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    Clinical Trial Results:
    Phase 3, Multicenter, Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Certolizumab Pegol in Subjects With Adult-Onset Active and Progressive Psoriatic Arthritis (PsA)

    Summary
    EudraCT number
    2009-011720-59
    Trial protocol
    FR   DE   ES   GB   BE   HU   NL   CZ   IE   IT  
    Global end of trial date
    24 Aug 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Sep 2016
    First version publication date
    08 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PsA001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01087788
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB BIOSCIENCES GmbH
    Sponsor organisation address
    Alfred-Nobel-Strasse 10, Monheim, Germany, 40789
    Public contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
    Scientific contact
    Clin Trial Reg & 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 Apr 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the efficacy of Certolizumab pegol (CZP) administered sc at the dose of 200mg every two weeks (Q2W) or 400mg every four weeks (Q4W) after loading with 400mg at Weeks 0, 2, and 4 on the signs and symptoms of active psoriatic arthritis (PsA) and on the inhibition of progression of structural damage in adults with active PsA
    Protection of trial subjects
    Not applicable
    Background therapy
    Not applicable
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    02 Mar 2010
    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
    Canada: 14
    Country: Number of subjects enrolled
    United States: 84
    Country: Number of subjects enrolled
    Argentina: 50
    Country: Number of subjects enrolled
    Brazil: 6
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Ireland: 1
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Czech Republic: 67
    Country: Number of subjects enrolled
    Hungary: 28
    Country: Number of subjects enrolled
    Poland: 101
    Worldwide total number of subjects
    409
    EEA total number of subjects
    251
    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)
    383
    From 65 to 84 years
    26
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study started to enroll patients in March 2010 and concluded in August 2015.

    Pre-assignment
    Screening details
    The study included a 24-week Double-Blind, a 24-week Dose-Blind, and an Open-Label Treatment Period. 409 subjects are included in Randomized Set (RS) shown in the Participant Flow, which is an Intention- to- Treat (ITT) dataset.

    Period 1
    Period 1 title
    24-weeks Double-blind Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Matching Placebo to Certolizumab Pegol (CZP) injections from Week 0 to Week 24. Placebo subjects who did not achieve certain predefined response criteria at both Weeks 14 and 16 left the Placebo group and were re-randomized to either CZP 200 mg Q2W or CZP 400 mg Q4W arm on Week 16. After 24 weeks, all subjects were re-randomized to active treatment with CZP 200 mg every two weeks (Q2W) or CZP 400 mg every four weeks (Q4W).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Solution for injection/infusion 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 200 mg Q2W
    Arm description
    Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 200 mg CZP sc every 2 weeks (Q2W) from Week 6 onwards. At every visit, subjects received one injection of 200 mg CZP and one injection of Placebo to maintain the study blind.
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    Certolizumab pegol
    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 400 mg every 4 Weeks

    Arm title
    CZP 400 mg Q4W
    Arm description
    Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 400 mg CZP sc every 4 weeks (Q4W) from Week 8 onwards. Subjects received 2 injections of Placebo every 4 weeks in between the 2 injections of 200 mg CZP to maintain the study blind.
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    Certolizumab pegol
    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 400 mg every 4 Weeks

    Number of subjects in period 1
    Placebo CZP 200 mg Q2W CZP 400 mg Q4W
    Started
    136
    138
    135
    Completed
    120
    128
    120
    Not completed
    16
    10
    15
         AE, unknown type
    -
    -
    1
         Protocol deviation
    -
    1
    -
         Lack of efficacy
    2
    -
    1
         Other reason
    1
    2
    1
         AE, serious fatal
    -
    1
    1
         AE, non-serious non-fatal
    2
    1
    2
         Consent withdrawn by subject
    7
    2
    5
         AE, serious non-fatal
    -
    2
    3
         Lost to follow-up
    4
    1
    1
    Period 2
    Period 2 title
    24-weeks Double-blind Period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Assessor, Carer, Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Matching Placebo to Certolizumab Pegol (CZP) injections from Week 0 to Week 24. Placebo subjects who did not achieve certain predefined response criteria at both Weeks 14 and 16 left the Placebo group and were re-randomized to either CZP 200 mg Q2W or CZP 400 mg Q4W arm on Week 16. After 24 weeks, all subjects were re-randomized to active treatment with CZP 200 mg every two weeks (Q2W) or CZP 400 mg every four weeks (Q4W).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Solution for injection/infusion 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 200 mg Q2W
    Arm description
    Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 200 mg CZP sc every 2 weeks (Q2W) from Week 6 onwards. At every visit, subjects received one injection of 200 mg CZP and one injection of Placebo to maintain the study blind.
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    Certolizumab pegol
    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 400 mg every 4 Weeks

    Arm title
    CZP 400 mg Q4W
    Arm description
    Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 400 mg CZP sc every 4 weeks (Q4W) from Week 8 onwards. Subjects received 2 injections of Placebo every 4 weeks in between the 2 injections of 200 mg CZP to maintain the study blind.
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    Certolizumab pegol
    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 400 mg every 4 Weeks

    Number of subjects in period 2
    Placebo CZP 200 mg Q2W CZP 400 mg Q4W
    Started
    120
    128
    120
    Completed
    113
    123
    114
    Not completed
    7
    5
    6
         Lack of efficacy
    -
    2
    1
         AE, serious fatal
    -
    1
    -
         AE, non-serious non-fatal
    2
    1
    1
         Consent withdrawn by subject
    1
    -
    -
         AE, serious non-fatal
    2
    1
    2
         other
    1
    -
    1
         Lost to follow-up
    1
    -
    1
    Period 3
    Period 3 title
    Open-Label Period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Matching Placebo to Certolizumab Pegol (CZP) injections from Week 0 to Week 24. Placebo subjects who did not achieve certain predefined response criteria at both Weeks 14 and 16 left the Placebo group and were re-randomized to either CZP 200 mg Q2W or CZP 400 mg Q4W arm on Week 16. After 24 weeks, all subjects were re-randomized to active treatment with CZP 200 mg every two weeks (Q2W) or CZP 400 mg every four weeks (Q4W).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Solution for injection/infusion 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 200 mg Q2W
    Arm description
    Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 200 mg CZP sc every 2 weeks (Q2W) from Week 6 onwards. At every visit, subjects received one injection of 200 mg CZP and one injection of Placebo to maintain the study blind.
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    Certolizumab pegol
    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 400 mg every 4 Weeks

