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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

    Summary
    EudraCT number
    		 2011-001729-25
    Trial protocol
    		 BE   DE   IE   HU   ES   CZ   AT   SE   NL   IT   GB  
    Global end of trial date
    10 Sep 2015

    Results information
    Results version number
    		 v3
    This version publication date
    22 Jul 2016
    First version publication date
    24 Jul 2015
    Other versions
    		 v1 , v2 , v4
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    RA0055 Period 2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01521923
    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, clinicaltrials@ucb.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, 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
    Final
    Date of interim/final analysis
    13 Oct 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to demonstrate that both CZP + MTX dosing frequencies (the standard maintenance dose CZP 200 mg every 2 weeks + MTX and the reduced frequency maintenance dose CZP 200 mg every 4 weeks + MTX) are superior to PBO + MTX in maintaining subjects in LDA at Week 104
    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: 16
    Country: Number of subjects enrolled
    Australia: 19
    Country: Number of subjects enrolled
    Belgium: 19
    Country: Number of subjects enrolled
    Colombia: 13
    Country: Number of subjects enrolled
    Czech Republic: 26
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 40
    Country: Number of subjects enrolled
    Hungary: 16
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Mexico: 14
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Poland: 77
    Country: Number of subjects enrolled
    Romania: 3
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    United States: 71
    Worldwide total number of subjects
    357
    EEA total number of subjects
    222
    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)
    312
    From 65 to 84 years
    45
    85 years and over
    0

    Subject disposition

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

    Pre-assignment
    Screening details
    		 Participant Flow refers to the Safety Set 2 (SS2) which consists of all subjects randomized into Period 1 who had received at least 1 dose of study medication (CZP/PBO) in Period 2.

    Period 1
    Period 1 title
    Period 2 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PBO+MTX / PBO+MTX
    Arm description
    		 Placebo (PBO) + Methotrexate (MTX) in Period 1 1 syringe PBO every 2 Weeks + MTX in Period 2
    Arm type
    		 Placebo non-comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PBO
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections every 2 Weeks or every 4 Weeks

    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
    A dose of at least 15 mg per Week had to be taken to remain in the study. MTX was given every week from Week 52 onwards until Week 103

    Arm title
    		 CZP+MTX / PBO+MTX
    Arm description
    		 Certolizumab pegol (CZP) 200 mg Q2W + Methotrexate (MTX) in Period 1 1 syringe PBO every 2 Weeks + MTX in Period 2
    Arm type
    		 Placebo

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections: 200 mg every 2 Weeks or every 4 Weeks

    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
    A dose of at least 15 mg per Week had to be taken to remain in the study. MTX was given every week from Week 52 onwards until Week 103

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PBO
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections every 2 Weeks or every 4 Weeks

    Arm title
    		 CZP+MTX / CZP Q4W+MTX
    Arm description
    		 Certolizumab pegol (CZP) 200 mg Q2W + Methotrexate (MTX) in Period 1 1 syringe 200 mg Certolizumab pegol (CZP) every 4 Weeks/ 1 syringe Placebo (PBO) every 4 Weeks (CZP and PBO administration to be staggered 2 weeks apart to maintain blind) + MTX in Period 2
    Arm type
    		 Experimental

    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
    A dose of at least 15 mg per Week had to be taken to remain in the study. MTX was given every week from Week 52 onwards until Week 103

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections: 200 mg every 2 Weeks or every 4 Weeks

    Arm title
    		 CZP+MTX / CZP Q2W+MTX
    Arm description
    		 Certolizumab pegol (CZP) 200 mg Q2W + Methotrexate (MTX) in Period 1 1 syringe 200 mg Certolizumab pegol (CZP) every 2 Weeks + MTX in Period 2
    Arm type
    		 Experimental

    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
    A dose of at least 15 mg per Week had to be taken to remain in the study. MTX was given every week from Week 52 onwards until Week 103

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections: 200 mg every 2 Weeks or every 4 Weeks

    Number of subjects in period 1
    		PBO+MTX / PBO+MTX CZP+MTX / PBO+MTX CZP+MTX / CZP Q4W+MTX CZP+MTX / CZP Q2W+MTX
    Started
    66
    81
    127
    83
    Completed
    59
    72
    112
    70
    Not completed
    7
    9
    15
    13
         AE, serious fatal
    1
    -
    -
    -
         Consent withdrawn by subject
    1
    1
    1
    2
         Other
    2
    1
    3
    6
         AE, non-serious, non-fatal
    1
    3
    6
    2
         AE, captured in Period 1
    -
    1
    -
    1
         Lost to follow-up
    1
    -
    2
    1
         SAE, non-fatal
    -
    2
    2
    -
         SAE, non-fatal + AE, non-serious nonfatal
    -
    -
    -
    1
         Lack of efficacy
    1
    1
    -
    -
         Protocol deviation
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PBO+MTX / PBO+MTX
    Reporting group description
    		 Placebo (PBO) + Methotrexate (MTX) in Period 1 1 syringe PBO every 2 Weeks + MTX in Period 2

