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    Clinical Trial Results:
    Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Efficacy and Safety of Certolizumab Pegol in Subjects With Active Axial Spondyloarthritis

    Summary
    EudraCT number
    2009-011719-19
    Trial protocol
    FR   DE   GB   HU   BE   IT   NL   CZ  
    Global end of trial date
    18 Aug 2015

    Results information
    Results version number
    v2(current)
    This version publication date
    01 Feb 2017
    First version publication date
    02 Sep 2016
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    AS001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01087762
    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
    20 Apr 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to demonstrate the efficacy of CZP administered subcutaneously (sc) at the doses of CZP 200mg Q2W every 2 weeks and CZP 400mg Q4W every 4 weeks after a loading dose of CZP 400mg at Weeks 0, 2, and 4 on the signs and symptoms of active axial spondyloarthritis (axSpA).
    Protection of trial subjects
    During the conduct of the study all subjects were closely monitored.
    Background therapy
    Background therapy was permitted as defined in the study protocol.
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Apr 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
    Spain: 3
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    United States: 71
    Country: Number of subjects enrolled
    Argentina: 18
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Brazil: 6
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    Czech Republic: 39
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Mexico: 9
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 92
    Worldwide total number of subjects
    325
    EEA total number of subjects
    204
    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)
    317
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This is a multicenter study with 128 sites in North America, Latin America, Western Europe, and Central/Eastern Europe. 325 subjects are included in Randomized Set (RS) shown in Participant Flow for the interim period, and 315 for the final analysis (10 subjects dropped out before receiving a CZP dose), which is an Intention-to-Treat (ITT) dataset

    Pre-assignment
    Screening details
    Patients with positive Tuberculosis (TB) tests within Screening Period, but no signs and symptoms of active TB had to be treated with prophylactic TB treatment for at least 4 weeks prior to first study drug administration.

    Period 1
    Period 1 title
    Double Blind Period (Weeks 0-24)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject
    Blinding implementation details
    Double Blind (Weeks 0-24), Dose Blind (Weeks 24-48), Open-Label (Weeks 48-204).

    Arms
    Are arms mutually exclusive
    No

    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 on Week 16. After 24 weeks, all subjects were randomized to active treatment with CZP 200 mg every two weeks (Q2W) or CZP 400 mg every four weeks (Q4W). Placebo : Matching Placebo to CZP injection.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PL
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo administered sc.

    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. Placebo : Matching Placebo to CZP injection. CZP 200 mg Q2W : 200 mg subcutaneous (sc) injection of Certolizumab Pegol (CZP) every 2 weeks (Q2W).
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    CZP administered sc at a dose of 200mg or 400mg.

    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. Placebo : Matching Placebo to CZP injection. CZP 400 mg Q4W : 400 mg subcutaneous (sc) injection of Certolizumab Pegol (CZP) every 4 weeks (Q4W).
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    CZP administered sc at a dose of 200mg or 400mg.

    Number of subjects in period 1
    Placebo CZP 200 mg Q2W CZP 400 mg Q4W
    Started
    107
    111
    107
    Completed
    95
    105
    98
    Not completed
    12
    6
    9
         Protocol deviation
    6
    -
    1
         Lack of efficacy
    2
    -
    3
         SAE, non-fatal
    2
    2
    3
         Consent withdrawn by subject
    1
    2
    1
         Lost to follow-up
    1
    2
    1
    Period 2
    Period 2 title
    Open-Label Period (Weeks 48-204)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Double Blind (Weeks 0-24), Dose Blind (Weeks 24-48), Open-Label (Weeks 48-204).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    All CZP 200 mg
    Arm description
    All subjects who received CZP at the specified dose (200 mg) at some point during the study, including subjects who were originally randomized to receive placebo and were switched to CZP at Week 16 or Week 24. Placebo : Matching Placebo to CZP injection. CZP 200 mg Q2W : 200 mg subcutaneous (sc) injection of Certolizumab Pegol (CZP) every 2 weeks (Q2W).
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    CZP administered sc at a dose of 200mg or 400mg.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PL
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo administered sc.

    Arm title
    All CZP 400 mg
    Arm description
    All subjects who received CZP at the specified dose (400 mg) at some point during the study, including subjects who were originally randomized to receive placebo and were switched to CZP at Week 16 or Week 24. Placebo : Matching Placebo to CZP injection. CZP 400 mg Q4W : 400 mg subcutaneous (sc) injection of Certolizumab Pegol (CZP) every 4 weeks (Q4W).
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    CZP administered sc at a dose of 200mg or 400mg.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PL
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo administered sc.

    Number of subjects in period 2
    All CZP 200 mg All CZP 400 mg
    Started
    158
    157
    Completed
    99
    100
    Not completed
    59
    57
         Protocol deviation
    1
    1
         Lack of efficacy
    4
    14
         SAE, non-fatal
    7
    4
         SAE, non-fatal + AE, non-serious/fatal
    2
    4
         Consent withdrawn by subject
    22
    15
         AE, non-serious non-fatal
    16
    13
         Unspecified
    2
    4
         Lost to follow-up
    5
    2

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    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 on Week 16. After 24 weeks, all subjects were randomized to active treatment with CZP 200 mg every two weeks (Q2W) or CZP 400 mg every four weeks (Q4W). Placebo : Matching Placebo to CZP injection.

    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. Placebo : Matching Placebo to CZP injection. CZP 200 mg Q2W : 200 mg subcutaneous (sc) injection of Certolizumab Pegol (CZP) every 2 weeks (Q2W).

    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. Placebo : Matching Placebo to CZP injection. CZP 400 mg Q4W : 400 mg subcutaneous (sc) injection of Certolizumab Pegol (CZP) every 4 weeks (Q4W).