    Arm title
    CZP 400 mg Q4W
    Arm description
    Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 400 mg CZP sc every 4 weeks (Q4W) from Week 8 onwards. Subjects received 2 injections of Placebo every 4 weeks in between the 2 injections of 200 mg CZP to maintain the study blind.
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    Certolizumab pegol
    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 400 mg every 4 Weeks

    Number of subjects in period 3 [1]
    Placebo CZP 200 mg Q2W CZP 400 mg Q4W
    Started
    111
    121
    114
    Completed
    81
    97
    86
    Not completed
    30
    24
    28
         Protocol deviation
    2
    1
    -
         AE, non-serious unknown
    1
    -
    -
         Lack of efficacy
    4
    2
    3
         AE, serious fatal
    2
    -
    1
         SAE, non-fatal+AE, non-serious non-fatal
    -
    1
    -
         AE, non-serious non-fatal
    6
    4
    4
         Consent withdrawn by subject
    13
    8
    10
         AE, serious non-fatal
    1
    3
    4
         other
    1
    1
    4
         Lost to follow-up
    -
    4
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 4 subjects completed the Dose-Blind Period and then withdrew from the study rather than entering the Open-Label Period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Matching Placebo to Certolizumab Pegol (CZP) injections from Week 0 to Week 24. Placebo subjects who did not achieve certain predefined response criteria at both Weeks 14 and 16 left the Placebo group and were re-randomized to either CZP 200 mg Q2W or CZP 400 mg Q4W arm on Week 16. After 24 weeks, all subjects were re-randomized to active treatment with CZP 200 mg every two weeks (Q2W) or CZP 400 mg every four weeks (Q4W).

    Reporting group title
    CZP 200 mg Q2W
    Reporting group description
    Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 200 mg CZP sc every 2 weeks (Q2W) from Week 6 onwards. At every visit, subjects received one injection of 200 mg CZP and one injection of Placebo to maintain the study blind.

    Reporting group title
    CZP 400 mg Q4W
    Reporting group description
    Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 400 mg CZP sc every 4 weeks (Q4W) from Week 8 onwards. Subjects received 2 injections of Placebo every 4 weeks in between the 2 injections of 200 mg CZP to maintain the study blind.

    Reporting group values
    Placebo CZP 200 mg Q2W CZP 400 mg Q4W Total
    Number of subjects
    136 138 135 409
    Age Categorical
    Units: Subjects
        <=18 years
    0 0 0 0
        Between 18 and 65 years
    129 126 128 383
        >=65 years
    7 12 7 26
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    47.3 ± 11.1 48.2 ± 12.3 47.1 ± 10.8 -
    Gender Categorical
    Units: Subjects
        Female
    79 74 73 226
        Male
    57 64 62 183

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Matching Placebo to Certolizumab Pegol (CZP) injections from Week 0 to Week 24. Placebo subjects who did not achieve certain predefined response criteria at both Weeks 14 and 16 left the Placebo group and were re-randomized to either CZP 200 mg Q2W or CZP 400 mg Q4W arm on Week 16. After 24 weeks, all subjects were re-randomized to active treatment with CZP 200 mg every two weeks (Q2W) or CZP 400 mg every four weeks (Q4W).

    Reporting group title
    CZP 200 mg Q2W
    Reporting group description
    Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 200 mg CZP sc every 2 weeks (Q2W) from Week 6 onwards. At every visit, subjects received one injection of 200 mg CZP and one injection of Placebo to maintain the study blind.

    Reporting group title
    CZP 400 mg Q4W
    Reporting group description
    Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 400 mg CZP sc every 4 weeks (Q4W) from Week 8 onwards. Subjects received 2 injections of Placebo every 4 weeks in between the 2 injections of 200 mg CZP to maintain the study blind.
    Reporting group title
    Placebo
    Reporting group description
    Matching Placebo to Certolizumab Pegol (CZP) injections from Week 0 to Week 24. Placebo subjects who did not achieve certain predefined response criteria at both Weeks 14 and 16 left the Placebo group and were re-randomized to either CZP 200 mg Q2W or CZP 400 mg Q4W arm on Week 16. After 24 weeks, all subjects were re-randomized to active treatment with CZP 200 mg every two weeks (Q2W) or CZP 400 mg every four weeks (Q4W).

    Reporting group title
    CZP 200 mg Q2W
    Reporting group description
    Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 200 mg CZP sc every 2 weeks (Q2W) from Week 6 onwards. At every visit, subjects received one injection of 200 mg CZP and one injection of Placebo to maintain the study blind.

    Reporting group title
    CZP 400 mg Q4W
    Reporting group description
    Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 400 mg CZP sc every 4 weeks (Q4W) from Week 8 onwards. Subjects received 2 injections of Placebo every 4 weeks in between the 2 injections of 200 mg CZP to maintain the study blind.
    Reporting group title
    Placebo
    Reporting group description
    Matching Placebo to Certolizumab Pegol (CZP) injections from Week 0 to Week 24. Placebo subjects who did not achieve certain predefined response criteria at both Weeks 14 and 16 left the Placebo group and were re-randomized to either CZP 200 mg Q2W or CZP 400 mg Q4W arm on Week 16. After 24 weeks, all subjects were re-randomized to active treatment with CZP 200 mg every two weeks (Q2W) or CZP 400 mg every four weeks (Q4W).

