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    Clinical Trial Results:
    A Phase III, Two-Part, Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial to Assess the Relative Efficacy and Tolerability of Two Doses of MK-0663/Etoricoxib in Patients with Rheumatoid Arthritis (MK-0663-107)

    Summary
    EudraCT number
    		 2010-019871-31
    Trial protocol
    		 FI   BE   AT   LT   GB   DE   SK   CZ  
    Global end of trial date
    29 Jul 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    19 Mar 2016
    First version publication date
    03 Jun 2015
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    0663-107
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01208181
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Protocol number: MK-0663-107
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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
    29 Jul 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a 2-part (6 weeks duration for each part), randomized, double-blind, placebo-controlled study in participants with rheumatoid arthritis. The hypothesis is that etoricoxib (60 mg and 90 mg) administration will demonstrate superior efficacy compared to placebo after 6 weeks of treatment, as measured by the greater mean improvement from baseline in the Disease Activity Score C-Reactive Protein (DAS-28 CRP), and by the greater mean improvement in Patient Global Assessment of Pain (PGAP) from baseline over 6 weeks of treatment. Additionally, the added benefit of increasing the dose of etoricoxib from 60 mg to 90 mg will be assessed in the second part of the study.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Sep 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 216
    Country: Number of subjects enrolled
    Slovakia: 6
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Czech Republic: 40
    Country: Number of subjects enrolled
    Finland: 2
    Country: Number of subjects enrolled
    Germany: 36
    Country: Number of subjects enrolled
    Lithuania: 24
    Country: Number of subjects enrolled
    Panama: 1
    Country: Number of subjects enrolled
    Peru: 39
    Country: Number of subjects enrolled
    Romania: 127
    Country: Number of subjects enrolled
    Russian Federation: 35
    Country: Number of subjects enrolled
    South Africa: 69
    Country: Number of subjects enrolled
    Taiwan: 74
    Country: Number of subjects enrolled
    United States: 309
    Country: Number of subjects enrolled
    Argentina: 154
    Country: Number of subjects enrolled
    Canada: 28
    Country: Number of subjects enrolled
    Colombia: 49
    Country: Number of subjects enrolled
    Guatemala: 51
    Country: Number of subjects enrolled
    India: 83
    Country: Number of subjects enrolled
    Mexico: 57
    Worldwide total number of subjects
    1404
    EEA total number of subjects
    455
    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)
    1148
    From 65 to 84 years
    256
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 164 sites enrolled participants in this study.

    Pre-assignment
    Screening details
    		 A total of 1765 patients were screened for inclusion in the study and 1404 of these patients were randomized. Of the 361 patients who were not randomized; 295 of these patients were excluded due to screen failures and 66 of these patients were not randomized due to other reasons.

    Period 1
    Period 1 title
    Treatment Period 1
    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
    		 Part 1: Placebo
    Arm description
    		 The placebo treatment group will receive placebo to etoricoxib tablets administered orally once daily for 6 weeks in Part 1 of the study.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The placebo treatment group will receive placebo to etoricoxib tablets administered orally once daily for 6 weeks in Part 1 of the study.

    Arm title
    		 Part 1: Etoricoxib 60 mg
    Arm description
    		 The etoricoxib 60 mg treatment group will receive etoricoxib 60 mg tablets administered orally once daily for 6 weeks in Part 1 of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etoricoxib 60 mg
    Investigational medicinal product code
    Other name
    MK-0663
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The etoricoxib 60 mg treatment group will receive etoricoxib 60 mg tablets administered orally once daily for 6 weeks in Part 1 of the study.

    Arm title
    		 Part 1: Etoricoxib 90 mg
    Arm description
    		 The etoricoxib 90 mg treatment sequence will receive etoricoxib 90 mg tablets administered orally once daily for 6 weeks in Part 1 of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etoricoxib 90 mg
    Investigational medicinal product code
    Other name
    MK-0663
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The etoricoxib 90 mg treatment sequence will receive etoricoxib 90 mg tablets administered orally once daily for 6 weeks in Part 1 of the study.

