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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-blind, Placebo and Active Comparator- Controlled Study Evaluating the Efficacy and Safety of Guselkumab for the Treatment of Subjects with Moderate to Severe Plaque-type Psoriasis with Randomized Withdrawal and Retreatment

    Summary
    EudraCT number
    2014-000720-18
    Trial protocol
    DE   CZ   PL   ES  
    Global end of trial date
    01 Jul 2020

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CNTO1959PSO3002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02207244
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen Pharmaceutical
    Sponsor organisation address
    1400 McKean Rd., Spring House, United States,
    Public contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.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
    01 Jul 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of this study were to evaluate the efficacy, safety, and tolerability of guselkumab in the treatment of subjects with moderate to severe plaque-type psoriasis.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. The safety and tolerability of guselkumab and adalimumab were monitored by collecting information on adverse events (AEs), including injection-site reactions (ISRs) and allergic reactions, clinical laboratory tests, physical examinations, vital signs, electrocardiograms (ECGs), concomitant medication review, and early detection of active tuberculosis (TB).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    03 Nov 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 51
    Country: Number of subjects enrolled
    Canada: 130
    Country: Number of subjects enrolled
    Czechia: 31
    Country: Number of subjects enrolled
    Germany: 84
    Country: Number of subjects enrolled
    Spain: 43
    Country: Number of subjects enrolled
    Korea, Republic of: 98
    Country: Number of subjects enrolled
    Poland: 265
    Country: Number of subjects enrolled
    Russian Federation: 100
    Country: Number of subjects enrolled
    United States: 190
    Worldwide total number of subjects
    992
    EEA total number of subjects
    423
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    949
    From 65 to 84 years
    43
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 1279 subjects were screened. Of these 1279, 992 subjects were randomized.

    Period 1
    Period 1 title
    Placebo Controlled Period: Week 0 - 16
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo (Week 0 - 16)
    Arm description
    Subjects received placebo matched to guselkumab subcutaneous (SC) injection at Weeks 0, 4, and 12 and placebo matched to adalimumab (2 SC injections) at Week 0, followed by placebo matched to adalimumab (1 SC injection) at Week 1 and every other week thereafter through Week 15 to maintain the blind during placebo controlled period (PCP).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (for guselkumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection in pre-filled syringe, Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matching to guselkumab was administered subcutaneously at Weeks 0, 4 and 12 in PCP.

    Investigational medicinal product name
    Placebo (for adalimumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matching to adalimumab was administered subcutaneously (2 doses) at Week 0 followed by single subcutaneous dose thereafter through Week 15 in PCP.

    Arm title
    Guselkumab 100 mg (Week 0 - 16)
    Arm description
    Subjects received guselkumab 100 milligram (mg) SC injection at Weeks 0, 4 and 12, and placebo matched to adalimumab (2 SC injections) at Week 0 followed by placebo matched to adalimumab (1 SC injection) at Week 1 and every other week thereafter through Week 15 during PCP.
    Arm type
    Experimental

    Investigational medicinal product name
    Guselkumab
    Investigational medicinal product code
    Other name
    CNTO1959
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Guselkumab 100 mg was administered subcutaneously at Weeks 0, 4, and 12.

    Arm title
    Adalimumab (Week 0 - 16)
    Arm description
    Subjects received adalimumab 80 mg (2 SC injections) at Week 0 followed by adalimumab 40 mg (1 SC injection) at Week 1 and every other week thereafter through Week 15 and placebo matched to guselkumab SC injection at Weeks 0, 4, and 12 during PCP.
    Arm type
    Active comparator

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Adalimumab 80 mg was administered subcutaneously (2 doses) at Week 0 followed by single subcutaneous dose of adalimumab 40 mg at Week 1 and thereafter through Week 15.

    Number of subjects in period 1
    Placebo (Week 0 - 16) Guselkumab 100 mg (Week 0 - 16) Adalimumab (Week 0 - 16)
    Started
    248
    496
    248
    Completed
    233
    478
    237
    Not completed
    15
    18
    11
         Consent withdrawn by subject
    7
    1
    -
         Adverse event, non-fatal
    2
    9
    4
         Unspecified
    -
    2
    2
         Lost to follow-up
    1
    3
    2
         Protocol deviation
    1
    3
    1
         Lack of efficacy
    4
    -
    2
    Period 2
    Period 2 title
    Placebo crossover and ACP: Week 16 - 28
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo then Guselkumab 100 mg (Week 16 - 28)
    Arm description
    Subjects who started receiving placebo in the first period were crossed over to receive guselkumab 100 mg SC injection at Weeks 16 and 20 and placebo matched to adalimumab (1 SC injection) at Weeks 17, 19, 21, and 23 during the active comparator controlled period (ACP).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (for adalimumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matching to adalimumab was administered subcutaneously at Weeks 17, 19, 21, 23, and q2w in active controlled period.

    Investigational medicinal product name
    Guselkumab
    Investigational medicinal product code
    Other name
    CNTO1959
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Guselkumab 100 mg was administered subcutaneously to subjects receiving matching placebo in PCP and crossed over to receive guselkumab in ACP.

    Arm title
    Guselkumab 100 mg (Week 16 - 28)
    Arm description
    Subjects who started receiving guselkumab in the first period, received placebo matched to guselkumab SC injection at Week 16 followed by guselkumab 100 mg SC injection at Week 20 and placebo matched to adalimumab (1 SC injection) at Weeks 17, 19, 21 and 23.
    Arm type
    Experimental

    Investigational medicinal product name
    Guselkumab
    Investigational medicinal product code
    Other name
    CNTO1959
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Guselkumab 100 mg was administered subcutaneously q8w in ACP to subjects initially receiving guselkumab 100 mg in PCP.

    Arm title
    Adalimumab (Week 16 - 28)
    Arm description
    Subjects who received adalimumab in the first period, continued to receive adalimumab 40 mg (1 SC injection) every 2 weeks (q2w) from Week 17 through Week 23 and placebo matched to guselkumab SC injection at Weeks 16 and 20.
    Arm type
    Active comparator

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Adalimumab 40 mg was administered to subcutaneously q2w in ACP to subjects who were initially receiving adalimumab in PCP.

    Number of subjects in period 2
    Placebo then Guselkumab 100 mg (Week 16 - 28) Guselkumab 100 mg (Week 16 - 28) Adalimumab (Week 16 - 28)
    Started
    233
    478
    237
    Completed
    227
    470
    228
    Not completed
    6
    8
    9
         Consent withdrawn by subject
    3
    3
    2
         Adverse event, non-fatal
    -
    3
    2
         Unspecified
    1
    -
    -
         Lost to follow-up
    1
    2
    2
         Protocol deviation
    1
    -
    1
         Lack of efficacy
    -
    -
    2
    Period 3
    Period 3 title
    Withdrawal and Re-treatment: Week 28-72
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo then Guselkumab 100 mg (Week 28 - 72)
    Arm description
    Subjects assigned to the placebo, then guselkumab arm through Week 28 were assessed for psoriasis area and severity index (PASI) 90 response at Week 28. Subjects who were PASI 90 non-responders received guselkumab 100 mg SC injection at Week 28 and then every 8 weeks (q8w) thereafter through Week 72 and placebo matched to guselkumab SC injection at Week 32 and then q8w through Week 72. Subjects who were PASI 90 responders at Week 28 received placebo matched to guselkumab SC injection at Week 28 and every 4 weeks (q4w) thereafter through Week 72 or until loss of greater than or equal to (>=) 50 percentage (%) in the improvement in PASI (Withdrawal and retreatment period). If they lost response according to this definition, they were retreated with guselkumab.
    Arm type
    Placebo

    Investigational medicinal product name
    Guselkumab
    Investigational medicinal product code
    Other name
    CNTO1959
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Guselkumab 100 mg was administered subcutaneously to PASI 90 non-responders at Week 28 and then q8w thereafter through Week 72.

    Investigational medicinal product name
    Placebo (for guselkumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matching to guselkumab was administered subcutaneously to PASI 90 non-responders at Week 32 and then q8w through Week 72 whereas placebo matching to guselkumab was administered subcutaneously to PASI 90 responders at Week 28 and q4w thereafter through Week 72 or until loss of >=50% the improvement in PASI.

    Arm title
    Guselkumab 100 mg (Week 28 - 72)
    Arm description
    Subjects assigned to the guselkumab arm through Week 28 were assessed for PASI 90 response at Week 28. Subjects who were PASI 90 non-responders at Week 28 received guselkumab 100 mg SC injection at Week 28 and q8w thereafter through Week 72 and placebo matched to guselkumab at Week 32 and then q8w through Week 72. Subjects who were PASI 90 responders were re-randomized to either guselkumab or placebo. Subjects re-randomized to guselkumab, received guselkumab 100 mg SC injection at Week 28 and q8w thereafter through Week 72 and placebo matched to guselkumab SC injection at Weeks 32 and then q8w through Week 72. Subjects re-randomized to placebo, received placebo matched to guselkumab SC injection q4w through Week 72 or until loss of >=50% in the improvement in PASI (Withdrawal and retreatment period). If they lost response according to this definition, they were retreated with guselkumab.
    Arm type
    Experimental

    Investigational medicinal product name
    Guselkumab
    Investigational medicinal product code
    Other name
    CNTO1959
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Guselkumab 100 mg was administered subcutaneously to PASI 90 non-responders at Week 28 and q8w thereafter through Week 72 whereas PASI 90 responders were re-randomized to guselkumab through Week 72.

