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    Clinical Trial Results:
    A Phase 4 Trial Assessing the ImPact of Residual Inflammation Detected Via Imaging TEchniques, Drug Levels and Patient Characteristics on the Outcome of Dose TaperIng of Adalimumab in Clinical Remission Rheumatoid ArThritis (RA) Subjects (PREDICTRA)

    Summary
    EudraCT number
    2014-001114-26
    Trial protocol
    DE   IE   GB   SE   ES   HU   IT   NL   AT   GR   FR  
    Global end of trial date
    08 Aug 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Aug 2019
    First version publication date
    11 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M14-500
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02198651
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AbbVie Deutschland GmbH & Co. KG
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6-4UB
    Public contact
    Global Medical Services, AbbVie, 001 8006339110,
    Scientific contact
    Ivan Lagunes, AbbVie, ivan.lagunesgalindo@abbvie.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
    08 Aug 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to investigate the association between residual disease activity at Baseline as detected by Magnetic Resonance Imaging (MRI) and the occurrence of flares in subjects with rheumatoid arthritis (RA) randomized to an adalimumab dose tapering regimen controlled by adalimumab withdrawal. The study included a Screening period of up to 28 days (unless extended with approval of study-designated physician), a 4-week Lead-In Period with open label (OL) 40 mg adalimumab administered subcutaneously (sc) every other week (eow), and a randomized 36-week double-blind period with 40 mg adalimumab sc every 3 weeks (q3wks; tapering arm) or placebo sc q3wks (withdrawal arm). Subjects were randomized in a 5:1 ratio (tapering arm: withdrawal arm) after confirmation of meeting the disease activity score (DAS) criteria. Subjects who experienced a protocol-defined flare at any time were to enter a rescue arm with OL 40 mg adalimumab administered sc eow for 16 weeks.
    Protection of trial subjects
    Prior to the initiation of any screening or study-specific procedures, the investigator or his or her representative explained the nature of the study to the subject or his or her representative and answered all questions regarding this study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Jan 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    Sweden: 11
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    United States: 17
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Canada: 15
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 28
    Country: Number of subjects enrolled
    Greece: 9
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Ireland: 4
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    Netherlands: 11
    Worldwide total number of subjects
    149
    EEA total number of subjects
    113
    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)
    93
    From 65 to 84 years
    56
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    146 subjects enrolled in the study and received at least 1 dose of study drug during the Lead-in period. Three subjects enrolled in the study but were not treated during the Lead-in period.

    Period 1
    Period 1 title
    Lead-in Period
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Adalimumab 40 mg Eow
    Arm description
    40 mg adalimumab administered subcutaneously every other week (eow) from Week 0 to Week 4 (Lead-in Period)
    Arm type
    Experimental

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    ABT-D2E7, Humira
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    40 mg adalimumab administered subcutaneously every other week (eow) from Week 0 to Week 4 (Lead-in Period)

    Number of subjects in period 1 [1]
    Adalimumab 40 mg Eow
    Started
    146
    Subjects treated in Lead-in Period
    146
    Completed
    110
    Not completed
    36
         Other, not specified
    22
         Adverse event, non-fatal
    2
         Consent withdrawn by subject
    12
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The All Lead-in-Treated Subject population consists of subjects who were enrolled in the study and received at least 1 dose of study drug during the Lead-in period. Three participants enrolled in the study but were not treated during the Lead-in period.
    Period 2
    Period 2 title
    Double-blind Period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Adalimumab Tapering
    Arm description
    40 mg adalimumab administered subcutaneously every three weeks from Week 4 to Week 40 (Double-blind Period)
    Arm type
    Active comparator

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    ABT-D2E7, Humira
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    40 mg adalimumab administered subcutaneously every three weeks from Week 4 to Week 40 (Double-blind Period)

    Arm title
    Adalimumab Withdrawal Arm
    Arm description
    Placebo administered subcutaneously every three weeks from Week 4 to Week 40 (Double-blind Period)
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    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 administered subcutaneously every three weeks from Week 4 to Week 40 (Double-blind Period)

    Number of subjects in period 2
    Adalimumab Tapering Adalimumab Withdrawal Arm
    Started
    102
    20
    Completed
    93
    19
    Not completed
    9
    1
         Other, not specified
    4
    1
         Adverse event, non-fatal
    1
    -
         Consent withdrawn by subject
    4
    -
    Period 3
    Period 3 title
    Open-Label Rescue Period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Adalimumab Tapering to Rescue Arm
    Arm description
    40 mg adalimumab administered subcutaneously every other week (eow) from Flare Week 0 to Flare Week 16 (Open-Label Rescue Period)
    Arm type
    Experimental

    Investigational medicinal product name
    Adalimumab 40 mg eow Rescue Arm
    Investigational medicinal product code
    Other name
    ABT-D2E7, Humira
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    40 mg adalimumab administered subcutaneously every other week from Flare Week 0 to Flare Week 16 (Open-label Rescue Period)

    Arm title
    Adalimumab Withdrawal to Rescue Arm
    Arm description
    40 mg adalimumab administered subcutaneously every other week (eow) from Flare Week 0 to Flare Week 16 (Open-Label Rescue Period)
    Arm type
    Experimental

    Investigational medicinal product name
    Adalimumab 40 mg eow Rescue Arm
    Investigational medicinal product code
    Other name
    ABT-D2E7, Humira
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    40 mg adalimumab administered subcutaneously every other week from Flare Week 0 to Flare Week 16 (Open-label Rescue Period)

    Number of subjects in period 3
    Adalimumab Tapering to Rescue Arm Adalimumab Withdrawal to Rescue Arm
    Started
    31
    8
    Completed
    28
    8
    Not completed
    3
    0
         Incorrectly entered Open-Label Rescue Period
    1
    -
         Consent withdrawn by subject
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lead-in Period
    Reporting group description
    All Lead-in-Treated Subject population: participants who were enrolled in the study and received at least 1 dose of study drug during the Lead-in period. Three participants enrolled in the study but were not treated during the Lead-in period.

    Reporting group values
    Lead-in Period Total
    Number of subjects
    146 146
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    59.6 ± 10.30 -
    Gender categorical
    Units: Subjects
        Female
    109 109
        Male
    37 37
    Tobacco Use
    Units: Subjects
        Current
    22 22
        Former
    46 46
        Never
    76 76
        Unknown
    2 2
    Previous treatment with conventional synthetic disease modifying antirheumatic drugs (csDMARDs)
    Units: Subjects
        Yes
    145 145
        No
    1 1
    Previous Tx with biological disease-modifying anti-rheumatic drugs (bDMARDs; excluding adalimumab)
    Units: Subjects
        Yes
    38 38
        No
    108 108
    Previous Tx with csDMARDS or bDMARDs (excluding adalimumab)
    Units: Subjects
        Yes
    146 146
        No
    0 0
    Disease duration
    Participants with available data, n=142
    Units: years
        arithmetic mean (standard deviation)
    12.9 ± 9.99 -
    Duration of adalimumab therapy
    Units: years
        arithmetic mean (standard deviation)
    5.4 ± 3.27 -
    Duration of remission
    Participants with available data, n=125
    Units: years
        arithmetic mean (standard deviation)
    2.2 ± 1.99 -
    Participants' Global Assessment of Disease Activity
    Participants rated the severity of their rheumatoid arthritis symptoms and how well they were doing during the last 24 hours by placing a vertical mark on a line with a range of 0 (very well) to 100 mm (very poorly).
    Units: units on a scale
        arithmetic mean (standard deviation)
    8.7 ± 11.84 -
    Mean C-Reactive Protein (CRP)
    C-Reactive Protein (CRP; mg/L) was measured from blood samples as a marker for inflammation.
    Units: mg/L
        arithmetic mean (standard deviation)
    2.4 ± 2.58 -
    HAQ-DI Score
    The Health Assessment Questionnaire- Disability Index (HAQ-DI) is specific for rheumatoid arthritis. 20 questions refer to eight domains:dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants rated their ability to do each task over the past 7 days: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability.
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.4 ± 0.51 -

    End points

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    End points reporting groups
    Reporting group title
    Adalimumab 40 mg Eow
    Reporting group description
    40 mg adalimumab administered subcutaneously every other week (eow) from Week 0 to Week 4 (Lead-in Period)
    Reporting group title
    Adalimumab Tapering
    Reporting group description
    40 mg adalimumab administered subcutaneously every three weeks from Week 4 to Week 40 (Double-blind Period)

    Reporting group title
    Adalimumab Withdrawal Arm
    Reporting group description
    Placebo administered subcutaneously every three weeks from Week 4 to Week 40 (Double-blind Period)
    Reporting group title
    Adalimumab Tapering to Rescue Arm
    Reporting group description
    40 mg adalimumab administered subcutaneously every other week (eow) from Flare Week 0 to Flare Week 16 (Open-Label Rescue Period)

    Reporting group title
    Adalimumab Withdrawal to Rescue Arm
    Reporting group description
    40 mg adalimumab administered subcutaneously every other week (eow) from Flare Week 0 to Flare Week 16 (Open-Label Rescue Period)

    Subject analysis set title
    Flared Participants
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants who experienced flare during the Double-blind Period

    Subject analysis set title
    Non-Flared Participants
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants who did not experience flare during the Double-blind Period

    Subject analysis set title
    DAS28 (ESR) < 2.6
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Disease Activity Score 28 (DAS28 ESR) < 2.6

    Subject analysis set title
    SDAI ≤ 3.3
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Simplified Disease Activity Index (SDAI) score ≤ 3.3

    Subject analysis set title
    CDAI ≤ 2.8
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Clinical Disease Activity Index (CDAI) score ≤ 2.8

    Primary: Association Between a Composite of Baseline Hand and Wrist Synovitis and Bone Marrow Edema RAMRIS Scores and Flare up to Week 40 in the Tapering Arm

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    End point title
    Association Between a Composite of Baseline Hand and Wrist Synovitis and Bone Marrow Edema RAMRIS Scores and Flare up to Week 40 in the Tapering Arm [1]
    End point description
    The composite score is the sum of the baseline hand and wrist synovitis and bone marrow edema RAMRIS scores. Flare is defined as an increase from Double-blind Baseline in DAS (Disease Activity Score) 28 erythrocyte sedimentation rate (ESR) of > 0.6 AND DAS28 [ESR] > 2.6, OR an increase in DAS28 (ESR) of ≥ 1.2 irrespective of the resulting DAS28 [ESR]. The association between the composite baseline hand and wrist synovitis score and baseline bone marrow edema rheumatoid arthritis MRI scoring system (RAMRIS) score and occurrence of rheumatoid arthritis flare up to Week 40 in the Tapering arm was examined using logistic regression, and the 95% confidence interval of the odds ratio was calculated.
    End point type
    Primary
    End point timeframe
    From Week 4 to Week 40
    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: Wald Chi test was performed; p=0.688
    End point values
    Adalimumab Tapering
    Number of subjects analysed
    102 [2]
    Units: odds ratio
        number (confidence interval 95%)
    0.979 (0.885 to 1.084)
    Notes
    [2] - Subjects in Tapering arm who received at least 1 dose of study drug during the Double-blind period
    No statistical analyses for this end point