    Reporting group title
    CZP+MTX / PBO+MTX
    Reporting group description
    		 Certolizumab pegol (CZP) 200 mg Q2W + Methotrexate (MTX) in Period 1 1 syringe PBO every 2 Weeks + MTX in Period 2

    Reporting group title
    CZP+MTX / CZP Q4W+MTX
    Reporting group description
    		 Certolizumab pegol (CZP) 200 mg Q2W + Methotrexate (MTX) in Period 1 1 syringe 200 mg Certolizumab pegol (CZP) every 4 Weeks/ 1 syringe Placebo (PBO) every 4 Weeks (CZP and PBO administration to be staggered 2 weeks apart to maintain blind) + MTX in Period 2

    Reporting group title
    CZP+MTX / CZP Q2W+MTX
    Reporting group description
    		 Certolizumab pegol (CZP) 200 mg Q2W + Methotrexate (MTX) in Period 1 1 syringe 200 mg Certolizumab pegol (CZP) every 2 Weeks + MTX in Period 2

    Reporting group values
    		 PBO+MTX / PBO+MTX CZP+MTX / PBO+MTX CZP+MTX / CZP Q4W+MTX CZP+MTX / CZP Q2W+MTX Total
    Number of subjects
    		 66 81 127 83 357
    Age Categorical
    Units: Subjects
        <=18 years
    		 0 0 2 0 2
        Adults (18-64 years)
    		 54 70 114 72 310
        >=65 years
    		 12 11 11 11 45
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.2 ( 13.7 ) 47.9 ( 14.1 ) 49.1 ( 12.5 ) 49.1 ( 13.2 ) -
    Gender Categorical
    Units: Subjects
        Male
    		 12 22 40 18 92
        Female
    		 54 59 87 65 265

    End points

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    End points reporting groups
    Reporting group title
    PBO+MTX / PBO+MTX
    Reporting group description
    		 Placebo (PBO) + Methotrexate (MTX) in Period 1 1 syringe PBO every 2 Weeks + MTX in Period 2

    Reporting group title
    CZP+MTX / PBO+MTX
    Reporting group description
    		 Certolizumab pegol (CZP) 200 mg Q2W + Methotrexate (MTX) in Period 1 1 syringe PBO every 2 Weeks + MTX in Period 2

    Reporting group title
    CZP+MTX / CZP Q4W+MTX
    Reporting group description
    		 Certolizumab pegol (CZP) 200 mg Q2W + Methotrexate (MTX) in Period 1 1 syringe 200 mg Certolizumab pegol (CZP) every 4 Weeks/ 1 syringe Placebo (PBO) every 4 Weeks (CZP and PBO administration to be staggered 2 weeks apart to maintain blind) + MTX in Period 2

    Reporting group title
    CZP+MTX / CZP Q2W+MTX
    Reporting group description
    		 Certolizumab pegol (CZP) 200 mg Q2W + Methotrexate (MTX) in Period 1 1 syringe 200 mg Certolizumab pegol (CZP) every 2 Weeks + MTX in Period 2

    Subject analysis set title
    CZP+MTX / PBO+MTX (Full Analysis Set)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Certolizumab pegol (CZP) 200 mg Q2W + Methotrexate (MTX) in Period 1 1 syringe PBO every 2 Weeks + MTX in Period 2

    Subject analysis set title
    CZP+MTX / CZP Q4W+MTX (Full Analysis Set)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Certolizumab pegol (CZP) 200 mg Q2W + Methotrexate (MTX) in Period 1 1 syringe 200 mg Certolizumab pegol (CZP) every 4 Weeks/ 1 syringe Placebo (PBO) every 4 Weeks (CZP and PBO administration to be staggered 2 weeks apart to maintain blind) + MTX in Period 2

    Subject analysis set title
    CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Certolizumab pegol (CZP) 200 mg Q2W + Methotrexate (MTX) in Period 1 1 syringe 200 mg Certolizumab pegol (CZP) every 2 Weeks + MTX in Period 2

    Subject analysis set title
    CZP+MTX / PBO+MTX (Radiographic Set)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Certolizumab pegol (CZP) 200 mg Q2W + Methotrexate (MTX) in Period 1 1 syringe PBO every 2 Weeks + MTX in Period 2

    Subject analysis set title
    CZP+MTX / CZP Q4W+MTX (Radiographic Set)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Certolizumab pegol (CZP) 200 mg Q2W + Methotrexate (MTX) in Period 1 1 syringe 200 mg Certolizumab pegol (CZP) every 4 Weeks/ 1 syringe Placebo (PBO) every 4 Weeks (CZP and PBO administration to be staggered 2 weeks apart to maintain blind) + MTX in Period 2

    Subject analysis set title
    CZP+MTX / CZP Q2W+MTX (Radiographic Set)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Certolizumab pegol (CZP) 200 mg Q2W + Methotrexate (MTX) in Period 1 1 syringe 200mg Certolizumab pegol (CZP) every 2 Weeks + MTX in Period 2

    Primary: Percentage of subjects with Disease Activity Score [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) <= 3.2 at Week 104 in RA0055 Period 2 without flaring

