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    Clinical Trial Results:
    A Randomized, Double-Blind, Parallel-Group, Placebo- and Active-Controlled, Multicenter Phase III Study of the Efficacy and Safety of Olokizumab in Subjects with Moderately to Severely Active Rheumatoid Arthritis Inadequately Controlled by Methotrexate Therapy

    Summary
    EudraCT number
    2015-005307-83
    Trial protocol
    LV   CZ   DE   LT   HU   PL   BG  
    Global end of trial date
    05 Nov 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Nov 2020
    First version publication date
    15 Nov 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL04041023
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02760407
    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
    05 Nov 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate superiority of Olokizumab (OKZ) 64 milligrams (mg) administered subcutaneously (SC) once every 2 weeks (q2w) or once every 4 weeks (q4w) plus methotrexate (MTX) relative to placebo plus MTX and non-inferiority of OKZ 64 mg q2w or q4w administered SC plus MTX relative to Adalimumab plus MTX with respect to the American College of Rheumatology 20% response criteria (ACR20) at Week 12 in subjects with moderately to severely active rheumatoid arthritis (RA) inadequately controlled by MTX 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 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
    06 Jun 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Taiwan: 8
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    United States: 257
    Country: Number of subjects enrolled
    Argentina: 153
    Country: Number of subjects enrolled
    Brazil: 112
    Country: Number of subjects enrolled
    Bulgaria: 65
    Country: Number of subjects enrolled
    Colombia: 59
    Country: Number of subjects enrolled
    Czech Republic: 189
    Country: Number of subjects enrolled
    Estonia: 13
    Country: Number of subjects enrolled
    Germany: 40
    Country: Number of subjects enrolled
    Hungary: 51
    Country: Number of subjects enrolled
    Korea, Republic of: 11
    Country: Number of subjects enrolled
    Latvia: 4
    Country: Number of subjects enrolled
    Lithuania: 74
    Country: Number of subjects enrolled
    Mexico: 215
    Country: Number of subjects enrolled
    Poland: 308
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Russian Federation: 77
    Worldwide total number of subjects
    1648
    EEA total number of subjects
    756
    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)
    1327
    From 65 to 84 years
    320
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    This was a randomized, double-blind, parallel-group, placebo- and active-controlled, multicenter Phase III study conducted at 209 study centers in 18 countries between 06 June 2016 and 05 November 2019. A total of 3359 subjects were screened, of which 1711 subjects were screen failures and 1648 subjects were randomized in the study.

    Pre-assignment
    Screening details
    Subjects with moderately to severely active, adult onset, RA with an inadequate response to MTX therapy for at least 12 weeks prior to Screening were assessed for eligibility. Eligible subjects were randomized in a 2:2:2:1 ratio to receive 64 mg OKZ q4w, 64 mg OKZ q2w, adalimumab 40 mg q2w, or placebo in a 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
    Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    Since the study treatments were distinguishable, they were prepared by the unblinded pharmacist (or their unblinded designee) and administered by a trained, unblinded study team member who was not involved in the management of study subjects.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    OKZ 64 mg q4w
    Arm description
    Subjects received a 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 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 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 a 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
    Adalimumab 40 mg q2w
    Arm description
    Subjects received a SC injection of adalimumab 40 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
    Active comparator

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Humira®
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 40 mg q2w adalimumab by SC injection in either abdomen or thigh, prepared in blinded syringes of either 0.4 or 0.8 mL.