    Primary: Association Between Baseline Hand and Wrist Synovitis Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (RAMRIS) Score and Flare up to Week 40 in the Tapering Arm

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    End point title
    Association Between Baseline Hand and Wrist Synovitis Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (RAMRIS) Score and Flare up to Week 40 in the Tapering Arm [3]
    End point description
    Synovitis was assessed in three wrist regions (the distal radioulnar joint; the radiocarpal joint; the intercarpal and carpometacarpal joints) and in each Metacarpophalangeal joint (MCP) joint. The first carpometacarpal joint and the first MCP joint are not scored. The scale is 0–3. Score 0 is normal, and 1–3 (mild, moderate, severe) are by thirds of the presumed maximum volume of enhancing tissue in the synovial compartment. Flare is defined as an increase from Double-blind Baseline in DAS (Disease Activity Score) 28 erythrocyte sedimentation rate (ESR) of > 0.6 AND DAS28 [ESR] > 2.6, OR an increase in DAS28 (ESR) of ≥ 1.2 irrespective of the resulting DAS28 [ESR]. The association between baseline hand and wrist synovitis RAMRIS score and occurrence of rheumatoid arthritis flare up to Week 40 in the Tapering arm was examined using logistic regression, and the 95% confidence interval of the odds ratio was calculated.
    End point type
    Primary
    End point timeframe
    From Week 4 to Week 40
    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: Wald Chi test was performed; p=0.943
    End point values
    Adalimumab Tapering
    Number of subjects analysed
    102 [4]
    Units: odds ratio
        number (confidence interval 95%)
    0.993 (0.822 to 1.199)
    Notes
    [4] - Subjects in tapering arm who received at least 1 dose of study drug during the Double-blind period
    No statistical analyses for this end point

    Primary: Association Between Baseline Bone Marrow Edema RAMRIS Score and Flare up to Week 40 in the Tapering Arm

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    End point title
    Association Between Baseline Bone Marrow Edema RAMRIS Score and Flare up to Week 40 in the Tapering Arm [5]
    End point description
    Bone marrow edema in each bone was scored separately. The scale is 0–3 based on the proportion of bone with edema, as follows—0: no edema; 1: 1–33% of bone edematous; 2: 34–66% of bone edematous; 3: 67–100%. Flare is defined as an increase from Double-blind Baseline in DAS (Disease Activity Score) 28 erythrocyte sedimentation rate (ESR) of > 0.6 AND DAS28 [ESR] > 2.6, OR an increase in DAS28 (ESR) of ≥ 1.2 irrespective of the resulting DAS28 [ESR]. The association between baseline bone marrow edema rheumatoid arthritis MRI scoring system (RAMRIS) score and occurrence of rheumatoid arthritis flare up to Week 40 in the Tapering arm was examined using logistic regression, and the 95% confidence interval of the odds ratio was calculated.
    End point type
    Primary
    End point timeframe
    From Week 4 to Week 40
    Notes
    [5] - 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: Wald Chi test was performed; p=0.592
    End point values
    Adalimumab Tapering
    Number of subjects analysed
    102 [6]
    Units: odd ratio
        number (confidence interval 95%)
    0.959 (0.821 to 1.119)
    Notes
    [6] - Subjects in Tapering arm who received at least 1 dose of study drug during the Double-blind period
    No statistical analyses for this end point

    Secondary: Median time to flare

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    End point title
    Median time to flare
    End point description
    Time to flare was defined as the number of weeks from the date of the first dose of study drug in the Double-blind period to the date of flare.
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40
    End point values
    Adalimumab Tapering Adalimumab Withdrawal Arm
    Number of subjects analysed
    102 [7]
    20 [8]
    Units: weeks
        median (confidence interval 95%)
    999 (36.4 to 999)
    999 (12.1 to 999)
    Notes
    [7] - 999 = not calculable/estimable due to an insufficient number of subjects with events
    [8] - 999 = not calculable/estimable due to an insufficient number of subjects with events
    No statistical analyses for this end point

    Secondary: Participants' Assessment of Flare Severity

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    End point title
    Participants' Assessment of Flare Severity
    End point description
    Participants rated the severity of flare at the Flare Week 0 visit from 0 (not severe) to 10 (very severe). The number of participants within each level of flare severity is presented.
    End point type
    Secondary
    End point timeframe
    At the Flare Week 0 Visit
    End point values
    Adalimumab Tapering to Rescue Arm Adalimumab Withdrawal to Rescue Arm
    Number of subjects analysed
    30 [9]
    8 [10]
    Units: Number of participants
        Score of 0
    1
    0
        Score of 1
    2
    1
        Score of 2
    2
    2
        Score of 3
    3
    0
        Score of 4
    4
    0
        Score of 5
    1
    1
        Score of 6
    4
    1
        Score of 7
    1
    0
        Score of 8
    2
    0
        Score of 9
    0
    0
        Score of 10
    2
    0
        Missing
    8
    3
    Notes
    [9] - Open-label-rescue-treated subjects excluding those who falsely entered the Open-label rescue period
    [10] - Open-label-rescue-treated subjects excluding those who falsely entered the Open-label rescue period
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a Flare

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    End point title
    Percentage of Participants With a Flare
    End point description
    Flare was defined as an increase from Double-blind Baseline in DAS (Disease Activity Score) 28 erythrocyte sedimentation rate (ESR) of > 0.6 AND DAS28 [ESR] > 2.6, OR an increase in DAS28 (ESR) of ≥ 1.2 irrespective of the resulting DAS28 [ESR].
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40
    End point values
    Adalimumab Tapering Adalimumab Withdrawal Arm
    Number of subjects analysed
    102 [11]
    20 [12]
    Units: percentage of participants
        number (confidence interval 95%)
    36.3 (27.0 to 46.4)
    45.0 (23.1 to 68.5)
    Notes
    [11] - Subjects who received at least 1 dose of study drug during the Double-blind period
    [12] - Subjects who received at least 1 dose of study drug during the Double-blind period
    No statistical analyses for this end point

    Secondary: Physicians' Assessment of Flare Severity

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    End point title
    Physicians' Assessment of Flare Severity
    End point description
    Physicians rated the severity of flare at the Flare Week 0 visit from 0 (not severe) to 10 (very severe). The number of participants within each level of flare severity is presented.
    End point type
    Secondary
    End point timeframe
    At the Flare Week 0 Visit
    End point values
    Adalimumab Tapering to Rescue Arm Adalimumab Withdrawal to Rescue Arm
    Number of subjects analysed
    30 [13]
    8 [14]
    Units: Number of participants
        Score of 0
    1
    1
        Score of 1
    2
    0
        Score of 2
    3
    0
        Score of 3
    3
    1
        Score of 4
    6
    2
        Score of 5
    1
    1
        Score of 6
    4
    0
        Score of 7
    1
    0
        Score of 8
    0
    0
        Score of 9
    0
    0
        Score of 10
    0
    0
        Missing
    9
    3
    Notes
    [13] - Open-label-rescue-treated subjects excluding those who falsely entered the Open-label rescue period
    [14] - Open-label-rescue-treated subjects excluding those who falsely entered the Open-label rescue period
    No statistical analyses for this end point

    Secondary: Number of Participants Who Regained Clinical Remission in the Open-Label Rescue Arm Over Time

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    End point title
    Number of Participants Who Regained Clinical Remission in the Open-Label Rescue Arm Over Time
    End point description
    The Disease Activity Score 28 (DAS28) is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, the erythrocyte sedimentation rate (ESR; mm/hour), and the participant's assessment of global disease activity (on a visual analog scale [VAS] from 0 to 10 cm) are included in the DAS28 (ESR) score. Scores on the DAS28 range from 0 to 10; higher scores indicate more disease activity. Clinical remission was defined as DAS28 (ESR) < 2.6.
    End point type
    Secondary
    End point timeframe
    From Flare Week 0 to Flare Week 16
    End point values
    Adalimumab Tapering to Rescue Arm Adalimumab Withdrawal to Rescue Arm
    Number of subjects analysed
    30 [15]
    8 [16]
    Units: Number of participants
        Flare Week 0 (n=30;8)
    3
    1
        Flare Week 4 (n= 29;7)
    14
    1
        Flare Week 10 (n=29;7)
    17
    3
        Flare Week 16 (n=29;8)
    13
    4
    Notes
    [15] - Open-label-rescue-treated subjects excluding those who incorrectly entered the Rescue period; LOCF
    [16] - Open-label-rescue-treated subjects excluding those who incorrectly entered the Rescue period; LOCF
    No statistical analyses for this end point

    Secondary: Median Time to Clinical Remission From the Occurrence of Flare

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    End point title
    Median Time to Clinical Remission From the Occurrence of Flare
    End point description
    The Disease Activity Score 28 (DAS28) is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, the erythrocyte sedimentation rate (ESR; mm/hour), and the participant's assessment of global disease activity (on a visual analog scale [VAS] from 0 to 10 cm) are included in the DAS28 (ESR) score. Scores on the DAS28 range from 0 to 10; higher scores indicate more disease activity. Clinical remission was defined as DAS28 (ESR) < 2.6. Time to clinical remission was defined as the number of weeks from the occurrence of flare to the first date of clinical remission.
    End point type
    Secondary
    End point timeframe
    From Flare Week 0 to Flare Week 16
    End point values
    Adalimumab Tapering to Rescue Arm Adalimumab Withdrawal to Rescue Arm
    Number of subjects analysed
    30 [17]
    8 [18]
    Units: weeks
        median (confidence interval 95%)
    6.1 (4.1 to 16.3)
    18.0 (0.1 to 18.0)
    Notes
    [17] - Open-label-rescue-treated subjects excluding those who incorrectly entered the Rescue period
    [18] - Open-label-rescue-treated subjects excluding those who incorrectly entered the Rescue period
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Disease Activity Score 28 (DAS28)

