core Set values: • TJC (68 joint count) • SJC (66 joint count) An improvement of at least 50% in at least 3 of the following 5 components: 1) Patient Global Assessment of Disease Activity (VAS); 2) Subject Assessment of Pain (VAS); 3) HAQ-DI; 4) Physician Global Assessment (VAS); 5) Level of acute phase reactant (CRP). Subjects must have been remaining on randomized treatment and in the study at Week 12. Analysis was performed on the ITT population, which included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    		 OKZ 64 mg q4w OKZ 64 mg q2w Placebo
    Number of subjects analysed
    161
    138
    69
    Units: Percentage of subjects
        number (not applicable)
    32.3
    33.3
    15.9
    Statistical analysis title
    		 Comparison of OKZ 64 mg q4w Vs Placebo
    Comparison groups
    OKZ 64 mg q4w v Placebo
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.0054 [10]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.164
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.278
    Notes
    [9] - Due to the hierarchy in the statistical gate-keeping strategy, the p-value cannot be used for formal inference because superiority was not shown for the HAQ-DI Improvement at Week 12 secondary endpoint.
    [10] - P-values are 1-sided p-values from 2x2 chi-square test. Confidence interval was calculated using Newcombe hybrid score method.
    Statistical analysis title
    		 Comparison of OKZ 64 mg q2w Vs Placebo
    Comparison groups
    OKZ 64 mg q2w v Placebo
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.0041 [12]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.174
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.027
         upper limit
    		 0.294
    Notes
    [11] - Due to the hierarchy in the statistical gate-keeping strategy, the p-value cannot be used for formal inference because superiority was not shown for the HAQ-DI Improvement at Week 12 secondary endpoint.
    [12] - P-values are 1-sided p-values from 2x2 chi-square test. Confidence interval was calculated using Newcombe hybrid score method.

    Secondary: Percentage of Subjects Achieving Remission, Defined as Clinical Disease Activity Index (CDAI) ≤2.8 (Remission) at Week 12

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    End point title
    		 Percentage of Subjects Achieving Remission, Defined as Clinical Disease Activity Index (CDAI) ≤2.8 (Remission) at Week 12
    End point description
    The CDAI was calculated using the SJC (28 joints), TJC (28 joints), the Patient Global Assessment of Disease Activity (VAS) [in centimeters (cm)], and the Physician Global Assessment (VAS) (in cm) according to the formula: CDAI = SJC + TJC + Patient Global Assessment of Disease Activity (VAS) + Physician Global Assessment (VAS). Subjects were classed as in remission if they remained on randomized treatment and in the study at Week 12 and with a CDAI of ≤2.8. Analysis was performed on the ITT population, which included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    At Week 12
    End point values
    		 OKZ 64 mg q4w OKZ 64 mg q2w Placebo
    Number of subjects analysed
    161
    138
    69
    Units: Percentage of subjects
        number (not applicable)
    3.1
    6.5
    0
    Statistical analysis title
    		 Comparison of OKZ 64 mg q4w Vs Placebo
    Comparison groups
    OKZ 64 mg q4w v Placebo
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.1619 [14]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.031
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -0.052
         upper limit
    		 0.083
    Notes
    [13] - Due to the hierarchy in the statistical gate-keeping strategy, the p-value cannot be used for formal inference because superiority was not shown for the HAQ-DI Improvement at Week 12 secondary endpoint.
    [14] - P-values are 1-sided p-values from 2x2 chi-square test. Confidence interval was calculated using Newcombe hybrid score method.
    Statistical analysis title
    		 Comparison of OKZ 64 mg q2w Vs Placebo
    Comparison groups
    OKZ 64 mg q2w v Placebo
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.0353 [16]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.065
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -0.023
         upper limit
    		 0.134
    Notes
    [15] - Due to the hierarchy in the statistical gate-keeping strategy, the p-value cannot be used for formal inference because superiority was not shown for the HAQ-DI Improvement at Week 12 secondary endpoint.
    [16] - P-values are 1-sided p-values from 2x2 chi-square test. Confidence interval was calculated using Newcombe hybrid score method.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment emergent adverse events (TEAEs) were recorded after the first dose of the study treatment until the last visit of the subject in the study (up to 44 weeks in total) regardless of relationship to study treatment.
    Adverse event reporting additional description
    The safety population included all subjects who received at least 1 dose of study treatment. Data for TEAEs were reported below. A TEAE was defined as an adverse event that first occurred or worsened in severity after the first dose of the study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    OKZ 64 mg q4w
    Reporting group description
    		 Subjects received an SC injection of OKZ 64 mg q4w alternating with SC injections of placebo q4w to maintain blinding and stable dose of MTX. The last dose of study treatment was at Week 20 of the Treatment Period from Week 0 to Week 24. After completion of the double-blind Treatment Period at Week 24, subjects were offered the opportunity to enter the optional OLE study. Subjects who did not consent to participate in the OLE study attended the EoT Visit at Week 24. After the EoT Visit, these subjects were scheduled for 3 Safety Follow-Up Visits up to Week 44.