    Arm title
    Adalimumab then Guselkumab 100 mg (Week 28 - 72)
    Arm description
    Subjects who were assigned to the adalimumab arm through Week 28 were assessed for PASI 90 response at Week 28. Subjects who were PASI 90 non-responders at Week 28 received guselkumab 100 mg SC injection at Week 28 and 32 and q8w thereafter through Week 72 and placebo matched to guselkumab SC injection at Weeks 36 and 44. Subjects who were PASI 90 responders, received placebo matched to guselkumab SC injection q4w thereafter through Week 72 or until loss of >=50% in the improvement in PASI (Withdrawal and retreatment period). If they lost response according to this definition, they were treated with guselkumab.
    Arm type
    Active comparator

    Investigational medicinal product name
    Guselkumab
    Investigational medicinal product code
    Other name
    CNTO1959
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Guselkumab 100 mg was administered subcutaneously to PASI 90 non-responders at Week 28 and 32 and q8w thereafter through Week 72.

    Arm title
    Adalimumab (After ACP)
    Arm description
    Subjects who received adalimumab 80 mg at Week 0 and adalimumab 40 mg at Week 1 and every other week through Week 23 were assessed for PASI 90 response at Week 28. PASI 90 responders who did not crossover to guselkumab upon loss of >=50% in the improvement in PASI and did not continue any treatment at Week 28 are reported in this arm.
    Arm type
    Active comparator

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Adalimumab 40 mg was administered subcutaneously to subjects through Week 23.

    Number of subjects in period 3
    Placebo then Guselkumab 100 mg (Week 28 - 72) Guselkumab 100 mg (Week 28 - 72) Adalimumab then Guselkumab 100 mg (Week 28 - 72) Adalimumab (After ACP)
    Started
    227
    470
    220
    8
    Nonresponders
    80 [1]
    95 [2]
    112 [3]
    0
    Responders at Week (Wk) 28
    0 [4]
    375 [5]
    0 [6]
    0
    Responders at Wk 28, withdrawn treatment
    147 [7]
    0 [8]
    108 [9]
    0
    Completed
    213
    443
    211
    0
    Not completed
    14
    27
    9
    8
         Consent withdrawn by subject
    2
    7
    2
    2
         Adverse event, non-fatal
    1
    5
    3
    2
         Pregnancy
    -
    2
    -
    -
         Unspecified
    -
    2
    -
    -
         Subjects not retreated with guselkumab
    8
    -
    -
    -
         Lost to follow-up
    2
    7
    -
    2
         Lack of efficacy
    1
    3
    2
    2
         Protocol deviation
    -
    1
    1
    -
         Noncompliance
    -
    -
    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: There were only specified number of subjects in each arm of each milestone.
    [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: There were only specified number of subjects in each arm of each milestone.
    [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: There were only specified number of subjects in each arm of each milestone.
    [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: There were only specified number of subjects in each arm of each milestone.
    [5] - 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: There were only specified number of subjects in each arm of each milestone.
    [6] - 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: There were only specified number of subjects in each arm of each milestone.
    [7] - 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: There were only specified number of subjects in each arm of each milestone.
    [8] - 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: There were only specified number of subjects in each arm of each milestone.
    [9] - 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: There were only specified number of subjects in each arm of each milestone.
    Period 4
    Period 4 title
    Open-label Guselkumab: Week 72-264
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Guselkumab Combined
    Arm description
    All subjects who received guselkumab 100 mg subcutaneously q8w at Week 76 and thereafter through Week 252.
    Arm type
    Experimental

    Investigational medicinal product name
    Guselkumab
    Investigational medicinal product code
    Other name
    CNTO1959
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Guselkumab 100 mg was administered subcutaneously at Week 76 and then q8w through Week 252.

    Arm title
    Adalimumab then Guselkumab 100 mg (Week 72 - 264)
    Arm description
    All subjects received guselkumab 100 mg at Week 76 and then q8w through Week 252.
    Arm type
    Experimental

    Investigational medicinal product name
    Guselkumab
    Investigational medicinal product code
    Other name
    CNTO1959
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Guselkumab 100 mg was administered subcutaneously at Week 76 and then q8w through Week 252.

    Number of subjects in period 4
    Guselkumab Combined Adalimumab then Guselkumab 100 mg (Week 72 - 264)
    Started
    656
    211
    Completed
    554
    173
    Not completed
    102
    38
         Adverse event, serious fatal
    1
    1
         Consent withdrawn by subject
    30
    10
         Adverse event, non-fatal
    21
    12
         Pregnancy
    2
    -
         Unspecified
    19
    8
         Lost to follow-up
    26
    5
         Lack of efficacy
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo (Week 0 - 16)
    Reporting group description
    Subjects received placebo matched to guselkumab subcutaneous (SC) injection at Weeks 0, 4, and 12 and placebo matched to adalimumab (2 SC injections) at Week 0, followed by placebo matched to adalimumab (1 SC injection) at Week 1 and every other week thereafter through Week 15 to maintain the blind during placebo controlled period (PCP).

    Reporting group title
    Guselkumab 100 mg (Week 0 - 16)
    Reporting group description
    Subjects received guselkumab 100 milligram (mg) SC injection at Weeks 0, 4 and 12, and placebo matched to adalimumab (2 SC injections) at Week 0 followed by placebo matched to adalimumab (1 SC injection) at Week 1 and every other week thereafter through Week 15 during PCP.

    Reporting group title
    Adalimumab (Week 0 - 16)
    Reporting group description
    Subjects received adalimumab 80 mg (2 SC injections) at Week 0 followed by adalimumab 40 mg (1 SC injection) at Week 1 and every other week thereafter through Week 15 and placebo matched to guselkumab SC injection at Weeks 0, 4, and 12 during PCP.

    Reporting group values
    Placebo (Week 0 - 16) Guselkumab 100 mg (Week 0 - 16) Adalimumab (Week 0 - 16) Total
    Number of subjects
    248 496 248 992
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    239 473 237 949
        From 65 to 84 years
    9 23 11 43
        85 years and over
    0 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    43.3 ± 12.38 43.7 ± 12.23 43.2 ± 11.92 -
    Title for Gender
    Units: subjects
        Female
    75 147 78 300
        Male
    173 349 170 692

    End points

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    End points reporting groups
    Reporting group title
    Placebo (Week 0 - 16)
    Reporting group description
    Subjects received placebo matched to guselkumab subcutaneous (SC) injection at Weeks 0, 4, and 12 and placebo matched to adalimumab (2 SC injections) at Week 0, followed by placebo matched to adalimumab (1 SC injection) at Week 1 and every other week thereafter through Week 15 to maintain the blind during placebo controlled period (PCP).

    Reporting group title
    Guselkumab 100 mg (Week 0 - 16)
    Reporting group description
    Subjects received guselkumab 100 milligram (mg) SC injection at Weeks 0, 4 and 12, and placebo matched to adalimumab (2 SC injections) at Week 0 followed by placebo matched to adalimumab (1 SC injection) at Week 1 and every other week thereafter through Week 15 during PCP.

    Reporting group title
    Adalimumab (Week 0 - 16)
    Reporting group description
    Subjects received adalimumab 80 mg (2 SC injections) at Week 0 followed by adalimumab 40 mg (1 SC injection) at Week 1 and every other week thereafter through Week 15 and placebo matched to guselkumab SC injection at Weeks 0, 4, and 12 during PCP.
    Reporting group title
    Placebo then Guselkumab 100 mg (Week 16 - 28)
    Reporting group description
    Subjects who started receiving placebo in the first period were crossed over to receive guselkumab 100 mg SC injection at Weeks 16 and 20 and placebo matched to adalimumab (1 SC injection) at Weeks 17, 19, 21, and 23 during the active comparator controlled period (ACP).

    Reporting group title
    Guselkumab 100 mg (Week 16 - 28)
    Reporting group description
    Subjects who started receiving guselkumab in the first period, received placebo matched to guselkumab SC injection at Week 16 followed by guselkumab 100 mg SC injection at Week 20 and placebo matched to adalimumab (1 SC injection) at Weeks 17, 19, 21 and 23.