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    End point title
    Mean Change From Double-blind Baseline in Disease Activity Score 28 (DAS28)
    End point description
    The Disease Activity Score 28 (DAS28) is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, the erythrocyte sedimentation rate (ESR; mm/hour), and the participant's assessment of global disease activity (on a visual analog scale [VAS] from 0 to 10 cm) are included in the DAS28 (ESR) score. Scores on the DAS28 range from 0 to 10; higher scores indicate more disease activity. Negative values indicate improvement from baseline. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [19]
    76 [20]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Double Blind Week 10- Tapering Arm (n=37;63)
    0.7 ± 1.27
    0.1 ± 0.46
        Double Blind Week 10- Withdrawal Arm (n=9;11)
    0.1 ± 0.47
    0.1 ± 0.55
        Double Blind Week 16- Tapering Arm (n=35;63)
    1.2 ± 1.34
    0.1 ± 0.39
        Double Blind Week 16- Withdrawal Arm (n=9;11)
    0.9 ± 0.58
    0.0 ± 0.43
        Double Blind Week 22- Tapering Arm (n=19;63)
    0.7 ± 1.18
    -0.0 ± 0.53
        Double Blind Week 22- Withdrawal Arm (n=4;11)
    0.5 ± 0.31
    0.1 ± 0.24
        Double Blind Week 28- Tapering Arm (n=16;63)
    0.8 ± 1.16
    0.1 ± 0.50
        Double Blind Week 28- Withdrawal Arm (n=4;11)
    1.0 ± 1.54
    0.2 ± 0.25
        Double Blind Week 34- Tapering Arm (n=12;63)
    0.7 ± 0.59
    -0.0 ± 0.54
        Double Blind Week 34- Withdrawal Arm (n=2;11)
    -0.7 ± 0.11
    -0.0 ± 0.46
        Double Blind Week 40- Tapering Arm (n=11;63)
    1.5 ± 1.20
    0.0 ± 0.52
        Double Blind Week 40- Withdrawal Arm (n=2;11)
    0.8 ± 2.18
    0.2 ± 0.38
        Flare Week 0- Tapering Arm (n=30:0)
    2.3 ± 1.15
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=8;0)
    1.9 ± 0.96
    999 ± 999
        Flare Week 4- Tapering Arm (n=29;0)
    1.3 ± 1.05
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=7;0)
    1.2 ± 1.14
    999 ± 999
        Flare Week 10- Tapering Arm (n=29;0)
    0.9 ± 0.81
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=7;0)
    0.7 ± 0.50
    999 ± 999
        Flare Week 16- Tapering Arm (n=29;0)
    1.2 ± 1.04
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=8;0)
    0.6 ± 0.80
    999 ± 999
    Notes
    [19] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [20] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Clinical Disease Activity Index (CDAI) Score

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    End point title
    Mean Change From Double-blind Baseline in Clinical Disease Activity Index (CDAI) Score
    End point description
    The CDAI is a validated measure of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, global health assessed by the participant on a visual analogue scale from 0 to 10 (cm), and global health assessed by an investigator on a visual analogue scale from 0 to 10 (cm) were included in the CDAI score. Scores on the CDAI range from 0 to 76; higher scores indicate more disease activity. Negative values indicate improvement from the Double-blind baseline score. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [21]
    76 [22]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Double Blind Week 10- Tapering Arm (n=37;62)
    4.4 ± 7.68
    0.6 ± 1.34
        Double Blind Week 10- Withdrawal Arm (n=9;11)
    1.0 ± 2.45
    1.4 ± 2.85
        Double Blind Week 16- Tapering Arm (n=35;63)
    7.0 ± 9.35
    0.4 ± 1.30
        Double Blind Week 16- Withdrawal Arm (n=9;11)
    2.9 ± 2.42
    -0.1 ± 0.88
        Double Blind Week 22- Tapering Arm (n=19;63)
    3.2 ± 4.98
    0.3 ± 1.38
        Double Blind Week 22- Withdrawal Arm (n=4;11)
    2.2 ± 1.93
    0.1 ± 0.73
        Double Blind Week 28- Tapering Arm (n=16;63)
    3.7 ± 6.19
    0.5 ± 1.37
        Double Blind Week 28- Withdrawal Arm (n=4;11)
    6.3 ± 8.40
    -0.1 ± 0.80
        Double Blind Week 34- Tapering Arm (n=12;63)
    2.7 ± 3.04
    0.2 ± 1.08
        Double Blind Week 34- Withdrawal Arm (n=2;11)
    -0.1 ± 0.14
    0.0 ± 0.92
        Double Blind Week 40- Tapering Arm (n=11;63)
    7.4 ± 10.04
    0.1 ± 1.33
        Double Blind Week 40- Withdrawal Arm (n=2;11)
    7.7 ± 11.38
    -0.3 ± 0.48
        Flare Week 0- Tapering Arm (n=30;0)
    12.3 ± 9.56
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=8;0)
    9.4 ± 9.13
    999 ± 999
        Flare Week 4- Tapering Arm (n=28;0)
    5.0 ± 6.55
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=7;0)
    5.4 ± 9.59
    999 ± 999
        Flare Week 10- Tapering Arm (n=29;0)
    3.5 ± 4.55
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=7;0)
    3.6 ± 2.52
    999 ± 999
        Flare Week 16- Tapering Arm (n=29;0)
    4.5 ± 6.14
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=8;0)
    2.8 ± 4.19
    999 ± 999
    Notes
    [21] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [22] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Simplified Disease Activity Index (SDAI) Score

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    End point title
    Mean Change From Double-blind Baseline in Simplified Disease Activity Index (SDAI) Score
    End point description
    The SDAI is a validated measure of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, global health assessed by the participant on a visual analogue scale from 0 to 10 (cm), global health assessed by an investigator on a visual analogue scale from 0 to 10 (cm), and serum levels of C-reactive protein levels (mg/dL) were included in the SDAI score. Scores on the SDAI range from 0 to 86; higher scores indicate more disease activity. Negative values indicate improvement from the Double-blind baseline score. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [23]
    76 [24]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Double Blind Week 10- Tapering Arm (n=36;62)
    3.7 ± 8.57
    0.8 ± 1.85
        Double Blind Week 10- Withdrawal Arm (n=9;11)
    0.9 ± 2.59
    1.3 ± 2.67
        Double Blind Week 16- Tapering Arm (n=35;63)
    6.3 ± 10.25
    0.4 ± 1.35
        Double Blind Week 16- Withdrawal Arm (n=9;11)
    3.6 ± 2.80
    -0.1 ± 0.90
        Double Blind Week 22- Tapering Arm (n=19;63)
    3.6 ± 5.18
    0.3 ± 1.47
        Double Blind Week 22- Withdrawal Arm (n=4;11)
    2.3 ± 1.95
    -0.0 ± 0.88
        Double Blind Week 28- Tapering Arm (n=16;63)
    3.8 ± 6.34
    0.4 ± 1.37
        Double Blind Week 28- Withdrawal Arm (n=4;11)
    6.4 ± 8.40
    0.1 ± 1.61
        Double Blind Week 34- Tapering Arm (n= 12;63)
    3.0 ± 3.29
    0.2 ± 1.17
        Double Blind Week 34- Withdrawal Arm (n=2;11)
    0.1 ± 0.33
    0.1 ± 1.07
        Double Blind Week 40- Tapering Arm (n=11;63)
    7.5 ± 10.27
    0.1 ± 1.37
        Double Blind Week 40- Withdrawal Arm (n=2;11)
    8.5 ± 10.23
    -0.3 ± 0.62
        Flare Week 0- Tapering Arm (n=30;0)
    11.6 ± 11.17
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=8;0)
    9.9 ± 8.31
    999 ± 999
        Flare Week 4- Tapering Arm (n=28;0)
    4.1 ± 8.73
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=7;0)
    5.2 ± 9.64
    999 ± 999
        Flare Week 10- Tapering Arm (n=29;0)
    2.5 ± 7.53
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=7;0)
    3.5 ± 2.51
    999 ± 999
        Flare Week 16- Tapering Arm (n=29;0)
    3.6 ± 6.63
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=8;0)
    2.7 ± 4.20
    999 ± 999
    Notes
    [23] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [24] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Number of Participants Maintaining Clinical Remission Defined By DAS28 (ESR) < 2.6, SDAI ≤ 3.3, and CDAI ≤ 2.8 at Each Visit By Treatment Arm

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    End point title
    Number of Participants Maintaining Clinical Remission Defined By DAS28 (ESR) < 2.6, SDAI ≤ 3.3, and CDAI ≤ 2.8 at Each Visit By Treatment Arm
    End point description
    The maintenance of clinical remission after regaining remission during the Open-label rescue period was defined as either Disease Activity Score 28 (DAS28 ESR) < 2.6, Simplified Disease Activity Index (SDAI) score ≤ 3.3, or Clinical Disease Activity Index (CDAI) score ≤ 2.8). For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period.
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
    End point values
    DAS28 (ESR) < 2.6 SDAI ≤ 3.3 CDAI ≤ 2.8
    Number of subjects analysed
    122 [25]
    122 [26]
    122 [27]
    Units: Number of participants
        Double Blind Baseline- Tapering Arm (n=102;102;102
    102
    89
    85
        Double Blind Baseline- Withdrawal Arm (n=20;20;20)
    20
    19
    19
        Double Blind Week 10- Tapering Arm (n=100;98;99)
    85
    63
    62
        Double Blind Week 10- Withdrawal Arm (n=20;20;20)
    18
    16
    14
        Double Blind Week 16- Tapering Arm (n=98;98;98)
    78
    64
    62
        Double Blind Week 16- Withdrawal Arm (n=20;20;20)
    15
    13
    15
        Double Blind Week 22- Tapering Arm (n=82,82,82)
    75
    59
    58
        Double Blind Week 22- Withdrawal Arm (n=15;15;15)
    14
    13
    13
        Double Blind Week 28- Tapering Arm (n= 79;79;79)
    69
    58
    57
        Double Blind Week 28- Withdrawal Arm (n=15;15;15)
    13
    12
    13
        Double Blind Week 34- Tapering Arm (n=75;75;75)
    70
    58
    58
        Double Blind Week 34- Withdrawal Arm (n=13;13;13)
    13
    13
    13
        Double Blind Week 40- Tapering Arm (n=74;74;74)
    64
    57
    56
        Double Blind Week 40- Withdrawal Arm (n=13;13;13)
    11
    12
    12
        Flare Week 0- Tapering Arm (n=31;31;31)
    4
    4
    4
        Flare Week 0- Withdrawal Arm (n=8;8;8)
    1
    0
    2
        Flare Week 4- Tapering Arm (n=29;28;28)
    14
    13
    13
        Flare Week 4- Withdrawal Arm (n=7;7;7)
    1
    2
    2
        Flare Week 10- Tapering Arm (n=29;29;29)
    17
    14
    14
        Flare Week 10- Withdrawal Arm (n=7;7;7)
    3
    2
    2
        Flare Week 16- Tapering Arm (n=29;29;29)
    13
    13
    13
        Flare Week 16- Withdrawal Arm (n=8;8;8)
    4
    4
    4
    Notes
    [25] - Subjects who received at least 1 dose of study drug during the Double-blind period; LOCF
    [26] - Subjects who received at least 1 dose of study drug during the Double-blind period; LOCF
    [27] - Subjects who received at least 1 dose of study drug during the Double-blind period; LOCF
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline to Week 40 or Final Visit in Magnetic Resonance Imaging (MRI) Synovitis Score