    Number of subjects in period 1
    		Part 1: Placebo Part 1: Etoricoxib 60 mg Part 1: Etoricoxib 90 mg
    Started
    118
    818
    468
    Completed
    96
    719
    413
    Not completed
    22
    99
    55
         Consent withdrawn by subject
    -
    11
    10
         Physician decision
    -
    4
    -
         Technical problem
    -
    5
    -
         Adverse event, non-fatal
    4
    26
    24
         Non-compliance with study drug
    -
    1
    1
         Lost to follow-up
    1
    5
    3
         Lack of efficacy
    17
    37
    12
         Protocol deviation
    -
    10
    5
    Period 2
    Period 2 title
    Treatment Period 2
    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
    		 Part 1/2: Etoricoxib 60 mg/etoricoxib 60 mg
    Arm description
    		 The Etoricoxib 60 mg/etoricoxib 60 mg treatment sequence will receive etoricoxib 60 mg tablets administered orally once daily for 6 weeks in Part 1 and Part 2 of the study
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etoricoxib 60 mg/etoricoxib 60 mg
    Investigational medicinal product code
    Other name
    MK-0663
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The Etoricoxib 60 mg/etoricoxib 60 mg treatment sequence will receive etoricoxib 60 mg tablets administered orally once daily for 6 weeks in Part 1 and Part 2 of the study.

    Arm title
    		 Part 1/2: Etoricoxib 60 mg/etoricoxib 90 mg
    Arm description
    		 The etoricoxib 60 mg/etoricoxib 90 mg treatment sequence will receive etoricoxib 60 mg tablets administered orally once daily for 6 weeks in Part 1 of the study and etoricoxib 90 mg tablets administered orally once daily for 6 weeks in Part 2 of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etoricoxib 60 mg/etoricoxib 90 mg
    Investigational medicinal product code
    Other name
    MK-0663
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The etoricoxib 60 mg/etoricoxib 90 mg treatment sequence will receive etoricoxib 60 mg tablets administered orally once daily for 6 weeks in Part 1 of the study and etoricoxib 90 mg tablets administered orally once daily for 6 weeks in Part 2 of the study.

    Number of subjects in period 2 [1]
    		Part 1/2: Etoricoxib 60 mg/etoricoxib 60 mg Part 1/2: Etoricoxib 60 mg/etoricoxib 90 mg
    Started
    350
    363
    Completed
    334
    343
    Not completed
    16
    20
         Physician decision
    1
    2
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    6
    7
         Non-compliance with study drug
    1
    1
         Lost to follow-up
    1
    2
         Lack of efficacy
    5
    7
         Protocol deviation
    1
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Participants who received etoricoxib 60 mg and completed Part I of the trial continued into Part II and received either etoricoxib 60 mg or etoricoxib 90 mg. Therefore, the number of participants completing Part I for each study arm is not consistent with the number of participants starting Part II for each study arm.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: Placebo
    Reporting group description
    		 The placebo treatment group will receive placebo to etoricoxib tablets administered orally once daily for 6 weeks in Part 1 of the study.

    Reporting group title
    Part 1: Etoricoxib 60 mg
    Reporting group description
    		 The etoricoxib 60 mg treatment group will receive etoricoxib 60 mg tablets administered orally once daily for 6 weeks in Part 1 of the study.

    Reporting group title
    Part 1: Etoricoxib 90 mg
    Reporting group description
    		 The etoricoxib 90 mg treatment sequence will receive etoricoxib 90 mg tablets administered orally once daily for 6 weeks in Part 1 of the study.

    Reporting group values
    		 Part 1: Placebo Part 1: Etoricoxib 60 mg Part 1: Etoricoxib 90 mg Total
    Number of subjects
    		 118 818 468 1404
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 102 671 375 1148
        From 65-84 years
    		 16 147 93 256
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.6 ( 11 ) 53.8 ( 11.9 ) 54 ( 12.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 100 677 395 1172
        Male
    		 18 141 73 232
    Disease Activity Score using C reactive protein (DAS28-CRP)
    The DAS28-CRP index (0 - 10 Range) is a composite score of weighted components including tender joint counts of 28, swollen joint counts of 28, patient global assessment of disease activity, and C-reactive protein (CRP). For each observation (Baseline, Week 2, 4, 6, 10, 12), components were combined into a single DAS28-CRP score using the following algorithm: 0.56*square root (sqrt) (tender joint count [28])+0.28*sqrt(swollen joint count [28] )+0.36* ln(crp+1) + 0.014* Patient Global Assessment of Disease Activity + 0.96. (N = 732, 426, 103 for Etoricoxib 60 mg and 90 mg, and Placebo)
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    		 5.65 ( 1.12 ) 5.64 ( 0.99 ) 5.62 ( 1 ) -
    Patient Global Assessment of Pain
    A participant overall assessment of pain on a visual analog scale (VAS) were assessed with a question concerning the amount of pain due to arthritis during the past 48 hours. Pain was assessed on an 100 mm VAS scale with a left-hand marker "no pain" (0 mm) or right-hand marker "extreme pain" (100 mm). (N = 751, 430, 108 for Etoricoxib 60 mg, Etoricoxib 90 mg, and Placebo)
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    		 74.08 ( 14.23 ) 70.84 ( 15.5 ) 70.58 ( 15.02 ) -