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    End point title
    		 Percentage of subjects with Disease Activity Score [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) <= 3.2 at Week 104 in RA0055 Period 2 without flaring
    End point description
    This Outcome Measure includes all subjects that have a DAS28 [ESR] <= 3.2 from the start of RA0055 Period 2 (Week 52 of RA0055 Period 1) to Week 104 in RA0055 Period 2 without flaring.
    End point type
    Primary
    End point timeframe
    Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: percentage of subjects
    number (not applicable)
        Maintained LDA
    39.2
    53.2
    48.8
    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 a hierarchical order beginning with the CZP standard maintenance dosing (200 mg Q2W) + MTX group vs the CZP stopped dosing (PBO) + MTX group. If this analysis was statistically significant at the alpha = 0.05 level, an additional comparison of the CZP reduced frequency dosing (200 mg Q4W) + MTX group vs the CZP stopped dosing + MTX group was performed with testing at the alpha = 0.05 level
    Comparison groups
    CZP+MTX / PBO+MTX (Full Analysis Set) v CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.112
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.719
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.881
         upper limit
    		 3.354
    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 a hierarchical order. A hierarchical test procedure was applied to protect the Overall significance level for the multiplicity of endpoints. Hypothesis testing was performed in the following predefined order, each at a 2-sided 95 % alpha level
    Comparison groups
    CZP+MTX / PBO+MTX (Full Analysis Set) v CZP+MTX / CZP Q4W+MTX (Full Analysis Set)
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.041
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.889
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.026
         upper limit
    		 3.48

    Secondary: Percentage of subjects with Disease Activity Score 28 [ESR] (DAS28 [ESR]) < 2.6 at Week 52 in previous study RA0055 Period 1 who maintain a DAS28 [ESR] < 2.6 from Week 52 in RA0055 Period 1 through Week 104 in RA0055 Period 2 without flaring

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    End point title
    		 Percentage of subjects with Disease Activity Score 28 [ESR] (DAS28 [ESR]) < 2.6 at Week 52 in previous study RA0055 Period 1 who maintain a DAS28 [ESR] < 2.6 from Week 52 in RA0055 Period 1 through Week 104 in RA0055 Period 2 without flaring
    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
    From Week 52 in RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    51
    83
    50
    Units: percentage of subjects
    number (not applicable)
        Maintained Remitter
    33.3
    43.4
    44
    No statistical analyses for this end point

    Secondary: Change from Baseline in previous study RA0055 Period 1 in modified Total Sharp Score (mTSS) to Week 104 in RA0055 Period 2

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    End point title
    		 Change from Baseline in previous study RA0055 Period 1 in modified Total Sharp Score (mTSS) to Week 104 in RA0055 Period 2
    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 64 and 52 joints, respectively, with higher scores representing greater damage.
    End point type
    Secondary
    End point timeframe
    From Baseline (Week 0) in RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Radiographic Set) CZP+MTX / CZP Q4W+MTX (Radiographic Set) CZP+MTX / CZP Q2W+MTX (Radiographic Set)
    Number of subjects analysed
    75
    113
    72
    Units: units on a scale
    median (full range (min-max))
        median (full range)
    0 (-5 to 28)
    0 (-9 to 9)
    0 (-2 to 9)
    No statistical analyses for this end point

    Secondary: Change from Week 52 in previous study RA0055 Period 1 in modified Total Sharp Score (mTSS) to Week 104 in RA0055 Period 2

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    End point title
    		 Change from Week 52 in previous study RA0055 Period 1 in modified Total Sharp Score (mTSS) to Week 104 in RA0055 Period 2
    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 64 and 52 joints, respectively, with higher scores representing greater damage.
    End point type
    Secondary
    End point timeframe
    From Week 52 in RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Radiographic Set) CZP+MTX / CZP Q4W+MTX (Radiographic Set) CZP+MTX / CZP Q2W+MTX (Radiographic Set)
    Number of subjects analysed
    75
    113
    72
    Units: units on a scale
    median (full range (min-max))
        median (full range)
    0 (-3 to 50)
    0 (-9 to 7)
    0 (-4 to 4)
    No statistical analyses for this end point

    Secondary: Percentage of subjects with radiographic non-progression from Baseline in previous study RA0055 Period 1 to Week 104 in RA0055 Period 2

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    End point title
    		 Percentage of subjects with radiographic non-progression from Baseline in previous study RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point description
    Radiographic nonprogression is defined as change in modified Total Sharp Score (mTSS) <= 0.5.
    End point type
    Secondary
    End point timeframe
    From Baseline (Week 0) in RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Radiographic Set) CZP+MTX / CZP Q4W+MTX (Radiographic Set) CZP+MTX / CZP Q2W+MTX (Radiographic Set)
    Number of subjects analysed
    75
    113
    72
    Units: percentage of subjects
    number (not applicable)
        Subjects with Nonprogression
    69.3
    77.9
    79.2
    No statistical analyses for this end point

    Secondary: Percentage of subjects with radiographic non-progression from Week 52 in previous study RA0055 Period 1 to Week 104 in RA0055 Period 2

