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    Clinical Trial Results:
    A multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of Certolizumab Pegol in combination with Methotrexate for inducing and sustaining clinical response in the treatment of DMARD-Naïve adults with early active Rheumatoid Arthritis (c-early)

    Summary
    EudraCT number
    2011-001729-25
    Trial protocol
    BE   DE   IE   HU   ES   CZ   AT   SE   NL   IT   GB  
    Global end of trial date

    Results information
    Results version number
    v2
    This version publication date
    05 Feb 2016
    First version publication date
    24 Jul 2015
    Other versions
    v1 , v3 , v4
    Version creation reason
    • Correction of full data set
    Updated results entries to be consistent with results on Clinicaltrials.gov after NIH comments.

    Trial information

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    Trial identification
    Sponsor protocol code
    RA0055 Period 1
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01519791
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB Pharma SA
    Sponsor organisation address
    Allée de la Recherche 60, Brussels, Belgium, B-1070
    Public contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 4815 15, clinicaltrials@ucb.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 48 15 15, clinicaltrials@ucb.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    03 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jul 2014
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to demonstrate that the combination of CZP + MTX is superior to PBO + MTX in achieving sustained remission by Week 52.
    Protection of trial subjects
    Not applicable
    Background therapy
    Not applicable
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    25 Jan 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 35
    Country: Number of subjects enrolled
    Australia: 37
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 25
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Colombia: 29
    Country: Number of subjects enrolled
    Czech Republic: 39
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Germany: 86
    Country: Number of subjects enrolled
    Hungary: 42
    Country: Number of subjects enrolled
    Ireland: 7
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    Mexico: 42
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Poland: 118
    Country: Number of subjects enrolled
    Romania: 16
    Country: Number of subjects enrolled
    Spain: 16
    Country: Number of subjects enrolled
    Sweden: 15
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    United Kingdom: 25
    Country: Number of subjects enrolled
    United States: 302
    Worldwide total number of subjects
    879
    EEA total number of subjects
    423
    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)
    745
    From 65 to 84 years
    133
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    This study started to enroll subjects in January 2012.

    Pre-assignment
    Screening details
    A total of 880 subjects were randomized. Three subjects were randomized in error, were not dosed, and withdrawn shortly afterwards as screen failures. Two of them were included in the Randomized Set 1 (RS1) only and one of these three subjects was conservatively excluded from any output. Therefore, 879 subjects are in RS1.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo + Methotrexate
    Arm description
    Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX.The MTX treatment is to be initiated at a dose of 10 mg per Week. The MTX dosage should be escalated by 5 mg every 2 Weeks such that the maximum dosage of 25 mg per Week is achieved by Week 6 to Week 8.
    Arm type
    Placebo

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    MTX
    Other name
    Trexan
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The MTX treatment is to be initiated at a dose of 10 mg per Week (oral tablets at the strength of 2.5 mg/tablet). The MTX dosage should be escalated by 5 mg every 2 Weeks such that the maximum dosage of 25 mg per Week is achieved by Week 6 to Week 8. Patients who could not tolerate ≥ 15 mg/week MTX by Week 8 were withdrawn while the maximum tolerated dose per patient (optimized dose) was maintained to Week 52.

    Arm title
    Certolizumab Pegol + Methotrexate
    Arm description
    Certolizumab Pegol + Methotrexate (MTX) Prefilled syringes containing an injectable volume of 1 ml of solution for injection CZP for single use at a dosage strength of 200 mg/ml. Injections will be given subcutaneously. CZP 400 mg + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. The MTX dosage should be escalated by 5 mg every 2 Weeks such that the maximum dosage of 25 mg per Week is achieved by Week 6 to Week 8.
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CDP870
    Other name
    Cimzia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections: CZP 400 mg at Baseline, Week 2 and Week 4, followed by a maintenance dose of 200 mg every 2 Weeks until Week 50.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    MTX
    Other name
    Trexan
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The MTX treatment is to be initiated at a dose of 10 mg per Week (oral tablets at the strength of 2.5 mg/tablet). The MTX dosage should be escalated by 5 mg every 2 Weeks such that the maximum dosage of 25 mg per Week is achieved by Week 6 to Week 8. Patients who could not tolerate ≥ 15 mg/week MTX by Week 8 were withdrawn while the maximum tolerated dose per patient (optimized dose) was maintained to Week 52.

    Number of subjects in period 1
    Placebo + Methotrexate Certolizumab Pegol + Methotrexate
    Started
    219
    660
    Completed Week 52
    143
    500
    Completed
    67
    292
    Not completed
    152
    368
         AE, serious fatal
    -
    1
         Consent withdrawn by subject
    15
    37
         SAE, fatal + SAE, non-fatal
    -
    1
         AE, non-serious non-fatal
    12
    31
         Other Reason
    87
    222
         subjects randomized in error
    2
    -
         Lost to follow-up
    6
    14
         SAE, non-fatal
    6
    22
         SAE, non-fatal + AE, non-serious non-fatal
    2
    1
         Lack of efficacy
    16
    20
         Protocol deviation
    6
    19

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo + Methotrexate
    Reporting group description
    Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX.The MTX treatment is to be initiated at a dose of 10 mg per Week. The MTX dosage should be escalated by 5 mg every 2 Weeks such that the maximum dosage of 25 mg per Week is achieved by Week 6 to Week 8.