    Reporting group title
    CZP 200 mg Q2W
    Reporting group description
    Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 200 mg CZP sc every 2 weeks (Q2W) from Week 6 onwards. At every visit, subjects received one injection of 200 mg CZP and one injection of Placebo to maintain the study blind.

    Reporting group title
    CZP 400 mg Q4W
    Reporting group description
    Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 400 mg CZP sc every 4 weeks (Q4W) from Week 8 onwards. Subjects received 2 injections of Placebo every 4 weeks in between the 2 injections of 200 mg CZP to maintain the study blind.

    Subject analysis set title
    All CZP 200 mg Q2W
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    This arm includes all subjects who were randomized to CZP 200 mg Q2W at Baseline and those subjects who escaped or were re-randomized from Placebo to CZP 200 mg Q2W. Subjects received one injection of 200 mg CZP and one injection of Placebo every two weeks to maintain the study blind.

    Subject analysis set title
    All CZP 400 mg Q4W
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    This arm includes all subjects who were randomized to CZP 400 mg Q4W at Baseline and those subjects who escaped or were re-randomized from Placebo to CZP 400 mg Q4W. Subjects received two injections of Placebo every four weeks in between the two injections of 200 mg CZP to maintain the study blind.

    Subject analysis set title
    All CZP 200 mg + 400 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    This arm shows all patients treated with Certolizumab Pegol (CZP) at least once. Hence, this arm is a combination of arm All CZP 200 mg Q2W and arm All CZP 400 mg Q4W.

    Subject analysis set title
    Placebo (Randomized Set)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Matching Placebo to Certolizumab Pegol (CZP) injections from Week 0 to Week 24. Placebo subjects who did not achieve certain predefined response criteria at both Weeks 14 and 16 left the Placebo group and were re-randomized to either CZP 200 mg Q2W or CZP 400 mg Q4W arm on Week 16. After 24 weeks, all subjects were re-randomized to active treatment with CZP 200 mg every two weeks (Q2W) or CZP 400 mg every four weeks (Q4W).

    Subject analysis set title
    CZP 200 mg Q2W (Randomized Set)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 200 mg CZP sc every 2 weeks (Q2W) from Week 6 onwards. At every visit, subjects received one injection of 200 mg CZP and one injection of Placebo to maintain the study blind.

    Subject analysis set title
    CZP 400 mg Q4W (Randomized Set)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 400 mg CZP sc every 4 weeks (Q4W) from Week 8 onwards. Subjects received 2 injections of Placebo every 4 weeks in between the 2 injections of 200 mg CZP to maintain the study blind.

    Subject analysis set title
    CZP 200 mg Q2W and CZP 400 mg Q4W (Randomized Set)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    This combined group includes subjects of the two treatment arms CZP 200 mg Q2W and CZP 400 mg Q4W used in some analyses. Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 200 mg CZP sc every 2 weeks (Q2W)/ 400 mg CZP sc every 4 weeks (Q4W) from Week 6/ Week 8 onwards. Subjects in both CZP arms received additional placebo injections to maintain the study blind.

    Primary: American College of Rheumatology 20 (ACR20) response at Week 12

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    End point title
    American College of Rheumatology 20 (ACR20) response at Week 12
    End point description
    ACR20 responders are those subjects with at least 20 % improvement from Baseline for Tender Joint Count (TJC), Swollen Joint Count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS).
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    Placebo (Randomized Set) CZP 200 mg Q2W (Randomized Set) CZP 400 mg Q4W (Randomized Set)
    Number of subjects analysed
    136
    138
    135
    Units: percentage of participants
    number (confidence interval 95%)
        Percentage of participants
    24.3 (17.1 to 31.5)
    58 (49.7 to 66.2)
    51.9 (43.4 to 60.3)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    A hierarchical test procedure was applied to protect the overall significance level for the multiplicity of dose groups and endpoints. Conditional on the first test being significant, the second hypothesis was tested with the same alpha level of 5 %. Statistical testing for the following hypotheses was performed only if the previous null hypothesis in the hierarchy was rejected.
    Comparison groups
    Placebo (Randomized Set) v CZP 200 mg Q2W (Randomized Set)
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.001 [1]
    Method
    Wald-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    33.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    22.8
         upper limit
    44.6
    Notes
    [1] - Difference of Certolizumab Pegol 200 mg versus Placebo (and corresponding 95 % Confidence Interval and p-value) were estimated using a standard two-sided Wald asymptotic test with a 5 % alpha level.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    A hierarchical test procedure was applied to protect the overall significance level for the multiplicity of dose groups and endpoints. Conditional on the first test being significant, the second hypothesis was tested with the same alpha level of 5 %. Statistical testing for the following hypotheses was performed only if the previous null hypothesis in the hierarchy was rejected.
    Comparison groups
    Placebo (Randomized Set) v CZP 400 mg Q4W (Randomized Set)
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.001 [2]
    Method
    Wald-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    27.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    16.5
         upper limit
    38.7
    Notes
    [2] - Difference of Certolizumab Pegol 400 mg versus Placebo (and corresponding 95 % Confidence Interval and p-value) were estimated using a standard two-sided Wald asymptotic test with a 5 % alpha level.