    Arm title
    Placebo
    Arm description
    Subjects received a SC injection of Placebo 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
    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 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 Adalimumab 40 mg q2w Placebo
    Started
    479
    464
    462
    243
    Received Treatment
    478
    462
    462
    243
    Completed Treatment Period
    437 [1]
    421
    413
    208
    Continued into Safety Follow Up Period
    37 [2]
    28 [3]
    35 [4]
    17 [5]
    Enrolled in OLE
    422 [6]
    410 [7]
    397 [8]
    199 [9]
    Completed
    443
    421
    412
    207
    Not completed
    36
    43
    50
    36
         Death
    2
    3
    1
    1
         Other
    8
    2
    8
    4
         Consent withdrawn by subject
    25
    31
    37
    25
         Lost to follow-up
    1
    7
    4
    6
    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 in each milestone is for information only and does not impact the number of subjects that completed the study.
    [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 in each milestone is for information only and does not impact the number of subjects that completed the study.
    [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 in each milestone is for information only and does not impact the number of subjects that completed the study.
    [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 in each milestone is for information only and does not impact the number of subjects that completed the study.
    [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 in each milestone is for information only and does not impact the number of subjects that completed the study.
    [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 in each milestone is for information only and does not impact the number of subjects that completed the study.
    [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 in each milestone is for information only and does not impact the number of subjects that completed the study.
    [8] - 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 in each milestone is for information only and does not impact the number of subjects that completed the study.
    [9] - 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 in each milestone is for information only and does not impact the number of subjects that completed the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    OKZ 64 mg q4w
    Reporting group description
    Subjects received a 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 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 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 a 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
    Adalimumab 40 mg q2w
    Reporting group description
    Subjects received a SC injection of adalimumab 40 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 a SC injection of Placebo 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 values
    OKZ 64 mg q4w OKZ 64 mg q2w Adalimumab 40 mg q2w Placebo Total
    Number of subjects
    479 464 462 243 1648
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    389 379 367 192 1327
        From 65-84 years
    90 85 95 50 320
        85 years and over
    0 0 0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.7 ± 12.09 53.3 ± 11.92 54.3 ± 12.32 54.7 ± 11.85 -
    Gender categorical
    Units: Subjects
        Female
    378 352 363 190 1283
        Male
    101 112 99 53 365
    Race
    Units: Subjects
        Asian
    6 10 4 5 25
        Black or African American
    15 20 23 11 69
        White
    406 382 385 203 1376
        Other / Mixed
    52 52 50 24 178

    End points

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    End points reporting groups
    Reporting group title
    OKZ 64 mg q4w
    Reporting group description
    Subjects received a 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 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 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 a 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
    Adalimumab 40 mg q2w
    Reporting group description
    Subjects received a SC injection of adalimumab 40 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 a SC injection of Placebo 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.

    Primary: Percentage of Subjects Meeting the ACR20 at Week 12 (OKZ Comparison with Placebo)

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    End point title
    Percentage of Subjects Meeting the ACR20 at Week 12 (OKZ Comparison with Placebo) [1]
    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) Subject 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
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting group "Adalimumab 40 mg q2w" was not analyzed for this endpoint.
    End point values
    OKZ 64 mg q4w OKZ 64 mg q2w Placebo
    Number of subjects analysed
    479
    464
    243
    Units: Percentage of subjects
        number (not applicable)
    71.4
    70.3
    44.4
    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
    722
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    0.27
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    0.183
         upper limit
    0.352
    Notes
    [2] - P-values are 1-sided α=0.025 significance level from 2x2 chi-square test.
    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
    707
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    0.258
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    0.171
         upper limit
    0.341
    Notes
    [3] - P-values are 1-sided α=0.025 significance level from 2x2 chi-square test.

    Secondary: Percentage of Subjects Meeting the ACR20 at Week 12 (OKZ Comparison with Adalimumab)

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    End point title
    Percentage of Subjects Meeting the ACR20 at Week 12 (OKZ Comparison with Adalimumab)
    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: • TJC (68 joint count) • SJC (66 joint count) An improvement of at least 20% from baseline in at least 3 of the following 5 components: 1) Subject 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). 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 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 Adalimumab 40 mg q2w Placebo
    Number of subjects analysed
    479
    464
    462
    243
    Units: Percentage of subjects
        number (not applicable)
    71.4
    70.3
    66.9
    44.4
    Statistical analysis title
    Comparison of Adalimumab 40 mg q2w Vs Placebo
    Comparison groups
    Adalimumab 40 mg q2w v Placebo
    Number of subjects included in analysis
    705
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [4]
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    0.224
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.148
         upper limit
    0.298
    Notes
    [4] - P-values are 1-sided α=0.025 significance level from 2x2 chi-square test.
    Statistical analysis title
    Comparison of OKZ 64 mg q4w Vs Adalimumab 40mg q2w
    Comparison groups
    Adalimumab 40 mg q2w v OKZ 64 mg q4w
    Number of subjects included in analysis
    941
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [5]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    0.045
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    -0.022
         upper limit
    0.112
    Notes
    [5] - Non-inferiority for each OKZ dosing regimen versus adalimumab is achieved if the lower limit of the 97.5% confidence interval is greater than the protocol defined non-inferiority margin of -12%.
    Statistical analysis title
    Comparison of OKZ 64 mg q2w Vs Adalimumab 40mg q2w
    Comparison groups
    OKZ 64 mg q2w v Adalimumab 40 mg q2w
    Number of subjects included in analysis
    926
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [6]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    0.034
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    -0.035
         upper limit
    0.102
    Notes
    [6] - Non-inferiority for each OKZ dosing regimen versus adalimumab is achieved if the lower limit of the 97.5% confidence interval is greater than the protocol defined non-inferiority margin of -12%.