    Reporting group title
    Certolizumab Pegol + Methotrexate
    Reporting group description
    Certolizumab Pegol + Methotrexate (MTX) Prefilled syringes containing an injectable volume of 1 ml of solution for injection CZP for single use at a dosage strength of 200 mg/ml. Injections will be given subcutaneously. CZP 400 mg + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. The MTX dosage should be escalated by 5 mg every 2 Weeks such that the maximum dosage of 25 mg per Week is achieved by Week 6 to Week 8.

    Reporting group values
    Placebo + Methotrexate Certolizumab Pegol + Methotrexate Total
    Number of subjects
    219 660 879
    Age categorical
    Units: Subjects
        <=18
    1 2 3
        >18-<65
    182 560 742
        >=65
    36 98 134
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    51.3 ± 13.2 50.5 ± 13.6 -
    Gender Categorical
    Units: Subjects
        Male
    44 161 205
        Female
    175 499 674

    End points

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    End points reporting groups
    Reporting group title
    Placebo + Methotrexate
    Reporting group description
    Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX.The MTX treatment is to be initiated at a dose of 10 mg per Week. The MTX dosage should be escalated by 5 mg every 2 Weeks such that the maximum dosage of 25 mg per Week is achieved by Week 6 to Week 8.

    Reporting group title
    Certolizumab Pegol + Methotrexate
    Reporting group description
    Certolizumab Pegol + Methotrexate (MTX) Prefilled syringes containing an injectable volume of 1 ml of solution for injection CZP for single use at a dosage strength of 200 mg/ml. Injections will be given subcutaneously. CZP 400 mg + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. The MTX dosage should be escalated by 5 mg every 2 Weeks such that the maximum dosage of 25 mg per Week is achieved by Week 6 to Week 8.

    Subject analysis set title
    Certolizumab Pegol + Methotrexate (Full Analysis Set)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Certolizumab Pegol + Methotrexate (MTX) Prefilled syringes containing an injectable volume of 1 ml of solution for injection CZP for single use at a dosage strength of 200 mg/ml. Injections will be given subcutaneously. CZP 400 mg + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. The MTX dosage should be escalated by 5 mg every 2 Weeks such that the maximum dosage of 25 mg per Week is achieved by Week 6 to Week 8. Full Analysis Set Period 1 (FAS1) consisted of all subjects with valid Baseline and valid post-Baseline efficacy measurement within Period 1 for DAS28(ESR).

    Subject analysis set title
    Placebo + Methotrexate (Radiographic Set)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. The MTX dosage should be escalated by 5 mg every 2 Weeks such that the maximum dosage of 25 mg per Week is achieved by Week 6 to Week 8. The Radiographic Set Period 1 (RAD1) consisted of those subjects in the FAS1 who had provided valid radiographs (ie, radiographs resulting in a nonmissing mTSS score) at Baseline and at Week 52 or the Withdrawal Visit.

    Subject analysis set title
    Certolizumab Pegol + Methotrexate (Radiographic Set)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Certolizumab Pegol + Methotrexate (MTX) Prefilled syringes containing an injectable volume of 1 ml of solution for injection CZP for single use at a dosage strength of 200 mg/ml. Injections will be given subcutaneously. CZP 400 mg + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. The MTX dosage should be escalated by 5 mg every 2 Weeks such that the maximum dosage of 25 mg per Week is achieved by Week 6 to Week 8. The Radiographic Set Period 1 (RAD1) consisted of those subjects in the FAS1 who had provided valid radiographs (ie, radiographs resulting in a nonmissing mTSS score) at Baseline and at Week 52 or the Withdrawal Visit.

    Subject analysis set title
    Placebo + Methotrexate (Full Analysis Set)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. The MTX dosage should be escalated by 5 mg every 2 Weeks such that the maximum dosage of 25 mg per Week is achieved by Week 6 to Week 8. Full Analysis Set Period 1 (FAS1) consisted of all subjects with valid Baseline and valid post-Baseline efficacy measurement within Period 1 for DAS28(ESR).