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    End point title
    Mean Change From Double-blind Baseline to Week 40 or Final Visit in Magnetic Resonance Imaging (MRI) Synovitis Score
    End point description
    Synovitis was assessed in three wrist regions (the distal radioulnar joint; the radiocarpal joint; the intercarpal and carpometacarpal joints) and in each Metacarpophalangeal joint (MCP) joint. The first carpometacarpal joint and the first MCP joint are not scored. The scale is 0–3. Score 0 is normal, and 1–3 (mild, moderate, severe) are by thirds of the presumed maximum volume of enhancing tissue in the synovial compartment. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data; 9999= not calculable/estimable due to an insufficient number of subjects with an observation
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40 or Final visit
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    45 [28]
    76 [29]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Double Blind Week 40- Tapering Arm (n=6;51)
    -0.1 ± 1.20
    0.1 ± 1.33
        Double Blind Week 40- Withdrawal Arm (n=1;10)
    0.0 ± 9999
    -0.1 ± 0.90
        Flare Week 16- Tapering Arm (n=25;0)
    0.8 ± 1.84
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=7;0)
    0.1 ± 1.81
    999 ± 999
    Notes
    [28] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [29] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline to Week 40 or Final Visit in Bone Marrow Edema (BME) Score

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    End point title
    Mean Change From Double-blind Baseline to Week 40 or Final Visit in Bone Marrow Edema (BME) Score
    End point description
    Bone edema in each bone was scored separately. The scale is 0–3 based on the proportion of bone with edema, as follows—0: no edema; 1: 1–33% of bone edematous; 2: 34–66% of bone edematous; 3: 67–100%. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data; 9999= not calculable/estimable due to an insufficient number of subjects with an observation
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40 or Final visit
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [30]
    76 [31]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Double Blind Week 40- Tapering Arm (n=6;52)
    -0.5 ± 0.84
    0.0 ± 1.07
        Double Blind Week 40- Withdrawal Arm (n=1;10)
    0.0 ± 9999
    1.2 ± 3.52
        Flare Week 16- Tapering Arm (n=26;0)
    -0.1 ± 0.47
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=8;0)
    0.3 ± 0.38
    999 ± 999
    Notes
    [30] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [31] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline to Week 40 or Final Visit in Bone Erosions Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (RAMRIS) Score

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    End point title
    Mean Change From Double-blind Baseline to Week 40 or Final Visit in Bone Erosions Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (RAMRIS) Score
    End point description
    Bone erosions in each bone (wrists: carpal bones, distal radius, distal ulna, metacarpal bases; MCP joints: metacarpal heads, phalangeal bases) were scored separately. The scale is 0–10, based on the proportion of eroded bone compared to the ‘‘assessed bone volume’’, judged on all available images—0: no erosion; 1: 1–10% of bone eroded; 2; 11–20%, etc. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data; 9999= not calculable/estimable due to an insufficient number of subjects with an observation
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40 or Final Visit
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [32]
    76 [33]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Double Blind Week 40- Tapering Arm (n=6;52)
    -0.5 ± 1.73
    0.1 ± 0.52
        Double Blind Week 40- Withdrawal Arm (n=1;10)
    -2.0 ± 9999
    0.0 ± 1.08
        Flare Week 16- Tapering Arm (n=26;0)
    0.3 ± 1.02
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=8;0)
    0.1 ± 0.88
    999 ± 999
    Notes
    [32] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [33] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Health Assessment Questionnaire- Disability Index (HAQ-DI) Score Over Time

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    End point title
    Mean Change From Double-blind Baseline in Health Assessment Questionnaire- Disability Index (HAQ-DI) Score Over Time
    End point description
    The Health Assessment Questionnaire - Disability Index (HAQ-DI) is a questionnaire specific for rheumatoid arthritis. It consists of 20 questions over 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Subjects assessed their ability to do each task over the past week using the categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where 0 represents no disability and 3 very severe, high-dependency disability. The minimal clinically important difference (MCID) defined for the HAQ-DI is ≥ 0.22. For Double-blind period data, missing values were only imputed up to the time when the subject entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data; 9999= not calculable/estimable due to an insufficient number of subjects with an observation
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [34]
    76 [35]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Double Blind Week 10- Tapering Arm (n=30;62)
    0.1 ± 0.3
    0.0 ± 0.18
        Double Blind Week 10- Withdrawal Arm (n=9;11)
    0.3 ± 0.61
    0.0 ± 0.17
        Double Blind Week 16- Tapering Arm (n=19;63)
    0.2 ± 0.40
    -0.0 ± 0.28
        Double Blind Week 16- Withdrawal Arm (n=5;11)
    0.3 ± 0.54
    -0.0 ± 0.12
        Double Blind Week 22- Tapering Arm (n=15;63)
    0.1 ± 0.37
    -0.0 ± 0.26
        Double Blind Week 22- Withdrawal Arm (n=4;11)
    0.4 ± 0.79
    0.1 ± 0.39
        Double Blind Week 28- Tapering Arm (n=12;63)
    0.2 ± 0.43
    -0.0 ± 0.27
        Double Blind Week 28- Withdrawal Arm (n=3;11)
    0.7 ± 0.69
    -0.1 ± 0.15
        Double Blind Week 34- Tapering Arm (n=11;63)
    0.3 ± 0.49
    -0.0 ± 0.30
        Double Blind Week 34- Withdrawal Arm (n=2;11)
    0.2 ± 0.27
    0.1 ± 0.17
        Double Blind Week 40- Tapering Arm (n=7;63)
    0.4 ± 0.40
    -0.1 ± 0.33
        Double Blind Week 40- Withdrawal Arm (n=1;11)
    1.9 ± 9999
    0.0 ± 0.16
        Flare Week 0- Tapering Arm (n=25;0)
    0.4 ± 0.57
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=7;0)
    0.3 ± 0.29
    999 ± 999
        Flare Week 4- Tapering Arm (n=27;0)
    0.2 ± 0.49
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=7;0)
    0.2 ± 0.35
    999 ± 999
        Flare Week 10- Tapering Arm (n=27;0)
    0.1 ± 0.24
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=7;0)
    0.1 ± 0.20
    999 ± 999
        Flare Week 16- Tapering Arm (n=29;0)
    0.2 ± 0.39
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=7;0)
    0.1 ± 0.24
    999 ± 999
    Notes
    [34] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [35] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Number of Participants With Health Assessment Questionnaire- Disability Index (HAQ-DI) Score ≤ 0.5 at Double-blind Baseline and at Week 40

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    End point title
    Number of Participants With Health Assessment Questionnaire- Disability Index (HAQ-DI) Score ≤ 0.5 at Double-blind Baseline and at Week 40
    End point description
    The Health Assessment Questionnaire - Disability Index (HAQ-DI) is a participant-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. The number of participants with HAQ-DI score ≤ 0.5 (considered to be normal) was recorded.
    End point type
    Secondary
    End point timeframe
    Week 4 and Week 40
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [36]
    76 [37]
    Units: Number of participants
        Double Blind Week 4- Tapering Arm (n=37;65)
    21
    50
        Double Blind Week 4- Withdrawal Arm (n=9;11)
    7
    10
        Double Blind Week 40- Tapering Arm (n=7;63)
    2
    48
        Double Blind Week 40- Withdrawal Arm (n=1;11)
    0
    9
    Notes
    [36] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [37] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Routine Assessment of Patient Index Data (RAPID3) Questionnaire Scores Assessed During In-office Visits

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    End point title
    Mean Change From Double-blind Baseline in Routine Assessment of Patient Index Data (RAPID3) Questionnaire Scores Assessed During In-office Visits
    End point description
    The RAPID3 is an activity index derived from the Multi-dimensional Health Assessment Questionnaire (MD-HAQ). It includes an assessment of physical function, a pain Visual Analog Scale (VAS), and a participant global assessment of disease activity VAS. The total RAPID3 score ranges from 0 to 30 where higher scores represent severe disease. Negative values indicate improvement from the Double-blind baseline score. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [38]
    76 [39]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Double Blind Week 10- Tapering Arm (n=37;63)
    1.9 ± 3.92
    0.7 ± 3.20
        Double Blind Week 10- Withdrawal Arm (n=9;11)
    1.4 ± 3.73
    1.5 ± 4.67
        Double Blind Week 16- Tapering Arm (n=35;63)
    4.7 ± 5.66
    0.8 ± 2.80
        Double Blind Week 16- Withdrawal Arm (n=9;11)
    2.5 ± 4.59
    0.1 ± 1.37
        Double Blind Week 22- Tapering Arm (n=19;63)
    2.6 ± 4.83
    0.3 ± 2.83
        Double Blind Week 22- Withdrawal Arm (n=4;11)
    3.6 ± 4.18
    0.6 ± 3.31
        Double Blind Week 28- Tapering Arm (n=16;63)
    2.2 ± 4.20
    0.6 ± 2.47
        Double Blind Week 28- Withdrawal Arm (n=4;11)
    3.7 ± 4.45
    -0.3 ± 1.61
        Double Blind Week 34- Tapering Arm (n=12;63)
    2.2 ± 3.77
    -0.0 ± 1.93
        Double Blind Week 34- Withdrawal Arm (n=2;11)
    1.9 ± 2.62
    1.6 ± 2.33
        Double Blind Week 40- Tapering Arm (n=11;63)
    4.7 ± 6.22
    0.0 ± 2.39
        Double Blind Week 40- Withdrawal Arm (n=2;11)
    0.4 ± 0.92
    0.8 ± 1.62
        Flare Week 0- Tapering Arm (n=30;0)
    6.1 ± 6.64
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=8;0)
    3.9 ± 5.60
    999 ± 999
        Flare Week 4- Tapering Arm (n=27;0)
    3.1 ± 5.38
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=7;0)
    3.2 ± 4.15
    999 ± 999
        Flare Week 10- Tapering Arm (n=27;0)
    2.8 ± 3.93
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=7;0)
    2.3 ± 2.61
    999 ± 999
        Flare Week 16- Tapering Arm (n=29;0)
    2.9 ± 4.22
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=7;0)
    2.1 ± 3.01
    999 ± 999
    Notes
    [38] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [39] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Flare Week 0 in Routine Assessment of Patient Index Data (RAPID3) Questionnaire Scores Assessed at Home