    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 Subject 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 × Subject Global Assessment of Disease Activity (VAS) + 0.96. The 28 joints evaluated for the SJC and TJC were: shoulders, elbows, wrists, hands and knees. Subjects who remained on randomized treatment and who were in the study at Week 12 and had a DAS28 (CRP) <3.2 were classed as having low disease activity. 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 Adalimumab 40 mg q2w Placebo
    Number of subjects analysed
    479
    464
    462
    243
    Units: Percentage of subjects
        number (not applicable)
    45.7
    45.3
    38.3
    12.8
    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
    722
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [7]
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    0.33
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    0.255
         upper limit
    0.395
    Notes
    [7] - P-values are 1-sided α=0.025 significance level from 2x2 chi-square test.
    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
    707
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [8]
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    0.325
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    0.25
         upper limit
    0.391
    Notes
    [8] - P-values are 1-sided α=0.025 significance level from 2x2 chi-square test.
    Statistical analysis title
    Comparison of Adalimumab 40 mg q2w Vs Placebo
    Comparison groups
    Adalimumab 40 mg q2w v Placebo
    Number of subjects included in analysis
    705
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [9]
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    0.256
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.191
         upper limit
    0.313
    Notes
    [9] - P-values are 1-sided α=0.025 significance level from 2x2 chi-square test.
    Statistical analysis title
    Comparison of OKZ 64 mg q4w Vs Adalimumab 40mg q2w
    Comparison groups
    OKZ 64 mg q4w v Adalimumab 40 mg q2w
    Number of subjects included in analysis
    941
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [10]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    0.074
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    0.002
         upper limit
    0.145
    Notes
    [10] - Non-inferiority for each OKZ dosing regimen versus adalimumab is achieved if the lower limit of the 97.5% confidence interval is greater than the protocol defined non-inferiority margin of -7.5%.
    Statistical analysis title
    Comparison of OKZ 64 mg q2w Vs Adalimumab 40mg q2w
    Comparison groups
    OKZ 64 mg q2w v Adalimumab 40 mg q2w
    Number of subjects included in analysis
    926
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [11]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    0.069
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    -0.003
         upper limit
    0.141
    Notes
    [11] - Non-inferiority for each OKZ dosing regimen versus adalimumab is achieved if the lower limit of the 97.5% confidence interval is greater than the protocol defined non-inferiority margin of -7.5%.