    Primary: Change from Baseline in modified Total Sharp Score (mTSS) in modification for Psoriatic Arthritis at Week 24

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    End point title
    Change from Baseline in modified Total Sharp Score (mTSS) in modification for Psoriatic Arthritis at Week 24
    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. mTSS (bone erosions) ranges from 0 (best possible outcome) to 320 (worst possible outcome); mTSS (joint space narrowing) ranges from 0 (best possible outcome) to 208 (worst possible outcome); and total score ranges from 0 (best possible outcome) to 528 (worst possible outcome). For the pre-defined analysis of this outcome measure, 0 was used for Baseline and the maximum observed mTSS value was used for Week 24 for those subjects which had less than 2 radiographs. The re-analysis is restricted to those subjects in the Randomized Set who have at least 2 x-ray values at scheduled visits, which are at least 8 weeks apart.
    End point type
    Primary
    End point timeframe
    From Baseline to Week 24
    End point values
    Placebo (Randomized Set) CZP 200 mg Q2W (Randomized Set) CZP 400 mg Q4W (Randomized Set) CZP 200 mg Q2W and CZP 400 mg Q4W (Randomized Set)
    Number of subjects analysed
    136
    138
    135
    273
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Pre-defined results
    28.92 (13.73 to 44.11)
    11.52 (-3.4 to 26.45)
    25.05 (9.48 to 40.61)
    18.28 (6.34 to 30.23)
        Re-analysis results ( n = 123, 130, 123, 253)
    0.18 (0.04 to 0.33)
    -0.02 (-0.16 to 0.11)
    0.09 (-0.05 to 0.23)
    0.03 (-0.08 to 0.14)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    A hierarchical test procedure was applied to protect the overall significance level for the multiplicity of dose groups and endpoints. Conditional on the first test being significant, the second hypothesis was tested with the same alpha level of 5 %. Statistical testing for the following hypotheses was performed only if the previous null hypothesis in the hierarchy was rejected. This is the pre-defined primary analysis.
    Comparison groups
    Placebo (Randomized Set) v CZP 200 mg Q2W and CZP 400 mg Q4W (Randomized Set)
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.203 [3]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -10.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -27.05
         upper limit
    5.77
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.35
    Notes
    [3] - Difference of CZP 200 mg + 400 mg versus Placebo (and corresponding 95 % Confidence Interval and p-value) were estimated using an ANCOVA model with treatment, region and prior TNF-antagonist exposure as factors and Baseline mTSS score as a covariate.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    A hierarchical test procedure was applied to protect the overall significance level for the multiplicity of dose groups and endpoints. Conditional on the first test being significant, the second hypothesis was tested with the same alpha level of 5 %. Statistical testing for the following hypotheses was performed only if the previous null hypothesis in the hierarchy was rejected.
    Comparison groups
    Placebo (Randomized Set) v CZP 200 mg Q2W (Randomized Set)
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.017 [4]
    Method
    ANCOVA
    Parameter type
    Median difference (net)
    Point estimate
    -0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.38
         upper limit
    -0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.09
    Notes
    [4] - Difference of CZP 200 mg versus Placebo (and corresponding 95 % Confidence Interval and p-value) were estimated using an ANCOVA model with treatment, region and prior TNF-antagonist exposure as factors and Baseline mTSS score as a covariate.

    Secondary: American College of Rheumatology 20 (ACR20) response at Week 24

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    End point title
    American College of Rheumatology 20 (ACR20) response at Week 24
    End point description
    ACR20 responders are those subjects with at least 20 % improvement from Baseline for Tender Joint Count (TJC), Swollen Joint Count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS).
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo (Randomized Set) CZP 200 mg Q2W (Randomized Set) CZP 400 mg Q4W (Randomized Set)
    Number of subjects analysed
    136
    138
    135
    Units: percentage of participants
    number (confidence interval 95%)
        percentage of participants
    23.5 (16.4 to 30.7)
    63.8 (55.7 to 71.8)
    56.3 (47.9 to 64.7)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    A hierarchical test procedure was applied to protect the overall significance level for the multiplicity of dose groups and endpoints. Conditional on the first test being significant, the second hypothesis was tested with the same alpha level of 5 %. Statistical testing for the following hypotheses was performed only if the previous null hypothesis in the hierarchy was rejected.
    Comparison groups
    Placebo (Randomized Set) v CZP 200 mg Q2W (Randomized Set)
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.001 [5]
    Method
    Wald-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    40.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    29.5
         upper limit
    51
    Notes
    [5] - Difference of Certolizumab Pegol 200 mg versus Placebo (and corresponding 95 % Confidence Interval and p-value) were estimated using a standard two-sided Wald asymptotic test with a 5 % alpha level.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    A hierarchical test procedure was applied to protect the overall significance level for the multiplicity of dose groups and endpoints. Conditional on the first test being significant, the second hypothesis was tested with the same alpha level of 5 %. Statistical testing for the following hypotheses was performed only if the previous null hypothesis in the hierarchy was rejected.
    Comparison groups
    Placebo (Randomized Set) v CZP 400 mg Q4W (Randomized Set)
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.001 [6]
    Method
    Wald-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    32.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    21.8
         upper limit
    43.8
    Notes
    [6] - Difference of Certolizumab Pegol 400 mg versus Placebo (and corresponding 95 % Confidence Interval and p-value) were estimated using a standard two-sided Wald asymptotic test with a 5 % alpha level.

