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    Clinical Trial Results:
    Phase 3, Multicenter, Randomized, Placebo-Controlled, Double-Blind Study to Evaluate Efficacy and Safety of Certolizumab Pegol in Subjects With Active Axial Spondyloarthritis (axSpA) Without X-Ray Evidence of Ankylosing Spondylitis (AS) and Objective Signs of Inflammation

    Summary
    EudraCT number
    		 2015-001894-41
    Trial protocol
    		 HU   CZ   BG  
    Global end of trial date
    05 May 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 May 2021
    First version publication date
    16 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AS0006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02552212
    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
    09 Oct 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    05 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the efficacy of certolizumab pegol (CZP) 200 mg every 2 weeks (Q2W) on the signs and symptoms of subjects with active Axial Spondyloarthritis (axSpA) without x-ray evidence of Ankylosing Spondylitis (AS).
    Protection of trial subjects
    During the conduct of the study all subjects were closely monitored.
    Background therapy
    		 Background therapy as permitted in the protocol
    Evidence for comparator
    		 A Placebo-arm was used to investigate the natural course of the disease compared to the treatment with the Tumor Necrosis Factor (TNF)-inhibitor CZP.
    Actual start date of recruitment
    03 Sep 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 19
    Country: Number of subjects enrolled
    Bulgaria: 14
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Czechia: 73
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Poland: 112
    Country: Number of subjects enrolled
    Russian Federation: 55
    Country: Number of subjects enrolled
    Taiwan: 10
    Country: Number of subjects enrolled
    United States: 26
    Worldwide total number of subjects
    317
    EEA total number of subjects
    205
    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)
    314
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study started to enroll participants in September 2015. The study included a Screening Period, up to 6 weeks before Baseline, a Double-Blind (DB) Period from Baseline (Week 0) to Week 52, that included the open label CZP (OL-CZP) treatment and other treatment (OT) and an Open Label Safety Follow-up Extension (SFE) Period, up to Week 156.

    Pre-assignment
    Screening details
    		 The Participant Flow refers to the Randomized Set (RS).

    Period 1
    Period 1 title
    Double-Blind Period (Week 0 - 52)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Assessor, Investigator, Monitor
    Blinding implementation details
    Subjects who discontinued the double-blind (DB) study treatment entered the open-label treatment with CZP (OL), or received other treatment (OT) (including biologics).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Matching placebo to certolizumab pegol (CZP) injections were administered every 2 weeks from Week 0 onwards.
    Arm type
    		 Placebo

    Investigational medicinal product name
    PLACEBO
    Investigational medicinal product code
    PBO
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching placebo to certolizumab pegol (CZP) injections were administered every 2 weeks from Week 0 onwards.

    Arm title
    		 CZP 200 mg Q2W
    Arm description
    		 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CERTOLIZUMAB PEGOL
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Certolizumab pegol (CZP) 400 mg subcutaneous (sc) on Week 0, 2 and 4, followed by 200 mg CZP sc every 2 weeks (Q2W) from Week 6 onwards.

    Number of subjects in period 1
    		Placebo CZP 200 mg Q2W
    Started
    158
    159
    Received OL CZP
    96 [1]
    20 [2]
    Completed Week 52 without starting SFE
    20 [3]
    22 [4]
    Completed
    143
    142
    Not completed
    15
    17
         Consent withdrawn by subject
    3
    7
         Not eligible
    -
    1
         Adverse event, non-fatal
    6
    3
         As per suggestion
    -
    1
         Patient's decision
    -
    1
         Study non-compliance
    1
    1
         Lost to follow-up
    1
    -
         Missing/Unspecified
    1
    -
         Lack of efficacy
    2
    2
         Protocol deviation
    1
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Number of participants at this milestone reflect those who received OL CZP during the Double-Blind Period (Week 0 -52).
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Number of participants at this milestone reflect those who received OL CZP during the Double-Blind Period (Week 0 -52).
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Number of participants at this milestone reflect those who completed the Week 52 and did not sign the informed consent form for entering the SFE Period.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Number of participants at this milestone reflect those who completed the Week 52 and did not sign the informed consent form for entering the SFE Period.
    Period 2
    Period 2 title
    SFE Period (Week 52 - 156)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 SFE OL CZP 200 mg Q2W
    Arm description
    		 Subjects who completed Double-Blind Period received CZP 200 mg at Week 52, 54 and 56 to maintain the blinding and who completed the Week 52 Visit on placebo treatment received loading doses of CZP 400 mg at these visits. Subjects who completed the Week 52 Visit on CZP treatment received 1 injection of CZP 200 mg and 1 injection of placebo at these visits to continue their previous CZP treatment regimen and subjects who discontinued from Double-Blind Period and entered OL CZP treatment continued their OL CZP treatment regimen during Safety Follow-Up Extension (SFE) Period. Subjects received CZP 200 mg Q2W for up to 2 years during the SFE Period. An additional signed informed consent for the SFE was a pre-requisite For the additional milestone one (Received OL CZP; Completed Week 52 without starting SFE) reported in Double-Blind Period (Week 0 - 52).
    Arm type
    		 Experimental

    Investigational medicinal product name
    CERTOLIZUMAB PEGOL
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Certolizumab pegol (CZP) 400 mg subcutaneous (sc) on Week 0, 2 and 4, followed by 200 mg CZP sc every 2 weeks (Q2W) from Week 6 onwards.

    Number of subjects in period 2 [5]
    		SFE OL CZP 200 mg Q2W
    Started
    243
    Completed
    206
    Not completed
    37
         Consent withdrawn by subject
    18
         Patient's personal reason
    1
         Adverse event, non-fatal
    5
         Subject withdrew consent due to traveling to site
    1
         Patient travelling for study unable to continue
    1
         Investigator decision
    1
         Compassionate access
    2
         Return to standard-of-care /OL CZP
    1
         Lost to follow-up
    2
         Decision of Patient
    1
         Lack of efficacy
    4
    Notes
    [5] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 285 study participants completed the Double-Blind Period (Week 52). 42 study participants, 20 on placebo and 22 on Cimzia 200 mg Q2W, did not sign the additional informed consent required for the SFE Period. Only 243 study participants started the SFE Period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo to certolizumab pegol (CZP) injections were administered every 2 weeks from Week 0 onwards.