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Only patients who received at least one dose of CZP were included in the final analysis.
    Reporting group values
    Placebo CZP 200 mg Q2W CZP 400 mg Q4W Total
    Number of subjects
    107 111 107 325
    Age Categorical
    Units: Subjects
        <=18 years
    0 0 0 0
        Between 18 and 65 years
    102 110 105 317
        >=65 years
    5 1 2 8
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    39.9 ± 12.4 39.1 ± 11.9 39.8 ± 39.9 -
    Gender Categorical
    Units: Subjects
        Female
    42 44 39 125
        Male
    65 67 68 200
    Weight
    Units: kilogram (kg)
        arithmetic mean (standard deviation)
    82.142 ± 18.147 79.305 ± 18.599 83.893 ± 18.855 -
    Height
    Units: centimeter (cm)
        arithmetic mean (standard deviation)
    170.704 ± 9.692 171.769 ± 10.171 172.753 ± 9.607 -

    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 on Week 16. After 24 weeks, all subjects were randomized to active treatment with CZP 200 mg every two weeks (Q2W) or CZP 400 mg every four weeks (Q4W). Placebo : Matching Placebo to CZP injection.

    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. Placebo : Matching Placebo to CZP injection. CZP 200 mg Q2W : 200 mg subcutaneous (sc) injection of Certolizumab Pegol (CZP) every 2 weeks (Q2W).

    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. Placebo : Matching Placebo to CZP injection. CZP 400 mg Q4W : 400 mg subcutaneous (sc) injection of Certolizumab Pegol (CZP) every 4 weeks (Q4W).
    Reporting group title
    All CZP 200 mg
    Reporting group description
    All subjects who received CZP at the specified dose (200 mg) at some point during the study, including subjects who were originally randomized to receive placebo and were switched to CZP at Week 16 or Week 24. Placebo : Matching Placebo to CZP injection. CZP 200 mg Q2W : 200 mg subcutaneous (sc) injection of Certolizumab Pegol (CZP) every 2 weeks (Q2W).

    Reporting group title
    All CZP 400 mg
    Reporting group description
    All subjects who received CZP at the specified dose (400 mg) at some point during the study, including subjects who were originally randomized to receive placebo and were switched to CZP at Week 16 or Week 24. Placebo : Matching Placebo to CZP injection. CZP 400 mg Q4W : 400 mg subcutaneous (sc) injection of Certolizumab Pegol (CZP) every 4 weeks (Q4W).

    Subject analysis set title
    Placebo (FAS)
    Subject analysis set type
    Intention-to-treat
    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 on Week 16. After 24 weeks, all subjects were randomized to active treatment with CZP 200 mg every two weeks (Q2W) or CZP 400 mg every four weeks (Q4W). Placebo : Matching Placebo to CZP injection.

    Subject analysis set title
    CZP 200 mg Q2W (FAS)
    Subject analysis set type
    Intention-to-treat
    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. Placebo : Matching Placebo to CZP injection. CZP 200 mg Q2W : 200 mg subcutaneous (sc) injection of Certolizumab Pegol (CZP) every 2 weeks (Q2W).

    Subject analysis set title
    CZP 400 mg Q4W (FAS)
    Subject analysis set type
    Intention-to-treat
    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. Placebo : Matching Placebo to CZP injection. CZP 400 mg Q4W : 400 mg subcutaneous (sc) injection of Certolizumab Pegol (CZP) every 4 weeks (Q4W).

    Subject analysis set title
    CZP 200 mg Q2W and CZP 400 mg Q4W (FAS)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    This arm shows a combination of arm CZP 200 mg Q2W and arm CZP 400 mg Q4W. 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. Placebo : Matching Placebo to CZP injection. CZP 200 mg Q2W : 200 mg subcutaneous (sc) injection of Certolizumab Pegol (CZP) every 2 weeks (Q2W). CZP 400 mg Q4W : 400 mg subcutaneous (sc) injection of Certolizumab Pegol (CZP) every 4 weeks (Q4W).

    Subject analysis set title
    All CZP 200 mg (Safety Analysis)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received CZP at the specified dose (200 mg) at some point during the study, including subjects who were originally randomized to receive placebo and were switched to CZP at Week 16 or Week 24. Placebo : Matching Placebo to CZP injection. CZP 200 mg Q2W : 200 mg subcutaneous (sc) injection of Certolizumab Pegol (CZP) every 2 weeks (Q2W).

    Subject analysis set title
    All CZP 400 mg (Safety Analysis)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received CZP at the specified dose (400 mg) at some point during the study, including subjects who were originally randomized to receive placebo and were switched to CZP at Week 16 or Week 24. Placebo : Matching Placebo to CZP injection. CZP 400 mg Q4W : 400 mg subcutaneous (sc) injection of Certolizumab Pegol (CZP) every 4 weeks (Q4W).

    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 and arm All CZP 400 mg.

    Primary: Assessment in Axial Spondyloarthritis International Society 20 % (ASAS20) response criteria at Week 12

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    End point title
    Assessment in Axial Spondyloarthritis International Society 20 % (ASAS20) response criteria at Week 12
    End point description
    The ASAS20 is defined as an improvement of at least 20 % and absolute improvement of at least 1 unit on a 0 to 10 Numeric Rating Scale (NRS) in at least 3 of the 4 following domains: • Patient's Global Assessment of Disease Activity • Pain assessment (total spinal pain) • Function (represented by Bath Ankylosing Spondylitis Functional Index (BASFI)) • Inflammation (the mean of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) questions 5 and 6 concerning morning stiffness intensity and duration) and absence of deterioration in the potential remaining domain (deterioration is defined as a relative worsening of at least 20 % and an absolute worsening of at least 1 unit).
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    Placebo (FAS) CZP 200 mg Q2W (FAS) CZP 400 mg Q4W (FAS) CZP 200 mg Q2W and CZP 400 mg Q4W (FAS)
    Number of subjects analysed
    107
    111
    107
    218
    Units: percentage of participants
    number (confidence interval 95%)
        Percentage of subjects
    38.3 (29.1 to 47.5)
    57.7 (48.5 to 66.8)
    63.6 (54.4 to 72.7)
    60.6 (54.1 to 67)
    Statistical analysis title
    Difference in efficacy
    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 (FAS) v CZP 200 mg Q2W (FAS)
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004 [1]
    Method
    Wald-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    19.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.3
         upper limit
    32.4
    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
    Difference in efficacy
    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
    CZP 400 mg Q4W (FAS) v Placebo (FAS)
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [2]
    Method
    Wald-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    25.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    12.3
         upper limit
    38.2
    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.