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Placebo
    Reporting group description
    		 The placebo treatment group will receive placebo to etoricoxib tablets administered orally once daily for 6 weeks in Part 1 of the study.

    Reporting group title
    Part 1: Etoricoxib 60 mg
    Reporting group description
    		 The etoricoxib 60 mg treatment group will receive etoricoxib 60 mg tablets administered orally once daily for 6 weeks in Part 1 of the study.

    Reporting group title
    Part 1: Etoricoxib 90 mg
    Reporting group description
    		 The etoricoxib 90 mg treatment sequence will receive etoricoxib 90 mg tablets administered orally once daily for 6 weeks in Part 1 of the study.
    Reporting group title
    Part 1/2: Etoricoxib 60 mg/etoricoxib 60 mg
    Reporting group description
    		 The Etoricoxib 60 mg/etoricoxib 60 mg treatment sequence will receive etoricoxib 60 mg tablets administered orally once daily for 6 weeks in Part 1 and Part 2 of the study

    Reporting group title
    Part 1/2: Etoricoxib 60 mg/etoricoxib 90 mg
    Reporting group description
    		 The etoricoxib 60 mg/etoricoxib 90 mg treatment sequence will receive etoricoxib 60 mg tablets administered orally once daily for 6 weeks in Part 1 of the study and etoricoxib 90 mg tablets administered orally once daily for 6 weeks in Part 2 of the study.

    Subject analysis set title
    Part 1: Etoricoxib 60 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The etoricoxib 60 mg treatment group will receive etoricoxib 60 mg tablets administered orally once daily for 6 weeks in Part 1 of the study.

    Primary: Time-Weighted Average Change From Baseline in Disease Activity Score Using C-Reactive Protein [DAS28-CRP] in Part 1 (Etoricoxib vs. Placebo)

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    End point title
    		 Time-Weighted Average Change From Baseline in Disease Activity Score Using C-Reactive Protein [DAS28-CRP] in Part 1 (Etoricoxib vs. Placebo)
    End point description
    The DAS28-CRP index (0-10 Range) is a composite score of weighted components including tender joint counts of 28, swollen joint counts of 28, patient global assessment of disease activity, and C-reactive protein (CRP). For each observation (Baseline, Week 2, 4, 6, 10, 12), components were combined into a single DAS28-CRP score using the following algorithm: 0.56*square root (sqrt) (tender joint count [28])+0.28*sqrt(swollen joint count [28] )+0.36* ln(crp+1) + 0.014* Patient Global Assessment of Disease Activity + 0.96. The primary objectives of the study compared the efficacy of etoricoxib (90 mg, 60 mg) to placebo in Part 1 of this study so data for only these 3 arms are displayed. The modified intention-to-treat (mITT) population in Part 1 consisted of all randomized participants receiving at least 1 dose of study medication, had baseline data for the analysis endpoint, and least one post-randomization measurement for that endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Week 6
    End point values
    		 Part 1: Placebo Part 1: Etoricoxib 60 mg Part 1: Etoricoxib 90 mg
    Number of subjects analysed
    103
    732
    426
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -1.1 (-1.29 to -0.9)
    -1.39 (-1.48 to -1.3)
    -1.37 (-1.48 to -1.26)
    Statistical analysis title
    		 Treatment Difference (Etoricoxib 60 mg v. Placebo)
    Statistical analysis description
    Difference in the least squares means between change from baseline in DAS28-CRP for participants taking Etoricoxib 60 mg at Week 6 vs. change from baseline in DAS28-CRP for participants taking Placebo at Week 6.
    Comparison groups
    Part 1: Etoricoxib 60 mg v Part 1: Placebo
    Number of subjects included in analysis
    835
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Tukey-Ciminera-Heysetrend test
    Parameter type
    		 Difference in least squares mean
    Point estimate
    -0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.49
         upper limit
    		 -0.09
    Statistical analysis title
    		 Treatment Difference (Etoricoxib 90 mg v. Placebo)
    Statistical analysis description
    Difference in the least squares means between change from baseline in DAS28-CRP for participants taking Etoricoxib 90 mg at Week 6 vs. change from baseline in DAS28-CRP for participants taking Placebo at Week 6
    Comparison groups
    Part 1: Placebo v Part 1: Etoricoxib 90 mg
    Number of subjects included in analysis
    529
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.034
    Method
    		 Tukey-Ciminera-Heysetrend test
    Parameter type
    		 Difference in least squares mean
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 -0.06