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    End point title
    Mean Change From Flare Week 0 in Routine Assessment of Patient Index Data (RAPID3) Questionnaire Scores Assessed at Home
    End point description
    The RAPID3 is an activity index derived from the Multi-dimensional Health Assessment Questionnaire (MD-HAQ). It includes an assessment of physical function, a pain Visual Analog Scale (VAS), and a participant global assessment of disease activity VAS. The total RAPID3 score ranges from 0 to 30 where higher scores represent severe disease. Negative values indicate improvement from the Double-blind baseline score.
    End point type
    Secondary
    End point timeframe
    Flare Week 0 and Flare Weeks 1, 2, 3, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15
    End point values
    Flared Participants
    Number of subjects analysed
    33 [40]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Flare Week 1- Tapering Arm (n=19)
    -1.6 ± 4.92
        Flare Week 1- Withdrawal Arm (n=3)
    3.7 ± 7.20
        Flare Week 2- Tapering Arm (n=22)
    -3.1 ± 5.41
        Flare Week 2- Withdrawal Arm (n=4)
    0.8 ± 6.89
        Flare Week 3- Tapering Arm (n=25)
    -3.8 ± 6.78
        Flare Week 3- Withdrawal Arm (n=6)
    -0.4 ± 7.94
        Flare Week 5- Tapering Arm (n=26)
    -3.8 ± 6.61
        Flare Week 5- Withdrawal Arm (n=6)
    -0.8 ± 6.56
        Flare Week 6- Tapering Arm (n=26)
    -4.1 ± 6.81
        Flare Week 6- Withdrawal Arm (n=6)
    -0.9 ± 6.97
        Flare Week 7- Tapering Arm (n=26)
    -3.7 ± 6.86
        Flare Week 7- Withdrawal Arm (n=6)
    -0.6 ± 6.26
        Flare Week 8- Tapering Arm (n=27)
    -4.4 ± 7.17
        Flare Week 8- Withdrawal Arm (n=6)
    -0.6 ± 5.56
        Flare Week 9- Tapering Arm (n=27)
    -3.3 ± 5.81
        Flare Week 9- Withdrawal Arm (n=6)
    -1.0 ± 5.89
        Flare Week 11- Tapering Arm (n=27)
    -3.7 ± 5.69
        Flare Week 11- Withdrawal Arm (n=6)
    -1.0 ± 5.85
        Flare Week 12- Tapering Arm (n=27)
    -3.4 ± 5.84
        Flare Week 12- Withdrawal Arm (n=6)
    -2.3 ± 4.46
        Flare Week 13- Tapering Arm (n=27)
    -3.5 ± 5.72
        Flare Week 13- Withdrawal Arm (n=6)
    -2.5 ± 4.78
        Flare Week 14- Tapering Arm (n=27)
    -3.1 ± 5.54
        Flare Week 14- Withdrawal Arm (n=6)
    -2.4 ± 4.79
        Flare Week 15- Tapering Arm (n=27)
    -3.5 ± 6.69
        Flare Week 15- Withdrawal Arm (n=6)
    -2.2 ± 4.70
    Notes
    [40] - Open-label-rescue-treated subjects with available data; last observation carried forward
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Swollen Joint Count 28

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    End point title
    Mean Change From Double-blind Baseline in Swollen Joint Count 28
    End point description
    Twenty-eight joints, excluding hip joints, were assessed for swelling by physical examination. Swelling of each joint was classified as present (1) or absent (0), for a total possible score of 0 (0 joints with swelling) to 28 (worst possible score/28 joints with swelling). Negative values indicate improvement from baseline. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [41]
    76 [42]
    Units: swollen joint counts
    arithmetic mean (standard deviation)
        Double Blind Week 10- Tapering Arm (n=37;64)
    0.9 ± 2.09
    0.1 ± 0.58
        Double Blind Week 10- Withdrawal Arm (n=9;11)
    0.1 ± 0.33
    -0.1 ± 0.30
        Double Blind Week 16- Tapering Arm (n=35;63)
    1.2 ± 2.15
    -0.0 ± 0.34
        Double Blind Week 16- Withdrawal Arm (n=9;11)
    0.3 ± 0.50
    0.0 ± 0.45
        Double Blind Week 22- Tapering Arm (n=19;63)
    0.6 ± 1.64
    0.1 ± 0.64
        Double Blind Week 22- Withdrawal Arm (n=4;11)
    0.5 ± 0.58
    -0.1 ± 0.30
        Double Blind Week 28- Tapering Arm (n=16;63)
    0.5 ± 0.89
    0.0 ± 0.33
        Double Blind Week 28- Withdrawal Arm (n=4;11)
    2.0 ± 2.45
    -0.1 ± 0.30
        Double Blind Week 34- Tapering Arm (n=12;63)
    0.0 ± 0.43
    0.0 ± 0.46
        Double Blind Week 34- Withdrawal Arm (n=2;11)
    0.0 ± 0.00
    -0.1 ± 0.30
        Double Blind Week 40- Tapering Arm (n=11;63)
    1.5 ± 3.01
    0.0 ± 0.42
        Double Blind Week 40- Withdrawal Arm (n=2;11)
    2.0 ± 2.83
    -0.1 ± 0.30
        Flare Week 0- Tapering Arm (n=30;0)
    2.3 ± 2.60
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=8;0)
    1.9 ± 2.10
    999 ± 999
        Flare Week 4- Tapering Arm (n=30;0)
    1.2 ± 1.98
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=8;0)
    0.6 ± 1.06
    999 ± 999
        Flare Week 10- Tapering Arm (n=30;0)
    0.4 ± 0.89
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=8;0)
    0.1 ± 0.35
    999 ± 999
        Flare Week 16- Tapering Arm (n=30;0)
    0.9 ± 1.81
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=8;0)
    0.3 ± 0.46
    999 ± 999
    Notes
    [41] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [42] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Swollen Joint Count 66

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    End point title
    Mean Change From Double-blind Baseline in Swollen Joint Count 66
    End point description
    Sixty-six joints were assessed for swelling by physical examination. Swelling of each joint was classified as present (1) or absent (0), for a total possible score of 0 (0 joints with swelling) to 66 (worst possible score/66 joints with swelling). Negative values indicate improvement from baseline. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [43]
    76 [44]
    Units: swollen joint counts
    arithmetic mean (standard deviation)
        Double Blind Week 10- Tapering Arm (n=37;64)
    1.1 ± 2.36
    0.1 ± 0.67
        Double Blind Week 10- Withdrawal Arm (n=9;11)
    0.1 ± 0.33
    -0.2 ± 0.40
        Double Blind Week 16- Tapering Arm (n=35;63)
    1.4 ± 2.56
    -0.0 ± 0.34
        Double Blind Week 16- Withdrawal Arm (n=9;11)
    0.4 ± 0.53
    0.0 ± 0.45
        Double Blind Week 22- Tapering Arm (n=19;63)
    0.6 ± 1.64
    0.1 ± 0.73
        Double Blind Week 22- Withdrawal Arm (n=4;11)
    1.0 ± 1.41
    -0.1 ± 0.30
        Double Blind Week 28- Tapering Arm (n=16;63)
    0.5 ± 0.89
    0.1 ± 0.66
        Double Blind Week 28- Withdrawal Arm (n=4;11)
    3.3 ± 4.72
    -0.2 ± 0.40
        Double Blind Week 34- Tapering Arm (n=12;63)
    0.0 ± 0.43
    0.0 ± 0.54
        Double Blind Week 34- Withdrawal Arm (n=2;11)
    0.0 ± 0.00
    -0.2 ± 0.40
        Double Blind Week 40- Tapering Arm (n=11;63)
    1.5 ± 3.01
    0.0 ± 0.46
        Double Blind Week 40- Withdrawal Arm (n=2;11)
    2.0 ± 2.83
    -0.2 ± 0.40
        Flare Week 0- Tapering Arm (n=30;0)
    2.6 ± 2.90
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=8;0)
    2.6 ± 3.38
    999 ± 999
        Flare Week 4- Tapering Arm (n=30;0)
    1.3 ± 1.99
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=8;0)
    0.6 ± 1.06
    999 ± 999
        Flare Week 10- Tapering Arm (n=30;0)
    0.6 ± 1.10
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=8;0)
    0.4 ± 0.52
    999 ± 999
        Flare Week 16- Tapering Arm (n=30;0)
    1.1 ± 2.21
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=8;0)
    0.4 ± 0.74
    999 ± 999
    Notes
    [43] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [44] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Tender Joint Count 28