    Secondary: Assessment in Axial Spondyloarthritis International Society 20 % (ASAS20) response criteria at Week 24

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    End point title
    Assessment in Axial Spondyloarthritis International Society 20 % (ASAS20) response criteria at Week 24
    End point description
    The ASAS20 is defined as an improvement of at least 20 % and absolute improvement of at least 1 unit on a 0 to 10 Numeric Rating Scale (NRS) in at least 3 of the 4 following domains: • Patient's Global Assessment of Disease Activity • Pain assessment (total spinal pain) • Function (represented by Bath Ankylosing Spondylitis Functional Index (BASFI)) • Inflammation (the mean of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) questions 5 and 6 concerning morning stiffness intensity and duration) and absence of deterioration in the potential remaining domain (deterioration is defined as a relative worsening of at least 20 % and an absolute worsening of at least 1 unit).
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo (FAS) CZP 200 mg Q2W (FAS) CZP 400 mg Q4W (FAS) CZP 200 mg Q2W and CZP 400 mg Q4W (FAS)
    Number of subjects analysed
    107
    111
    107
    218
    Units: percentage of participants
    number (confidence interval 95%)
        Percentage of subjects
    29 (20.4 to 37.6)
    66.7 (57.9 to 75.4)
    70.1 (61.4 to 78.8)
    68.3 (62.2 to 74.5)
    Statistical analysis title
    Difference in efficacy
    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 (FAS) v CZP 200 mg Q2W (FAS)
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [3]
    Method
    Wald-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    37.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    25.4
         upper limit
    50
    Notes
    [3] - 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
    Difference in efficacy
    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 (FAS) v CZP 400 mg Q4W (FAS)
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [4]
    Method
    Wald-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    41.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    28.9
         upper limit
    53.3
    Notes
    [4] - 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 the Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 12

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    End point title
    Change from Baseline in the Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 12
    End point description
    The BASFI assesses physical function in comprising 10 items relating to activities during the past week. Each item ranges from 0 (“Easy”) to 10 (“Impossible”). The BASFI is the mean of the 10 scores such that the total score ranges from 0 to 10, with lower scores indicating better physical function. A negative value in BASFI change from Baseline indicates an improvement from Baseline. The higher the negative value the better the improvement.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    Placebo (FAS) CZP 200 mg Q2W (FAS) CZP 400 mg Q4W (FAS) CZP 200 mg Q2W and CZP 400 mg Q4W (FAS)
    Number of subjects analysed
    107
    111
    107
    218
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Least square mean
    -0.53 (-0.96 to -0.1)
    -2.01 (-2.48 to -1.55)
    -2.02 (-2.5 to -1.55)
    -2.02 (-2.4 to -1.63)
    Statistical analysis title
    Difference in efficacy
    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
    CZP 200 mg Q2W and CZP 400 mg Q4W (FAS) v Placebo (FAS)
    Number of subjects included in analysis
    325
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [5]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.96
         upper limit
    -1.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.24
    Notes
    [5] - Difference of CZP 200 mg + 400 mg vs. Placebo was estimated using an ANCOVA model with treatment, region, modified New York criteria and prior TNF-antagonist exposure as factors and Baseline BASFI score as a covariate.

    Secondary: Change from Baseline in the Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 24

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    End point title
    Change from Baseline in the Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 24
    End point description
    The BASFI assesses physical function in comprising 10 items relating to activities during the past week. Each item ranges from 0 (“Easy”) to 10 (“Impossible”). The BASFI is the mean of the 10 scores such that the total score ranges from 0 to 10, with lower scores indicating better physical function. A negative value in BASFI change from Baseline indicates an improvement from Baseline. The higher the negative value the better the improvement.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    Placebo (FAS) CZP 200 mg Q2W (FAS) CZP 400 mg Q4W (FAS) CZP 200 mg Q2W and CZP 400 mg Q4W (FAS)
    Number of subjects analysed
    107
    111
    107
    218
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Least square mean
    -0.4 (-0.85 to 0.06)
    -2.36 (-2.85 to -1.87)
    -2.2 (-2.7 to -1.7)
    -2.28 (-2.68 to -1.87)
    Statistical analysis title
    Difference in efficacy
    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 (FAS) v CZP 200 mg Q2W and CZP 400 mg Q4W (FAS)
    Number of subjects included in analysis
    325
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [6]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.38
         upper limit
    -1.38
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.25
    Notes
    [6] - Difference of CZP 200 mg + 400 mg vs. Placebo was estimated using an ANCOVA model with treatment, region, modified New York criteria and prior TNF-antagonist exposure as factors and Baseline BASFI score as a covariate.

    Secondary: Change from Baseline in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at Week 12

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    End point title
    Change from Baseline in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at Week 12
    End point description
    The BASDAI is a validated self-reported instrument which consists of six 10 unit horizontal Numerical Rating Scales (NRSs) to measure severity of fatigue, spinal and peripheral joint pain and swelling, enthesitis, and morning stiffness (both severity and duration, respectively) over the last week. The final BASDAI score ranges from 0 to 10, with lower scores indicating lower disease activity. A negative value in BASDAI change from Baseline indicates an improvement from Baseline. The higher the negative value the better the improvement.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    Placebo (FAS) CZP 200 mg Q2W (FAS) CZP 400 mg Q4W (FAS) CZP 200 mg Q2W and CZP 400 mg Q4W (FAS)
    Number of subjects analysed
    107
    111
    107
    218
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Least square mean
    -1.22 (-1.65 to -0.78)
    -2.82 (-3.29 to -2.35)
    -2.8 (-3.28 to -2.33)
    -2.81 (-3.2 to -2.43)
    Statistical analysis title
    Difference in efficacy
    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 (FAS) v CZP 200 mg Q2W and CZP 400 mg Q4W (FAS)
    Number of subjects included in analysis
    325
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [7]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.07
         upper limit
    -1.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.24
    Notes
    [7] - Difference of CZP 200 mg + 400 mg vs. Placebo was estimated using an ANCOVA model with treatment, region, modified New York criteria and prior TNF-antagonist exposure as factors and Baseline BASDAI score as a covariate.