    Reporting group title
    Adalimumab (Week 16 - 28)
    Reporting group description
    Subjects who received adalimumab in the first period, continued to receive adalimumab 40 mg (1 SC injection) every 2 weeks (q2w) from Week 17 through Week 23 and placebo matched to guselkumab SC injection at Weeks 16 and 20.
    Reporting group title
    Placebo then Guselkumab 100 mg (Week 28 - 72)
    Reporting group description
    Subjects assigned to the placebo, then guselkumab arm through Week 28 were assessed for psoriasis area and severity index (PASI) 90 response at Week 28. Subjects who were PASI 90 non-responders received guselkumab 100 mg SC injection at Week 28 and then every 8 weeks (q8w) thereafter through Week 72 and placebo matched to guselkumab SC injection at Week 32 and then q8w through Week 72. Subjects who were PASI 90 responders at Week 28 received placebo matched to guselkumab SC injection at Week 28 and every 4 weeks (q4w) thereafter through Week 72 or until loss of greater than or equal to (>=) 50 percentage (%) in the improvement in PASI (Withdrawal and retreatment period). If they lost response according to this definition, they were retreated with guselkumab.

    Reporting group title
    Guselkumab 100 mg (Week 28 - 72)
    Reporting group description
    Subjects assigned to the guselkumab arm through Week 28 were assessed for PASI 90 response at Week 28. Subjects who were PASI 90 non-responders at Week 28 received guselkumab 100 mg SC injection at Week 28 and q8w thereafter through Week 72 and placebo matched to guselkumab at Week 32 and then q8w through Week 72. Subjects who were PASI 90 responders were re-randomized to either guselkumab or placebo. Subjects re-randomized to guselkumab, received guselkumab 100 mg SC injection at Week 28 and q8w thereafter through Week 72 and placebo matched to guselkumab SC injection at Weeks 32 and then q8w through Week 72. Subjects re-randomized to placebo, received placebo matched to guselkumab SC injection q4w through Week 72 or until loss of >=50% in the improvement in PASI (Withdrawal and retreatment period). If they lost response according to this definition, they were retreated with guselkumab.

    Reporting group title
    Adalimumab then Guselkumab 100 mg (Week 28 - 72)
    Reporting group description
    Subjects who were assigned to the adalimumab arm through Week 28 were assessed for PASI 90 response at Week 28. Subjects who were PASI 90 non-responders at Week 28 received guselkumab 100 mg SC injection at Week 28 and 32 and q8w thereafter through Week 72 and placebo matched to guselkumab SC injection at Weeks 36 and 44. Subjects who were PASI 90 responders, received placebo matched to guselkumab SC injection q4w thereafter through Week 72 or until loss of >=50% in the improvement in PASI (Withdrawal and retreatment period). If they lost response according to this definition, they were treated with guselkumab.

    Reporting group title
    Adalimumab (After ACP)
    Reporting group description
    Subjects who received adalimumab 80 mg at Week 0 and adalimumab 40 mg at Week 1 and every other week through Week 23 were assessed for PASI 90 response at Week 28. PASI 90 responders who did not crossover to guselkumab upon loss of >=50% in the improvement in PASI and did not continue any treatment at Week 28 are reported in this arm.
    Reporting group title
    Guselkumab Combined
    Reporting group description
    All subjects who received guselkumab 100 mg subcutaneously q8w at Week 76 and thereafter through Week 252.

    Reporting group title
    Adalimumab then Guselkumab 100 mg (Week 72 - 264)
    Reporting group description
    All subjects received guselkumab 100 mg at Week 76 and then q8w through Week 252.

    Subject analysis set title
    Guselkumab Combined
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All subjects who crossed over to receive guselkumab 100 mg subcutaneously at Week 16 from placebo group and subjects who were randomized to guselkumab 100 mg group at Week 0. Placebo crossover subjects were included in the guselkumab column after crossover to guselkumab.

    Subject analysis set title
    Withdrawal Group (Through Week 72)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects in withdrawal group received guselkumab 100 mg SC injection at Weeks 0, 4 and 12 and placebo matched to adalimumab (2 SC injections) at Week 0, followed by placebo matched to adalimumab (1 SC injection) at Weeks 1, 3, 5 and q2w through Week 15 to maintain the blind during PCP. Subjects received placebo matched to guselkumab SC injection at Week 16 then guselkumab 100 mg SC injection at Week 20 and placebo matched to adalimumab (1 SC injection) at q2w from Week 17 through Week 23. These subjects who were PASI 90 responders at Week 28 were randomized to receive placebo matched to guselkumab SC injection at Week 28 and q4w thereafter through Week 72 until loss of >=50% in the improvement in PASI.

    Subject analysis set title
    Guselkumab Maintenance Group (Through Week 72)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects of maintenance group received guselkumab 100 mg SC injection at Weeks 0, 4 and 12, and placebo matched to adalimumab (2 SC injections) at Week 0 then placebo matched to adalimumab (1 SC injection) at Weeks 1, 3, 5, 7, and q2w through Week 15. Subjects received placebo matched to guselkumab SC injection at Week 16 then guselkumab 100 mg SC injection at Week 20 and placebo matched to adalimumab (1 SC injection) at q2w from Week 17 through Week 23. These subjects were PASI 90 responders who were randomized to receive guselkumab 100 mg SC injection at Week 28 and q8w thereafter through Week 72 and placebo matched to guselkumab SC injection at Weeks 32, 40 and thereafter through Week 72.

    Subject analysis set title
    Guselkumab 100 mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects received guselkumab 100 mg SC injection at Weeks 0, 4 and 12, and placebo matched to adalimumab (2 SC injections) at Week 0 then placebo matched to adalimumab (1 SC injection) at Weeks 1, 3, 5 and q2w thereafter through Week 15. Subjects received placebo matched to guselkumab SC injection at Week 16 then guselkumab 100 mg SC injection at Week 20 and placebo matched to adalimumab (1 SC injection) at Weeks 17, 19, 21 and 23.

    Subject analysis set title
    Adalimumab
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects received adalimumab 80 mg (2 SC injections) at Week 0 followed by adalimumab 40 mg (1 SC injection) at Weeks 1, 3, 5 and every other week thereafter through Week 15 and placebo matched to guselkumab SC injection at Weeks 0, 4, and 12. Subjects who received adalimumab in the first period, continued to receive adalimumab 40 mg (1 SC injection) q2w from Week 17 through Week 23 and placebo matched to guselkumab SC injection at Weeks 16 and 20.

    Subject analysis set title
    Adalimumab then Guselkumab 100 mg (Week 28 - 264)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects who were assigned to the adalimumab arm through Week 28 were assessed for PASI 90 response at Week 28. Subjects who were PASI 90 non-responders at Week 28 received guselkumab 100 mg SC injection at Week 28 and 32 and q8w thereafter through Week 72 and placebo matched to guselkumab SC injection at Weeks 36 and 44. Subjects who were PASI 90 responders, received placebo matched to guselkumab SC injection q4w thereafter through Week 72 or until loss of >=50% in the improvement in PASI (Withdrawal and retreatment period). If they lost response according to this definition, they were treated with guselkumab. All subjects received guselkumab 100 mg at Week 76 and then q8w through Week 252.

    Primary: Percentage of Subjects Who Achieved an Investigator's Global Assessment (IGA) Score of Cleared (0) or Minimal (1) in the Guselkumab Group Compared to the Placebo Group at Week 16

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    End point title
    Percentage of Subjects Who Achieved an Investigator's Global Assessment (IGA) Score of Cleared (0) or Minimal (1) in the Guselkumab Group Compared to the Placebo Group at Week 16 [1]
    End point description
    The IGA documents the investigator's assessment of the subject's psoriasis at a given time point. Overall lesions are graded for induration, erythema, and scaling. The subject's psoriasis was assessed as cleared (0), minimal (1), mild (2), moderate (3), or severe (4). Randomized analysis set included all subjects who were randomized at Week 0. Nonresponder imputation (subjects who met treatment-failure criteria before Week 16 or who did not come for evaluation at week 16 were considered nonresponders) was used to impute missing values.
    End point type
    Primary
    End point timeframe
    Week 16
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    Placebo (Week 0 - 16) Guselkumab 100 mg (Week 0 - 16)
    Number of subjects analysed
    248
    495
    Units: percentage of subjects
        number (not applicable)
    8.5
    84.1
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo (Week 0 - 16) v Guselkumab 100 mg (Week 0 - 16)
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel chi-square test
    Confidence interval

    Primary: Percentage of Subjects Who Achieved Psoriasis Area and Severity Index (PASI) 90 Response in the Guselkumab Group Compared to the Placebo Group at Week 16

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    End point title
    Percentage of Subjects Who Achieved Psoriasis Area and Severity Index (PASI) 90 Response in the Guselkumab Group Compared to the Placebo Group at Week 16 [2]
    End point description
    The PASI is a system used for assessing and grading the severity of psoriatic lesions. In the PASI system, the body is divided into 4 regions: the head, trunk, upper extremities, and lower extremities. Each of these area was assessed separately for the percentage of the area involved, which translates to a numeric score that ranges from 0 to 6, and for erythema, induration, and scaling, which are each rated on a scale of 0 to 4. The PASI produces a numeric score that can range from 0 to 72. A higher score indicates more severe disease. A PASI 90 response represents subjects who achieved at least a 90 percent improvement from baseline in the PASI score. Randomized analysis set included all subjects who were randomized at Week 0. Nonresponder imputation (subjects who met treatment-failure criteria before Week 16 or who did not come for evaluation at week 16 were considered nonresponders) was used to impute missing values.
    End point type
    Primary
    End point timeframe
    Week 16
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    Placebo (Week 0 - 16) Guselkumab 100 mg (Week 0 - 16)
    Number of subjects analysed
    248
    496
    Units: percentage of subjects
        number (not applicable)
    2.4
    70.0
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo (Week 0 - 16) v Guselkumab 100 mg (Week 0 - 16)
    Number of subjects included in analysis
    744
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel chi-square test
    Confidence interval