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    End point title
    		 Percentage of subjects with radiographic non-progression from Week 52 in previous study RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point description
    Radiographic nonprogression is defined as change in modified Total Sharp Score (mTSS) <= 0.5.
    End point type
    Secondary
    End point timeframe
    From Week 52 in RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Radiographic Set) CZP+MTX / CZP Q4W+MTX (Radiographic Set) CZP+MTX / CZP Q2W+MTX (Radiographic Set)
    Number of subjects analysed
    75
    113
    72
    Units: percentage of subjects
    number (not applicable)
        Subjects with Nonprogression
    80
    84.1
    90.3
    No statistical analyses for this end point

    Secondary: Change from Baseline in previous study RA0055 Period 1 in the joint erosion score to Week 104 in RA0055 Period 2

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    End point title
    		 Change from Baseline in previous study RA0055 Period 1 in the joint erosion score to Week 104 in RA0055 Period 2
    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) in RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Radiographic Set) CZP+MTX / CZP Q4W+MTX (Radiographic Set) CZP+MTX / CZP Q2W+MTX (Radiographic Set)
    Number of subjects analysed
    75
    113
    72
    Units: units on a scale
    median (full range (min-max))
        median (full range)
    0 (-4 to 18)
    0 (-8 to 7)
    0 (-2 to 9)
    No statistical analyses for this end point

    Secondary: Change from Week 52 in previous study RA0055 Period 1 in the joint erosion score to Week 104 in RA0055 Period 2

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    End point title
    		 Change from Week 52 in previous study RA0055 Period 1 in the joint erosion score to Week 104 in RA0055 Period 2
    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 Week 52 in RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Radiographic Set) CZP+MTX / CZP Q4W+MTX (Radiographic Set) CZP+MTX / CZP Q2W+MTX (Radiographic Set)
    Number of subjects analysed
    75
    113
    72
    Units: units on a scale
    median (full range (min-max))
        median (full range)
    0 (-3 to 36)
    0 (-8 to 5)
    0 (-2 to 4)
    No statistical analyses for this end point

    Secondary: Change from Baseline in previous study RA0055 Period 1 in the joint narrowing score to Week 104 in RA0055 Period 2

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    End point title
    		 Change from Baseline in previous study RA0055 Period 1 in the joint narrowing score to Week 104 in RA0055 Period 2
    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) in RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Radiographic Set) CZP+MTX / CZP Q4W+MTX (Radiographic Set) CZP+MTX / CZP Q2W+MTX (Radiographic Set)
    Number of subjects analysed
    75
    113
    72
    Units: units on a scale
    median (full range (min-max))
        median (full range)
    0 (-3 to 12)
    0 (-4 to 4)
    0 (-2 to 2)
    No statistical analyses for this end point

    Secondary: Change from Week 52 in previous study RA0055 Period 1 in the joint narrowing score to Week 104 in RA0055 Period 2

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    End point title
    		 Change from Week 52 in previous study RA0055 Period 1 in the joint narrowing score to Week 104 in RA0055 Period 2
    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 Week 52 in RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Radiographic Set) CZP+MTX / CZP Q4W+MTX (Radiographic Set) CZP+MTX / CZP Q2W+MTX (Radiographic Set)
    Number of subjects analysed
    75
    113
    72
    Units: units on a scale
    median (full range (min-max))
        median (full range)
    0 (-2 to 14)
    0 (-3 to 5)
    0 (-4 to 2)
    No statistical analyses for this end point

    Secondary: Percentage of subjects meeting the American College of Rheumatology 20 % response criteria (ACR20) at Week 104 in RA0055 Period 2

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    End point title
    		 Percentage of subjects meeting the American College of Rheumatology 20 % response criteria (ACR20) at Week 104 in RA0055 Period 2
    End point description
    The assessments are based on a 20 % or greater improvement from Baseline in previous study RA0055 Period 1 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) in RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: percentage of subjects
    number (not applicable)
        Responder
    74.7
    86.5
    73.8
    No statistical analyses for this end point

    Secondary: Percentage of subjects meeting the American College of Rheumatology 50 % response criteria (ACR50) at Week 104 in RA0055 Period 2

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    End point title
    		 Percentage of subjects meeting the American College of Rheumatology 50 % response criteria (ACR50) at Week 104 in RA0055 Period 2
    End point description
    The assessments are based on a 50 % or greater improvement from Baseline in previous study RA0055 Period 1 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) in RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: percentage of subjects
    number (not applicable)
        Responder
    68.4
    80.2
    71.4
    No statistical analyses for this end point

    Secondary: Percentage of subjects meeting the American College of Rheumatology 70 % response criteria (ACR70) at Week 104 in RA0055 Period 2

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    End point title
    		 Percentage of subjects meeting the American College of Rheumatology 70 % response criteria (ACR70) at Week 104 in RA0055 Period 2
    End point description
    The assessments are based on a 70 % or greater improvement from Baseline in previous study RA0055 Period 1 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) in RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: percentage of subjects
    number (not applicable)
        Responder
    60.8
    70.6
    63.1
    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 104 in RA0055 Period 2