    Reporting group title
    CZP 200 mg Q2W
    Reporting group description
    		 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.

    Reporting group values
    		 Placebo CZP 200 mg Q2W Total
    Number of subjects
    		 158 159 317
    Age categorical
    Units: Subjects
        <=18 years
    		 3 1 4
        Between 18 and 65 years
    		 154 156 310
        >=65 years
    		 1 2 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.4 ( 10.8 ) 37.3 ( 10.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 82 81 163
        Male
    		 76 78 154

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo to certolizumab pegol (CZP) injections were administered every 2 weeks from Week 0 onwards.

    Reporting group title
    CZP 200 mg Q2W
    Reporting group description
    		 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.
    Reporting group title
    SFE OL CZP 200 mg Q2W
    Reporting group description
    		 Subjects who completed Double-Blind Period received CZP 200 mg at Week 52, 54 and 56 to maintain the blinding and who completed the Week 52 Visit on placebo treatment received loading doses of CZP 400 mg at these visits. Subjects who completed the Week 52 Visit on CZP treatment received 1 injection of CZP 200 mg and 1 injection of placebo at these visits to continue their previous CZP treatment regimen and subjects who discontinued from Double-Blind Period and entered OL CZP treatment continued their OL CZP treatment regimen during Safety Follow-Up Extension (SFE) Period. Subjects received CZP 200 mg Q2W for up to 2 years during the SFE Period. An additional signed informed consent for the SFE was a pre-requisite For the additional milestone one (Received OL CZP; Completed Week 52 without starting SFE) reported in Double-Blind Period (Week 0 - 52).

    Subject analysis set title
    Placebo (SS)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Matching placebo to certolizumab pegol (CZP) injections were administered every 2 weeks from Week 0 onwards. Subjects formed the Safety Set (SS).

    Subject analysis set title
    CZP 200 mg Q2W (SS)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    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. Subjects formed the SS.

    Subject analysis set title
    Placebo->OL CZP (SS)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subset of subjects from the Placebo group, who discontinued the CZP double-blind treatment and entered the open-label CZP treatment. The subjects were included in the SS for safety analysis.

    Subject analysis set title
    CZP->OL CZP (SS)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subset of subjects from the CZP 200 mg Q2W group, who discontinued the CZP double-blind treatment and entered the CZP open-label treatment. The subjects were included in the SS for safety analysis.

    Subject analysis set title
    SFE OL CZP 200 mg Q2W (SS)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who completed Double-Blind Period received CZP 200 mg at Week 52, 54 and 56 to maintain the blinding and who completed the Week 52 Visit on placebo treatment received loading doses of CZP 400 mg at these visits. Subjects who completed the Week 52 Visit on CZP treatment received 1 injection of CZP 200 mg and 1 injection of placebo at these visits to continue their previous CZP treatment regimen and subjects who discontinued from Double-Blind Period and entered OL CZP treatment continued their OL CZP treatment regimen during SFE Period. The subjects were included in the SS for safety analysis. Subjects received CZP 200 mg Q2W for up to 2 years during the SFE Period. An additional signed informed consent for the SFE was a pre-requisite For the additional milestone one (Received OL CZP; Completed Week 52 without starting SFE) reported in Double-Blind Period (Week 0 - 52).

    Subject analysis set title
    Placebo (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Matching placebo to certolizumab pegol (CZP) injections were administered every 2 weeks from Week 0 onwards. Subjects formed the Full Analysis Set (FAS).

    Subject analysis set title
    CZP 200 mg Q2W (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    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. Subjects formed the FAS.

    Subject analysis set title
    SFE OL CZP 200 mg Q2W (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who completed Double-Blind Period received CZP 200 mg at Week 52, 54 and 56 to maintain the blinding and who completed the Week 52 Visit on placebo treatment received loading doses of CZP 400 mg at these visits. Subjects who completed the Week 52 Visit on CZP treatment received 1 injection of CZP 200 mg and 1 injection of placebo at these visits to continue their previous CZP treatment regimen and subjects who discontinued from Double-Blind Period and entered OL CZP treatment continued their OL CZP treatment regimen during SFE Period. Subjects formed the FAS. Subjects received CZP 200 mg Q2W for up to 2 years during the SFE Period. An additional signed informed consent for the SFE was a pre-requisite For the additional milestone one (Received OL CZP; Completed Week 52 without starting SFE) reported in Double-Blind Period (Week 0 - 52).

    Primary: Percentage of subjects with Ankylosing Spondylitis Disease Activity Score major improvement (ASDAS-MI) response criteria response at Week 52

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    End point title
    		 Percentage of subjects with Ankylosing Spondylitis Disease Activity Score major improvement (ASDAS-MI) response criteria response at Week 52
    End point description
    This variable was considered as primary in all countries except for Canada (and any other country where applicable or where requested by Regulatory Authorities) where it was considered as secondary variable. ASDAS-MI was achieved when there was a reduction (improvement) >= 2.0 in the ASDAS relative to Baseline, or when the lowest possible ASDAS score (0.6) was reached. The ASDAS was calculated as the sum of the following components: 0.121 × Back pain (BASDAI Q2 result) 0.058 × Duration of morning stiffness (BASDAI Q6 result) 0.110 × Patient’s Global Assessment of Disease Activity (PGADA) 0.073 × Peripheral pain/swelling (BASDAI Q3 result) 0.579 × (natural logarithm [ln] of the (CRP [mg/L] + 1)) Back pain, PGADA, duration of morning stiffness, peripheral pain/swelling and fatigue were all assessed on a numerical scale (0 to 10 units, where 0 is “not active” and 10 is “very active”). The FAS consisted of all subjects in the RS who have received at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Week 52
    End point values
    		 Placebo (FAS) CZP 200 mg Q2W (FAS)
    Number of subjects analysed
    158
    159
    Units: percentage of subjects
        number (not applicable)
    7.0
    47.2
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Odds ratio: CZP/Placebo and p-value were calculated using logistic regression with factors for treatment, region and Magnetic Resonance Imaging/C- Reactive Protein (MRI/CRP) classification.
    Comparison groups
    Placebo (FAS) v CZP 200 mg Q2W (FAS)
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    15.231
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.336
         upper limit
    		 31.623

    Primary: Percentage of subjects with Axial SpondyloArthritis international Society 40% response criteria (ASAS40) response at Week 12