    Primary: Time-Weighted Average Change From Baseline in Patient Global Assessment of Pain in Part 1 (Etoricoxib vs. Placebo)

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    End point title
    		 Time-Weighted Average Change From Baseline in Patient Global Assessment of Pain in Part 1 (Etoricoxib vs. Placebo)
    End point description
    A participant overall assessment of pain on a visual analog scale (VAS) was assessed with a question concerning the amount of pain due to arthritis during the past 48 hours. Pain was assessed on an 100 mm VAS scale with a left-hand marker "no pain" (0 mm) or right-hand marker "extreme pain" (100 mm). The primary objectives of the study compared the efficacy of etoricoxib (90 mg, 60 mg) to placebo in Part 1 of this study so data for only these 3 arms are displayed. The mITT population in Part 1 consisted of all randomized participants receiving at least 1 dose of study medication, had baseline data for the analysis endpoint, and least one post-randomization measurement for that endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Week 6
    End point values
    		 Part 1: Placebo Part 1: Etoricoxib 60 mg Part 1: Etoricoxib 90 mg
    Number of subjects analysed
    108
    751
    430
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -20.26 (-24.04 to -16.48)
    -28.25 (-30.05 to -26.44)
    -30.96 (-33.13 to -28.79)
    Statistical analysis title
    		 Treatment Difference (Etoricoxib 60 mg v. Placebo)
    Statistical analysis description
    Change from baseline in Patient Global Assessment of Disease Activity at Week 6 for participants treated with Etoricoxib 60 mg minus change from baseline in Patient Global Assessment of Disease Activity at Week 6 for participants treated with Placebo.
    Comparison groups
    Part 1: Etoricoxib 60 mg v Part 1: Placebo
    Number of subjects included in analysis
    859
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Tukey-Ciminera-Heyse trend test
    Parameter type
    		 Difference in the least squares mean
    Point estimate
    -7.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.85
         upper limit
    		 -4.13
    Statistical analysis title
    		 Treatment Difference (Etoricoxib 90 mg v. Placebo)
    Statistical analysis description
    Change from baseline in Patient Global Assessment of Disease Activity at Week 6 for participants treated with Etoricoxib 90 mg minus change from baseline in Patient Global Assessment of Disease Activity at Week 6 for participants treated with Placebo.
    Comparison groups
    Part 1: Placebo v Part 1: Etoricoxib 90 mg
    Number of subjects included in analysis
    538
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Tukey-Ciminera-Heyse trend test
    Parameter type
    		 Difference in least squares mean
    Point estimate
    -10.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.74
         upper limit
    		 -6.66

    Primary: Percentage of Participants Who Experienced at Least One Adverse Event (AE) in Part 1 and Part 2

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    End point title
    		 Percentage of Participants Who Experienced at Least One Adverse Event (AE) in Part 1 and Part 2 [1] [2]
    End point description
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure. All Subjects as Treated (ASaT) population, defined as all randomized participants who received at least one study drug. Participants were included in the treatment group corresponding to the study treatment they actually received for the analysis of safety data using the ASaT population.
    End point type
    Primary
    End point timeframe
    Up to Week 16
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis of this end point was specified in the protocol or the statistical analysis plan.
    [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: No statistical analysis of this end point was specified in the protocol or the statistical analysis plan.
    End point values
    		 Part 1: Placebo Part 1/2: Etoricoxib 60 mg/etoricoxib 60 mg Part 1/2: Etoricoxib 60 mg/etoricoxib 90 mg Part 1: Etoricoxib 90 mg Part 1: Etoricoxib 60 mg
    Number of subjects analysed
    118
    350
    363
    467
    819
    Units: Percentage of Participants
        number (not applicable)
    25.4
    19.1
    24.5
    36
    30.3
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Discontinued Study Drug Due to an AE in Part 1 and Part 2