    Secondary: Change from Baseline in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at Week 24

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    End point title
    Change from Baseline in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at Week 24
    End point description
    The BASDAI is a validated self-reported instrument which consists of six 10 unit horizontal Numerical Rating Scales (NRSs) to measure severity of fatigue, spinal and peripheral joint pain and swelling, enthesitis, and morning stiffness (both severity and duration, respectively) over the last week. The final BASDAI score ranges from 0 to 10, with lower scores indicating lower disease activity. A negative value in BASDAI change from Baseline indicates an improvement from Baseline. The higher the negative value the better the improvement.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    Placebo (FAS) CZP 200 mg Q2W (FAS) CZP 400 mg Q4W (FAS) CZP 200 mg Q2W and CZP 400 mg Q4W (FAS)
    Number of subjects analysed
    107
    111
    107
    218
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Least square mean
    -1.05 (-1.5 to -0.6)
    -3.08 (-3.57 to -2.6)
    -3.01 (-3.5 to -2.52)
    -3.05 (-3.45 to -2.65)
    Statistical analysis title
    Difference in efficacy
    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 (FAS) v CZP 200 mg Q2W and CZP 400 mg Q4W (FAS)
    Number of subjects included in analysis
    325
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [8]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.49
         upper limit
    -1.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.25
    Notes
    [8] - Difference of CZP 200 mg + 400 mg vs. Placebo was estimated using an ANCOVA model with treatment, region, modified New York criteria and prior TNF-antagonist exposure as factors and Baseline BASDAI score as a covariate.

    Secondary: Change from Baseline in the Bath Ankylosing Spondylitis Metrology Index (BASMI) at Week 12

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    End point title
    Change from Baseline in the Bath Ankylosing Spondylitis Metrology Index (BASMI) at Week 12
    End point description
    The BASMI characterizes the spinal mobility of subjects with axial Spondyloarthritis (SpA) and Ankylosing Spondylitis (AS). It is a disease-specific measure consisting of 5 clinical measures to reflect subject axial status: cervical rotation; tragus to wall distance; lateral lumbar flexion; lumbar flexion (modified Schober test); intermalleolar distance. According to the linear definition of the BASMI a score of 0 to 10 is calculated for each item based on the measurement. The mean of the sum of the 5 scores provides the BASMI score. The higher the BASMI score the more severe the patient’s limitation of movement due to their axial SpA. A negative value in BASMI change from Baseline indicates an improvement from Baseline. The higher the negative value the better the improvement.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    Placebo (FAS) CZP 200 mg Q2W (FAS) CZP 400 mg Q4W (FAS) CZP 200 mg Q2W and CZP 400 mg Q4W (FAS)
    Number of subjects analysed
    107
    111
    107
    218
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Least square mean
    -0.13 (-0.31 to 0.05)
    -0.6 (-0.79 to -0.4)
    -0.46 (-0.66 to -0.26)
    -0.53 (-0.69 to -0.37)
    Statistical analysis title
    Difference in efficacy
    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 (FAS) v CZP 200 mg Q2W and CZP 400 mg Q4W (FAS)
    Number of subjects included in analysis
    325
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [9]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Notes
    [9] - Difference of CZP 200 mg + 400 mg vs. Placebo was estimated using an ANCOVA model with treatment, region, modified New York criteria and prior TNF-antagonist exposure as factors and Baseline BASMI score as a covariate.

    Secondary: Change from Baseline in the Bath Ankylosing Spondylitis Metrology Index (BASMI) at Week 24

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    End point title
    Change from Baseline in the Bath Ankylosing Spondylitis Metrology Index (BASMI) at Week 24
    End point description
    The BASMI characterizes the spinal mobility of subjects with axial SpA and AS. It is a disease-specific measure consisting of 5 clinical measures to reflect subject axial status: cervical rotation; tragus to wall distance; lateral lumbar flexion; lumbar flexion (modified Schober test); intermalleolar distance. According to the linear definition of the BASMI a score of 0 to 10 is calculated for each item based on the measurement. The mean of the sum of the 5 scores provides the BASMI score. The higher the BASMI score the more severe the patient’s limitation of movement due to their axial SpA. A negative value in BASMI change from Baseline indicates an improvement from Baseline. The higher the negative value the better the improvement.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    Placebo (FAS) CZP 200 mg Q2W (FAS) CZP 400 mg Q4W (FAS) CZP 200 mg Q2W and CZP 400 mg Q4W (FAS)
    Number of subjects analysed
    107
    111
    107
    218
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Least square mean
    -0.07 (-0.27 to 0.12)
    -0.54 (-0.75 to -0.34)
    -0.49 (-0.7 to -0.28)
    -0.52 (-0.69 to -0.34)
    Statistical analysis title
    Difference in efficacy
    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 (FAS) v CZP 200 mg Q2W and CZP 400 mg Q4W (FAS)
    Number of subjects included in analysis
    325
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [10]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.66
         upper limit
    -0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [10] - Difference of CZP 200 mg + 400 mg vs. Placebo was estimated using an ANCOVA model with treatment, region, modified New York criteria and prior TNF-antagonist exposure as factors and Baseline BASMI score as a covariate.