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    End point title
    		 Percentage of subjects with Axial SpondyloArthritis international Society 40% response criteria (ASAS40) response at Week 12
    End point description
    This variable was considered as primary for Canada (and any other country where applicable or where requested by Regulatory Authorities) and as secondary variable in all other countries. The ASAS40 response was defined as relative improvements of at least 40 % and absolute improvement of at least 2 units on a 0 to 10 Numeric Rating Scale (NRS), where 0 is “not active” and 10 is “very active” in at least 3 of the 4 domains: Patient's Global Assessment of Disease Activity (PGADA), Pain assessment (total spinal pain NRS scores), Function (Bath Ankylosing Spondylitis Functional Index (BASFI), Inflammation (mean of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)) questions 5 and 6 concerning morning stiffness intensity and duration) and no worsening at all in the remaining domain. The FAS consisted of all subjects in the RS who have received at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    		 Placebo (FAS) CZP 200 mg Q2W (FAS)
    Number of subjects analysed
    158
    159
    Units: percentage of subjects
        number (not applicable)
    11.4
    47.8
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Odds ratio: CZP/Placebo and p-value were calculated using logistic regression with factors for treatment, region and MRI/CRP classification.
    Comparison groups
    Placebo (FAS) v CZP 200 mg Q2W (FAS)
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    7.436
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.127
         upper limit
    		 13.401

    Primary: Certolizumab pegol plasma concentration at Baseline

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    End point title
    		 Certolizumab pegol plasma concentration at Baseline [1]
    End point description
    Certolizumab pegol plasma concentration was measured at Baseline in micrograms per millilitre (µg/mL). The Safety Set (SS) consisted of all subjects who have received at least 1 dose of study medication. Note: None of the Safety Set subjects had Pharmacokinetic (PK) concentrations above the lower limit of quantification.
    End point type
    Primary
    End point timeframe
    Baseline (Week 0)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    		 Placebo (SS) CZP 200 mg Q2W (SS)
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: µg/mL
        geometric mean (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [2] - Pharmacokinetic (PK) concentrations were below the lower limit of quantification.
    [3] - Pharmacokinetic (PK) concentrations were below the lower limit of quantification.
    No statistical analyses for this end point

    Primary: Certolizumab pegol plasma concentration at Week 1

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    End point title
    		 Certolizumab pegol plasma concentration at Week 1 [4]
    End point description
    Certolizumab pegol plasma concentration was measured at Week 1, in µg/mL. The SS consisted of all subjects who received at least 1 dose of study treatment. Note: No samples taken at Week 1 for the Placebo->OL CZP.
    End point type
    Primary
    End point timeframe
    Week 1
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    		 CZP 200 mg Q2W (SS) Placebo->OL CZP (SS)
    Number of subjects analysed
    148
    0 [5]
    Units: µg/mL
        geometric mean (confidence interval 95%)
    50.5 (48.0 to 53.0)
    ( to )
    Notes
    [5] - No samples taken at Week 1 for the Placebo->OL CZP.
    No statistical analyses for this end point

    Primary: Certolizumab pegol plasma concentration at Week 2

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    End point title
    		 Certolizumab pegol plasma concentration at Week 2 [6]
    End point description
    Certolizumab pegol plasma concentration was measured at Week 2, in µg/mL. The SS consisted of all subjects who received at least 1 dose of study treatment. Note: No samples taken at Week 2 for the Placebo->OL CZP.
    End point type
    Primary
    End point timeframe
    Week 2
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    		 CZP 200 mg Q2W (SS) Placebo->OL CZP (SS)
    Number of subjects analysed
    153
    0 [7]
    Units: µg/mL
        geometric mean (confidence interval 95%)
    36.4 (33.0 to 40.1)
    ( to )
    Notes
    [7] - No samples taken at Week 2 for the Placebo->OL CZP.
    No statistical analyses for this end point

    Primary: Certolizumab pegol plasma concentration at Week 4

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    End point title
    		 Certolizumab pegol plasma concentration at Week 4 [8]
    End point description
    Certolizumab pegol plasma concentration was measured at Week 4, in µg/mL. The SS consisted of all subjects who received at least 1 dose of study treatment.
    End point type
    Primary
    End point timeframe
    Week 4
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    		 CZP 200 mg Q2W (SS) Placebo->OL CZP (SS)
    Number of subjects analysed
    155
    93
    Units: µg/mL
        geometric mean (confidence interval 95%)
    54.6 (51.4 to 58.0)
    48.8 (42.2 to 56.4)
    No statistical analyses for this end point

    Primary: Certolizumab pegol plasma concentration at Week 12

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    End point title
    		 Certolizumab pegol plasma concentration at Week 12 [9]
    End point description
    Certolizumab pegol plasma concentration was measured at Week 12, in µg/mL. The SS consisted of all subjects who received at least 1 dose of study treatment.
    End point type
    Primary
    End point timeframe
    Week 12
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    		 CZP 200 mg Q2W (SS) Placebo->OL CZP (SS)
    Number of subjects analysed
    143
    93
    Units: µg/mL
        geometric mean (confidence interval 95%)
    29.1 (24.0 to 35.2)
    30.5 (26.4 to 35.3)
    No statistical analyses for this end point

    Primary: Certolizumab pegol plasma concentration at Week 24

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    End point title
    		 Certolizumab pegol plasma concentration at Week 24 [10]
    End point description
    Certolizumab pegol plasma concentration was measured at Week 24, in µg/mL. The SS consisted of all subjects who received at least 1 dose of study treatment.
    End point type
    Primary
    End point timeframe
    Week 24
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    		 CZP 200 mg Q2W (SS) Placebo->OL CZP (SS)
    Number of subjects analysed
    135
    86
    Units: µg/mL
        geometric mean (confidence interval 95%)
    23.5 (18.5 to 29.7)
    24.8 (20.6 to 29.9)
    No statistical analyses for this end point

    Primary: Certolizumab pegol plasma concentration at Week 36

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    End point title
    		 Certolizumab pegol plasma concentration at Week 36 [11]
    End point description
    Certolizumab pegol plasma concentration was measured at Week 36, in µg/mL. The SS consisted of all subjects who received at least 1 dose of study treatment.
    End point type
    Primary
    End point timeframe
    Week 36
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    		 CZP 200 mg Q2W (SS) Placebo->OL CZP (SS)
    Number of subjects analysed
    123
    65
    Units: µg/mL
        geometric mean (confidence interval 95%)
    24.0 (19.0 to 30.4)
    22.9 (18.3 to 28.7)
    No statistical analyses for this end point