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    End point title
    		 Percentage of Participants Who Discontinued Study Drug Due to an AE in Part 1 and Part 2 [3] [4]
    End point description
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure. ASaT population defined as all randomized participants who received at least one study drug. Participants were included in the treatment group corresponding to the study treatment they actually received for the analysis of safety data using the ASaT population.
    End point type
    Primary
    End point timeframe
    Up to Week 12
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis of this end point was specified in the protocol or the statistical analysis plan.
    [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: No statistical analysis of this end point was specified in the protocol or the statistical analysis plan.
    End point values
    		 Part 1: Placebo Part 1/2: Etoricoxib 60 mg/etoricoxib 60 mg Part 1/2: Etoricoxib 60 mg/etoricoxib 90 mg Part 1: Etoricoxib 90 mg Part 1: Etoricoxib 60 mg
    Number of subjects analysed
    118
    350
    363
    467
    819
    Units: Percentage of Participants
        number (not applicable)
    3.4
    1.4
    1.9
    5.1
    3.3
    No statistical analyses for this end point

    Secondary: Time-Weighted Average Change From Baseline in DAS28-CRP in Part 1 (Etoricoxib 90 mg vs. Etoricoxib 60 mg)

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    End point title
    		 Time-Weighted Average Change From Baseline in DAS28-CRP in Part 1 (Etoricoxib 90 mg vs. Etoricoxib 60 mg)
    End point description
    The DAS28-CRP index (0 - 10 range) is a composite score of weighted components including tender joint counts of 28, swollen joint counts of 28, patient global assessment of disease activity, and C-reactive protein (CRP). For each observation (Baseline, Week 2, 4, 6, 10, 12), components were combined into a single DAS28-CRP score using the following algorithm: 0.56*square root (sqrt) (tender joint count [28])+0.28*sqrt(swollen joint count [28] )+0.36* ln(crp+1) + 0.014* Patient Global Assessment of Disease Activity + 0.96. A key secondary objective was to compare the relative efficacy between etoricoxib 90 mg and 60 mg in Part 1 of this study. The mITT population in Part 1 consisted of all randomized participants receiving at least 1 dose of study medication, had baseline data for the analysis endpoint, and least one post-randomization measurement for that endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6
    End point values
    		 Part 1: Placebo Part 1: Etoricoxib 60 mg Part 1: Etoricoxib 90 mg
    Number of subjects analysed
    103
    732
    426
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -1.1 (-1.29 to -0.9)
    -1.39 (-1.48 to -1.3)
    -1.37 (-1.48 to -1.26)
    Statistical analysis title
    		 Treatment Difference (Etoricoxib 60 mg vs. 90 mg)
    Statistical analysis description
    Difference in the least squares means between change from baseline in DAS28-CRP for participants taking Etoricoxib 60 mg at Week 6 vs. change from baseline in DAS28-CRP for participants taking Etoricoxib 90 mg at Week 6.
    Comparison groups
    Part 1: Etoricoxib 60 mg v Part 1: Etoricoxib 90 mg
    Number of subjects included in analysis
    1158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.73
    Method
    		 Tukey-Ciminera-Heysetrend test
    Parameter type
    		 Difference in least squares mean
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.14

    Secondary: Time-Weighted Mean Change From Baseline in Patient Global Assessment of Pain in Part 1 (Etoricoxib 90 mg vs. Etoricoxib 60 mg)