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    End point title
    Mean Change From Double-blind Baseline in Tender Joint Count 28
    End point description
    Twenty-eight joints were assessed for tenderness by physical examination. Pain or tenderness of each joint was classified as present (1) or absent (0), for a total possible score of 0 (0 joints with tenderness) to 28 (worst possible score/28 joints with tenderness). Negative values indicate improvement from baseline. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [45]
    76 [46]
    Units: tender joint counts
    arithmetic mean (standard deviation)
        Double Blind Week 10- Tapering Arm (n=37;64)
    1.3 ± 2.74
    0.1 ± 0.54
        Double Blind Week 10- Withdrawal Arm (n=9;11)
    -0.1 ± 0.60
    0.5 ± 1.21
        Double Blind Week 16- Tapering Arm (n=35;63)
    2.5 ± 4.49
    0.1 ± 0.41
        Double Blind Week 16- Withdrawal Arm (n=9;11)
    1.0 ± 0.87
    0.0 ± 0.00
        Double Blind Week 22- Tapering Arm (n=19;63)
    0.9 ± 1.66
    -0.0 ± 0.42
        Double Blind Week 22- Withdrawal Arm (n=4;11)
    0.8 ± 1.50
    0.1 ± 0.30
        Double Blind Week 28- Tapering Arm (n=16;63)
    1.6 ± 3.39
    0.0 ± 0.51
        Double Blind Week 28- Withdrawal Arm (n=4;11)
    1.8 ± 2.36
    0.2 ± 0.40
        Double Blind Week 34- Tapering Arm (n=12;63)
    1.0 ± 1.65
    -0.0 ± 0.42
        Double Blind Week 34- Withdrawal Arm (n=2;11)
    0.0 ± 0.00
    0.0 ± 0.00
        Double Blind Week 40- Tapering Arm (n=11;63)
    2.0 ± 2.65
    0.0 ± 0.51
        Double Blind Week 40- Withdrawal Arm (n=2;11)
    3.5 ± 4.95
    0.0 ± 0.00
        Flare Week 0- Tapering Arm (n=30;0)
    4.4 ± 4.63
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=8;0)
    3.6 ± 3.81
    999 ± 999
        Flare Week 4- Tapering Arm (n=30;0)
    1.5 ± 2.27
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=8;0)
    2.5 ± 5.13
    999 ± 999
        Flare Week 10- Tapering Arm (n=30;0)
    0.9 ± 1.84
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=8;0)
    1.1 ± 1.46
    999 ± 999
        Flare Week 16- Tapering Arm (n=30;0)
    1.8 ± 2.64
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=8;0)
    1.1 ± 1.89
    999 ± 999
    Notes
    [45] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [46] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Tender Joint Count 68

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    End point title
    Mean Change From Double-blind Baseline in Tender Joint Count 68
    End point description
    Sixty-eight joints were assessed for tenderness by physical examination. Pain or tenderness of each joint was classified as present (1) or absent (0), for a total possible score of 0 (0 joints with tenderness) to 68 (worst possible score/68 joints with tenderness). Negative values indicate improvement from baseline. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [47]
    76 [48]
    Units: tender joint counts
    arithmetic mean (standard deviation)
        Double Blind Week 10- Tapering Arm (n=37;64)
    1.9 ± 3.45
    0.3 ± 1.47
        Double Blind Week 10- Withdrawal Arm (n=9;11)
    0.1 ± 0.60
    0.9 ± 1.64
        Double Blind Week 16- Tapering Arm (n=35;63)
    3.5 ± 6.33
    0.2 ± 1.36
        Double Blind Week 16- Withdrawal Arm (n=9;11)
    1.4 ± 1.13
    0.2 ± 0.60
        Double Blind Week 22- Tapering Arm (n=19;63)
    1.2 ± 2.27
    0.2 ± 1.35
        Double Blind Week 22- Withdrawal Arm (n=4;11)
    2.0 ± 2.83
    0.4 ± 1.03
        Double Blind Week 28- Tapering Arm (n=16;63)
    2.5 ± 5.34
    0.1 ± 0.96
        Double Blind Week 28- Withdrawal Arm (n=4;11)
    3.8 ± 4.50
    0.3 ± 0.47
        Double Blind Week 34- Tapering Arm (n=12;63)
    1.9 ± 2.87
    0.0 ± 0.73
        Double Blind Week 34- Withdrawal Arm (n=2;11)
    0.0 ± 0.00
    0.1 ± 0.30
        Double Blind Week 40- Tapering Arm (n=11;63)
    3.0 ± 4.24
    0.0 ± 0.68
        Double Blind Week 40- Withdrawal Arm (n=2;11)
    9.0 ± 12.73
    -0.1 ± 0.30
        Flare Week 0- Tapering Arm (n=30;0)
    6.2 ± 6.93
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=8;0)
    6.1 ± 6.27
    999 ± 999
        Flare Week 4- Tapering Arm (n=30;0)
    1.9 ± 2.50
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=8;0)
    4.1 ± 8.48
    999 ± 999
        Flare Week 10- Tapering Arm (n=30;0)
    1.5 ± 2.69
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=8;0)
    2.3 ± 2.31
    999 ± 999
        Flare Week 16- Tapering Arm (n=30;0)
    2.1 ± 3.37
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=8;0)
    1.6 ± 1.85
    999 ± 999
    Notes
    [47] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [48] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Participant's Global Assessment of Disease Activity

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    End point title
    Mean Change From Double-blind Baseline in Participant's Global Assessment of Disease Activity
    End point description
    Participants rated the severity of their rheumatoid arthritis symptoms and how well they were doing during the last 24 hours by placing a vertical mark on a line with a range of 0 (very well) to 100 mm (very poorly). Negative values indicate improvement from baseline. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [49]
    76 [50]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Double Blind Week 10- Tapering Arm (n=37;63)
    11.6 ± 19.0
    2.6 ± 8.49
        Double Blind Week 10- Withdrawal Arm (n=9;11)
    8.0 ± 21.66
    9.6 ± 20.27
        Double Blind Week 16- Tapering Arm (n=35;63)
    20.5 ± 26.97
    2.4 ± 9.27
        Double Blind Week 16- Withdrawal Arm (n=9;11)
    10.7 ± 19.97
    -0.3 ± 5.76
        Double Blind Week 22- Tapering Arm (n=19;63)
    10.7 ± 17.74
    1.7 ± 9.14
        Double Blind Week 22- Withdrawal Arm (n=4;11)
    5.8 ± 8.73
    0.2 ± 8.87
        Double Blind Week 28- Tapering Arm (n=16;63)
    9.4 ± 21.03
    2.7 ± 10.03
        Double Blind Week 28- Withdrawal Arm (n=4;11)
    15.0 ± 25.76
    -1.0 ± 7.82
        Double Blind Week 34- Tapering Arm (n=12;63)
    11.5 ± 13.70
    1.2 ± 7.23
        Double Blind Week 34- Withdrawal Arm (n=2;11)
    -1.0 ± 1.41
    0.7 ± 7.25
        Double Blind Week 40- Tapering Arm (n=11;63)
    22.9 ± 35.32
    0.0 ± 7.60
        Double Blind Week 40- Withdrawal Arm (n=2;11)
    2.0 ± 9.90
    -1.7 ± 4.45
        Flare Week 0- Tapering Arm (n=30;0)
    29.5 ± 29.43
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=8;0)
    21.6 ± 27.07
    999 ± 999
        Flare Week 4- Tapering Arm (n=29;0)
    13.7 ± 22.93
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=7;0)
    11.7 ± 21.96
    999 ± 999
        Flare Week 10- Tapering Arm (n=29;0)
    11.7 ± 16.89
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=7;0)
    14.1 ± 10.35
    999 ± 999
        Flare Week 16- Tapering Arm (n=29;0)
    9.4 ± 13.47
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=8;0)
    6.9 ± 9.31
    999 ± 999
    Notes
    [49] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [50] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Participant's Global Assessment of Rheumatoid Arthritis Pain

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    End point title
    Mean Change From Double-blind Baseline in Participant's Global Assessment of Rheumatoid Arthritis Pain
    End point description
    Participants rated the severity of their rheumatoid arthritis pain in the past week by placing a vertical mark on a line with a range of 0 (no pain) to 100 mm (severe pain). Negative values indicate improvement from baseline. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [51]
    76 [52]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Double Blind Week 10- Tapering Arm (n=37;63)
    8.0 ± 17.96
    3.5 ± 14.33
        Double Blind Week 10- Withdrawal Arm (n=9;11)
    6.4 ± 19.05
    9.3 ± 21.04
        Double Blind Week 16- Tapering Arm (n=35;63)
    17.8 ± 27.16
    3.0 ± 12.48
        Double Blind Week 16- Withdrawal Arm (n=9;11)
    10.7 ± 18.93
    -0.6 ± 9.65
        Double Blind Week 22- Tapering Arm (n=19;63)
    10.4 ± 19.55
    0.3 ± 7.82
        Double Blind Week 22- Withdrawal Arm (n=4;11)
    4.0 ± 4.90
    -1.1 ± 11.20
        Double Blind Week 28- Tapering Arm (n=16;63)
    8.3 ± 17.57
    1.6 ± 9.83
        Double Blind Week 28- Withdrawal Arm (n=4;11)
    14.0 ± 24.59
    -1.4 ± 10.93
        Double Blind Week 34- Tapering Arm (n=12;63)
    11.6 ± 14.61
    -0.3 ± 7.61
        Double Blind Week 34- Withdrawal Arm (n=2;11)
    -3.5 ± 2.12
    2.1 ± 8.40
        Double Blind Week 40- Tapering Arm (n=11;63)
    24.0 ± 32.67
    -0.5 ± 10.00
        Double Blind Week 40- Withdrawal Arm (n=2;11)
    -0.5 ± 20.51
    -0.9 ± 5.07
        Flare Week 0- Tapering Arm (n=30;0)
    24.4 ± 31.66
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=8;0)
    17.0 ± 19.38
    999 ± 999
        Flare Week 4- Tapering Arm (n=29;0)
    9.0 ± 21.68
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=7;0)
    11.1 ± 17.46
    999 ± 999
        Flare Week 10- Tapering Arm (n=29;0)
    7.5 ± 14.93
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=7;0)
    8.3 ± 9.60
    999 ± 999
        Flare Week 16- Tapering Arm (n=29;0)
    8.0 ± 14.41
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=8;0)
    4.3 ± 6.32
    999 ± 999
    Notes
    [51] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [52] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Physician's Global Assessment of Disease Activity