    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 the impact of the disease and its treatment on physical function. The HAQ-DI assessed the degree of difficulty experienced in 8 domains of daily living activities using 20 questions. For each question, the 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 the maximum score of each question. The HAQ-DI was calculated by dividing the sum of the category scores by the number of categories with at least 1 question answered. 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 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 Adalimumab 40 mg q2w Placebo
    Number of subjects analysed
    423
    404
    394
    197
    Units: Units on HAQ-DI scale
        least squares mean (standard error)
    -0.61 ± 0.026
    -0.64 ± 0.027
    -0.61 ± 0.027
    -0.42 ± 0.038
    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
    620
    Analysis specification
    Pre-specified
    Analysis type
    superiority [12]
    P-value
    < 0.0001 [13]
    Method
    ANCOVA
    Parameter type
    LSM difference
    Point estimate
    -0.19
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    -0.29
         upper limit
    -0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.046
    Notes
    [12] - ANCOVA model included treatment as fixed effect and baseline value as a covariate. LSMs and P-value were obtained using Rubins's rule.
    [13] - P-values represent a 1-sided combined test for treatment effect from the ANCOVA model.
    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
    601
    Analysis specification
    Pre-specified
    Analysis type
    superiority [14]
    P-value
    < 0.0001 [15]
    Method
    ANCOVA
    Parameter type
    LSM difference
    Point estimate
    -0.22
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    -0.33
         upper limit
    -0.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.046
    Notes
    [14] - ANCOVA model included treatment as fixed effect and baseline value as a covariate. LSMs and P-value were obtained using Rubins's rule.
    [15] - P-values represent a 1-sided combined test for treatment effect from the ANCOVA model.
    Statistical analysis title
    Comparison of Adalimumab 40 mg q2w Vs Placebo
    Comparison groups
    Adalimumab 40 mg q2w v Placebo
    Number of subjects included in analysis
    591
    Analysis specification
    Pre-specified
    Analysis type
    superiority [16]
    Method
    Parameter type
    LSM difference
    Point estimate
    -0.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.28
         upper limit
    -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.046
    Notes
    [16] - ANCOVA model included treatment as fixed effect and baseline value as a covariate. LSMs were obtained using Rubins's rule.
    Statistical analysis title
    Comparison of OKZ 64 mg q4w Vs Adalimumab 40mg q2w
    Comparison groups
    OKZ 64 mg q4w v Adalimumab 40 mg q2w
    Number of subjects included in analysis
    817
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [17]
    Method
    Parameter type
    LSM difference
    Point estimate
    0
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    -0.08
         upper limit
    0.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.037
    Notes
    [17] - ANCOVA model included treatment as fixed effect and baseline value as a covariate. LSMs were obtained using Rubins's rule.
    Statistical analysis title
    Comparison of OKZ 64 mg q2w Vs Adalimumab 40mg q2w
    Comparison groups
    OKZ 64 mg q2w v Adalimumab 40 mg q2w
    Number of subjects included in analysis
    798
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [18]
    Method
    Parameter type
    LSM difference
    Point estimate
    -0.03
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    -0.12
         upper limit
    0.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.038
    Notes
    [18] - ANCOVA model included treatment as fixed effect and baseline value as a covariate. LSMs were obtained using Rubins's rule.

    Secondary: Percentage of Subjects Achieving American College of Rheumatology 50% Response Criteria (ACR50) at Week 24

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    End point title
    Percentage of Subjects Achieving American College of Rheumatology 50% Response Criteria (ACR50) at Week 24
    End point description
    To meet ACR50 response criteria at Week 24, 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) Subject 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 24. Analysis was performed on the ITT population, which included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    OKZ 64 mg q4w OKZ 64 mg q2w Adalimumab 40 mg q2w Placebo
    Number of subjects analysed
    479
    464
    462
    243
    Units: Percentage of subjects
        number (not applicable)
    50.1
    50.4
    46.3
    22.6
    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
    722
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [19]
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    0.275
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    0.192
         upper limit
    0.349
    Notes
    [19] - P-values are 1-sided α=0.025 significance level from 2x2 chi-square test.
    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
    707
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [20]
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    0.278
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    0.195
         upper limit
    0.353
    Notes
    [20] - P-values are 1-sided α=0.025 significance level from 2x2 chi-square test.
    Statistical analysis title
    Comparison of Adalimumab 40 mg q2w Vs Placebo
    Comparison groups
    Adalimumab 40 mg q2w v Placebo
    Number of subjects included in analysis
    705
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    0.237
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.165
         upper limit
    0.303
    Statistical analysis title
    Comparison of OKZ 64 mg q4w Vs Adalimumab 40mg q2w
    Comparison groups
    OKZ 64 mg q4w v Adalimumab 40 mg q2w
    Number of subjects included in analysis
    941
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [21]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    0.038
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    -0.035
         upper limit
    0.11
    Notes
    [21] - Confidence Interval is calculated using Newcombe hybrid score method.
    Statistical analysis title
    Comparison of OKZ 64 mg q2w Vs Adalimumab 40mg q2w
    Comparison groups
    OKZ 64 mg q2w v Adalimumab 40 mg q2w
    Number of subjects included in analysis
    926
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [22]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    0.041
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    -0.032
         upper limit
    0.114
    Notes
    [22] - Confidence Interval is calculated using Newcombe hybrid score method.