    Primary: Certolizumab pegol plasma concentration at Week 52

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    End point title
    		 Certolizumab pegol plasma concentration at Week 52 [12]
    End point description
    Certolizumab pegol plasma concentration was measured at Week 52, in µg/mL. The SS consisted of all subjects who received at least 1 dose of study treatment. Note: No samples taken at OL Week 52 for the Placebo->OL CZP.
    End point type
    Primary
    End point timeframe
    Week 52
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    		 CZP 200 mg Q2W (SS) Placebo->OL CZP (SS)
    Number of subjects analysed
    123
    0 [13]
    Units: µg/mL
        geometric mean (confidence interval 95%)
    22.6 (17.8 to 28.6)
    ( to )
    Notes
    [13] - No samples taken at OL Week 52 for the Placebo->OL CZP.
    No statistical analyses for this end point

    Primary: Certolizumab pegol plasma concentration at Follow-Up (FU) Visit

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    End point title
    		 Certolizumab pegol plasma concentration at Follow-Up (FU) Visit [14]
    End point description
    Certolizumab pegol plasma concentration was measured at the Follow-Up Visit, in µg/mL. Follow-Up Visit was defined as 8 weeks after Week 52 or Withdrawal (WD) visit for subjects not participating in the Safety Follow-Up Extension (SFE) Period. The SS consisted of all subjects who received at least 1 dose of study treatment. Only participants included, who had a SFU Visit at 8 weeks after Week 52/WD visit for those not participating in the SFE period.
    End point type
    Primary
    End point timeframe
    Follow-up Visit (up to Week 60)
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    		 CZP 200 mg Q2W (SS) Placebo->OL CZP (SS)
    Number of subjects analysed
    17
    10
    Units: µg/mL
        geometric mean (confidence interval 95%)
    0.2 (0.1 to 0.7)
    999 (999 to 999)
    No statistical analyses for this end point

    Secondary: Percentage of subjects with Axial SpondyloArthritis international Society 40% response criteria (ASAS40) response at Week 52

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    End point title
    		 Percentage of subjects with Axial SpondyloArthritis international Society 40% response criteria (ASAS40) response at Week 52
    End point description
    The ASAS40 response was defined as relative improvements of at least 40% and absolute improvement of at least 2 units on a 0 to 10 Numeric Rating Scale (NRS), where 0 is “not active” and 10 is “very active” in at least 3 of the 4 domains: Patient's Global Assessment of Disease Activity (PGADA), Pain assessment (total spinal pain NRS scores), Function (Bath Ankylosing Spondylitis Functional Index (BASFI)), Inflammation (mean of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)) questions 5 and 6 concerning morning stiffness intensity and duration) and no worsening at all in the remaining domain. The FAS consisted of all subjects in the RS who have received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Placebo (FAS) CZP 200 mg Q2W (FAS)
    Number of subjects analysed
    158
    159
    Units: percentage of subjects
        number (not applicable)
    15.8
    56.6
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Odds ratio: CZP/Placebo and p-value were calculated using logistic regression with factors for treatment, region MRI/CRP classification.
    Comparison groups
    Placebo (FAS) v CZP 200 mg Q2W (FAS)
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    7.359
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.286
         upper limit
    		 12.636

    Secondary: Change from Baseline to Week 12 in the Bath Ankylosing Spondylitis Functional Index (BASFI)

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    End point title
    		 Change from Baseline to Week 12 in the Bath Ankylosing Spondylitis Functional Index (BASFI)
    End point description
    The BASFI is a validated disease-specific instrument for assessing physical function. The BASFI comprises 10 items relating to the past week. The BASFI is the mean of the 10 scores such that the total score ranges from 0 (Easy) to 10 (Impossible), with lower scores indicating better physical function. The change from Baseline is calculated, a negative value indicating improvement and a positive value worsening. The FAS consisted of all subjects in the RS who have received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    		 Placebo (FAS) CZP 200 mg Q2W (FAS)
    Number of subjects analysed
    158
    159
    Units: scores on a scale
        least squares mean (standard error)
    -0.38 ( 0.21 )
    -2.07 ( 0.20 )
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    From an ANCOVA model including scores at Baseline, treatment group, region and MRI/CRP classification.
    Comparison groups
    Placebo (FAS) v CZP 200 mg Q2W (FAS)
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference
    Point estimate
    -1.696
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.11
         upper limit
    		 -1.282

    Secondary: Change from Baseline to Week 52 in the Bath Ankylosing Spondylitis Functional Index (BASFI)

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    End point title
    		 Change from Baseline to Week 52 in the Bath Ankylosing Spondylitis Functional Index (BASFI)
    End point description
    The BASFI is a validated disease-specific instrument for assessing physical function. The BASFI comprises 10 items relating to the past week. The BASFI is the mean of the 10 scores such that the total score ranges from 0 (Easy) to 10 (Impossible), with lower scores indicating better physical function. The change from Baseline is calculated, a negative value indicating improvement and a positive value worsening. The FAS consisted of all subjects in the RS who have received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Placebo (FAS) CZP 200 mg Q2W (FAS)
    Number of subjects analysed
    158
    159
    Units: scores on a scale
        least squares mean (standard error)
    -1.44 ( 0.30 )
    -3.03 ( 0.24 )
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    From an ANCOVA model including scores at Baseline, treatment group, region and MRI/CRP classification.
    Comparison groups
    Placebo (FAS) v CZP 200 mg Q2W (FAS)
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference
    Point estimate
    -1.585
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.132
         upper limit
    		 -1.038