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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 104 in RA0055 Period 2
    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) <= 10 mm.
    End point type
    Secondary
    End point timeframe
    Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: percentage of subjects
    number (not applicable)
        Remitter
    34.2
    52.4
    46.4
    No statistical analyses for this end point

    Secondary: Percentage of subjects with Clinical Disease Activity Index (CDAI) <= 2.8 at Week 104 in RA0055 Period 2

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    End point title
    		 Percentage of subjects with Clinical Disease Activity Index (CDAI) <= 2.8 at Week 104 in RA0055 Period 2
    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 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: percentage of subjects
    number (not applicable)
        Remitter
    43
    55.6
    52.4
    No statistical analyses for this end point

    Secondary: Percentage of subjects with Simplified Disease Activity Index (SDAI) <= 3.3 at Week 104 in RA0055 Period 2

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    End point title
    		 Percentage of subjects with Simplified Disease Activity Index (SDAI) <= 3.3 at Week 104 in RA0055 Period 2
    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 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: percentage of subjects
    number (not applicable)
        Remitter
    41.8
    57.1
    53.6
    No statistical analyses for this end point

    Secondary: Percentage of subjects with Disease Activity Score [Erythrocyte Sedimentation Rate] (DAS28[ESR]) < 2.6 at Week 104 in RA0055 Period 2

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    End point title
    		 Percentage of subjects with Disease Activity Score [Erythrocyte Sedimentation Rate] (DAS28[ESR]) < 2.6 at Week 104 in RA0055 Period 2
    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 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: percentage of subjects
    number (not applicable)
        Remitter
    44.3
    63.5
    52.4
    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 104 in RA0055 Period 2

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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 104 in RA0055 Period 2
    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) <= 10 mm.
    End point type
    Secondary
    End point timeframe
    Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: percentage of subjects
    number (not applicable)
        Remitter
    35.4
    52.4
    50
    No statistical analyses for this end point

    Secondary: Percentage of subjects achieving a good or moderate European League Against Rheumatism (EULAR) response at Week 104 in RA0055 Period 2

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    End point title
    		 Percentage of subjects achieving a good or moderate European League Against Rheumatism (EULAR) response at Week 104 in RA0055 Period 2
    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) in RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: percentage of subjects
    number (not applicable)
        Good or Moderate Response
    88.6
    98.4
    94
    No statistical analyses for this end point

    Secondary: Change from Baseline in previous study RA0055 Period 1 in Disease Activity Score [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) to Week 104 in RA0055 Period 2

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    End point title
    		 Change from Baseline in previous study RA0055 Period 1 in Disease Activity Score [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) to Week 104 in RA0055 Period 2
    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) in RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: units on a scale
    arithmetic mean (standard deviation)
        mean (standard deviation)
    -3.436 ( 1.711 )
    -4.252 ( 1.275 )
    -3.901 ( 1.546 )
    No statistical analyses for this end point

    Secondary: Change from Week 52 in previous study RA0055 Period 1 in Disease Activity Score [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) to Week 104 in RA0055 Period 2

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    End point title
    		 Change from Week 52 in previous study RA0055 Period 1 in Disease Activity Score [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) to Week 104 in RA0055 Period 2
    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 Week 52 in RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: units on a scale
    arithmetic mean (standard deviation)
        mean (standard deviation)
    1.145 ( 1.372 )
    0.414 ( 1.033 )
    0.511 ( 1.215 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in previous study RA0055 Period 1 in Clinical Disease Activity Index (CDAI) to Week 104 in RA0055 Period 2

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    End point title
    		 Change from Baseline in previous study RA0055 Period 1 in Clinical Disease Activity Index (CDAI) to Week 104 in RA0055 Period 2
    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. A negative value in CDAI change from Baseline indicates an improvement from Baseline.
    End point type
    Secondary
    End point timeframe
    From Baseline (Week 0) in RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: units on a scale
    arithmetic mean (standard deviation)
        arithmetic mean (standard deviation)
    -30.7 ( 16.4 )
    -37.2 ( 12.1 )
    -32.6 ( 15.5 )
    No statistical analyses for this end point

    Secondary: Change from Week 52 in previous study RA0055 Period 1 in Clinical Disease Activity Index (CDAI) to Week 104 in RA0055 Period 2

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    End point title
    		 Change from Week 52 in previous study RA0055 Period 1 in Clinical Disease Activity Index (CDAI) to Week 104 in RA0055 Period 2
    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. A negative value in CDAI change from Baseline indicates an improvement from Baseline.
    End point type
    Secondary
    End point timeframe
    From Week 52 in RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: units on a scale
    arithmetic mean (standard deviation)
        arithmetic mean (standard deviation)
    6 ( 10.4 )
    1.7 ( 5.9 )
    2.5 ( 7.9 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in previous study RA0055 Period 1 in Simplified Disease Activity Index (SDAI) to Week 104 in RA0055 Period 2