    Reporting group title
    OKZ 64 mg q2w
    Reporting group description
    		 Subjects received an SC injection of OKZ 64 mg q2w and stable dose of MTX. The last dose of study treatment was at Week 22 of the Treatment Period from Week 0 to Week 24. After completion of the double-blind Treatment Period at Week 24, subjects were offered the opportunity to enter the optional OLE study. Subjects who did not consent to participate in the OLE study attended the EoT Visit at Week 24. After the EoT Visit, these subjects were scheduled for 3 Safety Follow-Up Visits up to Week 44.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received an SC injection of Placebo q2w and stable dose of MTX. The last dose of placebo was at Week 14 of the Treatment Period from Week 0 to Week 24. Subjects were re-randomized in a blinded fashion to receive either OKZ 64 mg q4w alternating with placebo q4w or OKZ 64 mg q2w starting at Week 16 and continuing for the remainder of the double-blind Treatment Period. After completion of the double-blind Treatment Period at Week 24, subjects were offered the opportunity to enter the optional OLE study. Subjects who did not consent to participate in the OLE study attended the EoT Visit at Week 24. After the EoT Visit, these subjects were scheduled for 3 Safety Follow-Up Visits up to Week 44. TEAEs that occur after the first administration of placebo and prior to any administration of OKZ at or after Week 16 are summarized as a TEAE under placebo reporting group.

    Reporting group title
    Placebo - OKZ 64 mg q4w
    Reporting group description
    		 Subjects received an SC injection of Placebo q2w and stable dose of MTX. The last dose of placebo was at Week 14 of the Treatment Period from Week 0 to Week 24. Subjects were re-randomized in a blinded fashion to receive OKZ 64 mg q4w alternating with placebo q4w starting at Week 16 and continuing for the remainder of the double-blind Treatment Period. After completion of the double-blind Treatment Period at Week 24, subjects were offered the opportunity to enter the optional OLE study. Subjects who did not consent to participate in the OLE study attended the EoT Visit at Week 24. After the EoT Visit, these subjects were scheduled for 3 Safety Follow-Up Visits up to Week 44. TEAEs that occur after the first administration of OKZ 64 mg q4w at or after Week 16 are summarized as a TEAE under Placebo-OKZ 64 mg q4w reporting group.

    Reporting group title
    Placebo - OKZ 64 mg q2w
    Reporting group description
    		 Subjects received an SC injection of Placebo q2w and stable dose of MTX. The last dose of placebo was at Week 14 of the Treatment Period from Week 0 to Week 24. Subjects were re-randomized in a blinded fashion to receive OKZ 64 mg q2w starting at Week 16 and continuing for the remainder of the double-blind Treatment Period. After completion of the double-blind Treatment Period at Week 24, subjects were offered the opportunity to enter the optional OLE study. Subjects who did not consent to participate in the OLE study attended the EoT Visit at Week 24. After the EoT Visit, these subjects were scheduled for 3 Safety Follow-Up Visits up to Week 44. TEAEs that occur after the first administration of OKZ 64 mg q2w at or after Week 16 are summarized as a TEAE under Placebo-OKZ 64 mg q2w reporting group.