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    End point title
    Mean Change From Double-blind Baseline in Physician's Global Assessment of Disease Activity
    End point description
    Physicians assessed participants’ current rheumatoid arthritis disease activity at the time of the visit (independent of the participant’s self-assessment) by placing a vertical mark on a line with a range of 0 (very low) to 100 mm (very high). Negative values indicate improvement from baseline. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [53]
    76 [54]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Double Blind Week 10- Tapering Arm (n=37;62)
    10.2 ± 19.54
    1.3 ± 4.27
        Double Blind Week 10- Withdrawal Arm (n=9;11)
    1.6 ± 4.67
    0.5 ± 4.74
        Double Blind Week 16- Tapering Arm (n=35;63)
    13.2 ± 21.48
    0.9 ± 5.07
        Double Blind Week 16- Withdrawal Arm (n=9;11)
    5.0 ± 3.35
    -0.5 ± 2.98
        Double Blind Week 22- Tapering Arm (n=19;63)
    6.9 ± 14.83
    0.9 ± 5.05
        Double Blind Week 22- Withdrawal Arm (n=4;11)
    3.8 ± 2.87
    0.4 ± 3.26
        Double Blind Week 28- Tapering Arm (n=16;63)
    7.3 ± 16.51
    1.7 ± 5.51
        Double Blind Week 28- Withdrawal Arm (n=4;11)
    10.0 ± 10.89
    -0.9 ± 2.74
        Double Blind Week 34- Tapering Arm (n=12;63)
    5.5 ± 12.27
    0.8 ± 3.60
        Double Blind Week 34- Withdrawal Arm (n=2;11)
    0.0 ± 0.00
    0.6 ± 4.13
        Double Blind Week 40- Tapering Arm (n=11;63)
    16.2 ± 26.91
    1.0 ± 5.32
        Double Blind Week 40- Withdrawal Arm (n=2;11)
    19.5 ± 26.16
    -0.6 ± 2.42
        Flare Week 0- Tapering Arm (n=30;0)
    26.5 ± 23.28
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=8;0)
    17.4 ± 15.37
    999 ± 999
        Flare Week 4- Tapering Arm (n=29;0)
    12.2 ± 17.06
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=7;0)
    9.3 ± 20.27
    999 ± 999
        Flare Week 10- Tapering Arm (n=30;0)
    10.2 ± 13.82
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=7;0)
    12.9 ± 11.51
    999 ± 999
        Flare Week 16- Tapering Arm (n=30;0)
    8.6 ± 12.48
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=8;0)
    7.6 ± 20.00
    999 ± 999
    Notes
    [53] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [54] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Morning Stiffness Duration

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    End point title
    Mean Change From Double-blind Baseline in Morning Stiffness Duration
    End point description
    The duration of morning stiffness was reported by participants as the average daily length during the past week in minutes (from time of awaking to time of maximal improvement). Negative values indicate improvement from baseline. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    45 [55]
    74 [56]
    Units: minutes
    arithmetic mean (standard deviation)
        Double Blind Week 10- Tapering Arm (n=36;62)
    3.5 ± 17.33
    1.8 ± 7.19
        Double Blind Week 10- Withdrawal Arm (n=8;10)
    1.1 ± 3.60
    1.5 ± 5.97
        Double Blind Week 16- Tapering Arm (n=34;61)
    6.6 ± 24.41
    2.3 ± 12.54
        Double Blind Week 16- Withdrawal Arm (n=9;11)
    9.2 ± 19.78
    -0.6 ± 5.05
        Double Blind Week 22- Tapering Arm (n=18;61)
    -1.6 ± 8.07
    1.5 ± 9.67
        Double Blind Week 22- Withdrawal Arm (n=4;11)
    1.0 ± 2.00
    0.5 ± 3.70
        Double Blind Week 28- Tapering Arm (n=15;61)
    2.6 ± 13.09
    2.4 ± 10.53
        Double Blind Week 28- Withdrawal Arm (n=4;11)
    17.3 ± 28.81
    0.0 ± 3.71
        Double Blind Week 34- Tapering Arm (n=12;61)
    0.6 ± 10.97
    1.4 ± 8.86
        Double Blind Week 34- Withdrawal Arm (n=2;11)
    0.0 ± 0.00
    -1.1 ± 6.64
        Double Blind Week 40- Tapering Arm (n=11;61)
    2.0 ± 12.49
    0.4 ± 9.33
        Double Blind Week 40- Withdrawal Arm (n=2;11)
    0.0 ± 0.00
    -0.2 ± 5.78
        Flare Week 0- Tapering Arm (n=29;0)
    13.5 ± 25.21
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=8;0)
    18.5 ± 26.25
    999 ± 999
        Flare Week 4- Tapering Arm (n=29;0)
    25.0 ± 110.77
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=8;0)
    19.9 ± 26.51
    999 ± 999
        Flare Week 10- Tapering Arm (n=29;0)
    8.1 ± 30.20
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=8;0)
    7.9 ± 9.72
    999 ± 999
        Flare Week 16- Tapering Arm (n=29;0)
    17.3 ± 36.46
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=8;0)
    9.6 ± 20.65
    999 ± 999
    Notes
    [55] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [56] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Morning Stiffness Severity

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    End point title
    Mean Change From Double-blind Baseline in Morning Stiffness Severity
    End point description
    Morning stiffness severity was assessed by a numeric rating-scale (NRS). Participants rated the severity of morning stiffness during the past week from 0 to 10 with 0 representing "not severe" and 10 "very severe". Negative values indicate improvement from baseline. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [57]
    76 [58]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Double Blind Week 10- Tapering Arm (n=37;63)
    0.6 ± 1.51
    0.4 ± 1.01
        Double Blind Week 10- Withdrawal Arm (n=9;11)
    0.4 ± 1.81
    0.6 ± 1.29
        Double Blind Week 16- Tapering Arm (n=35;63)
    0.8 ± 1.73
    0.3 ± 1.11
        Double Blind Week 16- Withdrawal Arm (n=9;11)
    0.7 ± 2.24
    -0.1 ± 1.04
        Double Blind Week 22- Tapering Arm (n=19;63)
    0.9 ± 1.27
    0.2 ± 0.85
        Double Blind Week 22- Withdrawal Arm (n=4;11)
    0.8 ± 0.96
    0.4 ± 1.75
        Double Blind Week 28- Tapering Arm (n=16;63)
    0.9 ± 1.69
    0.2 ± 1.10
        Double Blind Week 28- Withdrawal Arm (n=4;11)
    1.3 ± 2.75
    -0.2 ± 0.87
        Double Blind Week 34- Tapering Arm (n=12;63)
    1.3 ± 1.71
    0.1 ± 0.85
        Double Blind Week 34- Withdrawal Arm (n=2;11)
    0.0 ± 1.41
    -0.2 ± 1.08
        Double Blind Week 40- Tapering Arm (n=11;63)
    1.8 ± 2.52
    0.1 ± 0.94
        Double Blind Week 40- Withdrawal Arm (n=2;11)
    -1.0 ± 1.41
    -0.4 ± 1.03
        Flare Week 0- Tapering Arm (n=30;0)
    1.6 ± 2.11
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=8;0)
    0.9 ± 1.96
    999 ± 999
        Flare Week 4- Tapering Arm (n=29;0)
    0.8 ± 2.21
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=7;0)
    0.6 ± 1.72
    999 ± 999
        Flare Week 10- Tapering Arm (n=29;0)
    0.6 ± 1.40
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=7;0)
    0.6 ± 1.27
    999 ± 999
        Flare Week 16- Tapering Arm (n=29;0)
    0.6 ± 1.45
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=8;0)
    -0.1 ± 1.13
    999 ± 999
    Notes
    [57] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [58] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Participant's Assessment of Sleep Disturbance

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    End point title
    Mean Change From Double-blind Baseline in Participant's Assessment of Sleep Disturbance
    End point description
    Participants rated the severity of their sleep disturbance in the past week by placing a vertical mark on a line with a range of 0 (sleep is no problem) to 100 mm (sleep is a major problem). Negative values indicate improvement from baseline. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [59]
    76 [60]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Double Blind Week 10- Tapering Arm (n=37;63)
    2.1 ± 15.37
    0.0 ± 8.99
        Double Blind Week 10- Withdrawal Arm (n=9;11)
    -3.2 ± 29.39
    0.8 ± 1.54
        Double Blind Week 16- Tapering Arm (n= 35;63)
    10.2 ± 19.12
    1.7 ± 15.96
        Double Blind Week 16- Withdrawal Arm (n=9;11)
    7.1 ± 22.42
    1.1 ± 3.02
        Double Blind Week 22- Tapering Arm (n=19;63)
    8.2 ± 19.59
    -0.3 ± 10.91
        Double Blind Week 22- Withdrawal Arm (n=4;11)
    8.3 ± 31.35
    3.5 ± 8.70
        Double Blind Week 28- Tapering Arm (n=16;63)
    1.8 ± 27.81
    2.1 ± 12.67
        Double Blind Week 28- Withdrawal Arm (n=4;11)
    4.5 ± 19.82
    -1.0 ± 7.63
        Double Blind Week 34- Tapering Arm (n=12;63)
    5.6 ± 22.99
    -0.4 ± 11.48
        Double Blind Week 34- Withdrawal Arm (n=2;11)
    -0.5 ± 30.41
    -0.4 ± 2.77
        Double Blind Week 40- Tapering Arm (n=11;63)
    17.7 ± 34.04
    -0.2 ± 12.40
        Double Blind Week 40- Withdrawal Arm (n=2;11)
    -8.0 ± 15.56
    -1.0 ± 4.43
        Flare Week 0- Tapering Arm (n=30;0)
    18.9 ± 26.53
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=8;0)
    4.0 ± 14.61
    999 ± 999
        Flare Week 4- Tapering Arm (n=29;0)
    4.9 ± 24.33
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=7;0)
    1.6 ± 10.05
    999 ± 999
        Flare Week 10- Tapering Arm (n=29;0)
    0.2 ± 21.26
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=7;0)
    3.9 ± 12.98
    999 ± 999
        Flare Week 16- Tapering Arm (n=29;0)
    2.3 ± 20.17
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=8;0)
    -7.3 ± 14.14
    999 ± 999
    Notes
    [59] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [60] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Effectiveness Score

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    End point title
    Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Effectiveness Score
    End point description
    Participants completed the 14-item Treatment Satisfaction Questionnaire for Medication (TSQM; Version 1.4) to assess satisfaction with their current rheumatoid arthritis treatment over the previous 2-3 weeks or since the last time that they took the medication. The TSQM consists of fourteen items over four domains (effectiveness, side effects, convenience, and global satisfaction). The 14 questions are answered either with yes/no or by means of a five or seven stage scale (ranging from very unsatisfied to satisfied). TSQM Scale scores for each domain range from 0 to 100 and higher scores represent higher satisfaction. Negative values indicate worsening from baseline. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data
    End point type
    Secondary
    End point timeframe
    At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [61]
    74 [62]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Double Blind Week 16- Tapering Arm (n=35;61)
    -8.3 ± 35.30
    0.2 ± 23.74
        Double Blind Week 16- Withdrawal Arm (n=8;11)
    2.8 ± 39.51
    -13.6 ± 43.84
        Double Blind Week 28- Tapering Arm (n=16;61)
    -10.1 ± 24.28
    -3.8 ± 17.82
        Double Blind Week 28- Withdrawal Arm (n=4;11)
    -5.6 ± 45.59
    -17.2 ± 30.48
        Double Blind Week 40- Tapering Arm (n=11;61)
    -15.2 ± 33.53
    -4.4 ± 27.82
        Double Blind Week 40- Withdrawal Arm (n=2;11)
    -19.4 ± 27.50
    -16.2 ± 45.10
        Flare Week 0- Tapering Arm (n=28;0)
    -10.9 ± 39.82
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=7;0)
    -9.5 ± 38.05
    999 ± 999
        Flare Week 4- Tapering Arm (n=25;0)
    -17.3 ± 40.07
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=6;0)
    -6.5 ± 48.23
    999 ± 999
        Flare Week 10- Tapering Arm (n=27;0)
    -10.7 ± 44.07
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=7;0)
    7.9 ± 34.23
    999 ± 999
        Flare Week 16- Tapering Arm (n=28;0)
    -7.5 ± 25.49
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=7;0)
    -16.7 ± 39.67
    999 ± 999
    Notes
    [61] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [62] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Side Effects Score