    Secondary: Change from Baseline in the spine Ankylosing Spondylitis spine Magnetic Resonance Imaging (MRI) scoring system for disease activity (ASspiMRI-a) in the Berlin modification at Week 12

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    End point title
    Change from Baseline in the spine Ankylosing Spondylitis spine Magnetic Resonance Imaging (MRI) scoring system for disease activity (ASspiMRI-a) in the Berlin modification at Week 12
    End point description
    The Berlin modification of the ASspiMRI-a is a scoring system with a concentration on Short-Tau-Inversion Recovery (STIR) sequences without other fat saturation techniques. It quantifies changes in 23 Vertebral Units (VU) of the spine. A VU is defined as the region between 2 virtual lines through the middle of each vertebra. Active inflammation is scored by grading the degree of bone marrow edema from 0 to 3 in 1 dimension on 1 or more consecutive slices that represent the highest level of inflammation in a particular VU. Total spine ASspiMRI-a score in the Berlin modification can range from 0 to 69 with higher scores indicating higher disease activity. A negative value in total spine ASspiMRI-a score change from Baseline indicates an improvement from Baseline. The higher the negative value the higher the reduction of inflammation.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    Placebo (FAS) CZP 200 mg Q2W (FAS) CZP 400 mg Q4W (FAS) CZP 200 mg Q2W and CZP 400 mg Q4W (FAS)
    Number of subjects analysed
    49
    47
    52
    99
    Units: units on a scale
    arithmetic mean (standard deviation)
        Mean
    0.39 ± 4.04
    -3.39 ± 5.59
    -2.16 ± 3.61
    -2.74 ± 4.67
    No statistical analyses for this end point

    Secondary: Change from Baseline in sacroiliac Spondyloarthritis Research Consortium of Canada (SPARCC) score at Week 12

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    End point title
    Change from Baseline in sacroiliac Spondyloarthritis Research Consortium of Canada (SPARCC) score at Week 12
    End point description
    The SPARCC scoring method for lesions found on the Magnetic Resonance Imaging (MRI) is based on an abnormal increased signal on the Short-Tau-Inversion Recovery (STIR) sequence, representing bone marrow edema. Total Sacroiliac (SI) joint SPARCC score can range from 0 to 72 with higher scores indicating higher joint inflammation. A negative value in SPARCC change from Baseline indicates an improvement from Baseline. The higher the negative value the higher the reduction of inflammation.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    Placebo (FAS) CZP 200 mg Q2W (FAS) CZP 400 mg Q4W (FAS) CZP 200 mg Q2W and CZP 400 mg Q4W (FAS)
    Number of subjects analysed
    45
    45
    50
    95
    Units: units on a scale
    arithmetic mean (standard deviation)
        Mean
    -1.33 ± 8.33
    -3.61 ± 6.94
    -4.98 ± 8.47
    -4.33 ± 7.77
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were collected from Baseline (Week 0) until study end (Week 204). AEs refer to the Safety Set including all randomized subjects who took at least 1 dose of CZP.
    Adverse event reporting additional description
    As per study design, placebo arm subjects shifted either at Week 16 or 24 to CZP treatment. For the Placebo (PBO) group, CZP data from PBO subjects are not utilized. The All CZP 200 mg + 400 mg group shows CZP 200 mg, CZP 400 mg and the escaped PBO subjects with their CZP data.
    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 (Safety Analysis)
    Reporting group description
    All subjects who received CZP at the specified dose (200 mg) at some point during the study, including subjects who were originally randomized to receive placebo and were switched to CZP at Week 16 or Week 24. Placebo : Matching Placebo to CZP injection. CZP 200 mg Q2W : 200 mg subcutaneous (sc) injection of Certolizumab Pegol (CZP) every 2 weeks (Q2W).

    Reporting group title
    All CZP 400 mg (Safety Analysis)
    Reporting group description
    All subjects who received CZP at the specified dose (400 mg) at some point during the study, including subjects who were originally randomized to receive placebo and were switched to CZP at Week 16 or Week 24. Placebo : Matching Placebo to CZP injection. CZP 400 mg Q4W : 400 mg subcutaneous (sc) injection of Certolizumab Pegol (CZP) every 4 weeks (Q4W).

    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 and arm All CZP 400 mg.

    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 on Week 16. After 24 weeks, all subjects were randomized to active treatment with CZP 200 mg every two weeks (Q2W) or CZP 400 mg every four weeks (Q4W). Placebo : Matching Placebo to CZP injection.