    Primary: Percentage of subjects in sustained remission at Week 52

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    End point title
    Percentage of subjects in sustained remission at Week 52
    End point description
    Sustained remission is defined as a Disease Activity Score [Erythrocyte Sedimentation Rate] (DAS28[ESR]) < 2.6 at both Weeks 40 and 52. DAS28[ESR] is calculated using the Tender Joint Count (TJC), Swollen Joint Count (SJC) Erythrocyte Sedimentation Rate (ESR in mm/hour), and the Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm) using the following formula: 0.56 x √(TJC) + 0.28 x √(SJC) + 0.70 x lognat (ESR) + 0.014 x PtGADA, where 28 joints are examined and a lower score indicates less disease activity.
    End point type
    Primary
    End point timeframe
    Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    655
    213
    Units: percentage of subjects
    number (not applicable)
        percentage of subjects
    28.9
    15
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    In order to control the overall study-wise Type I error rate at 5 %, hypothesis testing was performed in the following hierarchical order (each at a 2-sided 95 % alpha level): 1. Primary: sustained DAS28(ESR) remission at Week 52 2. Key secondary: sustained DAS28(ESR) LDA at Week 52 3. ACR50 response at Week 52 in relation to Baseline 4. Change from Baseline in HAQ-DI at Week 52 5. Change from Baseline in mTSS at Week 52
    Comparison groups
    Certolizumab Pegol + Methotrexate (Full Analysis Set) v Placebo + Methotrexate (Full Analysis Set)
    Number of subjects included in analysis
    868
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [1]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.283
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.503
         upper limit
    3.468
    Notes
    [1] - The Odds ratio measuring the treatment effect was estimated from a logistic regression model including terms for treatment, region and stratification factor. Nonresponder imputation (NRI) was used.

    Secondary: Percentage of subjects in sustained Low Disease Activity (LDA) at Week 52

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    End point title
    Percentage of subjects in sustained Low Disease Activity (LDA) at Week 52
    End point description
    Sustained LDA is defined as a Disease Activity Score [Erythrocyte Sedimentation Rate] (DAS28[ESR]) ≤ 3.2 at both Weeks 40 and 52.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    655
    213
    Units: percentage of subjects
    number (not applicable)
        percentage of subjects
    43.8
    28.6
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    In order to control the overall study-wise Type I error rate at 5 %, hypothesis testing was performed in the following hierarchical order (each at a 2-sided 95 % alpha level): 1. Primary: sustained DAS28(ESR) remission at Week 52 2. Key secondary: sustained DAS28(ESR) LDA at Week 52 3. ACR50 response at Week 52 in relation to Baseline 4. Change from Baseline in HAQ-DI at Week 52 5. Change from Baseline in mTSS at Week 52
    Comparison groups
    Placebo + Methotrexate (Full Analysis Set) v Certolizumab Pegol + Methotrexate (Full Analysis Set)
    Number of subjects included in analysis
    868
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [2]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.957
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.384
         upper limit
    2.767
    Notes
    [2] - The Odds ratio measuring the treatment effect was estimated from a logistic regression model including terms for treatment, region and stratification factor. Nonresponder imputation (NRI) was used.

    Secondary: Change from Baseline in modified Total Sharp Score (mTSS) to Week 52

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    End point title
    Change from Baseline in modified Total Sharp Score (mTSS) to Week 52
    End point description
    Van der Heijde modified Total Sharp Score (mTSS) is a methodology to assess the degree of joint damage by quantifying the extent of bone erosions and joint space narrowing for 44 and 42 joints, respectively. The mTSS ranges from 0 to 448, with higher scores representing greater damage.
    End point type
    Secondary
    End point timeframe
    From Baseline (Week 0) to Week 52
    End point values
    Placebo + Methotrexate (Radiographic Set) Certolizumab Pegol + Methotrexate (Radiographic Set)
    Number of subjects analysed
    163
    528
    Units: units on a scale
    arithmetic mean (standard deviation)
        arithmetic mean (standard deviation)
    1.8 ± 4.3
    0.2 ± 3.2
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    In order to control the overall study-wise Type I error rate at 5 %, hypothesis testing was performed in the following hierarchical order (each at a 2-sided 95 % alpha level): 1. Primary: sustained DAS28(ESR) remission at Week 52 2. Key secondary: sustained DAS28(ESR) LDA at Week 52 3. ACR50 response at Week 52 in relation to Baseline 4. Change from Baseline in HAQ-DI at Week 52 5. Change from Baseline in mTSS at Week 52
    Comparison groups
    Placebo + Methotrexate (Radiographic Set) v Certolizumab Pegol + Methotrexate (Radiographic Set)
    Number of subjects included in analysis
    691
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [3]
    Method
    ANCOVA on ranks
    Parameter type
    Hodges-Lehmann point estimate of shift
    Point estimate
    -0.978
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.005
         upper limit
    -0.5
    Notes
    [3] - ANCOVA model on the ranks with the terms for treatment, region, and time since RA diagnosis at Baseline (≤4 months or >4 months) as factors and rank Baseline value as a covariate. Confidence Interval is an asymptotic Moses CI.

    Secondary: Percentage of subjects with radiographic non-progression from Baseline to Week 52

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    End point title
    Percentage of subjects with radiographic non-progression from Baseline to Week 52
    End point description
    Radiographic non-progression is defined as change in mTSS ≤ 0.5.
    End point type
    Secondary
    End point timeframe
    From Baseline (Week 0) to Week 52
    End point values
    Placebo + Methotrexate (Radiographic Set) Certolizumab Pegol + Methotrexate (Radiographic Set)
    Number of subjects analysed
    163
    528
    Units: percentage of subjects
    number (not applicable)
        percentage of subjects
    49.7
    70.3
    No statistical analyses for this end point