    Secondary: Change from Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) at Week 24

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    End point title
    Change from Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) at Week 24
    End point description
    The HAQ-DI is a measure of function in Arthritis. There are 20 items in eight categories that represent a comprehensive set of functional activities on a scale from 0 (without difficulty) to 3 (unable to perform without assistance). The category scores are averaged into an overall HAQ-DI from 0 to 3. Scores of 0 to 1 generally represent mild to moderate difficulty, 1 to 2 represent moderate to severe disability, and 2 to 3 indicate severe to very severe disability. A negative value in HAQ-DI change from Baseline indicates an improvement from Baseline. The higher the negative value, the higher the improvement.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    Placebo (Randomized Set) CZP 200 mg Q2W (Randomized Set) CZP 400 mg Q4W (Randomized Set) CZP 200 mg Q2W and CZP 400 mg Q4W (Randomized Set)
    Number of subjects analysed
    136
    138
    135
    273
    Units: units on a scale
    least squares mean (confidence interval 95%)
        units on a scale
    -0.19 (-0.29 to -0.09)
    -0.54 (-0.64 to -0.44)
    -0.46 (-0.56 to -0.36)
    -0.5 (-0.58 to -0.42)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    A hierarchical test procedure was applied to protect the overall significance level for the multiplicity of dose groups and endpoints. Conditional on the first test being significant, the second hypothesis was tested with the same alpha level of 5 %. Statistical testing for the following hypotheses was performed only if the previous null hypothesis in the hierarchy was rejected.
    Comparison groups
    Placebo (Randomized Set) v CZP 200 mg Q2W and CZP 400 mg Q4W (Randomized Set)
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.001 [7]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.42
         upper limit
    -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Notes
    [7] - Difference of CZP 200 mg + 400 mg vs. Placebo (and corresponding 95 % Confidence Interval and pvalue) were estimated using an ANCOVA model with treatment, region and prior TNF-antagonist exposure as factors and Baseline HAQ-DI score as a covariate.

    Secondary: Psoriasis Area Severity Index (PASI75) response at Week 24 in the subgroup of subjects with Psoriasis (PSO) involving at least 3 % Body Surface Area (BSA) at Baseline

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    End point title
    Psoriasis Area Severity Index (PASI75) response at Week 24 in the subgroup of subjects with Psoriasis (PSO) involving at least 3 % Body Surface Area (BSA) at Baseline
    End point description
    The PASI75 response assessments are based on at least 75 % improvement in the PASI score from Baseline. The PASI score is a measure of the average redness, thickness, and scaliness of the psoriatic skin lesions (each graded on a 0 to 4 scale), weighted by the area of involvement.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo (Randomized Set) CZP 200 mg Q2W (Randomized Set) CZP 400 mg Q4W (Randomized Set) CZP 200 mg Q2W and CZP 400 mg Q4W (Randomized Set)
    Number of subjects analysed
    86
    90
    76
    166
    Units: percentage of participants
    number (confidence interval 95%)
        percentage of participants
    15.1 (7.5 to 22.7)
    62.2 (52.2 to 72.2)
    60.5 (49.5 to 71.5)
    61.4 (54 to 68.8)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    A hierarchical test procedure was applied to protect the overall significance level for the multiplicity of dose groups and endpoints. Conditional on the first test being significant, the second hypothesis was tested with the same alpha level of 5 %. Statistical testing for the following hypotheses was performed only if the previous null hypothesis in the hierarchy was rejected.
    Comparison groups
    Placebo (Randomized Set) v CZP 200 mg Q2W and CZP 400 mg Q4W (Randomized Set)
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.001 [8]
    Method
    Wald-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    46.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    35.7
         upper limit
    56.9
    Notes
    [8] - Difference of Certolizumab Pegol 200 mg + 400 mg versus Placebo (and corresponding 95 % Confidence Interval and p-value) were estimated using a standard two-sided Wald asymptotic test with a 5 % alpha level.

    Secondary: Change From Baseline in Modified Total Sharp Score (mTSS) at Week 48

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    End point title
    Change From Baseline in Modified Total Sharp Score (mTSS) at Week 48
    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. mTSS (bone erosions) ranges from 0 (best possible outcome) to 320 (worst possible outcome); mTSS (joint space narrowing) ranges from 0 (best possible outcome) to 208 (worst possible outcome); and total score ranges from 0 (best possible outcome) to 528 (worst possible outcome). For the analysis of this outcome measure, the change from Baseline to Week 48 was imputed using the median change from Baseline among all subjects for those subjects, which had less than 2 radiographs. The post-hoc analysis presented here is based on the subgroup of subjects which had a Baseline mTSS value greater than 6.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 48
    End point values
    Placebo (Randomized Set) CZP 200 mg Q2W (Randomized Set) CZP 400 mg Q4W (Randomized Set) CZP 200 mg Q2W and CZP 400 mg Q4W (Randomized Set)
    Number of subjects analysed
    136
    138
    135
    273
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Predefined results: Overall
    0.32 (0.1 to 0.55)
    0.15 (-0.07 to 0.37)
    0.11 (-0.12 to 0.34)
    0.13 (-0.05 to 0.31)
        Post-hoc results: Basel. mTSS > 6 (n=61,65,65,130)
    0.78 (0.31 to 1.25)
    0.31 (-0.15 to 0.77)
    0.22 (-0.24 to 0.67)
    0.26 (-0.09 to 0.62)
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    A hierarchical test procedure was applied to protect the overall significance level for the multiplicity of dose groups and endpoints. Conditional on the first test being significant, the second hypothesis was tested with the same alpha level of 5 %. Statistical testing for the following hypotheses was performed only if the previous null hypothesis in the hierarchy was rejected. This is the predefined analysis.
    Comparison groups
    Placebo (Randomized Set) v CZP 200 mg Q2W and CZP 400 mg Q4W (Randomized Set)
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.127 [9]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.43
         upper limit
    0.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Notes
    [9] - Difference of CZP 200 mg + 400 mg versus Placebo (and corresponding 95 % Confidence Interval and p-value) were estimated using an ANCOVA model with treatment, region and prior TNF-antagonist exposure as factors and Baseline mTSS score as a covariate.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    A hierarchical test procedure was applied to protect the overall significance level for the multiplicity of dose groups and endpoints. Conditional on the first test being significant, the second hypothesis was tested with the same alpha level of 5 %. Statistical testing for the following hypotheses was performed only if the previous null hypothesis in the hierarchy was rejected. This is the post-hoc analysis for the subgroup 'Baseline mTSS > 6'.
    Comparison groups
    Placebo (Randomized Set) v CZP 200 mg Q2W and CZP 400 mg Q4W (Randomized Set)
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.048 [10]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.04
         upper limit
    -0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.26
    Notes
    [10] - Difference of CZP 200 mg + 400 mg versus Placebo (and corresponding 95 % Confidence Interval and p-value) were estimated using an ANCOVA model with treatment, region and prior TNF-antagonist exposure as factors and Baseline mTSS score as a covariate.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were collected from Baseline (Week 0) over the whole Double-Blind, Dose-Blind and Open-Label Period.
    Adverse event reporting additional description
    PBO arm subjects shifted either at Wk 16 or 24 to CZP treatment. Thus, PBO arm had lower exposure compared to the CZP arms. The exposure imbalance across treatment arms could lead to misinterpretation & questionable conclusions comparing simple counts & percentages of AEs. Thus, AEs reported while the patient was on PBO-treatment are not included.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    All CZP 200 mg Q2W
    Reporting group description
    This arm includes all subjects who were randomized to CZP 200 mg Q2W at Baseline and those subjects who escaped or were re-randomized from Placebo to CZP 200 mg Q2W. Subjects received one injection of 200 mg CZP and one injection of Placebo every two weeks to maintain the study blind.