    Serious adverse events
    		 OKZ 64 mg q4w OKZ 64 mg q2w Placebo Placebo - OKZ 64 mg q4w Placebo - OKZ 64 mg q2w
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 160 (3.75%)
    12 / 139 (8.63%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 139 (0.00%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (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
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 139 (0.72%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (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
    Transaminases increased
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 139 (0.72%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 139 (0.72%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (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
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 139 (0.72%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (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
    Ulna fracture
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 139 (0.72%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (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
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 139 (0.72%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (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
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 139 (0.00%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (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
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 139 (0.00%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (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
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 139 (0.00%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (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
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 139 (0.72%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (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
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 139 (0.72%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (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
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 139 (0.00%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 139 (0.72%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 139 (0.72%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (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
    Osteoarthritis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 139 (0.72%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (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
    Cellulitis
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 139 (0.72%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 139 (0.72%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (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
    Pneumonia
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 139 (0.00%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (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
    Sepsis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 139 (0.72%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (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
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 OKZ 64 mg q4w OKZ 64 mg q2w Placebo Placebo - OKZ 64 mg q4w Placebo - OKZ 64 mg q2w
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 160 (23.75%)
    38 / 139 (27.34%)
    16 / 69 (23.19%)
    2 / 26 (7.69%)
    8 / 32 (25.00%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    13 / 160 (8.13%)
    10 / 139 (7.19%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    16
    13
    0
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 160 (5.00%)
    9 / 139 (6.47%)
    1 / 69 (1.45%)
    0 / 26 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    9
    10
    1
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 160 (0.63%)
    4 / 139 (2.88%)
    3 / 69 (4.35%)
    1 / 26 (3.85%)
    0 / 32 (0.00%)
         occurrences all number
    2
    4
    3
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 139 (0.72%)
    4 / 69 (5.80%)
    0 / 26 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    1
    1
    4
    0
    2
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    7 / 160 (4.38%)
    1 / 139 (0.72%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    13
    4
    0
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 160 (1.88%)
    6 / 139 (4.32%)
    0 / 69 (0.00%)
    0 / 26 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    4
    6
    0
    0
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 160 (4.38%)
    9 / 139 (6.47%)
    1 / 69 (1.45%)
    0 / 26 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    7
    9
    1
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 160 (3.75%)
    5 / 139 (3.60%)
    4 / 69 (5.80%)
    0 / 26 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    6
    6
    4
    0
    1
    Latent tuberculosis
         subjects affected / exposed
    6 / 160 (3.75%)
    4 / 139 (2.88%)
    0 / 69 (0.00%)
    1 / 26 (3.85%)
    2 / 32 (6.25%)
         occurrences all number
    6
    4
    0
    1
    2
    Influenza
         subjects affected / exposed
    0 / 160 (0.00%)
    5 / 139 (3.60%)
    4 / 69 (5.80%)
    0 / 26 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    5
    4
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Sep 2016
    The significant changes to the protocol included: • The primary efficacy assessment and all secondary efficacy endpoints which previously planned to be assessed at Week 14 were moved from Week 14 to Week 12. • Subjects who were identified as nonresponders at Week 14 were assigned rescue medication starting at or as close as possible to Week 14, rather than starting at Week 16. • One of the secondary efficacy endpoints was changed from percentage of subjects with Simplified Disease Activity Index ≤3.3 to percentage of subjects with CDAI ≤2.8. • The percentage of subjects with CDAI ≤2.8 at all other applicable time points and change from baseline to Weeks 12 and 24 in the Short Form 36 Mental Component Summary total score were added as new other efficacy endpoints. • The definition of moderate response in the other efficacy endpoint assessing the proportion of subjects with moderate to good response based on DAS28 (CRP) was revised to DAS28 (CRP) ≤5.1 with an improvement from baseline in DAS28 (CRP) >0.6 and ≤1.2, or DAS28 (CRP) >3.2 with an improvement from baseline in DAS28 (CRP) >1.2. • A study visit at Week 17 was deleted from the study. • Folic acid was added as a required concomitant medication to counteract the potential side-effects of MTX. • Subjects with a positive interferon-gamma release assay result at Screening or a history of untreated latent tuberculosis infection (LTBI) were allowed to enroll in the study if active tuberculosis was ruled out by a certified tuberculosis specialist or pulmonologist experienced in diagnosing and treating tuberculosis, subject completed at least 30 days of LTBI therapy prior to randomization, and subject agreed to complete the recommend course of LTBI therapy. • Additional guidance for monitoring and reporting events of potential hepatotoxicity was added and potential hepatotoxicity events that fulfilled certain criteria were to be recorded as serious. • Additional guidance for the management of LTBI was added.

    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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