    Serious adverse events
    All CZP 200 mg (Safety Analysis) All CZP 400 mg (Safety Analysis) All CZP 200 mg + 400 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 158 (22.15%)
    34 / 157 (21.66%)
    69 / 315 (21.90%)
    5 / 107 (4.67%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Surgical and medical procedures
    Bone graft
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abortion induced
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cholesterol granuloma
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Astrocytoma
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Morton's neuroma
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy on contraceptive
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 158 (0.63%)
    1 / 157 (0.64%)
    2 / 315 (0.63%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 158 (1.27%)
    0 / 157 (0.00%)
    2 / 315 (0.63%)
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    1 / 158 (0.63%)
    1 / 157 (0.64%)
    2 / 315 (0.63%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Conversion disorder
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Joint dislocation
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus lesion
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diffuse alveolar damage
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal congestion
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Hilar lymphadenopathy
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paratracheal lymphadenopathy
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Intracranial aneurysm
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular insufficiency
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 158 (1.27%)
    0 / 157 (0.00%)
    2 / 315 (0.63%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal vein occlusion
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 158 (0.00%)
    3 / 157 (1.91%)
    3 / 315 (0.95%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sigmoiditis
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 158 (0.00%)
    2 / 157 (1.27%)
    2 / 315 (0.63%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inflammatory bowel disease
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 157 (0.00%)
    0 / 315 (0.00%)
    1 / 107 (0.93%)
         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
    Renal and urinary disorders
    Ureteric obstruction
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 157 (0.00%)
    0 / 315 (0.00%)
    1 / 107 (0.93%)
         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
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 158 (0.00%)
    2 / 157 (1.27%)
    2 / 315 (0.63%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis migration
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Psoriasis
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermal cyst
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Arthritis
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 158 (0.63%)
    1 / 157 (0.64%)
    2 / 315 (0.63%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    3 / 158 (1.90%)
    0 / 157 (0.00%)
    3 / 315 (0.95%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankylosing spondylitis
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylitis
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mycobacterial infection
         subjects affected / exposed
    1 / 158 (0.63%)
    1 / 157 (0.64%)
    2 / 315 (0.63%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemophilus infection
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster disseminated
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 158 (1.90%)
    0 / 157 (0.00%)
    3 / 315 (0.95%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected dermal cyst
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Latent tuberculosis
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 157 (0.00%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 157 (0.64%)
    1 / 315 (0.32%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    All CZP 200 mg (Safety Analysis) All CZP 400 mg (Safety Analysis) All CZP 200 mg + 400 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    142 / 158 (89.87%)
    127 / 157 (80.89%)
    269 / 315 (85.40%)
    22 / 107 (20.56%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    20 / 158 (12.66%)
    11 / 157 (7.01%)
    31 / 315 (9.84%)
    4 / 107 (3.74%)
         occurrences all number
    26
    11
    37
    4
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    10 / 158 (6.33%)
    9 / 157 (5.73%)
    19 / 315 (6.03%)
    0 / 107 (0.00%)
         occurrences all number
    18
    11
    29
    0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    14 / 158 (8.86%)
    17 / 157 (10.83%)
    31 / 315 (9.84%)
    2 / 107 (1.87%)
         occurrences all number
    16
    23
    39
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    11 / 158 (6.96%)
    8 / 157 (5.10%)
    19 / 315 (6.03%)
    0 / 107 (0.00%)
         occurrences all number
    14
    10
    24
    0
    Tuberculin test positive
         subjects affected / exposed
    8 / 158 (5.06%)
    7 / 157 (4.46%)
    15 / 315 (4.76%)
    0 / 107 (0.00%)
         occurrences all number
    8
    7
    15
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 158 (3.80%)
    8 / 157 (5.10%)
    14 / 315 (4.44%)
    0 / 107 (0.00%)
         occurrences all number
    6
    9
    15
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 158 (8.23%)
    11 / 157 (7.01%)
    24 / 315 (7.62%)
    0 / 107 (0.00%)
         occurrences all number
    16
    13
    29
    0
    Oropharyngeal pain
         subjects affected / exposed
    12 / 158 (7.59%)
    6 / 157 (3.82%)
    18 / 315 (5.71%)
    0 / 107 (0.00%)
         occurrences all number
    15
    6
    21
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    7 / 158 (4.43%)
    8 / 157 (5.10%)
    15 / 315 (4.76%)
    0 / 107 (0.00%)
         occurrences all number
    8
    11
    19
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    17 / 158 (10.76%)
    18 / 157 (11.46%)
    35 / 315 (11.11%)
    7 / 107 (6.54%)
         occurrences all number
    25
    31
    56
    11
    Eye disorders
    Uveitis
         subjects affected / exposed
    11 / 158 (6.96%)
    8 / 157 (5.10%)
    19 / 315 (6.03%)
    0 / 107 (0.00%)
         occurrences all number
    15
    12
    27
    0
    Conjunctivitis
         subjects affected / exposed
    5 / 158 (3.16%)
    8 / 157 (5.10%)
    13 / 315 (4.13%)
    0 / 107 (0.00%)
         occurrences all number
    6
    9
    15
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    9 / 158 (5.70%)
    4 / 157 (2.55%)
    13 / 315 (4.13%)
    0 / 107 (0.00%)
         occurrences all number
    10
    5
    15
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    10 / 158 (6.33%)
    20 / 157 (12.74%)
    30 / 315 (9.52%)
    0 / 107 (0.00%)
         occurrences all number
    13
    26
    39
    0
    Gastritis
         subjects affected / exposed
    8 / 158 (5.06%)
    5 / 157 (3.18%)
    13 / 315 (4.13%)
    0 / 107 (0.00%)
         occurrences all number
    8
    5
    13
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    11 / 158 (6.96%)