    Secondary: Change from Baseline in the joint erosion score to Week 52

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    End point title
    Change from Baseline in the joint erosion score to Week 52
    End point description
    Erosions were assessed in 16 locations per hand and 6 joints per foot. Erosions for each hand location were scored from 0 to 5, with 0 indicating no erosion. Scores 1 to 5 may have included combinations of discrete erosion(s) and/or large erosions. Erosions for each foot joint were scored from 0 to 10, with 0 indicating no erosions. The maximum possible erosion score for all 32-hand joints was 160. The maximum possible erosion score for all 12 feet joints was 120. Thus, the maximum possible total erosion score for hands and feet was 280.
    End point type
    Secondary
    End point timeframe
    From Baseline (Week 0) to Week 52
    End point values
    Placebo + Methotrexate (Radiographic Set) Certolizumab Pegol + Methotrexate (Radiographic Set)
    Number of subjects analysed
    163
    528
    Units: units on a scale
    arithmetic mean (standard deviation)
        arithmetic mean (standard deviation)
    1.1 ± 3
    0.1 ± 2.1
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Joint narrowing score to Week 52

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    End point title
    Change from Baseline in the Joint narrowing score to Week 52
    End point description
    Joint space narrowing (JSN) was assessed in 15 locations per hand and 6 locations per foot. Joint space narrowing for each location was scored from 0 to 4, with 0 indicating no narrowing. The maximum possible score for JSN in all 30 hand joints was 120. The maximum possible score for JSN in all 12 feet joints was 48. Thus, the maximum possible total JSN score for Hands and feet was 168.
    End point type
    Secondary
    End point timeframe
    From Baseline (Week 0) to Week 52
    End point values
    Placebo + Methotrexate (Radiographic Set) Certolizumab Pegol + Methotrexate (Radiographic Set)
    Number of subjects analysed
    163
    528
    Units: units on a scale
    arithmetic mean (standard deviation)
        arithmetic mean (standard deviation)
    0.7 ± 2.3
    0.1 ± 1.7
    No statistical analyses for this end point

    Secondary: Percentage of subjects meeting the American College of Rheumatology 20 % response criteria (ACR20) at Week 52

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    End point title
    Percentage of subjects meeting the American College of Rheumatology 20 % response criteria (ACR20) at Week 52
    End point description
    The assessments are based on a 20 % or greater improvement from Baseline in the number of tender joints, a 20 % or more improvement in the number of swollen joints, and a 20 % or greater improvement in 3 of the 5 remaining core set measures: Patient's Global Assessment of Disease Activity (PtGADA), Physician's Global Assessment of Disease Activity (PhGADA), Patient's Assessment of Arthritis Pain (PtAAP), physical function as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and C-Reactive Protein (CRP).
    End point type
    Secondary
    End point timeframe
    From Baseline (Week 0) to Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    655
    213
    Units: percentage of subjects
    number (not applicable)
        percentage of subjects
    69
    61.5
    No statistical analyses for this end point

    Secondary: Percentage of subjects meeting the American College of Rheumatology 50 % response criteria (ACR50) at Week 52

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    End point title
    Percentage of subjects meeting the American College of Rheumatology 50 % response criteria (ACR50) at Week 52
    End point description
    The assessments are based on a 50 % or greater improvement from Baseline in the number of tender joints, a 50 %, or more improvement in the number of swollen joints, and a 50 % or greater improvement in 3 of the 5 remaining core set measures: Patient's Global Assessment of Disease Activity (PtGADA), Physician's Global Assessment of Disease Activity (PhGADA), Patient's Assessment of Arthritis Pain (PtAAP), physical function as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and C-Reactive Protein (CRP).
    End point type
    Secondary
    End point timeframe
    From Baseline (Week 0) to Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    655
    213
    Units: percentage of subjects
    number (not applicable)
        percentage of subjects
    61.8
    52.6
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    In order to control the overall study-wise Type I error rate at 5 %, hypothesis testing was performed in the following hierarchical order (each at a 2-sided 95 % alpha level): 1. Primary: sustained DAS28(ESR) remission at Week 52 2. Key secondary: sustained DAS28(ESR) LDA at Week 52 3. ACR50 response at Week 52 in relation to Baseline 4. Change from Baseline in HAQ-DI at Week 52 5. Change from Baseline in mTSS at Week 52
    Comparison groups
    Placebo + Methotrexate (Full Analysis Set) v Certolizumab Pegol + Methotrexate (Full Analysis Set)
    Number of subjects included in analysis
    868
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.023 [4]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.446
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.052
         upper limit
    1.989
    Notes
    [4] - The Odds ratio was estimated from a logistic regression model including terms for treatment, region and stratification factor. Nonresponder imputation (NRI) was used.