    Secondary: Percentage of Subjects Who Achieved an IGA Score of Cleared (0) in the Guselkumab Group Compared to the Adalimumab Group at Week 24

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    End point title
    Percentage of Subjects Who Achieved an IGA Score of Cleared (0) in the Guselkumab Group Compared to the Adalimumab Group at Week 24
    End point description
    The IGA documents the investigator's assessment of the subject's' psoriasis at a given time point. Overall lesions are graded for induration, erythema, and scaling. The subject's psoriasis was assessed as cleared (0), minimal (1), mild (2), moderate (3), or severe (4). Randomized analysis set included all subjects randomized at Week 0. Nonresponder imputation (subjects who met treatment-failure criteria before Week 24 or who did not come for evaluation at Week 24 were considered nonresponders) was used to impute missing values.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Guselkumab 100 mg Adalimumab
    Number of subjects analysed
    496
    248
    Units: percentage of subjects
        number (not applicable)
    51.8
    31.5
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Guselkumab 100 mg v Adalimumab
    Number of subjects included in analysis
    744
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel chi-square test
    Confidence interval

    Secondary: Percentage of Subjects Who Achieved an IGA Score of Cleared (0) or Minimal (1) in the Guselkumab Group Compared to the Adalimumab Group at Week 24

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    End point title
    Percentage of Subjects Who Achieved an IGA Score of Cleared (0) or Minimal (1) in the Guselkumab Group Compared to the Adalimumab Group at Week 24
    End point description
    The IGA documents the investigator's assessment of the subject's psoriasis at a given time point. Overall lesions are graded for induration, erythema, and scaling. The subject's psoriasis was assessed as cleared (0), minimal (1), mild (2), moderate (3), or severe (4). Randomized analysis set included all subjects randomized at Week 0. Nonresponder imputation (subjects who met treatment-failure criteria before Week 24 or who did not come for evaluation at Week 24 were considered nonresponders) was used to impute missing values.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Guselkumab 100 mg Adalimumab
    Number of subjects analysed
    496
    248
    Units: percentage of subjects
        number (not applicable)
    83.5
    64.9
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Guselkumab 100 mg v Adalimumab
    Number of subjects included in analysis
    744
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel chi-square test
    Confidence interval

    Secondary: Percentage of Subjects Who Achieved PASI 90 Response in the Guselkumab Group Compared to the Adalimumab Group at Week 24

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    End point title
    Percentage of Subjects Who Achieved PASI 90 Response in the Guselkumab Group Compared to the Adalimumab Group at Week 24
    End point description
    The PASI is a system used for assessing and grading the severity of psoriatic lesions. In the PASI system, the body is divided into 4 regions: the head, trunk, upper extremities, and lower extremities. Each of these areas were assessed separately for the percentage of the area involved, which translates to a numeric score that ranges from 0 to 6, and for erythema, induration, and scaling, which are each rated on a scale of 0 to 4. The PASI produces a numeric score that can range from 0 to 72. A higher score indicates more severe disease. A PASI 90 response represents subjects who achieved at least a 90 percent improvement from baseline in the PASI score. Randomized analysis set. Nonresponder imputation (subjects who met treatment-failure criteria before Week 24 or who did not come for evaluation at Week 24 were considered nonresponders) was used to impute missing values.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Guselkumab 100 mg Adalimumab
    Number of subjects analysed
    496
    248
    Units: percentage of subjects
        number (not applicable)
    75.2
    54.8
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Guselkumab 100 mg v Adalimumab
    Number of subjects included in analysis
    744
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel chi-square test
    Confidence interval

    Secondary: Cumulative Maintenance Rate of PASI 90 Response in the Placebo Group Compared to the Guselkumab Group Through Week 48 to Evaluate Loss of a PASI 90 Response

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    End point title
    Cumulative Maintenance Rate of PASI 90 Response in the Placebo Group Compared to the Guselkumab Group Through Week 48 to Evaluate Loss of a PASI 90 Response
    End point description
    The PASI is a system used for assessing and grading the severity of psoriatic lesions. In the PASI system, the body is divided into 4 regions: the head, trunk, upper extremities, and lower extremities. Each of these areas were assessed separately for the percentage of the area involved, which translates to a numeric score that ranges from 0 to 6, and for erythema, induration, and scaling, which are each rated on a scale of 0 to 4. The PASI produces a numeric score that can range from 0 to 72. A higher score indicates more severe disease. A PASI 90 response represents subjects who achieved at least a 90 percent improvement from baseline in the PASI score. Cumulative maintenance rate was defined as percentage of subjects who maintained their PASI 90 response through Week 48. Randomized analysis set who achieved a PASI 90 response at Week 28, were re-randomized to continue guselkumab or receive placebo and with at least one PASI assessment post Week 28.
    End point type
    Secondary
    End point timeframe
    Through Week 48
    End point values
    Withdrawal Group (Through Week 72) Guselkumab Maintenance Group (Through Week 72)
    Number of subjects analysed
    181
    193
    Units: percentage of subjects
        number (not applicable)
    35.4
    81.8
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    p value is based on the log-rank test stratified by investigator site (pooled).
    Comparison groups
    Withdrawal Group (Through Week 72) v Guselkumab Maintenance Group (Through Week 72)
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Logrank
    Confidence interval

    Secondary: Change From Baseline in Dermatology Life Quality Index (DLQI) Score at Week 16 in the Guselkumab Group Compared to the Placebo Group

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    End point title
    Change From Baseline in Dermatology Life Quality Index (DLQI) Score at Week 16 in the Guselkumab Group Compared to the Placebo Group [3]
    End point description
    The DLQI is a 10-item questionnaire that measures the impact of skin disease on participant's quality of life (QoL). Each question was evaluated on a 4-point scale ranging from 0 (not at all) to 3 (very much); where higher scores indicate more impact on QoL. The DLQI total score ranges from 0 (not at all) to 30 (very much): 0-1 = no effect at all on the subject's life; 2-6 = small effect on the subject's life; 7-12 = moderate effect on the subject's life; 13-18 = very large effect on the subject's life; 19-30 = extremely large effect on the subject's life. Higher scores indicate more impact on QoL of subjects. Randomized analysis set included all subjects who were randomized at Week 0 and with a baseline DLQI score.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    Placebo (Week 0 - 16) Guselkumab 100 mg (Week 0 - 16)
    Number of subjects analysed
    248
    495
    Units: units on a scale
        arithmetic mean (standard deviation)
    -2.6 ± 6.85
    -11.23 ± 6.82
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    p value is based on analysis of variance (ANOVA) model stratified by investigator site (pooled).
    Comparison groups
    Placebo (Week 0 - 16) v Guselkumab 100 mg (Week 0 - 16)
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANOVA
    Confidence interval

    Secondary: Percentage of Subjects Who Achieved an IGA Score of Cleared (0) or Minimal (1) in the Guselkumab Group Compared to the Adalimumab Group at Week 16

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    End point title
    Percentage of Subjects Who Achieved an IGA Score of Cleared (0) or Minimal (1) in the Guselkumab Group Compared to the Adalimumab Group at Week 16 [4]
    End point description
    The IGA documents the investigator's assessment of the subject's psoriasis at a given time point. Overall lesions are graded for induration, erythema, and scaling. The subject's psoriasis was assessed as cleared (0), minimal (1), mild (2), moderate (3), or severe (4). Randomized analysis set included all subjects who were randomized at Week 0. Nonresponder imputation (subjects who met treatment-failure criteria before Week 16 or who did not come for evaluation at week 16 were considered nonresponders) was used to impute missing values.
    End point type
    Secondary
    End point timeframe
    Week 16
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    Guselkumab 100 mg (Week 0 - 16) Adalimumab (Week 0 - 16)
    Number of subjects analysed
    496
    248
    Units: percentage of subjects
        number (not applicable)
    84.1
    67.7
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    p value is based on 1-sided Mantel Haenszel (MH) Z-test adjusted for investigator site (pooled).
    Comparison groups
    Guselkumab 100 mg (Week 0 - 16) v Adalimumab (Week 0 - 16)
    Number of subjects included in analysis
    744
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [5]
    P-value
    < 0.001
    Method
    MH Z-test
    Parameter type
    Difference in Percentage
    Point estimate
    16.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    10
         upper limit
    23.2
    Notes
    [5] - non-inferiority margin= -10.0%
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    p value is based on the Cochran-Mantel-Haenszel chi-square test stratified by investigator site (pooled).
    Comparison groups
    Guselkumab 100 mg (Week 0 - 16) v Adalimumab (Week 0 - 16)
    Number of subjects included in analysis
    744
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel chi-square test
    Confidence interval