    Reporting group title
    All CZP 200 mg + 400 mg
    Reporting group description
    This arm shows all patients treated with Certolizumab Pegol (CZP) at least once. Hence, this arm is a combination of arm All CZP 200 mg Q2W and arm All CZP 400 mg Q4W.

    Reporting group title
    All CZP 400 mg Q4W
    Reporting group description
    This arm includes all subjects who were randomized to CZP 400 mg Q4W at Baseline and those subjects who escaped or were re-randomized from Placebo to CZP 400 mg Q4W. Subjects received two injections of Placebo every four weeks in between the two injections of 200 mg CZP to maintain the study blind.

    Serious adverse events
    All CZP 200 mg Q2W All CZP 200 mg + 400 mg All CZP 400 mg Q4W
    Total subjects affected by serious adverse events
         subjects affected / exposed
    49 / 198 (24.75%)
    100 / 393 (25.45%)
    51 / 195 (26.15%)
         number of deaths (all causes)
    3
    6
    3
         number of deaths resulting from adverse events
    0
    2
    2
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 198 (0.51%)
    2 / 393 (0.51%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hip arthroplasty
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 198 (0.51%)
    3 / 393 (0.76%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Gastrointestinal cancer metastatic
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    Ovarian cancer
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign neoplasm of thyroid gland
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Pregnancy of partner
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy on contraceptive
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden death
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Pyrexia
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar I disorder
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute stress disorder
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post-traumatic stress disorder
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Metrorrhagia
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Genital prolapse
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    0 / 198 (0.00%)
    2 / 393 (0.51%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vulvar dysplasia
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Synovial rupture
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 198 (0.00%)
    2 / 393 (0.51%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Animal bite
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anastomotic complication
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery thrombosis
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 198 (0.51%)
    2 / 393 (0.51%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 198 (1.01%)
    2 / 393 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 198 (0.51%)
    2 / 393 (0.51%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 198 (1.52%)
    3 / 393 (0.76%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Splenomegaly
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 198 (0.51%)
    2 / 393 (0.51%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysgraphia
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Formication
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paralysis
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia oral
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal cyst
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    0 / 198 (0.00%)
    2 / 393 (0.51%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 198 (0.51%)
    3 / 393 (0.76%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 198 (0.00%)
    2 / 393 (0.51%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary dyskinesia
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cutaneous lupus erythematosus
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    3 / 198 (1.52%)
    4 / 393 (1.02%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    2 / 198 (1.01%)
    3 / 393 (0.76%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    0 / 198 (0.00%)
    2 / 393 (0.51%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lupus-like syndrome
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 198 (0.51%)
    4 / 393 (1.02%)
    3 / 195 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psoriatic arthropathy
         subjects affected / exposed
    5 / 198 (2.53%)
    8 / 393 (2.04%)
    3 / 195 (1.54%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 12
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obesity
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 198 (1.01%)
    2 / 393 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 198 (0.51%)
    4 / 393 (1.02%)
    3 / 195 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 5
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    Bronchitis
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HIV infection
         subjects affected / exposed
    1 / 198 (0.51%)
    2 / 393 (0.51%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    Staphylococcal abscess
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    2 / 198 (1.01%)
    2 / 393 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyoderma streptococcal
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Latent tuberculosis
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 198 (0.51%)
    2 / 393 (0.51%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic tonsillitis
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 198 (0.51%)
    3 / 393 (0.76%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 393 (0.25%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 393 (0.25%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    All CZP 200 mg Q2W All CZP 200 mg + 400 mg All CZP 400 mg Q4W