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

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    End point title
    		 Change from Baseline to Week 12 in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
    End point description
    The BASDAI is a validated self-reported instrument, which consists of six 10 unit horizontal Numeric Rating Scales to measure the disease activity of ankylosing spondylitis (AS) from the subject's perspective. It measures the severity of fatigue, spinal and peripheral joint pain and swelling, enthesitis, and morning stiffness (both severity and duration) over the last week. The final BASDAI scores ranges from 0 (not active) to 10 (very active), with lower scores indicating lower disease activity. The change from Baseline is calculated, a negative value indicating improvement and a positive value worsening. The FAS consisted of all subjects in the RS who have received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    		 Placebo (FAS) CZP 200 mg Q2W (FAS)
    Number of subjects analysed
    158
    159
    Units: scores on a scale
        least squares mean (standard error)
    -0.91 ( 0.22 )
    -2.73 ( 0.21 )
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    From an ANCOVA model including scores at Baseline, treatment group, region and MRI/CRP classification.
    Comparison groups
    Placebo (FAS) v CZP 200 mg Q2W (FAS)
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference
    Point estimate
    -1.819
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.25
         upper limit
    		 -1.388

    Secondary: Change from Baseline to Week 52 in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)

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    End point title
    		 Change from Baseline to Week 52 in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
    End point description
    The BASDAI is a validated self-reported instrument, which consists of six 10 unit horizontal Numeric Rating Scales to measure the disease activity of ankylosing spondylitis (AS) from the subject's perspective. It measures the severity of fatigue, spinal and peripheral joint pain and swelling, enthesitis, and morning stiffness (both severity and duration) over the last week. The final BASDAI scores ranges from 0 (not active) to 10 (very active), with lower scores indicating lower disease activity. The change from Baseline is calculated, a negative value indicating improvement and a positive value worsening. The FAS consisted of all subjects in the RS who have received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Placebo (FAS) CZP 200 mg Q2W (FAS)
    Number of subjects analysed
    158
    159
    Units: scores on a scale
        least squares mean (standard error)
    -2.59 ( 0.37 )
    -3.88 ( 0.27 )
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    From an ANCOVA model including scores at Baseline, treatment group, region and MRI/CRP classification.
    Comparison groups
    Placebo (FAS) v CZP 200 mg Q2W (FAS)
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference
    Point estimate
    -1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.909
         upper limit
    		 -0.672

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

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    End point title
    		 Change from Baseline to Week 12 in sacroiliac Spondyloarthritis Research Consortium of Canada (SI-SPARCC) score
    End point description
    The Spondyloarthritis Research Consortium of Canada (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. The change from Baseline is calculated, a negative value indicating improvement and a positive value worsening. The FAS consisted of all subjects in the RS who have received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    		 Placebo (FAS) CZP 200 mg Q2W (FAS)
    Number of subjects analysed
    158
    159
    Units: scores on a scale
        least squares mean (standard error)
    0.200 ( 0.772 )
    -4.669 ( 0.770 )
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    From an ANCOVA model including scores at Baseline, treatment group, region and MRI/CRP classification.
    Comparison groups
    Placebo (FAS) v CZP 200 mg Q2W (FAS)
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference
    Point estimate
    -4.8687
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.4014
         upper limit
    		 -3.336

    Secondary: Number of subjects without relevant changes to background medication from Baseline to Week 52

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    End point title
    		 Number of subjects without relevant changes to background medication from Baseline to Week 52
    End point description
    The number of subjects who did not have relevant changes to background medications during the study treatment period. A subject is without relevant changes to background medication if they do not have: the addition of a new disease-modifying antirheumatic drug (DMARD) or the change from one DMAR to another; the addition of an nonsteroidal anti-inflammatory drug (NSAID) or the change from one NSAID to another; an increased dose of chronic corticosteroids; the addition of a new chronic analgesic medication or increased dose in chronic analgesic medication; and they complete double-blind study treatment to Week 52. The FAS consisted of all subjects in the RS who have received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Placebo (FAS) CZP 200 mg Q2W (FAS)
    Number of subjects analysed
    158
    159
    Units: participants
    48
    115
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Odds ratio: CZP/Placebo and p-value were calculated using logistic regression with factors for treatment, region and MRI/CRP classification.
    Comparison groups
    Placebo (FAS) v CZP 200 mg Q2W (FAS)
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.223
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.8
         upper limit
    		 10.191

    Secondary: Change from Baseline in Ankylosing Spondylitis Quality of Life (ASQoL) at Week 52

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    End point title
    		 Change from Baseline in Ankylosing Spondylitis Quality of Life (ASQoL) at Week 52
    End point description
    The ASQoL score ranged from 0 to 18 with higher score indicating worse Health-Related Quality of Life (HRQoL) and 0 indicating good HRQoL. The change from Baseline is calculated, a negative value indicating improvement and a positive value worsening. The FAS consisted of all subjects in the RS who have received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Placebo (FAS) CZP 200 mg Q2W (FAS)
    Number of subjects analysed
    158
    159
    Units: scores on a scale
        least squares mean (standard error)
    -0.18 ( 0.04 )
    -0.36 ( 0.03 )
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    From an ANCOVA model including scores at Baseline, teratment group, region and MRI/CRP classification.
    Comparison groups
    Placebo (FAS) v CZP 200 mg Q2W (FAS)
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference
    Point estimate
    -0.183
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.25
         upper limit
    		 -0.117

    Secondary: Change from Baseline in ASQoL at Week 1

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    End point title
    		 Change from Baseline in ASQoL at Week 1
    End point description
    The ASQoL score ranged from 0 to 18 with higher score indicating worse Health-Related Quality of Life (HRQoL) and 0 indicating good HRQoL. The change from Baseline is calculated, a negative value indicating improvement and a positive value worsening. The FAS consisted of all subjects in the RS who have received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 1
    End point values
    		 Placebo (FAS) CZP 200 mg Q2W (FAS)
    Number of subjects analysed
    150
    147
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -0.03 ( 0.14 )
    -0.11 ( 0.21 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in ASQoL at Week 2

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    End point title
    		 Change from Baseline in ASQoL at Week 2
    End point description
    The ASQoL score ranged from 0 to 18 with higher score indicating worse Health-Related Quality of Life (HRQoL) and 0 indicating good HRQoL. The change from Baseline is calculated, a negative value indicating improvement and a positive value worsening. The FAS consisted of all subjects in the RS who have received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 2
    End point values
    		 Placebo (FAS) CZP 200 mg Q2W (FAS)
    Number of subjects analysed
    158
    156
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -0.03 ( 0.15 )
    -0.16 ( 0.23 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in ASQoL at Week 4