    Secondary: Percentage of Subjects Who Achieved PASI 90 Response, in the Guselkumab Group Compared to the Adalimumab Group at Week 16

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    End point title
    Percentage of Subjects Who Achieved PASI 90 Response, in the Guselkumab Group Compared to the Adalimumab Group at Week 16 [6]
    End point description
    The PASI is a system used for assessing and grading the severity of psoriatic lesions. In the PASI system, the body is divided into 4 regions: the head, trunk, upper extremities, and lower extremities. Each of these areas were assessed separately for the percentage of the area involved, which translates to a numeric score that ranges from 0 to 6, and for erythema, induration, and scaling, which are each rated on a scale of 0 to 4. The PASI produces a numeric score that can range from 0 to 72. A higher score indicates more severe disease. A PASI 90 response represents subjects who achieved at least a 90 percent improvement from baseline in the PASI score. Randomized analysis set included all subjects who were randomized at Week 0. Nonresponder imputation (subjects who met treatment-failure criteria before Week 16 or who did not come for evaluation at week 16 were considered nonresponders) was used to impute missing values.
    End point type
    Secondary
    End point timeframe
    Week 16
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    Guselkumab 100 mg (Week 0 - 16) Adalimumab (Week 0 - 16)
    Number of subjects analysed
    495
    248
    Units: percentage of subjects
        number (not applicable)
    70.0
    46.8
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    p value is based on the Cochran-Mantel-Haenszel chi-square test stratified by investigator site (pooled).
    Comparison groups
    Guselkumab 100 mg (Week 0 - 16) v Adalimumab (Week 0 - 16)
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel chi-square test
    Confidence interval
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    p value is based on 1-sided MH Z-test adjusted for investigator site (pooled).
    Comparison groups
    Guselkumab 100 mg (Week 0 - 16) v Adalimumab (Week 0 - 16)
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [7]
    P-value
    < 0.001
    Method
    MH Z-test
    Parameter type
    Difference in Percentage
    Point estimate
    23.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    16
         upper limit
    30.4
    Notes
    [7] - non-inferiority margin= -10.0%

    Secondary: Percentage of Subjects Who Achieved PASI 75 Response in the Guselkumab Group Compared to the Adalimumab Group at Week 16

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    End point title
    Percentage of Subjects Who Achieved PASI 75 Response in the Guselkumab Group Compared to the Adalimumab Group at Week 16 [8]
    End point description
    The PASI is a system used for assessing and grading the severity of psoriatic lesions. In the PASI system, the body is divided into 4 regions: the head, trunk, upper extremities, and lower extremities. Each of these areas were assessed separately for the percentage of the area involved, which translates to a numeric score that ranges from 0 to 6, and for erythema, induration, and scaling, which are each rated on a scale of 0 to 4. The PASI produces a numeric score that can range from 0 to 72. A higher score indicates more severe disease. A PASI 75 response represents subjects who achieved at least a 75 percent improvement from baseline in the PASI score. Randomized analysis set. Nonresponder imputation (subjects who met treatment-failure criteria before Week 16 or who did not come for evaluation at week 16 were considered nonresponders) was used to impute missing values.
    End point type
    Secondary
    End point timeframe
    Week 16
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    Guselkumab 100 mg (Week 0 - 16) Adalimumab (Week 0 - 16)
    Number of subjects analysed
    496
    248
    Units: percentage of subjects
        number (not applicable)
    86.3
    68.5
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    p value is based on the Cochran-Mantel-Haenszel chi-square test stratified by investigator site (pooled).
    Comparison groups
    Guselkumab 100 mg (Week 0 - 16) v Adalimumab (Week 0 - 16)
    Number of subjects included in analysis
    744
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel chi-square test
    Confidence interval
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    p value is based on 1-sided MH Z-test adjusted for investigator site (pooled).
    Comparison groups
    Guselkumab 100 mg (Week 0 - 16) v Adalimumab (Week 0 - 16)
    Number of subjects included in analysis
    744
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [9]
    P-value
    < 0.001
    Method
    MH Z-test
    Parameter type
    Difference in percentage
    Point estimate
    17.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.4
         upper limit
    24.4
    Notes
    [9] - non-inferiority margin= -10%

    Secondary: Percentage of Subjects who Achieved a Scalp-specific Investigator's Global Assessment (ss-IGA) Score of 0 or 1 and at Least a 2-Grade Improvement From Baseline at Week 16 in the Guselkumab Group Compared to the Placebo Group

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    End point title
    Percentage of Subjects who Achieved a Scalp-specific Investigator's Global Assessment (ss-IGA) Score of 0 or 1 and at Least a 2-Grade Improvement From Baseline at Week 16 in the Guselkumab Group Compared to the Placebo Group [10]
    End point description
    The ss-IGA instrument is used to evaluate the disease severity of scalp psoriasis. The lesions were assessed in terms of the clinical signs of redness, thickness, and scaliness, which are scored on a 5-point scale ranging from 0 = absence of disease, 1 = very mild disease, 2 = mild disease, 3 = moderate disease, and 4 = severe disease. Population analyzed included only randomized subjects who had an ss-IGA score greater than or equal to (>=) 2 at baseline. Here, N (Number of subjects analyzed) signifies subjects who were analyzed for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 16
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    Placebo (Week 0 - 16) Guselkumab 100 mg (Week 0 - 16)
    Number of subjects analysed
    202
    408
    Units: percentage of subjects
        number (not applicable)
    10.9
    80.6
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    p value is based on the Cochran-Mantel-Haenszel chi-square test stratified by investigator site (pooled).
    Comparison groups
    Placebo (Week 0 - 16) v Guselkumab 100 mg (Week 0 - 16)
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel chi-square test
    Confidence interval

    Secondary: Change From Baseline in Psoriasis Symptom and Sign Diary (PSSD) Symptom Score at Week 16 in the Guselkumab Group Compared to the Placebo Group

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    End point title
    Change From Baseline in Psoriasis Symptom and Sign Diary (PSSD) Symptom Score at Week 16 in the Guselkumab Group Compared to the Placebo Group [11]
    End point description
    The PSSD consisted of 11 items covering symptoms (itch, pain, stinging, burning, and skin tightness) and patient-observable signs (skin dryness, cracking, scaling, shedding or flaking, redness, and bleeding) using 0 (absent) to 10 (worst imaginable) numerical rating scales for severity. The average value is converted into 0-100 scoring, such that Symptom [or Sign] score=average value*10, where, 0=least severe and 100=most severe and higher score indicates more severe disease. PSSD analysis set included all subjects who had baseline PSSD scores as the average score of at least 4 days out of the 7 days prior to the Week 0 visit. This endpoint was planned to be compared only for groups Placebo and Guselkumab 100 mg.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    Placebo (Week 0 - 16) Guselkumab 100 mg (Week 0 - 16)
    Number of subjects analysed
    198
    411
    Units: units on a scale
        arithmetic mean (standard deviation)
    -8.3 ± 23.67
    -40.4 ± 26.52
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    p value is based on ANOVA model stratified by investigator site (pooled).
    Comparison groups
    Placebo (Week 0 - 16) v Guselkumab 100 mg (Week 0 - 16)
    Number of subjects included in analysis
    609
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANOVA
    Confidence interval

    Secondary: Percentage of Subjects who Achieved a PSSD Symptom Score of 0 in the Guselkumab Group Compared to the Adalimumab Group at Week 24

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    End point title
    Percentage of Subjects who Achieved a PSSD Symptom Score of 0 in the Guselkumab Group Compared to the Adalimumab Group at Week 24
    End point description
    The PSSD consisted of 11 items covering symptoms (itch, pain, stinging, burning, and skin tightness) and patient-observable signs (skin dryness, cracking, scaling, shedding or flaking, redness, and bleeding) using 0 (absent) to 10 (worst imaginable) numerical rating scales for severity. The average value is converted into 0-100 scoring, such that Symptom [or Sign] score=average value*10, where, 0=least severe and 100=most severe and higher score indicates more severe disease. PSSD analysis set included all subjects who were randomized at Week 0 and had baseline PSSD score greater than 0. This endpoint was planned to be compared only for groups Placebo and Guselkumab 100 mg.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Guselkumab 100 mg Adalimumab
    Number of subjects analysed
    410
    200
    Units: percentage of subjects
        number (not applicable)
    35.1
    22.5
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    p value is based on the Cochran-Mantel-Haenszel chi-square test stratified by investigator site (pooled).
    Comparison groups
    Guselkumab 100 mg v Adalimumab
    Number of subjects included in analysis
    610
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel chi-square test
    Confidence interval

    Secondary: Cumulative Maintenance Rate of PASI 90 Response in the Guselkumab Withdrawal Group Compared to the Guselkumab Maintenance Group Through Week 72 to Evaluate Loss of a PASI 90 Response