    Secondary: Percentage of Subjects Achieving Remission, Defined as Clinical Disease Activity Index (CDAI) ≤2.8 (Remission) at Week 24

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    End point title
    Percentage of Subjects Achieving Remission, Defined as Clinical Disease Activity Index (CDAI) ≤2.8 (Remission) at Week 24
    End point description
    The CDAI was calculated using the SJC (28 joints), TJC (28 joints), the Subject Global Assessment of Disease Activity (VAS) (in centimeters), and the Physician Global Assessment (VAS) (in centimeters) according to the formula: CDAI = SJC + TJC + Subject Global Assessment of Disease Activity (VAS) + Physician Global Assessment (VAS). Subjects remaining on randomized treatment and in the study at Week 24 and with a CDAI of ≤2.8 were classed as in remission. Analysis was performed on the ITT population, which included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    At Week 24
    End point values
    OKZ 64 mg q4w OKZ 64 mg q2w Adalimumab 40 mg q2w Placebo
    Number of subjects analysed
    479
    464
    462
    243
    Units: Percentage of subjects
        number (not applicable)
    12.1
    11.2
    13.0
    4.1
    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
    722
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003 [23]
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    0.08
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    0.031
         upper limit
    0.123
    Notes
    [23] - P-values are 1-sided α=0.025 significance level from 2x2 chi-square test.
    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
    707
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0008 [24]
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    0.071
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    0.022
         upper limit
    0.113
    Notes
    [24] - P-values are 1-sided α=0.025 significance level from 2x2 chi-square test.
    Statistical analysis title
    Comparison of Adalimumab 40 mg q2w Vs Placebo
    Comparison groups
    Adalimumab 40 mg q2w v Placebo
    Number of subjects included in analysis
    705
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    0.089
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.046
         upper limit
    0.127
    Statistical analysis title
    Comparison of OKZ 64 mg q4w Vs Adalimumab 40mg q2w
    Comparison groups
    OKZ 64 mg q4w v Adalimumab 40 mg q2w
    Number of subjects included in analysis
    941
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [25]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.009
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    -0.058
         upper limit
    0.04
    Notes
    [25] - Confidence Interval is calculated using Newcombe hybrid score method.
    Statistical analysis title
    Comparison of OKZ 64 mg q2w Vs Adalimumab 40mg q2w
    Comparison groups
    OKZ 64 mg q2w v Adalimumab 40 mg q2w
    Number of subjects included in analysis
    926
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [26]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.018
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    -0.066
         upper limit
    0.031
    Notes
    [26] - Confidence Interval is 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 a 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 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
    OKZ 64 mg q2w
    Reporting group description
    Subjects received a 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
    Adalimumab 40 mg q2w
    Reporting group description
    Subjects received a SC injection of adalimumab 40 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 a SC injection of Placebo 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.