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    End point title
    		 Change from Baseline in ASQoL at Week 4
    End point description
    The ASQoL score ranged from 0 to 18 with higher score indicating worse Health-Related Quality of Life (HRQoL) and 0 indicating good HRQoL. The change from Baseline is calculated, a negative value indicating improvement and a positive value worsening. The FAS consisted of all subjects in the RS who have received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 4
    End point values
    		 Placebo (FAS) CZP 200 mg Q2W (FAS)
    Number of subjects analysed
    158
    156
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -0.06 ( 0.19 )
    -0.18 ( 0.23 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in ASQoL at Week 12

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    End point title
    		 Change from Baseline in ASQoL at Week 12
    End point description
    The ASQoL score ranged from 0 to 18 with higher score indicating worse Health-Related Quality of Life (HRQoL) and 0 indicating good HRQoL. The change from Baseline is calculated, a negative value indicating improvement and a positive value worsening. The FAS consisted of all subjects in the RS who have received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    		 Placebo (FAS) CZP 200 mg Q2W (FAS)
    Number of subjects analysed
    158
    156
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -0.08 ( 0.22 )
    -0.28 ( 0.26 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in ASQoL at Week 24

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    End point title
    		 Change from Baseline in ASQoL at Week 24
    End point description
    The ASQoL score ranged from 0 to 18 with higher score indicating worse Health-Related Quality of Life (HRQoL) and 0 indicating good HRQoL. The change from Baseline is calculated, a negative value indicating improvement and a positive value worsening. The FAS consisted of all subjects in the RS who have received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Placebo (FAS) CZP 200 mg Q2W (FAS)
    Number of subjects analysed
    158
    156
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -0.09 ( 0.23 )
    -0.31 ( 0.27 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in ASQoL at Week 36

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    End point title
    		 Change from Baseline in ASQoL at Week 36
    End point description
    The ASQoL score ranged from 0 to 18 with higher score indicating worse Health-Related Quality of Life (HRQoL) and 0 indicating good HRQoL. The change from Baseline is calculated, a negative value indicating improvement and a positive value worsening. The FAS consisted of all subjects in the RS who have received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 36
    End point values
    		 Placebo (FAS) CZP 200 mg Q2W (FAS)
    Number of subjects analysed
    158
    156
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -0.11 ( 0.23 )
    -0.33 ( 0.29 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in ASQoL at Week 48

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    End point title
    		 Change from Baseline in ASQoL at Week 48
    End point description
    The ASQoL score ranged from 0 to 18 with higher score indicating worse Health-Related Quality of Life (HRQoL) and 0 indicating good HRQoL. The change from Baseline is calculated, a negative value indicating improvement and a positive value worsening. The FAS consisted of all subjects in the RS who have received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 48
    End point values
    		 Placebo (FAS) CZP 200 mg Q2W (FAS)
    Number of subjects analysed
    158
    156
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -0.10 ( 0.24 )
    -0.34 ( 0.30 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in nocturnal spinal pain Numerical Rating Scale (NRS) at Week 52

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    End point title
    		 Change from Baseline in nocturnal spinal pain Numerical Rating Scale (NRS) at Week 52
    End point description
    The nocturnal spinal pain experienced by subjects due to AS was measured by following question 'How much pain of your spine due to spondylitis do you have at night?'. The NRS ranged from 0 to 10, where 0 represented 'no pain' and 10 represented 'most severe pain'. The change from Baseline is calculated, a negative value indicating improvement and a positive value worsening. The FAS consisted of all subjects in the RS who have received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    		 Placebo (FAS) CZP 200 mg Q2W (FAS)
    Number of subjects analysed
    158
    159
    Units: scores on a scale
        least squares mean (standard error)
    -2.1 ( 0.5 )
    -4.0 ( 0.4 )
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    From an ANCOVA model including scores at Baseline, treatment group, region and MRI/CRP classification.
    Comparison groups
    Placebo (FAS) v CZP 200 mg Q2W (FAS)
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.62
         upper limit
    		 -1.18

    Secondary: Number of subjects with anterior uveitis (AU) or new AU flares through Week 52

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    End point title
    		 Number of subjects with anterior uveitis (AU) or new AU flares through Week 52
    End point description
    The number of subjects with AU or new AU flares during the study treatment period. The FAS consisted of all subjects in the RS who have received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    Throughout the study conduct (up to Week 52)
    End point values
    		 Placebo (FAS) CZP 200 mg Q2W (FAS)
    Number of subjects analysed
    158
    159
    Units: participants
    8
    4
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Odds ratio: CZP/PBO and p-value were calculated using logistic regression with factors for treatment, region and MRI/CRP classification.
    Comparison groups
    Placebo (FAS) v CZP 200 mg Q2W (FAS)
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.247
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.484
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.142
         upper limit
    		 1.653

    Secondary: Percentage of Subjects with Treatment-Emergent Adverse Events (TEAEs) During the Study

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    End point title
    		 Percentage of Subjects with Treatment-Emergent Adverse Events (TEAEs) During the Study
    End point description
    An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. The SS consisted of all subjects who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline up to the End of Safety Follow-up Extenision Period (up to Week 156)
    End point values
    		 Placebo (SS) CZP 200 mg Q2W (SS) Placebo->OL CZP (SS) CZP->OL CZP (SS) SFE OL CZP 200 mg Q2W (SS)
    Number of subjects analysed
    158
    159
    96
    20
    243
    Units: percentage of subjects
        number (not applicable)
    63.9
    75.5
    59.4
    65.0
    61.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Serious Adverse Events (SAEs) During the Study

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    End point title
    		 Percentage of Subjects with Serious Adverse Events (SAEs) During the Study
    End point description
    A serious adverse event (SAE) is any untoward medical occurrence that at any dose: - Results in death - Is life-threatening - Requires in patient hospitalization or prolongation of existing hospitalization - Is a congenital anomaly or birth defect - Is an infection that requires treatment parenteral antibiotics - Other important medical events which based on medical or scientific judgement may jeopardize the patients, or may require medical or surgical intervention to prevent any of the above. The SS consisted of all subjects who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline up to the End of Safety Follow-up Extenision Period (up to Week 156)
    End point values
    		 Placebo (SS) CZP 200 mg Q2W (SS) Placebo->OL CZP (SS) CZP->OL CZP (SS) SFE OL CZP 200 mg Q2W (SS)
    Number of subjects analysed
    158
    159
    96
    20
    243
    Units: percentage of subjects
        number (not applicable)
    2.5
    5.0
    3.1
    5.0
    6.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Adverse Events Leading to Withdrawal from Investigational Medicinal Product (IMP) During the Study