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    End point title
    Cumulative Maintenance Rate of PASI 90 Response in the Guselkumab Withdrawal Group Compared to the Guselkumab Maintenance Group Through Week 72 to Evaluate Loss of a PASI 90 Response
    End point description
    In PASI system, body is divided into 4 regions: head, trunk, upper and lower extremities. Each of these areas were assessed separately for the percentage of the area involved, which translates to a numeric score ranging from 0 to 6 and for erythema, induration, and scaling, which are each rated on a scale of 0 to 4. PASI produces a numeric score ranging from 0 to 72. Higher score=more severe disease. PASI 90 response represents subjects who achieved at least a 90 percent improvement from baseline in PASI score. Cumulative maintenance rate was determined for subjects who were withdrawn from study medication and who maintained guselkumab every 8 weeks dosing schedule and was defined as percentage of subjects who maintained their PASI 90 response through Week 72. Population analyzed included PASI 90 responders at Week 28 and who were randomized at Week 28 and treated with guselkumab. Here, N (Number of subjects analyzed) signifies subjects who were analyzed for this endpoint.
    End point type
    Secondary
    End point timeframe
    Through Week 72
    End point values
    Withdrawal Group (Through Week 72) Guselkumab Maintenance Group (Through Week 72)
    Number of subjects analysed
    181
    193
    Units: percentage of subjects
        number (not applicable)
    11.5
    86
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved PASI 90 Response at Week 252

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    End point title
    Percentage of Subjects Who Achieved PASI 90 Response at Week 252
    End point description
    In PASI system, body is divided into 4 regions: head, trunk, upper and lower extremities. Each of these areas were assessed separately for the percentage of the area involved, which translates to a numeric score ranging from 0 to 6, and for erythema, induration, and scaling, which are each rated on a scale of 0 to 4. PASI produces a numeric score that can range from 0 to 72. Higher score= more severe disease. PASI 90 response signify subjects who achieved at least a 90 percent improvement from baseline in the PASI score. Population analyzed included subjects who were randomized at Week 0 and treated with guselkumab. The analysis was performed using observed data after applying treatment failure rules. Here, N (Number of subjects analyzed) signifies subjects who were analyzed for this endpoint. As per planned analysis, subjects from the baseline guselkumab group and the placebo crossover group were combined into a single guselkumab group for assessment of this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 252
    End point values
    Guselkumab Combined Adalimumab then Guselkumab 100 mg (Week 28 - 264)
    Number of subjects analysed
    560
    177
    Units: percentage of subjects
        number (not applicable)
    82.0
    79.1
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved PASI 75 Response at Week 252

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    End point title
    Percentage of Subjects Who Achieved PASI 75 Response at Week 252
    End point description
    In PASI system, body is divided into 4 regions: head, trunk, upper and lower extremities. Each of these areas were assessed separately for the percentage of the area involved, which translates to a numeric score ranging from 0 to 6, and for erythema, induration, and scaling, which are each rated on a scale of 0 to 4. PASI produces a numeric score that can range from 0 to 72. Higher score= more severe disease. PASI 75 response signify subjects who achieved at least a 75 percent improvement from baseline in the PASI score. Population analyzed included subjects who were randomized at Week 0 and treated with guselkumab. The analysis was performed using observed data after applying treatment failure rules. Here, N (Number of subjects analyzed) signifies subjects who were analyzed for this endpoint. As per planned analysis, subjects from the baseline guselkumab group and the placebo crossover group were combined into a single guselkumab group for assessment of this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 252
    End point values
    Guselkumab Combined Adalimumab then Guselkumab 100 mg (Week 28 - 264)
    Number of subjects analysed
    560
    177
    Units: percentage of subjects
        number (not applicable)
    93.4
    92.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved an IGA Score of Cleared (0) or Minimal (1) at Week 252

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    End point title
    Percentage of Subjects Who Achieved an IGA Score of Cleared (0) or Minimal (1) at Week 252
    End point description
    The IGA documents the investigator's assessment of the subject's psoriasis at a given time point. Overall lesions are graded for induration, erythema, and scaling. The subject’s psoriasis was assessed as cleared (0), minimal (1), mild (2), moderate (3), or severe (4). Population analyzed included subjects who were randomized at Week 0 and treated with guselkumab. The analysis was performed using observed data after applying treatment failure rules. Here, N (Number of subjects analyzed) signifies subjects who were analyzed for this endpoint. As per planned analysis, subjects from the baseline guselkumab group and the placebo crossover group were combined into a single guselkumab group for assessment of this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 252
    End point values
    Guselkumab Combined Adalimumab then Guselkumab 100 mg (Week 28 - 264)
    Number of subjects analysed
    559
    177
    Units: percentage of subjects
        number (not applicable)
    85.0
    83.1
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with a DLQI Score of 0 or 1 at Week 252

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    End point title
    Percentage of Subjects with a DLQI Score of 0 or 1 at Week 252
    End point description
    DLQI measures impact of skin disease on subject's QoL. Each question was evaluated on a 4-point scale ranging from 0 (not at all) to 3 (very much). DLQI total score ranges from 0 (not at all) to 30 (very much): 0-1=no effect on subject's life; 2-6=small effect; 7-12=moderate effect; 13-18=very large effect; 19-30=extremely large effect. DLQI was calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. Higher scores indicate more impact on subject's QoL. Population analyzed included subjects randomized at Week 0 and treated with guselkumab with baseline DLQI score >1. The analysis was performed using observed data after applying treatment failure rules. Here, N (Number of subjects analyzed) signifies subjects who were analyzed for this endpoint. As per planned analysis, subjects from the baseline guselkumab group and the placebo crossover group were combined into a single guselkumab group for assessment of this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 252
    End point values
    Guselkumab Combined Adalimumab then Guselkumab 100 mg (Week 28 - 264)
    Number of subjects analysed
    550
    173
    Units: percentage of subjects
        number (not applicable)
    71.1
    69.9
    No statistical analyses for this end point

    Secondary: Percentage of Subjects who Achieved a PSSD Symptom Score of 0 at Week 252

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    End point title
    Percentage of Subjects who Achieved a PSSD Symptom Score of 0 at Week 252
    End point description
    The PSSD consisted of 11 items covering symptoms (itch, pain, stinging, burning, and skin tightness) and patient-observable signs (skin dryness, cracking, scaling, shedding or flaking, redness, and bleeding) using 0 (absent) to 10 (worst imaginable) numerical rating scales for severity. The average value is converted into 0-100 scoring, such that Symptom score=average value*10, where, 0=least severe and 100=most severe and higher score indicates more severe disease. Population analyzed included subjects who were randomized at Week 0 and treated with guselkumab with baseline PSSD symptom score >0. The analysis was performed using observed data after applying treatment failure rules. Here, N (Number of subjects analyzed) signifies subjects who were analyzed for this endpoint. As per planned analysis, subjects from the baseline guselkumab group and the placebo crossover group were combined into a single guselkumab group for assessment of this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 252
    End point values
    Guselkumab Combined Adalimumab then Guselkumab 100 mg (Week 28 - 264)
    Number of subjects analysed
    460
    145
    Units: percentage of subjects
        number (not applicable)
    42.0
    36.6
    No statistical analyses for this end point

    Secondary: Percentage of Subjects who Achieved a PSSD Sign Score of 0 at Week 252

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    End point title
    Percentage of Subjects who Achieved a PSSD Sign Score of 0 at Week 252
    End point description
    The PSSD consisted of 11 items covering symptoms (itch, pain, stinging, burning, and skin tightness) and patient-observable signs (skin dryness, cracking, scaling, shedding or flaking, redness, and bleeding) using 0 (absent) to 10 (worst imaginable) numerical rating scales for severity. The average value is converted into 0-100 scoring, such that Sign score=average value*10, where, 0=least severe and 100=most severe and higher score indicates more severe disease. Population analyzed included subjects who were randomized at Week 0 and treated with guselkumab with baseline PSSD sign score >0. The analysis was performed using observed data after applying treatment failure rules. Here, N (Number of subjects analyzed) signifies subjects who were analyzed for this endpoint. As per planned analysis, subjects from the baseline guselkumab group and the placebo crossover group were combined into a single guselkumab group for assessment of this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 252
    End point values
    Guselkumab Combined Adalimumab then Guselkumab 100 mg (Week 28 - 264)
    Number of subjects analysed
    461
    145
    Units: percentage of subjects
        number (not applicable)
    31.0
    24.1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline (Week 0) up to Week 264
    Adverse event reporting additional description
    All subjects who were randomized at Week 0, received >=1 dose of study agent (partial or complete). Subjects who discontinued treatment prematurely were followed for at least 12 weeks after last dose and who discontinued in the previous period and had safety follow-up continuing in the current period, were counted in both the periods.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Guselkumab 100 mg (Week 0 - 16)
    Reporting group description
    Subjects received guselkumab 100 milligram (mg) SC injection at Weeks 0, 4 and 12, and placebo matched to adalimumab (2 SC injections) at Week 0 followed by placebo matched to adalimumab (1 SC injection) at Week 1 and every other week thereafter through Week 15 during PCP.