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    158 / 198 (79.80%)
    311 / 393 (79.13%)
    153 / 195 (78.46%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    30 / 198 (15.15%)
    46 / 393 (11.70%)
    16 / 195 (8.21%)
         occurrences all number
    33
    53
    20
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    15 / 198 (7.58%)
    24 / 393 (6.11%)
    9 / 195 (4.62%)
         occurrences all number
    21
    31
    10
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    17 / 198 (8.59%)
    32 / 393 (8.14%)
    15 / 195 (7.69%)
         occurrences all number
    23
    48
    25
    Blood creatine phosphokinase increased
         subjects affected / exposed
    15 / 198 (7.58%)
    28 / 393 (7.12%)
    13 / 195 (6.67%)
         occurrences all number
    28
    53
    25
    Aspartate aminotransferase increased
         subjects affected / exposed
    9 / 198 (4.55%)
    20 / 393 (5.09%)
    11 / 195 (5.64%)
         occurrences all number
    13
    30
    17
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    8 / 198 (4.04%)
    20 / 393 (5.09%)
    12 / 195 (6.15%)
         occurrences all number
    11
    26
    15
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 198 (4.04%)
    22 / 393 (5.60%)
    14 / 195 (7.18%)
         occurrences all number
    9
    23
    14
    Oropharyngeal pain
         subjects affected / exposed
    6 / 198 (3.03%)
    16 / 393 (4.07%)
    10 / 195 (5.13%)
         occurrences all number
    6
    19
    13
    Nervous system disorders
    Headache
         subjects affected / exposed
    18 / 198 (9.09%)
    35 / 393 (8.91%)
    17 / 195 (8.72%)
         occurrences all number
    19
    39
    20
    Dizziness
         subjects affected / exposed
    5 / 198 (2.53%)
    15 / 393 (3.82%)
    10 / 195 (5.13%)
         occurrences all number
    5
    15
    10
    Psychiatric disorders
    Depression
         subjects affected / exposed
    11 / 198 (5.56%)
    20 / 393 (5.09%)
    9 / 195 (4.62%)
         occurrences all number
    12
    24
    12
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    15 / 198 (7.58%)
    26 / 393 (6.62%)
    11 / 195 (5.64%)
         occurrences all number
    20
    35
    15
    Abdominal pain
         subjects affected / exposed
    12 / 198 (6.06%)
    21 / 393 (5.34%)
    9 / 195 (4.62%)
         occurrences all number
    13
    23
    10
    Abdominal pain upper
         subjects affected / exposed
    14 / 198 (7.07%)
    19 / 393 (4.83%)
    5 / 195 (2.56%)
         occurrences all number
    16
    25
    9
    Nausea
         subjects affected / exposed
    10 / 198 (5.05%)
    18 / 393 (4.58%)
    8 / 195 (4.10%)
         occurrences all number
    11
    20
    9
    Skin and subcutaneous tissue disorders
    Psoriasis
         subjects affected / exposed
    22 / 198 (11.11%)
    41 / 393 (10.43%)
    19 / 195 (9.74%)
         occurrences all number
    31
    52
    21
    Rash
         subjects affected / exposed
    10 / 198 (5.05%)
    19 / 393 (4.83%)
    9 / 195 (4.62%)
         occurrences all number
    16
    25
    9
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    24 / 198 (12.12%)
    46 / 393 (11.70%)
    22 / 195 (11.28%)
         occurrences all number
    28
    54
    26
    Psoriatic arthropathy
         subjects affected / exposed
    24 / 198 (12.12%)
    39 / 393 (9.92%)
    15 / 195 (7.69%)
         occurrences all number
    41
    64
    23
    Arthralgia
         subjects affected / exposed
    20 / 198 (10.10%)
    38 / 393 (9.67%)
    18 / 195 (9.23%)
         occurrences all number
    28
    56
    28
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    44 / 198 (22.22%)
    93 / 393 (23.66%)
    49 / 195 (25.13%)
         occurrences all number
    81
    154
    73
    Nasopharyngitis
         subjects affected / exposed
    45 / 198 (22.73%)
    87 / 393 (22.14%)
    42 / 195 (21.54%)
         occurrences all number
    87
    178
    91
    Pharyngitis
         subjects affected / exposed
    24 / 198 (12.12%)
    51 / 393 (12.98%)
    27 / 195 (13.85%)
         occurrences all number
    44
    81
    37
    Urinary tract infection
         subjects affected / exposed
    13 / 198 (6.57%)
    39 / 393 (9.92%)
    26 / 195 (13.33%)
         occurrences all number
    18
    53
    35
    Bronchitis
         subjects affected / exposed
    28 / 198 (14.14%)
    50 / 393 (12.72%)
    22 / 195 (11.28%)
         occurrences all number
    36
    65
    29
    Sinusitis
         subjects affected / exposed
    19 / 198 (9.60%)
    32 / 393 (8.14%)
    13 / 195 (6.67%)
         occurrences all number
    32
    65
    33
    Gastroenteritis
         subjects affected / exposed
    14 / 198 (7.07%)
    22 / 393 (5.60%)
    8 / 195 (4.10%)
         occurrences all number
    18
    26
    8
    Oral herpes
         subjects affected / exposed
    10 / 198 (5.05%)
    21 / 393 (5.34%)
    11 / 195 (5.64%)
         occurrences all number
    25
    43
    18
    Influenza
         subjects affected / exposed
    13 / 198 (6.57%)
    21 / 393 (5.34%)
    8 / 195 (4.10%)
         occurrences all number
    15
    24
    9
    Tonsillitis
         subjects affected / exposed
    11 / 198 (5.56%)
    19 / 393 (4.83%)
    8 / 195 (4.10%)
         occurrences all number
    11
    23
    12
    Rhinitis
         subjects affected / exposed
    10 / 198 (5.05%)
    19 / 393 (4.83%)
    9 / 195 (4.62%)
         occurrences all number
    11
    20
    9
    Latent tuberculosis
         subjects affected / exposed
    6 / 198 (3.03%)
    18 / 393 (4.58%)
    12 / 195 (6.15%)
         occurrences all number
    6
    18
    12
    Viral infection
         subjects affected / exposed
    9 / 198 (4.55%)
    16 / 393 (4.07%)
    7 / 195 (3.59%)
         occurrences all number
    12
    19
    7