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    End point title
    		 Time-Weighted Mean Change From Baseline in Patient Global Assessment of Pain in Part 1 (Etoricoxib 90 mg vs. Etoricoxib 60 mg)
    End point description
    A participant overall assessment of pain on a visual analog scale (VAS) was assessed with a question concerning the amount of pain due to arthritis during the past 48 hours. Pain was assessed on an 100 mm VAS scale with a left-hand marker "no pain" (0 mm) or right-hand marker "extreme pain" (100 mm). A key secondary objective was to compare the relative efficacy between etoricoxib 90 mg and 60 mg in Part 1 of this study. The mITT population in Part 1 consisted of all randomized participants receiving at least 1 dose of study medication, had baseline data for the analysis endpoint, and least one post-randomization measurement for that endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6
    End point values
    		 Part 1: Placebo Part 1: Etoricoxib 60 mg Part 1: Etoricoxib 90 mg
    Number of subjects analysed
    108
    751
    430
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -20.26 (-24.04 to -16.48)
    -28.25 (-30.05 to -26.44)
    -30.96 (-33.13 to -28.79)
    Statistical analysis title
    		 Treatment Difference (Etoricoxib 60 mg vs. 90 mg)
    Statistical analysis description
    Change from baseline in Patient Global Assessment of Disease Activity at Week 6 for participants treated with Etoricoxib 60 mg minus change from baseline in Patient Global Assessment of Disease Activity at Week 6 for participants treated with Etoricoxib 90 mg.
    Comparison groups
    Part 1: Etoricoxib 60 mg v Part 1: Etoricoxib 90 mg
    Number of subjects included in analysis
    1181
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.019
    Method
    		 Tukey-Ciminera-Heyse trend test
    Parameter type
    		 Difference in least squares mean
    Point estimate
    -2.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.98
         upper limit
    		 -0.45

    Secondary: Average change from Week 6 in Patient Global Assessment of Pain Over Weeks 10 and 12 in Part 2 Among Pain Inadequate Responders from Part 1

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    End point title
    		 Average change from Week 6 in Patient Global Assessment of Pain Over Weeks 10 and 12 in Part 2 Among Pain Inadequate Responders from Part 1
    End point description
    A participant overall assessment of pain on a visual analog scale (VAS) was assessed with a question concerning the amount of pain due to arthritis during the past 48 hours assessed on an 100 mm VAS scale; left-hand "no pain" (0 mm) or right-hand "extreme pain" (100 mm). Inadequate responders to etoricoxib 60 mg in Part 1 (<50% improvement from baseline in PGAP [VAS] at Week 6) were evaluated for an incremental benefit of increasing the etoricoxib dose to 90 mg in Part 2 compared to remaining on 60 mg in Part 2 for average change from Week 6 over Weeks 10 and 12 in Patient Global Assessment of Pain score. Therefore, data for only these 2 arms are displayed. This population (a subpopulation of the mITT population) was composed of pain inadequate responder (PIRs) in Part 1. PIRs were defined as participants with <50% improvement from baseline in Patient Global Assessment of Pain (VAS) at Week 6 and received at least one dose of study medication in Part 2.
    End point type
    Secondary
    End point timeframe
    Week 6 and Week 10 to Week 12
    End point values
    		 Part 1/2: Etoricoxib 60 mg/etoricoxib 60 mg Part 1/2: Etoricoxib 60 mg/etoricoxib 90 mg
    Number of subjects analysed
    188
    187
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -11.96 (-14.96 to -8.97)
    -10.35 (-13.32 to -7.39)
    Statistical analysis title
    		 Treatment Difference (Etoricoxib 60 mg vs. 90 mg)
    Statistical analysis description
    Change from Week 6 in Patient Global Assessment of Disease Activity over Weeks 10 to 12 for participants treated with Etoricoxib 60 mg/Etoricoxib 60 mg minus change from Week 6 in Patient Global Assessment of Disease Activity over Weeks 10 to 12 for participants treated with Etoricoxib 60 mg/Etoricoxib 90 mg.
    Comparison groups
    Part 1/2: Etoricoxib 60 mg/etoricoxib 60 mg v Part 1/2: Etoricoxib 60 mg/etoricoxib 90 mg
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.327
    Method
    		 Covariance model
    Parameter type
    		 Difference in the least squares mean
    Point estimate
    1.61
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.49
         upper limit
    		 3.71

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 16
    Adverse event reporting additional description
    The All Participants as Treated (APaT) population was used for the analysis of safety data in this study and consisted of all randomized participants who received at least one dose of study treatment. Participants were included in the treatment group corresponding to the study treatment they actually received for the analysis of safety data.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Part 1: Placebo
    Reporting group description
    		 The placebo treatment group will receive placebo to etoricoxib tablets administered orally once daily in Part 1 of the study.

    Reporting group title
    Part 1: Etoricoxib 60 mg
    Reporting group description
    		 The Etoricoxib 60 mg treatment group will receive etoricoxib tablets 60 mg administered orally once daily in Part 1 of the study.

    Reporting group title
    Part 1: Etoricoxib 90 mg
    Reporting group description
    		 The Etoricoxib 90 mg treatment group will receive etoricoxib tablets 90 mg administered orally once daily in Part 1 of the study.