    Secondary: Percentage of subjects meeting the American College of Rheumatology 70 % response criteria (ACR70) at Week 52

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    End point title
    Percentage of subjects meeting the American College of Rheumatology 70 % response criteria (ACR70) at Week 52
    End point description
    The assessments are based on a 70 % or greater improvement from Baseline in the number of tender joints, a 70 %, or more improvement in the number of swollen joints, and a 70 % or greater improvement in 3 of the 5 remaining core set measures: Patient's Global Assessment of Disease Activity (PtGADA), Physician's Global Assessment of Disease Activity (PhGADA), Patient's Assessment of Arthritis Pain (PtAAP), physical function as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and C-Reactive Protein (CRP).
    End point type
    Secondary
    End point timeframe
    From Baseline (Week 0) to Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    655
    213
    Units: percentage of subjects
    number (not applicable)
        percentage of subjects
    51.3
    39.9
    No statistical analyses for this end point

    Secondary: Percentage of subjects meeting the 2011 American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) remission criteria at Week 52

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    End point title
    Percentage of subjects meeting the 2011 American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) remission criteria at Week 52
    End point description
    The ACR/EULAR 2011 remission criteria is defined as: Tender Joint Count (TJC) ≤ 1, Swollen Joint Count (SJC) ≤ 1, C-reactive protein (CRP) ≤ 1 mg/dl and Patient's Global Assessment of Disease Activity (PtGADA) ≤ 1.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    655
    213
    Units: percentage of subjects
    number (not applicable)
        percentage of subjects
    32.4
    20.7
    No statistical analyses for this end point

    Secondary: Percentage of subjects with Clinical Disease Activity Index (CDAI) ≤ 2.8 at Week 52

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    End point title
    Percentage of subjects with Clinical Disease Activity Index (CDAI) ≤ 2.8 at Week 52
    End point description
    CDAI is calculated as the sum of tender joint count (TJC), swollen joint count (SJC), Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm), and Physician's Global Assessment of Disease Activity - Visual Analog Scale (PhGADA-VAS in mm). 28 joints are examined where a lower score indicates less disease activity.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    655
    213
    Units: percentage of subjects
    number (not applicable)
        percentage of subjects
    38.9
    26.3
    No statistical analyses for this end point

    Secondary: Percentage of subjects with Simplified Disease Activity Index (SDAI) ≤ 3.3 at Week 52

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    End point title
    Percentage of subjects with Simplified Disease Activity Index (SDAI) ≤ 3.3 at Week 52
    End point description
    SDAI is calculated as the sum of tender joint count (TJC), swollen joint count (SJC), Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm), Physician's Global Assessment of Disease Activity - Visual Analog Scale (PhGADA-VAS in mm) and C-Reactive Protein (CRP in mg/L). 28 joints are examined where a lower score indicates less disease activity.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    655
    213
    Units: percentage of subjects
    number (not applicable)
        percentage of subjects
    38.9
    24.9
    No statistical analyses for this end point

    Secondary: Percentage of subjects with Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) < 2.6 at Week 52

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    End point title
    Percentage of subjects with Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) < 2.6 at Week 52
    End point description
    DAS28[ESR] is calculated using the Tender Joint Count (TJC), Swollen Joint Count (SJC) Erythrocyte Sedimentation Rate (ESR in mm/hour), and the Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm) using the following formula: 0.56 x √(TJC) + 0.28 x √(SJC) + 0.70 x lognat (ESR) + 0.014 x PtGADA, where 28 joints are examined and a lower score indicates less disease activity.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    655
    213
    Units: percentage of subjects
    number (not applicable)
        percentage of subjects
    42.6
    26.8
    No statistical analyses for this end point

    Secondary: Percentage of subjects meeting the 2011 American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) remission criteria simplified for clinical practice at Week 52

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    End point title
    Percentage of subjects meeting the 2011 American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) remission criteria simplified for clinical practice at Week 52
    End point description
    The 2011 ACR/EULAR remission criteria simplified for clinical practice is defined as: Tender Joint Count (TJC) ≤ 1, Swollen Joint Count (SJC) ≤ 1 and Patient's Global Assessment of Disease Activity (PtGADA) ≤ 1.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    655
    213
    Units: percentage of subjects
    number (not applicable)
        percentage of subjects
    35.3
    24.9
    No statistical analyses for this end point

    Secondary: Percentage of subjects achieving a good or moderate European League Against Rheumatism (EULAR) response at Week 52

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    End point title
    Percentage of subjects achieving a good or moderate European League Against Rheumatism (EULAR) response at Week 52
    End point description
    Good response is defined as: DAS28[ESR] ≤ 3.2 and decrease from Baseline by > 1.2; moderate response is defined as achievement of one of the following: - DAS28[ESR] ≤ 3.2 and decrease from Baseline > 0.6 and ≤ 1.2 - DAS28[ESR] > 3.2 and ≤ 5.1 and decrease from Baseline > 0.6 - DAS28[ESR] > 5.1 and decrease from Baseline >1.2.
    End point type
    Secondary
    End point timeframe
    From Baseline (Week 0) to Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    655
    213
    Units: percentage of subjects
    number (not applicable)
        percentage of subjects
    89.9
    82.2
    No statistical analyses for this end point

    Secondary: Change from Baseline in Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) to Week 52

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    End point title
    Change from Baseline in Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) to Week 52
    End point description
    DAS28[ESR] is calculated using the Tender Joint Count (TJC), Swollen Joint Count (SJC) Erythrocyte Sedimentation Rate (ESR in mm/hour), and the Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm) using the following formula: 0.56 x √(TJC) + 0.28 x √(SJC) + 0.70 x lognat (ESR) + 0.014 x PtGADA, where 28 joints are examined and a lower score indicates less disease activity. A negative value in DAS28[ESR] change from Baseline indicates an improvement from Baseline.
    End point type
    Secondary
    End point timeframe
    From Baseline (Week 0) to Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    646
    210
    Units: units on a scale
    least squares mean (standard error)
        least squares mean (standard error)
    -3.615 ± 0.069
    -3.014 ± 0.109
    No statistical analyses for this end point