    Reporting group title
    Placebo (Week 0 - 16)
    Reporting group description
    Subjects received placebo matched to guselkumab SC injection at Weeks 0, 4, and 12 and placebo matched to adalimumab (2 SC injections) at Week 0, followed by placebo matched to adalimumab (1 SC injection) at Week 1 and every other week thereafter through Week 15 to maintain the blind during placebo controlled period (PCP).

    Reporting group title
    Placebo then Guselkumab 100 mg (Week 16 - 28)
    Reporting group description
    Subjects who started receiving placebo in the first period were crossed over to receive guselkumab 100 mg SC injection at Weeks 16 and 20 and placebo matched to adalimumab (1 SC injection) at Weeks 17, 19, 21, and 23 during the active comparator controlled period (ACP).

    Reporting group title
    Adalimumab (Week 0 - 16)
    Reporting group description
    Subjects received adalimumab 80 mg (2 SC injections) at Week 0 followed by adalimumab 40 mg (1 SC injection) at Week 1 and every other week thereafter through Week 15 and placebo matched to guselkumab SC injection at Weeks 0, 4, and 12 during PCP.

    Reporting group title
    Guselkumab 100 mg (Week 16 - 28)
    Reporting group description
    Subjects who started receiving guselkumab in the first period, received placebo matched to guselkumab SC injection at Week 16 followed by guselkumab 100 mg SC injection at Week 20 and placebo matched to adalimumab (1 SC injection) at Weeks 17, 19, 21 and 23.

    Reporting group title
    Adalimumab (Week 16 - 28)
    Reporting group description
    Subjects who received adalimumab in the first period, continued to receive adalimumab 40 mg (1 SC injection) every 2 weeks (q2w) from Week 17 through Week 23 and placebo matched to guselkumab SC injection at Weeks 16 and 20.

    Reporting group title
    Placebo then Guselkumab 100 mg (Week 28 - 264)
    Reporting group description
    Subjects assigned to the placebo, then guselkumab arm through Week 28 were assessed for PASI 90 response at Week 28. Subjects who were PASI 90 non-responders received guselkumab 100 mg SC injection at Week 28 and then every 8 weeks (q8w) thereafter through Week 72 and placebo matched to guselkumab SC injection at Week 32 and then q8w through Week 72. Subjects who were PASI 90 responders at Week 28 received placebo matched to guselkumab SC injection at Week 28 and every 4 weeks (q4w) thereafter through Week 72 or until loss of greater than or equal to (>=) 50 percentage (%) in the improvement in PASI (Withdrawal and retreatment period). If they lost response according to this definition, they were retreated with guselkumab. Thereafter, subjects received guselkumab 100 mg at Week 76 and then q8w through Week 252.

    Reporting group title
    Guselkumab 100 mg (Week 28 - 264)
    Reporting group description
    Subjects assigned to the guselkumab arm through Week 28 were assessed for PASI 90 response at Week 28. Subjects who were PASI 90 non-responders at Week 28 received guselkumab 100 mg SC injection at Week 28 and q8w thereafter through Week 72 and placebo matched to guselkumab at Week 32 and then q8w through Week 72. Subjects who were PASI 90 responders were re-randomized to either guselkumab or placebo. Subjects re-randomized to guselkumab, received guselkumab 100 mg SC injection at Week 28 and q8w thereafter through Week 72 and placebo matched to guselkumab SC injection at Weeks 32 and then q8w through Week 72. Subjects re-randomized to placebo, received placebo matched to guselkumab SC injection q4w through Week 72 or until loss of >=50% in the improvement in PASI (Withdrawal and retreatment period). If they lost response according to this definition, they were retreated with guselkumab. Thereafter, subjects received guselkumab 100 mg at Week 76 and then q8w through Week 252.

    Reporting group title
    Adalimumab Then Guselkumab 100 mg (Week 28 - 264)
    Reporting group description
    Subjects who were assigned to the adalimumab arm through Week 28 were assessed for PASI 90 response at Week 28. Subjects who were PASI 90 non-responders received guselkumab 100 mg SC injection at Week 28 and 32 and q8w thereafter through Week 72 and placebo matched to guselkumab SC injection at Week 36 and q8w through Week 72. Subjects who were PASI 90 responders, received placebo matched to guselkumab SC injection q4w thereafter through Week 72 or until loss of >=50% in the improvement in PASI. If they lost response according to this definition, they were treated with guselkumab. Thereafter, subjects received guselkumab 100 mg at Week 76 and then q8w through Week 252. The presentation of data from the adalimumab group from Week 28 to Week 264 is divided into 2 arms (adalimumab then guselkumab 100 mg (Week 28 - 264) and adalimumab (After ACP) in order to represent exposure to 2 different active study agents (adalimumab vs guselkumab).

    Reporting group title
    Adalimumab (After ACP)
    Reporting group description
    Subjects who received adalimumab 80 mg at Week 0 and adalimumab 40 mg at Week 1 and every other week through Week 23 were assessed for PASI 90 response at Week 28. PASI 90 responders who did not crossover to guselkumab upon loss of >=50% in the improvement in PASI and did not continue any treatment at Week 28 are reported in this arm.