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    End point title
    		 Change from Baseline in previous study RA0055 Period 1 in Simplified Disease Activity Index (SDAI) to Week 104 in RA0055 Period 2
    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. A negative value in SDAI change from Baseline indicates an improvement from Baseline.
    End point type
    Secondary
    End point timeframe
    From Baseline (Week 0) in RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: units on a scale
    arithmetic mean (standard deviation)
        arithmetic mean (standard deviation)
    -31.6 ( 17.4 )
    -39.1 ( 13.5 )
    -34.3 ( 16.8 )
    No statistical analyses for this end point

    Secondary: Change from Week 52 in previous study RA0055 Period 1 in Simplified Disease Activity Index (SDAI) to Week 104 in RA0055 Period 2

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    End point title
    		 Change from Week 52 in previous study RA0055 Period 1 in Simplified Disease Activity Index (SDAI) to Week 104 in RA0055 Period 2
    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. A negative value in SDAI change from Baseline indicates an improvement from Baseline.
    End point type
    Secondary
    End point timeframe
    From Week 52 in RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: units on a scale
    arithmetic mean (standard deviation)
        arithmetic mean (standard deviation)
    6.5 ( 10.9 )
    1.7 ( 6 )
    2.6 ( 7.8 )
    No statistical analyses for this end point

    Secondary: Percentage of subjects with a Health Assessment Questionnaire- Disability Index (HAQ-DI) ≤ 0.5 at Week 104 in RA0055 Period 2

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    End point title
    		 Percentage of subjects with a Health Assessment Questionnaire- Disability Index (HAQ-DI) ≤ 0.5 at Week 104 in RA0055 Period 2
    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 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: percentage of subjects
    number (not applicable)
        Responder
    49.4
    63.5
    61.9
    No statistical analyses for this end point

    Secondary: Percentage of subjects with Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) <= 3.2 at Week 104 in RA0055 Period 2

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    End point title
    		 Percentage of subjects with Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) <= 3.2 at Week 104 in RA0055 Period 2
    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 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: percentage of subjects
    number (not applicable)
        LDA
    59.5
    73.8
    65.5
    No statistical analyses for this end point

    Secondary: Time to flare from Week 52 in RA0055 Period 1 to Week 104 in RA0055 Period 2

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    End point title
    		 Time to flare from Week 52 in RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point description
    Time to flare, defined as an increase of DAS28[ESR] >= 0.6 above Week 52 DAS28[ESR] level, having a DAS28[ESR] >= 3.2 and judged by the Investigator as due to RA and all three criteria confirmed at an additional visit two weeks thereafter, from Week 52 onwards. Data not available as > 75% of the participants failed to meet flare criteria. -999/-9999 = not estimable.
    End point type
    Secondary
    End point timeframe
    Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: days
    geometric mean (geometric coefficient of variation)
        Geometic Mean (Geo. Coeff. of Variation)
    -999 ( -9999 )
    -999 ( -9999 )
    -999 ( -9999 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in previous study RA0055 Period 1 in the Bristol Rheumatoid Arthritis Fatigue- Multidimensional Questionnaire (BRAF-MDQ) total score to Week 104 in RA0055 Period 2

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    End point title
    		 Change from Baseline in previous study RA0055 Period 1 in the Bristol Rheumatoid Arthritis Fatigue- Multidimensional Questionnaire (BRAF-MDQ) total score to Week 104 in RA0055 Period 2
    End point description
    BRAF-MDQ total score ranges from 0 to 70 (with higher scores indicating worse fatigue), whereas the score for each dimension is different due to the varied number of questions (0 –22 for physical, 0- 21 for living, 0- 15 for cognition, and 0- 12 for emotion). 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) in RA0055 Period 1 to Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: units on a scale
    arithmetic mean (standard deviation)
        mean (standard deviation)
    -15.9 ( 16.7 )
    -21.6 ( 16.9 )
    -20.7 ( 17.3 )
    No statistical analyses for this end point

    Secondary: Number of work days missed (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 104 in RA0055 Period 2

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    End point title
    		 Number of work days missed (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 104 in RA0055 Period 2
    End point description
    Number of work days missed in the last month for employed subjects.
    End point type
    Secondary
    End point timeframe
    Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: days
    arithmetic mean (standard deviation)
        mean (standard deviation)
    0.5 ( 1.46 )
    0.2 ( 0.89 )
    0.3 ( 0.86 )
    No statistical analyses for this end point

    Secondary: Number of work days with reduced productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 104 in RA0055 Period 2

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    End point title
    		 Number of work days with reduced productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 104 in RA0055 Period 2
    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 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    52
    79
    51
    Units: days
    arithmetic mean (standard deviation)
        mean (standard deviation)
    1.5 ( 4.88 )
    0.6 ( 2.01 )
    0.8 ( 2.29 )
    No statistical analyses for this end point

    Secondary: Interference with work productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 104 in RA0055 Period 2

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    End point title
    		 Interference with work productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 104 in RA0055 Period 2
    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 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    52
    79
    51
    Units: units on a scale
    arithmetic mean (standard deviation)
        mean (standard deviation)
    2.3 ( 2.84 )
    0.9 ( 1.6 )
    1.2 ( 2.19 )
    No statistical analyses for this end point

    Secondary: Number of days with no household work (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 104 in RA0055 Period 2