    Secondary: Change from Baseline in Clinical Disease Activity Index (CDAI) to Week 52

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    End point title
    Change from Baseline in Clinical Disease Activity Index (CDAI) to Week 52
    End point description
    CDAI is calculated as the sum of tender joint count (TJC), swollen joint count (SJC), Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm), and Physician's Global Assessment of Disease Activity - Visual Analog Scale (PhGADA-VAS in mm). 28 joints are examined where a lower score indicates less disease activity. The CDAI score ranges from 0 to 76, with a negative value in CDAI change from Baseline indicating an improvement from Baseline.
    End point type
    Secondary
    End point timeframe
    From Baseline (Week 0) to Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    644
    210
    Units: units on a scale
    least squares mean (standard error)
        least squares mean (standard error)
    -33.11 ± 0.52
    -29.09 ± 0.84
    No statistical analyses for this end point

    Secondary: Change from Baseline in Simplified Disease Activity Index (SDAI) to Week 52

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    End point title
    Change from Baseline in Simplified Disease Activity Index (SDAI) to Week 52
    End point description
    SDAI is calculated as the sum of tender joint count (TJC), swollen joint count (SJC), Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm), Physician's Global Assessment of Disease Activity - Visual Analog Scale (PhGADA-VAS in mm) and C-Reactive Protein (CRP in mg/L). 28 joints are examined where a lower score indicates less disease activity. The SDAI score ranges from 0 to 86, with a negative value in SDAI change from Baseline indicating an improvement from Baseline.
    End point type
    Secondary
    End point timeframe
    From Baseline (Week 0) to Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    644
    210
    Units: units on a scale
    least squares mean (standard error)
        least squares mean (standard error)
    -34.55 ± 0.55
    -30.24 ± 0.88
    No statistical analyses for this end point

    Secondary: Percentage of subjects with a Health Assessment Questionnaire- Disability Index (HAQ-DI) ≤ 0.5 at Week 52

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    End point title
    Percentage of subjects with a Health Assessment Questionnaire- Disability Index (HAQ-DI) ≤ 0.5 at Week 52
    End point description
    Normative physical function is defined as HAQ-DI score ≤ 0.5. The domains of the HAQ-DI are dressing and grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. The total score ranges from 0 to 3 with lower scores meaning lower disability.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    655
    213
    Units: percentage of subjects
    number (not applicable)
        percentage of subjects
    48.1
    35.7
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Health Assessment Questionnaire - Disability Index (HAQ-DI) to Week 52

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    End point title
    Change from Baseline in the Health Assessment Questionnaire - Disability Index (HAQ-DI) to Week 52
    End point description
    The domains of the HAQ-DI are dressing and grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. The total score ranges from 0 (no difficulty) to 3 (unable to do) with lower scores meaning lower disability. A negative value in HAQ-DI change from Baseline indicates an improvement from Baseline.
    End point type
    Secondary
    End point timeframe
    From Baseline (Week 0) to Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    645
    210
    Units: units on a scale
    least squares mean (standard error)
        least squares mean (standard error)
    -0.997 ± 0.028
    -0.819 ± 0.044
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    In order to control the overall study-wise Type I error rate at 5 %, hypothesis testing was performed in the following hierarchical order (each at a 2-sided 95 % alpha level): 1. Primary: sustained DAS28(ESR) remission at Week 52 2. Key secondary: sustained DAS28(ESR) LDA at Week 52 3. ACR50 response at Week 52 in relation to Baseline 4. Change from Baseline in HAQ-DI at Week 52 5. Change from Baseline in mTSS at Week 52
    Comparison groups
    Placebo + Methotrexate (Full Analysis Set) v Certolizumab Pegol + Methotrexate (Full Analysis Set)
    Number of subjects included in analysis
    855
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [5]
    Method
    ANCOVA
    Parameter type
    Difference in Least Squares (LS) Means
    Point estimate
    -0.177
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.273
         upper limit
    -0.082
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.049
    Notes
    [5] - The CfB in HAQ-DI at Week 52 was analyzed using an ANCOVA model with terms for treatment, region, and time since Rheumatoid Arthritis (RA) diagnosis at Baseline (≤4 months or >4 months) as factors and Baseline value as a covariate.