    Serious adverse events
    Guselkumab 100 mg (Week 0 - 16) Placebo (Week 0 - 16) Placebo then Guselkumab 100 mg (Week 16 - 28) Adalimumab (Week 0 - 16) Guselkumab 100 mg (Week 16 - 28) Adalimumab (Week 16 - 28) Placebo then Guselkumab 100 mg (Week 28 - 264) Guselkumab 100 mg (Week 28 - 264) Adalimumab Then Guselkumab 100 mg (Week 28 - 264) Adalimumab (After ACP)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 494 (1.62%)
    3 / 248 (1.21%)
    5 / 233 (2.15%)
    6 / 248 (2.42%)
    10 / 481 (2.08%)
    3 / 240 (1.25%)
    36 / 229 (15.72%)
    66 / 473 (13.95%)
    36 / 220 (16.36%)
    1 / 11 (9.09%)
         number of deaths (all causes)
    0
    1
    1
    3
    0
    3
    1
    0
    3
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-Cell Lymphoma
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign Neoplasm of Thyroid Gland
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast Cancer
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    2 / 229 (0.87%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial Carcinoma
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Endometrial Cancer
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ependymoma
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibroadenoma of Breast
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inflammatory Pseudotumour
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    1 / 233 (0.43%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant Melanoma
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteochondroma
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic Carcinoma Stage Iv
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate Cancer
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    1 / 481 (0.21%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal Cancer
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinonasal Papilloma
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine Leiomyoma
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    2 / 229 (0.87%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicose Vein
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Spontaneous
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ectopic Pregnancy
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 494 (0.20%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden Death
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Immune system disorders
    Anaphylactic Reaction
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug Hypersensitivity
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    1 / 233 (0.43%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Miscarriage of Partner
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian Cyst
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    1 / 481 (0.21%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine Haemorrhage
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Nasal Septum Deviation
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    2 / 473 (0.42%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Fibrosis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus Polyp
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sleep Apnoea Syndrome
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Device Dislocation
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alcoholism
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    1 / 248 (0.40%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 494 (0.20%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Chest Injury
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    1 / 233 (0.43%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral Injury
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye Injury
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head Injury
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint Dislocation
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament Rupture
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament Sprain
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower Limb Fracture
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus Injury
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple Fractures
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    1 / 233 (0.43%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple Injuries
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nerve Injury
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius Fracture
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Cord Injury Cervical
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural Haematoma
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural Haemorrhage
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    1 / 233 (0.43%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulnar Nerve Injury
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    1 / 233 (0.43%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    1 / 481 (0.21%)
    0 / 240 (0.00%)
    2 / 229 (0.87%)
    4 / 473 (0.85%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    1 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    1 / 248 (0.40%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    1 / 494 (0.20%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    1 / 481 (0.21%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    1 / 494 (0.20%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    1 / 248 (0.40%)
    1 / 481 (0.21%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    2 / 220 (0.91%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Myocardial Ischaemia
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebellar Stroke
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic Coma
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    1 / 240 (0.42%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelitis Transverse
         subjects affected / exposed
    1 / 494 (0.20%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelopathy
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral Nerve Lesion
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral Nerve Paresis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    1 / 233 (0.43%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    1 / 233 (0.43%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    1 / 481 (0.21%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal Vein Occlusion
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal Perforation
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    1 / 248 (0.40%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 494 (0.00%)
    1 / 248 (0.40%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal Haemorrhage
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    1 / 248 (0.40%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    2 / 473 (0.42%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Irritable Bowel Syndrome
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mallory-Weiss Syndrome
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    1 / 481 (0.21%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Submaxillary Gland Enlargement
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical Hernia
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis Acute
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    2 / 220 (0.91%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis Chronic
         subjects affected / exposed
    0 / 494 (0.00%)
    1 / 248 (0.40%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    2 / 473 (0.42%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    2 / 220 (0.91%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic Steatosis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    1 / 481 (0.21%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Colic
         subjects affected / exposed
    1 / 494 (0.20%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Retention
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral Disc Protrusion
         subjects affected / exposed
    1 / 494 (0.20%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular Weakness
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal Pain
         subjects affected / exposed
    0 / 494 (0.00%)
    1 / 248 (0.40%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    2 / 473 (0.42%)
    3 / 220 (1.36%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psoriatic Arthropathy
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    1 / 248 (0.40%)
    0 / 481 (0.00%)
    1 / 240 (0.42%)
    1 / 229 (0.44%)
    3 / 473 (0.63%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    0 / 1
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator Cuff Syndrome
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    2 / 229 (0.87%)
    4 / 473 (0.85%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis Perforated
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    1 / 481 (0.21%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    4 / 473 (0.85%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic Sinusitis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic Tonsillitis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disseminated Tuberculosis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    1 / 248 (0.40%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 494 (0.20%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hiv Infection
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injection Site Abscess
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    1 / 248 (0.40%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonsillar Abscess
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pilonidal Cyst
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    1 / 229 (0.44%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    2 / 229 (0.87%)
    2 / 473 (0.42%)
    2 / 220 (0.91%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    1 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal Abscess
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    1 / 220 (0.45%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft Tissue Infection
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    1 / 481 (0.21%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    1 / 240 (0.42%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vestibular Neuronitis
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound Infection
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    1 / 233 (0.43%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Obesity
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    1 / 473 (0.21%)
    0 / 220 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Guselkumab 100 mg (Week 0 - 16) Placebo (Week 0 - 16) Placebo then Guselkumab 100 mg (Week 16 - 28) Adalimumab (Week 0 - 16) Guselkumab 100 mg (Week 16 - 28) Adalimumab (Week 16 - 28) Placebo then Guselkumab 100 mg (Week 28 - 264) Guselkumab 100 mg (Week 28 - 264) Adalimumab Then Guselkumab 100 mg (Week 28 - 264) Adalimumab (After ACP)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    125 / 494 (25.30%)
    60 / 248 (24.19%)
    33 / 233 (14.16%)
    51 / 248 (20.56%)
    63 / 481 (13.10%)
    45 / 240 (18.75%)
    144 / 229 (62.88%)
    297 / 473 (62.79%)
    159 / 220 (72.27%)
    4 / 11 (36.36%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    10 / 494 (2.02%)
    4 / 248 (1.61%)
    1 / 233 (0.43%)
    6 / 248 (2.42%)
    4 / 481 (0.83%)
    1 / 240 (0.42%)
    27 / 229 (11.79%)
    43 / 473 (9.09%)
    20 / 220 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    11
    4
    1
    6
    4
    1
    30
    51
    23
    0
    Cardiac disorders
    Cardiac Failure Congestive
         subjects affected / exposed
    0 / 494 (0.00%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    0 / 481 (0.00%)
    0 / 240 (0.00%)
    0 / 229 (0.00%)
    0 / 473 (0.00%)
    0 / 220 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    25 / 494 (5.06%)
    7 / 248 (2.82%)
    5 / 233 (2.15%)
    5 / 248 (2.02%)
    6 / 481 (1.25%)
    4 / 240 (1.67%)
    9 / 229 (3.93%)
    31 / 473 (6.55%)
    17 / 220 (7.73%)
    0 / 11 (0.00%)
         occurrences all number
    27
    7
    5
    6
    6
    4
    18
    44
    25
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    11 / 494 (2.23%)
    2 / 248 (0.81%)
    0 / 233 (0.00%)
    4 / 248 (1.61%)
    3 / 481 (0.62%)
    3 / 240 (1.25%)
    11 / 229 (4.80%)
    15 / 473 (3.17%)
    12 / 220 (5.45%)
    0 / 11 (0.00%)
         occurrences all number
    12
    2
    0
    4
    3
    3
    13
    16
    14
    0
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    1 / 494 (0.20%)
    0 / 248 (0.00%)
    0 / 233 (0.00%)
    1 / 248 (0.40%)
    1 / 481 (0.21%)
    2 / 240 (0.83%)
    2 / 229 (0.87%)
    12 / 473 (2.54%)
    4 / 220 (1.82%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    1
    1
    2
    2
    13
    7
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 494 (1.62%)
    4 / 248 (1.61%)
    1 / 233 (0.43%)
    1 / 248 (0.40%)
    2 / 481 (0.42%)
    2 / 240 (0.83%)
    10 / 229 (4.37%)
    16 / 473 (3.38%)
    13 / 220 (5.91%)
    1 / 11 (9.09%)
         occurrences all number
    8
    4
    1
    1
    2
    2
    12
    22
    16
    1
    Skin and subcutaneous tissue disorders
    Dermatitis Contact
         subjects affected / exposed
    4 / 494 (0.81%)
    2 / 248 (0.81%)
    0 / 233 (0.00%)
    1 / 248 (0.40%)
    2 / 481 (0.42%)
    0 / 240 (0.00%)
    2 / 229 (0.87%)
    11 / 473 (2.33%)
    6 / 220 (2.73%)
    1 / 11 (9.09%)
         occurrences all number
    4
    2
    0
    1
    2
    0
    2
    14
    6
    1
    Psoriasis
         subjects affected / exposed
    1 / 494 (0.20%)
    3 / 248 (1.21%)
    0 / 233 (0.00%)
    5 / 248 (2.02%)
    1 / 481 (0.21%)
    1 / 240 (0.42%)
    3 / 229 (1.31%)
    8 / 473 (1.69%)
    9 / 220 (4.09%)
    1 / 11 (9.09%)
         occurrences all number
    1
    3
    0
    6
    1
    1
    3
    10
    9
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 494 (2.23%)
    6 / 248 (2.42%)
    0 / 233 (0.00%)
    2 / 248 (0.81%)
    8 / 481 (1.66%)
    6 / 240 (2.50%)
    17 / 229 (7.42%)
    46 / 473 (9.73%)
    22 / 220 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    12
    6
    0
    2
    8
    7
    36
    56
    32
    0
    Back Pain
         subjects affected / exposed
    4 / 494 (0.81%)
    6 / 248 (2.42%)
    0 / 233 (0.00%)
    0 / 248 (0.00%)
    6 / 481 (1.25%)
    0 / 240 (0.00%)
    18 / 229 (7.86%)
    25 / 473 (5.29%)
    16 / 220 (7.27%)
    1 / 11 (9.09%)
         occurrences all number
    4
    6
    0
    0
    7
    0
    26
    32
    16
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 494 (0.61%)
    3 / 248 (1.21%)
    6 / 233 (2.58%)
    5 / 248 (2.02%)
    3 / 481 (0.62%)
    3 / 240 (1.25%)
    15 / 229 (6.55%)
    23 / 473 (4.86%)
    21 / 220 (9.55%)
    0 / 11 (0.00%)
         occurrences all number
    3
    3
    7
    6
    3
    3
    16
    28
    23
    0
    Gastroenteritis
         subjects affected / exposed
    4 / 494 (0.81%)
    1 / 248 (0.40%)
    0 / 233 (0.00%)
    5 / 248 (2.02%)
    1 / 481 (0.21%)
    0 / 240 (0.00%)
    11 / 229 (4.80%)
    16 / 473 (3.38%)
    11 / 220 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    4
    1
    0
    5
    1
    0
    12
    18
    13
    0
    Nasopharyngitis
         subjects affected / exposed
    35 / 494 (7.09%)
    16 / 248 (6.45%)
    12 / 233 (5.15%)
    20 / 248 (8.06%)
    18 / 481 (3.74%)
    16 / 240 (6.67%)
    67 / 229 (29.26%)
    142 / 473 (30.02%)
    81 / 220 (36.82%)
    0 / 11 (0.00%)
         occurrences all number
    36
    17
    12
    20
    19
    17
    160
    296
    175
    0
    Pharyngitis
         subjects affected / exposed
    7 / 494 (1.42%)
    2 / 248 (0.81%)
    2 / 233 (0.86%)
    1 / 248 (0.40%)
    5 / 481 (1.04%)
    2 / 240 (0.83%)
    18 / 229 (7.86%)
    32 / 473 (6.77%)
    5 / 220 (2.27%)
    0 / 11 (0.00%)
         occurrences all number
    7
    2
    2
    1
    5
    2
    23
    43
    9
    0
    Sinusitis
         subjects affected / exposed
    3 / 494 (0.61%)
    3 / 248 (1.21%)
    1 / 233 (0.43%)
    2 / 248 (0.81%)
    3 / 481 (0.62%)
    2 / 240 (0.83%)
    16 / 229 (6.99%)
    23 / 473 (4.86%)
    11 / 220 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    3
    3
    1
    3
    3
    2
    20
    32