    14 / 157 (8.92%)
    25 / 315 (7.94%)
    2 / 107 (1.87%)
         occurrences all number
    15
    18
    33
    2
    Psoriasis
         subjects affected / exposed
    8 / 158 (5.06%)
    6 / 157 (3.82%)
    14 / 315 (4.44%)
    0 / 107 (0.00%)
         occurrences all number
    14
    9
    23
    0
    Eczema
         subjects affected / exposed
    4 / 158 (2.53%)
    8 / 157 (5.10%)
    12 / 315 (3.81%)
    0 / 107 (0.00%)
         occurrences all number
    6
    13
    19
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    22 / 158 (13.92%)
    11 / 157 (7.01%)
    33 / 315 (10.48%)
    0 / 107 (0.00%)
         occurrences all number
    42
    20
    62
    0
    Back pain
         subjects affected / exposed
    14 / 158 (8.86%)
    11 / 157 (7.01%)
    25 / 315 (7.94%)
    0 / 107 (0.00%)
         occurrences all number
    18
    19
    37
    0
    Spondylitis
         subjects affected / exposed
    12 / 158 (7.59%)
    13 / 157 (8.28%)
    25 / 315 (7.94%)
    0 / 107 (0.00%)
         occurrences all number
    22
    14
    36
    0
    Ankylosing spondylitis
         subjects affected / exposed
    11 / 158 (6.96%)
    5 / 157 (3.18%)
    16 / 315 (5.08%)
    0 / 107 (0.00%)
         occurrences all number
    17
    8
    25
    0
    Pain in extremity
         subjects affected / exposed
    10 / 158 (6.33%)
    3 / 157 (1.91%)
    13 / 315 (4.13%)
    0 / 107 (0.00%)
         occurrences all number
    11
    4
    15
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    35 / 158 (22.15%)
    28 / 157 (17.83%)
    63 / 315 (20.00%)
    3 / 107 (2.80%)
         occurrences all number
    53
    58
    111
    3
    Nasopharyngitis
         subjects affected / exposed
    47 / 158 (29.75%)
    43 / 157 (27.39%)
    90 / 315 (28.57%)
    7 / 107 (6.54%)
         occurrences all number
    80
    83
    163
    8
    Bronchitis
         subjects affected / exposed
    24 / 158 (15.19%)
    17 / 157 (10.83%)
    41 / 315 (13.02%)
    0 / 107 (0.00%)
         occurrences all number
    28
    18
    46
    0
    Pharyngitis
         subjects affected / exposed
    24 / 158 (15.19%)
    11 / 157 (7.01%)
    35 / 315 (11.11%)
    0 / 107 (0.00%)
         occurrences all number
    36
    17
    53
    0
    Sinusitis
         subjects affected / exposed
    17 / 158 (10.76%)
    8 / 157 (5.10%)
    25 / 315 (7.94%)
    0 / 107 (0.00%)
         occurrences all number
    21
    10
    31
    0
    Urinary tract infection
         subjects affected / exposed
    10 / 158 (6.33%)
    11 / 157 (7.01%)
    21 / 315 (6.67%)
    4 / 107 (3.74%)
         occurrences all number
    17
    15
    32
    4
    Rhinitis
         subjects affected / exposed
    15 / 158 (9.49%)
    6 / 157 (3.82%)
    21 / 315 (6.67%)
    0 / 107 (0.00%)
         occurrences all number
    22
    8
    30
    0
    Influenza
         subjects affected / exposed
    9 / 158 (5.70%)
    11 / 157 (7.01%)
    20 / 315 (6.35%)
    0 / 107 (0.00%)
         occurrences all number
    10
    14
    24
    0
    Tonsillitis
         subjects affected / exposed
    8 / 158 (5.06%)
    9 / 157 (5.73%)
    17 / 315 (5.40%)
    0 / 107 (0.00%)
         occurrences all number
    10
    11
    21
    0
    Oral herpes
         subjects affected / exposed
    9 / 158 (5.70%)
    6 / 157 (3.82%)
    15 / 315 (4.76%)
    0 / 107 (0.00%)
         occurrences all number
    23
    7
    30
    0
    Cystitis
         subjects affected / exposed
    8 / 158 (5.06%)
    6 / 157 (3.82%)
    14 / 315 (4.44%)
    0 / 107 (0.00%)
         occurrences all number
    13
    10
    21
    0
    Gastroenteritis
         subjects affected / exposed
    5 / 158 (3.16%)
    9 / 157 (5.73%)
    14 / 315 (4.44%)
    0 / 107 (0.00%)
         occurrences all number
    5
    9
    14
    0
    Viral infection
         subjects affected / exposed
    9 / 158 (5.70%)
    4 / 157 (2.55%)
    13 / 315 (4.13%)
    0 / 107 (0.00%)
         occurrences all number
    10
    4
    14
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Nov 2009
    The following changes were made throughout the protocol: - Inclusion criteria were broadened to include subjects meeting the ASAS clinical criteria and not limited only to subjects meeting the new ASAS imaging criteria. Subjects meeting the new imaging criteria represented at least 50% of subjects not meeting the mNY classification criteria. - Clarification was included that x-rays and MRIs documenting sacroiliitis for subjects meeting the new ASAS imaging criteria must be read by a radiologist (MRIs) and records (x-rays and MRIs) must be included in source documentation. - Update was made to permit samples collected for measurement of CZP plasma concentration to be possibly used for exploratory biomarker (Dickkopf-related protein 1 [DKK1] and sclerostin) research. - Update was made to Exclusion Criteria 6 and 7 to more clearly define exclusion of subjects with fibromyalgia. - The secondary objective assessment of subject symptomatic state was added, which included the secondary (Patient Acceptable Symptomatic State [PASS] and Physician Acceptable Symptomatic State) and exploratory (Patient’s Global Impression of Change [PGIC]) variables. - Update was made to collect SI joint x-ray at Baseline for all subjects not receiving a Baseline MRI. - The schematic of the injection schedule was corrected to remove placebo injection from Week 48 in the CZP 200mg group. - Information on the possible use of other MRI reading criteria in addition to the Spondyloarthritis Research Consortium of Canada (SPARCC) criteria (such as Berlin or modified Berlin criteria) was included. - Clarification was added that the 44 joint counts include both swollen and tender joint counts. - Clarification was added that recording of axSpA history includes relevant family history and prior and concomitant medication history.
    15 Mar 2010
    The following changes were made throughout the protocol: - The Full Analysis Set (FAS) was replaced by the RS for primary efficacy analyses. - The SAP was adjusted for multiple endpoints including implementation of the following: Addition of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (Weeks 12 and 24) and Bath Ankylosing Spondylitis Metrology Index (BASMI) (Weeks 12 and 24) to the key secondary variables. 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 for the following endpoints: ASAS20 response at Weeks 12 and 24 (200mg Q2W and 400mg Q4W), Bath Ankylosing Spondylitis Functional Index (BASFI) Weeks 12 and 24 (combined dose groups), BASDAI Weeks 12 and 24 (combined dose groups), and BASMI Weeks 12 and 24 (combined dose groups). - A marker for inflammation (C-reactive protein [CRP] >upper limit of normal [ULN]) was added to Inclusion Criterion #6. One retesting of subjects failing Screening due to CRP level was permitted. - Clarification was added that SI joint x-rays were performed at Baseline for all subjects. - Update was added that a SI joint x-ray performed <12 weeks (instead of <4 weeks) prior to the Baseline Visit may be used as the Baseline assessment provided that the film can be submitted and meets the requirements for central reading. - Clarification was added that subjects who were enrolled on the basis of meeting the imaging criteria must have been diagnosed on this basis prior to the Screening Visit. - Clarification was added that abatacept was both a prohibited medication (if used within 3 months prior to Baseline) and a prohibited concomitant and rescue treatment. - For TB testing, inconsistencies in visit referencing (eg, Baseline) with regards to purified protein derivative (PPD) tests were corrected to reference the Screening Visit. (Continued below)