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    End point title
    		 Percentage of Subjects with Adverse Events Leading to Withdrawal from Investigational Medicinal Product (IMP) During the Study
    End point description
    An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. The SS consisted of all subjects who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline up to the End of Safety Follow-up Extenision Period (up to Week 156)
    End point values
    		 Placebo (SS) CZP 200 mg Q2W (SS) Placebo->OL CZP (SS) CZP->OL CZP (SS) SFE OL CZP 200 mg Q2W (SS)
    Number of subjects analysed
    158
    159
    96
    20
    243
    Units: percentage of subjects
        number (not applicable)
    1.9
    1.9
    3.1
    0
    2.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline up to the End of Safety Follow-up Extenision Period (up to Week 156)
    Adverse event reporting additional description
    Adverse events were recorded for all subjects, including those who discontinued the blinded treatment and entered the open-label treatment with CZP (OL). Based on this the following groups were generated: Placebo, Placebo-> OL CZP, CZP, CZP->OL CZP and OL CZP during SFE Period for all subjects entering the SFE Period.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo (SS)
    Reporting group description
    		 Matching placebo to certolizumab pegol (CZP) injections were administered every 2 weeks from Week 0 onwards. Subjects formed the Safety Set (SS).

    Reporting group title
    CZP 200 mg Q2W (SS)
    Reporting group description
    		 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. Subjects formed the SS.

    Reporting group title
    Placebo->OL CZP (SS)
    Reporting group description
    		 Subset of subjects from the Placebo group, who discontinued the CZP double-blind treatment and entered the open-label CZP treatment. The subjects were included in the SS for safety analysis.

    Reporting group title
    CZP->OL CZP (SS)
    Reporting group description
    		 Subset of subjects from the CZP 200 mg Q2W group, who discontinued the CZP double-blind treatment and entered the CZP open-label treatment. The subjects were included in the SS for safety analysis.

    Reporting group title
    SFE OL CZP 200 mg Q2W (SS)
    Reporting group description
    		 Subjects who completed Double-Blind Period received CZP 200 mg at Week 52, 54 and 56 to maintain the blinding and who completed the Week 52 Visit on placebo treatment received loading doses of CZP 400 mg at these visits. Subjects who completed the Week 52 Visit on CZP treatment received 1 injection of CZP 200 mg and 1 injection of placebo at these visits to continue their previous CZP treatment regimen and subjects who discontinued from Double-Blind Period and entered OL CZP treatment continued their OL CZP treatment regimen during SFE Period. The subjects were included in the SS for safety analysis. Subjects received CZP 200 mg Q2W for up to 2 years during the SFE Period. An additional signed informed consent for the SFE was a pre-requisite For the additional milestone one (Received OL CZP; Completed Week 52 without starting SFE) reported in Double-Blind Period (Week 0 - 52).

    Serious adverse events
    		 Placebo (SS) CZP 200 mg Q2W (SS) Placebo->OL CZP (SS) CZP->OL CZP (SS) SFE OL CZP 200 mg Q2W (SS)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 158 (2.53%)
    8 / 159 (5.03%)
    3 / 96 (3.13%)
    1 / 20 (5.00%)
    15 / 243 (6.17%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 159 (0.63%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma stage I
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 159 (0.63%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cholecystectomy
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth extraction
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 159 (0.63%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Sarcoidosis
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervix neoplasms
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical polyp
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst ruptured
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 159 (0.63%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrosalpinx
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    1 / 96 (1.04%)
    0 / 20 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian enlargement
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 159 (0.63%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pharyngeal oedema
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 159 (0.63%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    1 / 96 (1.04%)
    0 / 20 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 159 (0.63%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iridocyclitis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 159 (0.63%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    1 / 20 (5.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity vasculitis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    1 / 96 (1.04%)
    0 / 20 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spinal pain
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    1 / 96 (1.04%)
    0 / 20 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Neuroborreliosis
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 159 (0.63%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic tonsillitis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Obesity
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 159 (0.00%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo (SS) CZP 200 mg Q2W (SS) Placebo->OL CZP (SS) CZP->OL CZP (SS) SFE OL CZP 200 mg Q2W (SS)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    59 / 158 (37.34%)
    75 / 159 (47.17%)
    27 / 96 (28.13%)
    7 / 20 (35.00%)
    69 / 243 (28.40%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    4 / 158 (2.53%)
    8 / 159 (5.03%)
    1 / 96 (1.04%)
    1 / 20 (5.00%)
    3 / 243 (1.23%)
         occurrences all number
    4
    9
    1
    1
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 158 (4.43%)
    11 / 159 (6.92%)
    0 / 96 (0.00%)
    3 / 20 (15.00%)
    9 / 243 (3.70%)
         occurrences all number
    9
    15
    0
    3
    11
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    10 / 158 (6.33%)
    8 / 159 (5.03%)
    1 / 96 (1.04%)
    0 / 20 (0.00%)
    4 / 243 (1.65%)
         occurrences all number
    10
    11
    1
    0
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 158 (5.06%)
    6 / 159 (3.77%)
    2 / 96 (2.08%)
    0 / 20 (0.00%)
    3 / 243 (1.23%)
         occurrences all number
    10
    6
    2
    0
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    10 / 158 (6.33%)
    9 / 159 (5.66%)
    2 / 96 (2.08%)
    2 / 20 (10.00%)
    6 / 243 (2.47%)
         occurrences all number
    12
    12
    2
    2
    6
    Axial spondyloarthritis
         subjects affected / exposed
    12 / 158 (7.59%)
    11 / 159 (6.92%)
    0 / 96 (0.00%)
    0 / 20 (0.00%)
    5 / 243 (2.06%)
         occurrences all number
    13
    13
    0
    0
    5
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    16 / 158 (10.13%)
    30 / 159 (18.87%)
    10 / 96 (10.42%)
    4 / 20 (20.00%)
    21 / 243 (8.64%)
         occurrences all number
    23
    38
    14
    5
    31
    Nasopharyngitis
         subjects affected / exposed
    13 / 158 (8.23%)
    21 / 159 (13.21%)
    10 / 96 (10.42%)
    0 / 20 (0.00%)
    26 / 243 (10.70%)
         occurrences all number
    17
    24
    13
    0
    33
    Bronchitis
         subjects affected / exposed
    5 / 158 (3.16%)
    8 / 159 (5.03%)
    5 / 96 (5.21%)
    0 / 20 (0.00%)
    10 / 243 (4.12%)
         occurrences all number
    5
    9
    5
    0
    11