    Serious adverse events
    OKZ 64 mg q4w OKZ 64 mg q2w Adalimumab 40 mg q2w Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 477 (4.19%)
    22 / 463 (4.75%)
    26 / 462 (5.63%)
    12 / 243 (4.94%)
         number of deaths (all causes)
    2
    3
    1
    1
         number of deaths resulting from adverse events
    2
    3
    1
    1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 477 (0.21%)
    1 / 463 (0.22%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 463 (0.00%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 463 (0.22%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Surgery
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 463 (0.00%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 477 (0.21%)
    1 / 463 (0.22%)
    0 / 462 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    0 / 462 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma stage IV
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 463 (0.22%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial carcinoma
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leiomyoma
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 463 (0.22%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma stage III
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    0 / 462 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Injection site inflammation
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 463 (0.22%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 463 (0.22%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polyp
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 463 (0.00%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    0 / 462 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine prolapse
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 463 (0.00%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 463 (0.22%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    0 / 462 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 477 (0.42%)
    1 / 463 (0.22%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 477 (0.00%)
    2 / 463 (0.43%)
    0 / 462 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    0 / 462 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Pericarditis
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 463 (0.00%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 463 (0.00%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    2 / 462 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 463 (0.22%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid lung
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Microcytic anaemia
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 463 (0.00%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 463 (0.22%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 463 (0.22%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 463 (0.22%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 463 (0.00%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 463 (0.22%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 463 (0.22%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 463 (0.00%)
    0 / 462 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 463 (0.22%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 463 (0.22%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic steatosis
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 463 (0.00%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 463 (0.22%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint effusion
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 477 (0.21%)
    1 / 463 (0.22%)
    6 / 462 (1.30%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    2 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 477 (0.21%)
    1 / 463 (0.22%)
    2 / 462 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    2 / 462 (0.43%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 477 (0.42%)
    0 / 463 (0.00%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 477 (0.21%)
    1 / 463 (0.22%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 463 (0.22%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    2 / 462 (0.43%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 463 (0.22%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    0 / 462 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Keratouveitis
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    0 / 462 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Latent tuberculosis
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lyme disease
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 463 (0.00%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 463 (0.00%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 463 (0.00%)
    1 / 462 (0.22%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 463 (0.22%)
    0 / 462 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    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 Adalimumab 40 mg q2w Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    177 / 477 (37.11%)
    183 / 463 (39.52%)
    129 / 462 (27.92%)
    71 / 243 (29.22%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    27 / 477 (5.66%)
    25 / 463 (5.40%)
    13 / 462 (2.81%)
    8 / 243 (3.29%)
         occurrences all number
    31
    26
    13
    8
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    53 / 477 (11.11%)
    41 / 463 (8.86%)
    9 / 462 (1.95%)
    4 / 243 (1.65%)
         occurrences all number
    88
    70
    20
    7
    Aspartate aminotransferase increased
         subjects affected / exposed
    24 / 477 (5.03%)
    23 / 463 (4.97%)
    8 / 462 (1.73%)
    2 / 243 (0.82%)
         occurrences all number
    38
    27
    15
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 477 (2.31%)
    10 / 463 (2.16%)
    14 / 462 (3.03%)
    12 / 243 (4.94%)
         occurrences all number
    12
    11
    17
    12
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    8 / 477 (1.68%)
    8 / 463 (1.73%)
    20 / 462 (4.33%)
    2 / 243 (0.82%)
         occurrences all number
    8
    12
    51
    2
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    20 / 477 (4.19%)
    29 / 463 (6.26%)
    6 / 462 (1.30%)
    3 / 243 (1.23%)
         occurrences all number
    20
    29
    6
    3
    Dyslipidaemia
         subjects affected / exposed
    15 / 477 (3.14%)
    25 / 463 (5.40%)
    4 / 462 (0.87%)
    4 / 243 (1.65%)
         occurrences all number
    15
    28
    4
    4
    Hyperlipidaemia
         subjects affected / exposed
    10 / 477 (2.10%)
    22 / 463 (4.75%)
    5 / 462 (1.08%)
    2 / 243 (0.82%)
         occurrences all number
    10
    24
    6
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    26 / 477 (5.45%)
    29 / 463 (6.26%)
    29 / 462 (6.28%)
    18 / 243 (7.41%)
         occurrences all number
    34
    35
    32
    23
    Upper respiratory tract infection
         subjects affected / exposed
    29 / 477 (6.08%)
    28 / 463 (6.05%)
    26 / 462 (5.63%)
    16 / 243 (6.58%)
         occurrences all number
    33
    31
    30
    17
    Urinary tract infection
         subjects affected / exposed
    14 / 477 (2.94%)
    7 / 463 (1.51%)
    19 / 462 (4.11%)
    9 / 243 (3.70%)
         occurrences all number
    14
    9
    20
    10
    Bronchitis
         subjects affected / exposed
    10 / 477 (2.10%)
    12 / 463 (2.59%)
    11 / 462 (2.38%)
    11 / 243 (4.53%)
         occurrences all number
    10
    12
    13
    11

    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. • A new secondary efficacy endpoint, the percentage of subjects achieving low disease activity, defined as DAS28 (CRP) <3.2 was added. • One of the secondary efficacy endpoints was changed from the percentage of subjects with Simplified Disease Activity Index ≤3.3 evaluated at Week 24 to the percentage of subjects with CDAI ≤2.8 evaluated at Week 24. • 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 other efficacy endpoints. • Folic acid was added as a required concomitant medication to counteract the potential side effects of MTX. • The prior use of all biologic disease-modifying anti-rheumatic drugs (including anakinra and abatacept) was made exclusionary. • Subjects with 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 who was experienced in diagnosing and treating tuberculosis and in case of presence prophylactic treatment of LTBI. • 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. • Guidance for the management of LTBI was added.
    23 Nov 2016
    The study protocol was amended to indicate that both the 0.4 mL and 0.8 mL prefilled syringes were to be used in the study. There were no changes to the conduct of the study as a result of this amendment.

    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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