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    End point title
    		 Number of days with no household work (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 104 in RA0055 Period 2
    End point description
    Number of days with no household work in the last month.
    End point type
    Secondary
    End point timeframe
    Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: days
    arithmetic mean (standard deviation)
        mean (standard deviation)
    1.4 ( 3.35 )
    0.7 ( 2.29 )
    0.8 ( 2.76 )
    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 104 in RA0055 Period 2

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    End point title
    		 Number of days with reduced household work productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 104 in RA0055 Period 2
    End point description
    Number of days with reduced household work productivity in the last month.
    End point type
    Secondary
    End point timeframe
    Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: days
    arithmetic mean (standard deviation)
        mean (standard deviation)
    1.8 ( 4.49 )
    0.9 ( 3.01 )
    1 ( 3.37 )
    No statistical analyses for this end point

    Secondary: Number of days with hired outside help (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 104 in RA0055 Period 2

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    End point title
    		 Number of days with hired outside help (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 104 in RA0055 Period 2
    End point description
    Number of days with hired outside help days in the last month.
    End point type
    Secondary
    End point timeframe
    Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: days
    arithmetic mean (standard deviation)
        mean (standard deviation)
    0.3 ( 0.98 )
    0.3 ( 2.7 )
    0.1 ( 0.45 )
    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 104 in RA0055 Period 2

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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 104 in RA0055 Period 2
    End point description
    Number of days missed of family/social/leisure activities in the last month.
    End point type
    Secondary
    End point timeframe
    Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: days
    arithmetic mean (standard deviation)
        mean (standard deviation)
    1.2 ( 3.36 )
    0.2 ( 1.8 )
    0.2 ( 0.75 )
    No statistical analyses for this end point

    Secondary: Interference with household work productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 104 in RA0055 Period 2

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    End point title
    		 Interference with household work productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 104 in RA0055 Period 2
    End point description
    The Arthritis interference in the last month with household productivity is measured on a scale that ranges from 0 (no interference) to 10 (complete interference).
    End point type
    Secondary
    End point timeframe
    Week 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: units on a scale
    arithmetic mean (standard deviation)
        mean (standard deviation)
    2 ( 2.63 )
    1 ( 1.53 )
    1.1 ( 1.95 )
    No statistical analyses for this end point

    Secondary: Percentage of subjects achieving Low Disease Activity (LDA) at Week 104 in RA0055 Period 2

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    End point title
    		 Percentage of subjects achieving Low Disease Activity (LDA) at Week 104 in RA0055 Period 2
    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 104 in RA0055 Period 2
    End point values
    		 CZP+MTX / PBO+MTX (Full Analysis Set) CZP+MTX / CZP Q4W+MTX (Full Analysis Set) CZP+MTX / CZP Q2W+MTX (Full Analysis Set)
    Number of subjects analysed
    79
    126
    84
    Units: percentage of subjects
    number (not applicable)
        LDA
    68.4
    74.6
    70.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events for Period 2 were collected from the date of the Week 52 study medication up to 70 days after the last (most recent) Certolizumab pegol (CZP) or Placebo (PBO) dose
    Adverse event reporting additional description
    For the safety results, the main comparisons of interest are across the 3 CZP re-randomized groups; the PBO+MTX/PBO+MTX group is included for completeness. For subjects induced/ re-induced with CZP due to flare, only AEs up to the time of induction/re-induction with CZP are included. Note that 3 SAEs occurred after induction/ re-induction.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    PBO+MTX / PBO+MTX
    Reporting group description
    		 Placebo (PBO) + Methotrexate (MTX) in Period 1 1 syringe PBO every 2 Weeks + MTX in Period 2

    Reporting group title
    CZP+MTX / PBO+MTX
    Reporting group description
    		 Certolizumab pegol (CZP) 200 mg Q2W + Methotrexate (MTX) in Period 1 1 syringe PBO every 2 Weeks + MTX in Period 2

    Reporting group title
    CZP+MTX / CZP Q4W+MTX
    Reporting group description
    		 Certolizumab pegol (CZP) 200 mg Q2W + Methotrexate (MTX) in Period 1 1 syringe 200 mg Certolizumab pegol (CZP) every 4 Weeks/ 1 syringe Placebo (PBO) every 4 Weeks (CZP and PBO administration to be staggered 2 weeks apart to maintain blind) + MTX in Period 2

    Reporting group title
    CZP+MTX / CZP Q2W+MTX
    Reporting group description
    		 Certolizumab pegol (CZP) 200 mg Q2W + Methotrexate (MTX) in Period 1 1 syringe 200 mg Certolizumab pegol (CZP) every 2 Weeks + MTX in Period 2