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Dec 2015
    Global Protocol Amendment 1 (15 Dec 2015) was implemented to clarify and/or add supporting information regarding the procedures and assessments, and to remove inconsistencies and errors: a range of sensitivity analyses, previously discussed with the regulatory authorities, to evaluate the impact of missing data on the analysis of the primary efficacy variable were added. Other changes included the following: the exclusion criterion regarding the upper limit of normal (ULN) of the liver function tests for subjects who were not treated with methotrexate (MTX), the requirement for plasma samples to be analyzed to confirm the washout of specific prohibited medications was removed, and the reporting-needs of particular physician completed assessments in the electronic Case Report Form (eCRF) were clarified. Two tables were included to assist the Investigators in identifying the assessments to be performed when subjects switched to alternative treatments. Inconsistencies in the laboratory assessments performed, the definition of study treatment, and the use of Week 52 and Week 52/Withdrawal (WD) Visit were corrected, study personal information was updated, and minor editorial changes were made.
    14 Mar 2016
    Global Protocol Amendment 2 (14 Mar 2016) was implemented to clarify some of the study procedures, as well as to update Inclusion Criteria 5 and 6 concerning the ASAS criteria, and to increase the number of participating sites and screened subjects. The rationale for the changes was as follows: -Inclusion Criterion 5 about subjects having a documented diagnosis of adult-onset axSpA as defined by the specified ASAS criteria was updated in order to: (i.) clarify that the ASAS criteria were classification criteria and were not intended to be used as diagnosis criteria and to avoid any misinterpretation, and (ii.) removed the part “with at least 12 months symptom duration before Screening,” since this part was added to the updated Inclusion Criterion. -Inclusion Criterion 6 about subjects having evidence of inflammatory back pain as defined by the ASAS criteria was updated to specify that subjects must have had back pain for at least 12 months before Screening. The reason was that the requirements for objective signs and symptoms of inflammation were clearly defined in Inclusion Criterion 9. The initial Inclusion Criterion 6 was therefore a repetition of this requirement. The updated version stressed the importance of having back pain as the lead symptom for axSpA for at least 12 months, to ensure that the pain was chronic in nature. -The number of participating sites and the number of screened subjects was increased from 95 to 120 and from 900 to 1200, respectively, in order to adjust for a higher screening failure rate, which was actually exceeding the expected rate of 67%.
    13 Feb 2017
    Global Protocol Amendment 3 (13 Feb 2017) was implemented to clarify the study details regarding the additional 2 years of long-term, Open-Label certolizumab pegol (OL-CZP) treatment that was to be provided to eligible subjects at the completion of the Week 52 visit. This period of the study was named the SFE Period and the protocol was updated throughout accordingly (eg, a new Schedule of Study Assessments was added and eligibility criteria, guidance for study treatment administration, and concomitant medication usage were updated). Additional changes included: -Allowing female subjects who became pregnant while participating in the AS0006 study the option to enroll in a separate, observational, pregnancy follow-up study sponsored by UCB. -Removal of the 40% cap on interactive response system (IXRS) randomization to each of the 3 clinical subgroups for magnetic resonance imaging/C-reactive protein (MRI/CRP) classifications: (MRI+/CRP+, MRI+/CRP-, or MRI-/CRP+) in order to reflect the real world situation. -Clarification that cases of potential Hy’s Law, defined as ≥3x upper limit of normal (ULN) alanine aminotransferase (ALT) or aspartate aminotransferase (AST) with coexisting ≥2xULN total bilirubin in the absence of ≥2xULN alkaline phosphatase (ALP), with no alternative explanation for the biochemical abnormality, were ALWAYS to be reported to UCB as an adverse event (AE) of interest (ie, without waiting for any additional etiologic investigations to have been concluded). -Minor typographical errors were corrected throughout the protocol.
    19 Dec 2017
    Global Protocol Amendment 4 (19 Dec 2017) was implemented to add an alternative primary efficacy variable for Canada and any other country where applicable or where requested by Regulatory Authorities. In response to feedback from the Canadian Health Authorities, the primary efficacy variable for Canada (and any other country where applicable or where requested by Regulatory Authorities) was the Assessment of SpondyloArthritis international Society 40% response (ASAS40) at Week 12. For these geographies, the Ankylosing Spondylitis Disease Activity Score major improvement (ASDAS-MI) at Week 52 was moved to the list of secondary efficacy variables. In addition, the following 3 efficacy variables were added to the bottom of the testing hierarchy lists for all countries: -Change from Baseline in ASQoL at Week 52 (elevated from “other” to “secondary” efficacy variable) -Change from Baseline in nocturnal spinal pain Numerical Rating Scale (NRS) at Week 52 (elevated from “other” to “secondary” efficacy variable) -Number of subjects with anterior uveitis (AU) or new AU flares through Week 52 (new variable).
    17 Dec 2018
    The purpose of this substantial amendment is to gain additional information about the longerterm disease progress and the effects of CZP treatment in patients with nr-axSpA. To support this, several PROs, a lab assessment, and an additional SI joint MRI will be taken at Week 156/SFE-WD. The visit windows for the SFE Period were also clarified. Additional changes include: -An update to other efficacy variables to include the Week 156/Safety Follow-Up Extension - Withdrawal (SFE-WD) timepoint. SFEWD added to Week 156 instances when needed to distinguish from Week 52/WD. -An update to remove collection of samples for CZP plasma concentration, anti-CZP antibodies, and Biomarkers as this is not done for subjects on alternative treatments. -An update to the subheadings in Section 4.2.2, Section 4.2.3, and Section 4.3 to clarify categorization of variables. -An update to Section 4.4 subheadings to clarify safety variables. -An update of ASDAS-MD to ASDAS-LD (Machado et al, 2018). -Minor editorial and administrative changes have been made throughout the protocol.

    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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