    15 Mar 2010
    (Global Substantial Protocol Amendment #3 - 15-Mar-2010 - belongs to the Global Amendment #2) - Clarification that the cited liver function tests (LFTs) >2xULN, 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 Exclusion Criterion #29. - The statement requiring x-ray or MRI documenting sacroiliitis within 6 months of Screening was removed. - Clarification was added that 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 in addition to the modified Stokes Ankylosing Spondylitis Spine Score (mSASSS), x-rays could be evaluated using other assessments. - Clarification was added that subjects meeting the definite AS diagnosis according to the mNY classification criteria were defined as subjects meeting the NY classification criteria in the context of this protocol. - Clarification on the definition for inflammatory back pain for axSpA was added.
    06 Dec 2010
    The following changes were made throughout the protocol: - The approximate number of subjects to be screened was increased from 400 to 600. - The approximate number of sites participating in the study was increased from 100 to 130. - Inclusion Criterion #5 was clarified to ensure that the symptom duration of adult-onset axSpA was at least 3 months and to reduce confusion about the requirements of the study population. - Inclusion Criterion #6 (and the respective study population information) was expanded to include subjects with MRI evidence of sacroiliitis. - Select sites could conduct prescreening activities, and prior to these activities, subjects were to read and sign a separate informed consent form that had been approved by an IEC/IRB and the Sponsor and which complied with regulatory requirements. - The specification for vital signs to be collected within 15 minutes prior to dosing was removed. - In several locations in the protocol, it was clarified that pregnancy testing should be done on women of childbearing potential. - It was clarified that the TB test would be repeated at Week 48 and Week 96 for subjects with a previously negative test result. - As the batch number was not included on the label, this information was removed from the labeling section of the protocol. - It was clarified that Investigators and subjects would remain blind to the assigned CZP dose regimen until the subject reaches the Week 48 Visit. - The sample size for each treatment group required to detect statistically significant differences in ASAS20 was changed from 100 to 105 because of a previous FDA request that the primary analysis population be changed from FAS to all randomized subjects. - Sponsor personnel and the corresponding contact information were updated. - Various administrative adjustments for internal consistency were made.
    27 Apr 2011
    The following global changes were made throughout the protocol: - The company name was changed from SCHWARZ BIOSCIENCES, GmbH, A Member of the UCB Group of Companies, to UCB BIOSCIENCES GmbH. - Addition of the requirement for MRI at Week 48. - The addition of a second interim analysis after all subjects complete Week 48.
    18 Jan 2013
    Protocol Amendment 5 (18 Jan 2013) was implemented to extend the open-label period for an additional 48 weeks. In order to obtain more information about the long-term impact of the use of CZP on structural damage spine x-ray, SI joint x-ray and MRI should have been repeated at the Completion Visit (or Early Withdrawal Visit). Within this amendment, new UCB internal standards for procedures regarding TB detection and monitoring were implemented in order to comply with the revised UCB policy applied to all UCBsponsored studies that included subjects with immunological diseases, who were at increased risk of TB infection either associated with the investigational drug, underlying disease, concomitant treatments, or other medical or sociological factors. These instructions are evidence-based and reflect the updated recommendations of various national guidelines Centers for Disease Control and Prevention diagnosis of latent TB infection. With respect to new scientific evidence, the list of biomarkers that may be of interest for later analysis was updated and alternative methods of analysis of CZP and its constituent moieties were added. The following global changes were made throughout the protocol: - New Clinical Project Manager, Biostatistician, and Clinical Program Director. - Wording regarding the extension of the open-label period. - Wording regarding the additional Investigations. - Wording regarding the new TB standards. - List of biomarkers that may be of interest for analysis was updated. - Visit scheduling of Week 158 (Completion/Early Withdrawal Visit) was shifted to Week 204 and last dosing visit at Week 156 now occurred at Week 202 for the Q2W regimen and Week 200 for the Q4W regimen. Regular last on-site visit and the final evaluation visit were combined to reduce the amount of investigations. - Chest x-ray was requested additionally at Week 156 and at Completion Visit (Week 204)/Early Withdrawal. (Continued below)
    18 Jan 2013
    (Global Substantial Protocol Amendment #7 - 18-Jan-2013 - belongs to the Global Amendment #6) - Spine x-ray, SI joint x-ray and MRI of spine and SI-joint were requested at the Completion Visit Week 204/Early Withdrawal. - Injections should have been administered having a minimum of 10 days between CZP 200mg Q2W injections and a minimum of 20 days between CZP 400mg Q4W injections. - Injections missed due to a reasonable interfering adverse event (AE), that did not allow administration of an anti-TNF due to safety reasons, were not to have been considered for the evaluation of subject compliance. - An error in the description of the ASAS definition was corrected in Section 9.1.1 (of the protocol). Interim analyses of database lock 1 and 2 were performed with the hereby corrected parameters according to the international standards. The modified definition as described within Protocol Amendment 4 was evaluated additionally in the interim analysis of database lock 1 only. - An error in the description of the BASMI evaluation in Section 9.1.8 (of the protocol) was corrected. Now the description matches the naming of the “linear BASMI” according to secondary efficacy variables described in Section 4.1.2 (of the protocol). - The AE of interest Section 11.3 (of the protocol) was updated to be consistent with current reporting requirements.
    15 Mar 2013
    Protocol Amendment 6 implemented administrative changes to correct errors that existed in Protocol Amendment 5.

    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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