    Reporting group title
    Part 1/2: Etoricoxib 60 mg/60 mg
    Reporting group description
    		 The Etoricoxib 60 mg/Etoricoxib 60 mg treatment sequence will receive etoricoxib tablets 60 mg administered orally once daily in Part 1 and Part 2 of the study.

    Reporting group title
    Part 1/2: Etoricoxib 60 mg/90 mg
    Reporting group description
    		 The Etoricoxib 60 mg/Etoricoxib 90 mg treatment sequence will receive etoricoxib tablets 60 mg administered orally once daily in Part 1 of the study and etoricoxib tablets 90 mg administered orally once daily in Part 2 of the study.

    Serious adverse events
    		 Part 1: Placebo Part 1: Etoricoxib 60 mg Part 1: Etoricoxib 90 mg Part 1/2: Etoricoxib 60 mg/60 mg Part 1/2: Etoricoxib 60 mg/90 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 118 (0.00%)
    7 / 819 (0.85%)
    2 / 467 (0.43%)
    4 / 350 (1.14%)
    5 / 363 (1.38%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    0 / 118 (0.00%)
    0 / 819 (0.00%)
    1 / 467 (0.21%)
    0 / 350 (0.00%)
    0 / 363 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 118 (0.00%)
    0 / 819 (0.00%)
    0 / 467 (0.00%)
    0 / 350 (0.00%)
    1 / 363 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 118 (0.00%)
    0 / 819 (0.00%)
    0 / 467 (0.00%)
    0 / 350 (0.00%)
    1 / 363 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 118 (0.00%)
    0 / 819 (0.00%)
    0 / 467 (0.00%)
    1 / 350 (0.29%)
    0 / 363 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 118 (0.00%)
    0 / 819 (0.00%)
    0 / 467 (0.00%)
    0 / 350 (0.00%)
    1 / 363 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 118 (0.00%)
    0 / 819 (0.00%)
    0 / 467 (0.00%)
    0 / 350 (0.00%)
    1 / 363 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 819 (0.12%)
    0 / 467 (0.00%)
    0 / 350 (0.00%)
    0 / 363 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 118 (0.00%)
    2 / 819 (0.24%)
    0 / 467 (0.00%)
    1 / 350 (0.29%)
    0 / 363 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 819 (0.12%)
    0 / 467 (0.00%)
    0 / 350 (0.00%)
    0 / 363 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroduodenitis
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 819 (0.12%)
    0 / 467 (0.00%)
    0 / 350 (0.00%)
    0 / 363 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 118 (0.00%)
    0 / 819 (0.00%)
    0 / 467 (0.00%)
    1 / 350 (0.29%)
    0 / 363 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 819 (0.12%)
    0 / 467 (0.00%)
    0 / 350 (0.00%)
    0 / 363 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 819 (0.12%)
    0 / 467 (0.00%)
    0 / 350 (0.00%)
    0 / 363 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 118 (0.00%)
    0 / 819 (0.00%)
    0 / 467 (0.00%)
    1 / 350 (0.29%)
    0 / 363 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 819 (0.12%)
    0 / 467 (0.00%)
    0 / 350 (0.00%)
    0 / 363 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 118 (0.00%)
    0 / 819 (0.00%)
    0 / 467 (0.00%)
    0 / 350 (0.00%)
    1 / 363 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyomyositis
         subjects affected / exposed
    0 / 118 (0.00%)
    0 / 819 (0.00%)
    0 / 467 (0.00%)
    0 / 350 (0.00%)
    1 / 363 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 118 (0.00%)
    0 / 819 (0.00%)
    1 / 467 (0.21%)
    0 / 350 (0.00%)
    0 / 363 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1: Placebo Part 1: Etoricoxib 60 mg Part 1: Etoricoxib 90 mg Part 1/2: Etoricoxib 60 mg/60 mg Part 1/2: Etoricoxib 60 mg/90 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 118 (5.08%)
    25 / 819 (3.05%)
    17 / 467 (3.64%)
    6 / 350 (1.71%)
    6 / 363 (1.65%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 118 (5.08%)
    25 / 819 (3.05%)
    17 / 467 (3.64%)
    6 / 350 (1.71%)
    6 / 363 (1.65%)
         occurrences all number
    8
    27
    27
    6
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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