    Secondary: Change from Baseline in the Bristol Rheumatoid Arthritis Fatigue- Multidimensional Questionnaire (BRAF-MDQ) total score to Week 52

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    End point title
    Change from Baseline in the Bristol Rheumatoid Arthritis Fatigue- Multidimensional Questionnaire (BRAF-MDQ) total score to Week 52
    End point description
    BRAF-MDQ total score ranges from 0 to 70 (with higher scores indicating worse fatigue). A negative value in BRAF-MDQ change from Baseline indicates an improvement from Baseline.
    End point type
    Secondary
    End point timeframe
    From Baseline (Week 0) to Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    636
    205
    Units: units on a scale
    least squares mean (standard error)
        least squares mean (standard error)
    -17.8 ± 0.6
    -15.6 ± 1
    No statistical analyses for this end point

    Secondary: Number of work days missed (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52

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    End point title
    Number of work days missed (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52
    End point description
    Number of work days missed in the last month for employed subjects.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    351
    106
    Units: days
    arithmetic mean (standard deviation)
        arithmetic mean (standard deviation)
    0.6 ± 2.6
    0.9 ± 2.5
    No statistical analyses for this end point

    Secondary: Number of work days with reduced productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52

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    End point title
    Number of work days with reduced productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52
    End point description
    Number of work days with reduced productivity in the last month for employed subjects.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    351
    106
    Units: days
    arithmetic mean (standard deviation)
        arithmetic mean (standard deviation)
    1 ± 3.4
    1.8 ± 4.7
    No statistical analyses for this end point

    Secondary: Interference with work productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52

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    End point title
    Interference with work productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52
    End point description
    The Arthritis interference in the last month with work productivity is measured on a scale that ranges from 0 (no interference) to 10 (complete interference) for employed subjects.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    351
    106
    Units: units on a scale
    arithmetic mean (standard deviation)
        arithmetic mean (standard deviation)
    1.4 ± 2
    1.9 ± 2.3
    No statistical analyses for this end point

    Secondary: Number of days with no household work (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52

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    End point title
    Number of days with no household work (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52
    End point description
    Number of days with no household work in the last month.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    640
    206
    Units: days
    arithmetic mean (standard deviation)
        arithmetic mean (standard deviation)
    1.9 ± 5.1
    3 ± 6.7
    No statistical analyses for this end point

    Secondary: Number of days with reduced household work productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52

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    End point title
    Number of days with reduced household work productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52
    End point description
    Number of days with reduced household work productivity in the last month.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    640
    206
    Units: days
    arithmetic mean (standard deviation)
        arithmetic mean (standard deviation)
    2.1 ± 5.3
    3 ± 6.6
    No statistical analyses for this end point

    Secondary: Number of days with hired outside help (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52

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    End point title
    Number of days with hired outside help (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52
    End point description
    Number of days with hired outside help in the last month.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    640
    206
    Units: days
    arithmetic mean (standard deviation)
        arithmetic mean (standard deviation)
    0.6 ± 3.2
    0.7 ± 3.3
    No statistical analyses for this end point

    Secondary: Number of days missed of family/social/leisure activities (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52

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    End point title
    Number of days missed of family/social/leisure activities (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52
    End point description
    Number of days missed of family/social/leisure activities in the last month.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    640
    206
    Units: days
    arithmetic mean (standard deviation)
        arithmetic mean (standard deviation)
    0.9 ± 3.6
    0.9 ± 3.1
    No statistical analyses for this end point

    Secondary: Interference with household work productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52

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    End point title
    Interference with household work productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52
    End point description
    The Arthritis interference in the last month with household work productivity is measured on a scale that ranges from 0 (no interference) to 10 (complete interference).
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    640
    206
    Units: units on a scale
    arithmetic mean (standard deviation)
        arithmetic mean (standard deviation)
    1.9 ± 2.5
    2.5 ± 2.8
    No statistical analyses for this end point

    Secondary: Percentage of subjects achieving Low Disease Activity (LDA) at Week 52

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    End point title
    Percentage of subjects achieving Low Disease Activity (LDA) at Week 52
    End point description
    LDA is defined as achieving a Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) ≤ 3.2.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Certolizumab Pegol + Methotrexate (Full Analysis Set) Placebo + Methotrexate (Full Analysis Set)
    Number of subjects analysed
    655
    213
    Units: percentage of subjects
    number (not applicable)
        percentage of subjects
    54.7
    39.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were collected from Screening over Baseline (Week 0) and Treatment Period 1 (Week 2 to Week 52) to the Safety Follow-Up Visit (Week 60).
    Adverse event reporting additional description
    Adverse Events presented below refer to the Safety Set 1 (SS1), which consisted of all subjects in the Randomized Set who had received at least 1 dose of study medication (CZP/PBO) in Period 1.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Placebo + Methotrexate
    Reporting group description
    Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. The MTX dosage should be escalated by 5 mg every 2 Weeks such that the maximum dosage of 25 mg per Week is achieved by Week 6 to Week 8.

    Reporting group title
    Certolizumab Pegol + Methotrexate
    Reporting group description
    Certolizumab Pegol + Methotrexate (MTX) Prefilled syringes containing an injectable volume of 1 ml of solution for injection CZP for single use at a dosage strength of 200 mg/ml. Injections will be given subcutaneously. CZP 400 mg + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. The MTX dosage should be escalated by 5 mg every 2 Weeks such that the maximum dosage of 25 mg per Week is achieved by Week 6 to Week 8.