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Nov 2009
    The protocol was amended to adapt to the most recent scientific developments in the field. In addition, the Sponsor Study Physician information was updated, a few typographical errors were corrected, and some clarifications were made to the protocol text. The original final PsA001 protocol (25 Sep 2009) was approved internally by the Sponsor; however, Protocol Amendment 1 (23 Nov 2009) was the first version of the protocol to be submitted to any regulatory health authority. The following changes were made throughout the protocol: - The Sponsor Study Physician information was updated - The Classification Criteria for Psoriatic Arthritis (CASPAR) were added to the inclusion criteria - Leflunomide was added to the list of allowed DMARDs, and hydroxychloroquine (HCQ) and DMARD combinations were now prohibited - The effect of CZP on axial involvement in a subgroup of affected subjects (BASDAI ≥4) at Baseline was added as another secondary objective - Measurement of human leukocyte antigen B27 (HLA-B27) at Baseline was included - Permission was given for samples collected for measurement of CZP plasma concentration to be possibly used for exploratory biomarker (Dickkopf-related protein 1 [DKK1] and sclerostin) research - The swollen joint count and tender joint count assessments were changed from the 76/78 joints to the 66/68 joints evaluation - Clarification that assessment of arthritis should include consideration of both joint and skin components in both the Patient’s and Physician’s Global Assessments of Disease Activity (PtGADA and PhGADA, respectively) was added - Clarification that the PhGADA (Likert Scale) was to be used only for the Psoriatic Arthritis Response Criteria (PsARC) assessment was added - Clarification that PsA history included relevant family history and prior and concomitant medication history was added
    21 Apr 2010
    The following changes were made throughout the protocol: - FAS was replaced by the RS for the primary efficacy analyses. - The SAP was adjusted for multiple endpoints. A hierarchical test procedure was applied to protect the overall significance level of the multiplicity of dose groups and endpoints with a predefined order of hypotheses testing. - Assessment of subjects with a PhGAP rating of “clear” or “almost clear” was added as a secondary endpoint to evaluate psoriatic skin lesions. - The specification that vital signs were to be performed within 15 minutes prior to dosing was removed. - A definition of PASI assessments was added. Clarification was added that the dactylitis assessment was to be performed using the LDI basic according to Healy and Helliwell (2007) and Helliwell et al (2005). - Clarification was added that the enthesitis assessment was to be performed on the elbows, knees, and heels. - Description of the mNAPSI assessment was modified in accordance with Cassell et al, 2007. - Clarification was added that abatacept (ABA) was both a prohibited medication (if used within 3 months prior to BL) and a prohibited concomitant and and rescue treatment. - For tuberculosis (TB) testing, inconsistencies in visit referencing (eg, BL) with regards to purified protein derivative (PPD) tests were corrected to reference the Screening Visit. - Clarification that the cited liver function tests >2x ULN, creatinine>ULN, or white blood cells (WBCs) <3.0x109/L represent examples of clinically significant laboratory abnormalities, which would exclude subject entry into the study, was added to the appropriate exclusion criterion. - Clarification was added that 1 rescreening of subjects with latent TB who were unable to complete a minimum of 4 weeks of TB therapy within the Screening Period was permitted. - Clarification was added that if the Elispot was neg. at Screening, it would be repeated at W48 and W96 for subjects with a previously negative Elispot test result
    22 Nov 2010
    The protocol was amended to increase the approximate number of centers participating in this study and the approximate number of subjects who would be screened because of a higher than expected screen failure rate. In addition, Sponsor personnel and the corresponding contact information were updated. Administrative changes for internal consistency were also implemented. The following changes were made throughout the protocol: - The approximate number of subjects who were to be screened was increased from 500 to 700 - The approximate number of centers participating in the study was increased from 100 to 130 - Based on previous feedback from the FDA, all randomized subjects must be used for primary analysis; therefore, the statement that 375 subjects would be available for the primary efficacy analyses was deleted
    30 Jan 2012
    The protocol was amended to comply with new FDA Safety Reporting Requirements (Food and Drug Administration, Guidance for Industry, 2010) and the corresponding change to the UCB Protocol Template, language was added to the Assessment of Safety Section to clarify procedures for reporting relatedness of an serious adverse event (SAE) and to define anticipated SAEs. In addition, the name of the Sponsor, Sponsor personnel, and the corresponding contact information were updated. Administrative changes for internal consistency were also implemented. The following changes were made throughout the protocol: - For the assessment of socioprofessional status, housing status of the subject was not obtained by site personnel - Additional guidance to Investigators was provided for including the casual relationship of study medication between an SAE and study medication when completing the SAE report form - Anticipated SAEs were identified
    25 Jan 2013
    The protocol was amended to implement the extension of the Open-Label Treatment Period for an additional 58 weeks. The following changes were made throughout the protocol: - A new Clinical Project Manager was identified. - Wording regarding the extension of the Open-Label Treatment Period, additional BSA assessments, and new TB standards were added. - The list of biomarkers that may have been analyzed was updated. - Visit scheduling of Week 158 (Completion/Withdrawal Visit) was shifted to Week 216 and the last dosing visit of Week 156 was changed to occur at Week 214 for the 200mg Q2W regimen and Week 212 for the 400mg Q4W regimen. The regular last site visit and the final evaluation visit were combined to reduce the amount of investigations and visits. - Chest x-ray was requested additionally at Week 156 and at the Completion Visit Week 216/ Withdrawal. - Hand and foot x-rays were added at Week 168 and at Withdrawal Visit if hand and foot x-ray was performed more than 8 weeks prior to Withdrawal Visit. - Assessment of BSA und PASI for all subjects at Weeks 156, 168, 180, 192, 204, and 216/ Withdrawal. - PPD and interferon-gamma release assay (IGRA) tests were requested additionally at Weeks 48, 96, 156, and Week 216/ Withdrawal. - Definition of minimal disease activity was added. - The adverse event (AE) of interest section was updated to be consistent with current reporting requirements.

    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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