    Serious adverse events
    		 PBO+MTX / PBO+MTX CZP+MTX / PBO+MTX CZP+MTX / CZP Q4W+MTX CZP+MTX / CZP Q2W+MTX
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 66 (6.06%)
    6 / 81 (7.41%)
    9 / 127 (7.09%)
    4 / 83 (4.82%)
         number of deaths (all causes)
    1
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 81 (0.00%)
    1 / 127 (0.79%)
    0 / 83 (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
    Lip squamous cell carcinoma
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 81 (0.00%)
    1 / 127 (0.79%)
    0 / 83 (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
    Myxoid liposarcoma
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 81 (0.00%)
    1 / 127 (0.79%)
    0 / 83 (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
    Prostate cancer
         subjects affected / exposed
    0 / 66 (0.00%)
    2 / 81 (2.47%)
    0 / 127 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 81 (1.23%)
    0 / 127 (0.00%)
    0 / 83 (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
    General disorders and administration site conditions
    Influenza like illness
    Additional description: Only subjects who were induced/re-induced with CZP in Period 2 due to flare are included
         subjects affected / exposed [1]
    0 / 3 (0.00%)
    0 / 10 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         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
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 81 (0.00%)
    0 / 127 (0.00%)
    1 / 83 (1.20%)
         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
    Cervical polyp
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 81 (0.00%)
    1 / 127 (0.79%)
    0 / 83 (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
    Respiratory, thoracic and mediastinal disorders
    Bronchial carcinoma
    Additional description: Only subjects who were induced/re-induced with CZP in Period 2 due to flare are included
         subjects affected / exposed [2]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 7 (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
    Psychiatric disorders
    Depression
    Additional description: Only subjects who were induced/re-induced with CZP in Period 2 due to flare are included
         subjects affected / exposed [3]
    0 / 3 (0.00%)
    1 / 10 (10.00%)
    0 / 3 (0.00%)
    0 / 7 (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
    Injury, poisoning and procedural complications
    Ligament rupture
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 81 (0.00%)
    1 / 127 (0.79%)
    0 / 83 (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
    Cardiac disorders
    Myocardial ischaemia
    alternative dictionary used: MedDRA 17.0
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 81 (0.00%)
    0 / 127 (0.00%)
    1 / 83 (1.20%)
         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
    Acute myocardial infarction
    alternative dictionary used: MedDRA 17.0
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 81 (0.00%)
    0 / 127 (0.00%)
    0 / 83 (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
    Cardiac failure
    alternative dictionary used: MedDRA 17.0
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 81 (0.00%)
    0 / 127 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Intercostal neuralgia
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 81 (0.00%)
    0 / 127 (0.00%)
    1 / 83 (1.20%)
         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
    Ear and labyrinth disorders
    Meniere's disease
    alternative dictionary used: MedDRA 17.0
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 81 (1.23%)
    0 / 127 (0.00%)
    0 / 83 (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
    Gastrointestinal disorders
    Gastroduodenitis
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 81 (0.00%)
    1 / 127 (0.79%)
    0 / 83 (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
    Pancreatitis acute
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 81 (0.00%)
    0 / 127 (0.00%)
    0 / 83 (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
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 81 (0.00%)
    1 / 127 (0.79%)
    0 / 83 (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
    Endocrine disorders
    Hyperthyroidism
    alternative dictionary used: MedDRA 17.0
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 81 (0.00%)
    1 / 127 (0.79%)
    0 / 83 (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
    Musculoskeletal and connective tissue disorders
    Tendon disorder
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 81 (0.00%)
    0 / 127 (0.00%)
    0 / 83 (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
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 81 (0.00%)
    0 / 127 (0.00%)
    1 / 83 (1.20%)
         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
    Gastroenteritis salmonella
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 81 (0.00%)
    0 / 127 (0.00%)
    0 / 83 (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
    Latent tuberculosis
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 81 (1.23%)
    1 / 127 (0.79%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 81 (1.23%)
    0 / 127 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Only subjects who were induced/re-induced with CZP in Period 2 due to flare are included.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Only subjects who were induced/re-induced with CZP in Period 2 due to flare are included.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Only subjects who were induced/re-induced with CZP in Period 2 due to flare are included.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 PBO+MTX / PBO+MTX CZP+MTX / PBO+MTX CZP+MTX / CZP Q4W+MTX CZP+MTX / CZP Q2W+MTX
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 66 (4.55%)
    13 / 81 (16.05%)
    32 / 127 (25.20%)
    13 / 83 (15.66%)
    Infections and infestations
    Urinary tract infection
    alternative dictionary used: MedDRA 17.0
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 66 (1.52%)
    2 / 81 (2.47%)
    4 / 127 (3.15%)
    5 / 83 (6.02%)
         occurrences all number
    1
    2
    4
    9
    Nasopharyngitis
         subjects affected / exposed
    0 / 66 (0.00%)
    5 / 81 (6.17%)
    13 / 127 (10.24%)
    4 / 83 (4.82%)
         occurrences all number
    0
    5
    15
    4
    Pharyngitis
         subjects affected / exposed
    0 / 66 (0.00%)
    5 / 81 (6.17%)
    5 / 127 (3.94%)
    2 / 83 (2.41%)
         occurrences all number
    0
    5
    5
    2
    Latent tuberculosis
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 81 (0.00%)
    7 / 127 (5.51%)
    1 / 83 (1.20%)
         occurrences all number
    0
    0
    7
    1
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    2 / 66 (3.03%)
    3 / 81 (3.70%)
    8 / 127 (6.30%)
    2 / 83 (2.41%)
         occurrences all number
    3
    3
    8
    3

    More information

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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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