    Serious adverse events
    Placebo + Methotrexate Certolizumab Pegol + Methotrexate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 217 (9.22%)
    70 / 659 (10.62%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondrosarcoma
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 217 (0.46%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Coronary arterial stent insertion
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leg amputation
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip arthroplasty
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food allergy
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine polyp
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    0 / 217 (0.00%)
    2 / 659 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Epiglottic cyst
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 217 (0.00%)
    2 / 659 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal polyp
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 217 (0.92%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 217 (0.92%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 217 (0.46%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 217 (0.00%)
    2 / 659 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 217 (0.46%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 217 (0.46%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 217 (0.46%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 217 (0.00%)
    3 / 659 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow toxicity
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 217 (0.00%)
    2 / 659 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erosive duodenitis
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal ulcer haemorrhage
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric panniculitis
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth ulceration
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 217 (0.00%)
    2 / 659 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bladder outlet obstruction
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 217 (0.46%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lupus-like syndrome
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid nodule
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 217 (0.00%)
    4 / 659 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    1 / 217 (0.46%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendiceal abscess
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 217 (0.46%)
    2 / 659 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impetigo
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Labyrinthitis
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 659 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Latent tuberculosis
         subjects affected / exposed
    2 / 217 (0.92%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 217 (1.38%)
    4 / 659 (0.61%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Staphylococcal infection
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis gastrointestinal
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Urosepsis
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 659 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo + Methotrexate Certolizumab Pegol + Methotrexate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    63 / 217 (29.03%)
    248 / 659 (37.63%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 217 (4.15%)
    42 / 659 (6.37%)
         occurrences all number
    13
    46
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 217 (3.69%)
    45 / 659 (6.83%)
         occurrences all number
    11
    65
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    22 / 217 (10.14%)
    83 / 659 (12.59%)
         occurrences all number
    22
    92
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 217 (5.07%)
    72 / 659 (10.93%)
         occurrences all number
    12
    86
    Urinary tract infection
         subjects affected / exposed
    16 / 217 (7.37%)
    48 / 659 (7.28%)
         occurrences all number
    18
    63
    Nasopharyngitis
         subjects affected / exposed
    13 / 217 (5.99%)
    46 / 659 (6.98%)
         occurrences all number
    17
    60

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jul 2012
    At the time of Global Protocol Amendment 1 (27 Jul 2012), enrollment was ongoing. The main change covered in this amendment was the incorporation of the updated UCB tuberculosis (TB) detection and monitoring policy. The recent changes in national guidelines recommended different TB testing (QuantiFERON®-TB GOLD test or purified protein derivative [PPD] Skin test) as the preferred test in a number of geographies. Therefore, this amendment offered the option for Investigators to stay within local guidelines and regulations. Also, some national guidelines were recommending different protocols of prophylactic treatment for latent TB. Thus, this amendment addressed these changes and gave Investigators the possibility to be compliant with current guidelines and regulations. Several other minor changes and clarifications were incorporated into Global Protocol Amendment 1. Those affecting study conduct included: - Stipulation for contraception use was extended from 10 weeks to at least 3 months (USA/Canada) or 6 months (Europe, Australia, and Latin America) after the last dose of study treatment. Similarly, the exclusion criterion was extended from 10 weeks to 6 months for female subjects who were breastfeeding, pregnant, or planned to become pregnant during the study or within 6 months following last dose of study treatment. - The Screening Period length was clarified. - MTX packaging and labeling were clarified. - Rescreening of subjects was clarified.
    06 Feb 2013
    At the time of Global Protocol Amendment 2 (06 Feb 2013), enrollment was ongoing. The main changes covered in this amendment were: - The PBO+MTX arm of Period 1 was prolonged in Period 2 until Week 104 to provide subjects extended treatment benefit with the treatment combination PBO+MTX. These subjects were in sustained LDA when reaching Week 52 and the subjects have at any time a rescue option available when they flare providing them the initiation of a CZP treatment and a maintenance on CZP until Week 104. - The prolongation of the PBO+MTX arm in Period 2 provided a higher protection of the Period 1 blind by allowing more time to clean the large amount of study data generated. - The prolongation of the PBO+MTX arm in Period 2 provided, as a consequence, additional exploratory data and allowed comparison of the outcomes of an initial treatment with or without CZP in Period 1 over a longer time. - Following the Statistical Analysis Plan (SAP) development, some updates were considered in the statistical section. - PBO+MTX nomenclature was replaced by MTX+CZP stopped dosing in sections related to Period 2. - The serious AE (SAE) reporting details were changed, an e-mail address was added. All other safety-related questions were to be addressed to the Study Physician or Medical Monitors assigned to the study.
    13 Jan 2014
    At the time of Global Protocol Amendment 3 (13 Jan 2014), all subjects were enrolled. The main changes covered in this amendment were: - TB language was expanded to reflect current UCB guidelines. - Additional endpoints in Period 1 and Period 2 and associated analyses of minimum clinically important differences (MCID) from Baseline in various assessment tools were added. - A change in wording in laboratory analyses from inorganic phosphorous to phosphorous. - Clarification on PK analyses was made to include CZP moiety analyses. - Additional subgroups of age, rheumatoid factor (RF), albumin, and presence of erosions at Baseline were considered for analyses. - Predictability analyses were added. - A Completer Set for Period 1 and associated sensitivity analyses were added. - Details on multiple comparisons/multiplicity were 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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