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    End point title
    Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Side Effects Score
    End point description
    Participants completed the 14-item Treatment Satisfaction Questionnaire for Medication (TSQM; Version 1.4) to assess satisfaction with their current rheumatoid arthritis treatment over the previous 2-3 weeks or since the last time that they took the medication. The TSQM consists of fourteen items over four domains (effectiveness, side effects, convenience, and global satisfaction). The 14 questions are answered either with yes/no or by means of a five or seven stage scale (ranging from very unsatisfied to satisfied). TSQM Scale scores for each domain range from 0 to 100 and higher scores represent higher satisfaction. Negative values indicate worsening from baseline. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data
    End point type
    Secondary
    End point timeframe
    At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [63]
    74 [64]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Double Blind Week 16- Tapering Arm (n=35;61)
    -8.0 ± 17.25
    -0.5 ± 11.26
        Double Blind Week 16- Withdrawal Arm (n=8;11)
    9.4 ± 20.04
    2.8 ± 9.42
        Double Blind Week 28- Tapering Arm (n=16;61)
    -2.7 ± 12.28
    1.1 ± 7.44
        Double Blind Week 28- Withdrawal Arm (n=4;11)
    14.1 ± 28.13
    2.8 ± 9.42
        Double Blind Week 40- Tapering Arm (n=11;61)
    -2.3 ± 14.86
    1.1 ± 11.61
        Double Blind Week 40- Withdrawal Arm (n=2;11)
    28.1 ± 39.77
    2.8 ± 9.42
        Flare Week 0- Tapering Arm (n=28;0)
    -5.1 ± 15.96
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=7;0)
    2.7 ± 7.09
    999 ± 999
        Flare Week 4- Tapering Arm (n=25;0)
    -5.0 ± 19.52
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=6;0)
    3.1 ± 7.65
    999 ± 999
        Flare Week 10- Tapering Arm (n=27;0)
    -3.7 ± 13.90
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=7;0)
    2.7 ± 7.09
    999 ± 999
        Flare Week 16- Tapering Arm (n=28;0)
    -2.0 ± 6.60
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=7;0)
    2.7 ± 7.09
    999 ± 999
    Notes
    [63] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [64] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Convenience Score

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    End point title
    Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Convenience Score
    End point description
    Participants completed the 14-item Treatment Satisfaction Questionnaire for Medication (TSQM; Version 1.4) to assess satisfaction with their current rheumatoid arthritis treatment over the previous 2-3 weeks or since the last time that they took the medication. The TSQM consists of fourteen items over four domains (effectiveness, side effects, convenience, and global satisfaction). The 14 questions are answered either with yes/no or by means of a five or seven stage scale (ranging from very unsatisfied to satisfied). TSQM Scale scores for each domain range from 0 to 100 and higher scores represent higher satisfaction. Negative values indicate worsening from baseline. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data
    End point type
    Secondary
    End point timeframe
    At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [65]
    74 [66]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Double Blind Week 16- Tapering Arm (n=35;61)
    -0.2 ± 16.96
    0.8 ± 13.45
        Double Blind Week 16- Withdrawal Arm (n=8;11)
    -4.9 ± 19.57
    4.0 ± 10.86
        Double Blind Week 28- Tapering Arm (n=16;61)
    0.0 ± 18.70
    -1.0 ± 15.47
        Double Blind Week 28- Withdrawal Arm (n=4;11)
    -4.2 ± 12.32
    -3.5 ± 13.21
        Double Blind Week 40- Tapering Arm (n=11;61)
    -4.0 ± 9.65
    -0.1 ± 16.50
        Double Blind Week 40- Withdrawal Arm (n=2;11)
    -16.7 ± 23.57
    2.5 ± 18.32
        Flare Week 0- Tapering Arm (n=28;0)
    4.2 ± 12.53
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=7;0)
    -7.1 ± 14.60
    999 ± 999
        Flare Week 4- Tapering Arm (n=25;0)
    4.4 ± 19.84
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=6;0)
    5.6 ± 18.92
    999 ± 999
        Flare Week 10- Tapering Arm (n=27;0)
    1.2 ± 10.60
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=7;0)
    0.8 ± 16.49
    999 ± 999
        Flare Week 16- Tapering Arm (n=28;0)
    1.6 ± 19.65
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=7;0)
    0.8 ± 20.89
    999 ± 999
    Notes
    [65] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [66] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Global Satisfaction Score

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    End point title
    Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Global Satisfaction Score
    End point description
    Participants completed the 14-item Treatment Satisfaction Questionnaire for Medication (TSQM; Version 1.4) to assess satisfaction with their current rheumatoid arthritis treatment over the previous 2-3 weeks or since the last time that they took the medication. The TSQM consists of fourteen items over four domains (effectiveness, side effects, convenience, and global satisfaction). The 14 questions are answered either with yes/no or by means of a five or seven stage scale (ranging from very unsatisfied to satisfied). TSQM Scale scores for each domain range from 0 to 100 and higher scores represent higher satisfaction. Negative values indicate worsening from baseline. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data
    End point type
    Secondary
    End point timeframe
    At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [67]
    74 [68]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Double Blind Week 16- Tapering Arm (n=35;61)
    -11.6 ± 24.99
    -3.4 ± 17.91
        Double Blind Week 16- Withdrawal Arm (n=8;11)
    -2.7 ± 15.24
    0.6 ± 22.69
        Double Blind Week 28- Tapering Arm (n=16;61)
    -2.2 ± 12.70
    -5.7 ± 14.97
        Double Blind Week 28- Withdrawal Arm (n=4;11)
    5.4 ± 15.84
    -4.5 ± 25.81
        Double Blind Week 40- Tapering Arm (n=11;61)
    -3.2 ± 13.31
    -2.6 ± 15.10
        Double Blind Week 40- Withdrawal Arm (n=2;11)
    0.0 ± 10.10
    -3.2 ± 21.98
        Flare Week 0- Tapering Arm (n=28;0)
    -11.7 ± 27.58
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=7;0)
    -9.2 ± 25.66
    999 ± 999
        Flare Week 4- Tapering Arm (n=25;0)
    -3.1 ± 20.32
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=6;0)
    -1.2 ± 24.08
    999 ± 999
        Flare Week 10- Tapering Arm (n=27;0)
    -0.8 ± 13.77
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=7;0)
    -2.0 ± 18.77
    999 ± 999
        Flare Week 16- Tapering Arm (n=28;0)
    -6.6 ± 24.20
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=7;0)
    -8.2 ± 16.72
    999 ± 999
    Notes
    [67] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [68] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Work Productivity and Activity Impairment (WPAI) Overall Work Impairment and Activity Impairment Scores

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    End point title
    Mean Change From Double-blind Baseline in Work Productivity and Activity Impairment (WPAI) Overall Work Impairment and Activity Impairment Scores
    End point description
    The Work Productivity and Activity Impairment (WPAI) questionnaire for general health is a validated tool in rheumatoid arthritis consisting of 6 questions, based on participant recall of the previous 7 days. WPAI assesses work time missed due to illness (absenteeism), impairment at work due to health (presenteeism), overall work impairment due to health (an aggregate measure of both absenteeism and presenteeism), and total non-occupational activity impairment due to health. WPAI scores are expressed as impairment percentages, with higher scores indicating worse outcomes. A negative change from baseline indicates improvement. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= 0 participants for this time point; 9999= not calculable/estimable due to an insufficient number of subjects with an observation
    End point type
    Secondary
    End point timeframe
    At Weeks 4, 28, and 40 and Flare Weeks 0, 10, and 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [69]
    75 [70]
    Units: percent impairment
    arithmetic mean (standard deviation)
        Overall Work Impairment Wk 28- Tapering (n=2;27)
    15.0 ± 21.21
    3.5 ± 10.68
        Overall Work Impairment Wk 28- Withdrawal (n=1;5)
    0.0 ± 9999
    0.6 ± 8.12
        Activity Impairment Wk 28- Tapering (n=14;61)
    5.0 ± 19.51
    2.8 ± 13.43
        Activity Impairment Wk 28- Withdrawal (n=3;11)
    10.0 ± 17.32
    -0.9 ± 7.01
        Overall Work Impairment Wk 40- Tapering (n=0;28)
    999 ± 999
    3.4 ± 18.78
        Overall Work Impairment Wk 40- Withdrawal (n=0;5)
    999 ± 999
    0.6 ± 8.12
        Activity Impairment Wk 40- Tapering (n=7;61)
    15.7 ± 9.76
    0.5 ± 13.59
        Activity Impairment Wk 40- Withdrawal (n=1;11)
    20.0 ± 9999
    0.0 ± 6.32
        Overall Work Impairment Flare 0- Tapering (5;0)
    14.0 ± 27.02
    999 ± 999
        Overall Work Impairment Flare 0-Withdrawal (n=2;0)
    5.0 ± 7.07
    999 ± 999
        Activity Impairment Flare Wk 0- Tapering (n=22;0)
    25.9 ± 31.57
    999 ± 999
        Activity Impairment Flare Wk 0- Withdrawal (n=5;0)
    8.0 ± 25.88
    999 ± 999
        Overall Work Impairment Flare 10-Tapering (n=8;0)
    -0.2 ± 8.78
    999 ± 999
        Overall Work Impairment Flare 10-Withdrawal (n=2;0
    5.0 ± 7.07
    999 ± 999
        Activity Impairment Flare Wk 10- Tapering (n=26;0)
    6.5 ± 15.48
    999 ± 999
        Activity Impairment Flare Wk 10-Withdrawal (n=7;0)
    12.9 ± 13.80
    999 ± 999
        Overall Work Impairment Flare 16-Tapering (n=8;0)
    10.0 ± 14.82
    999 ± 999
        Overall Work Impairment Flare 16-Withdrawal (n=3;0
    10.0 ± 10.00
    999 ± 999
        Activity Impairment Flare Wk 16-Tapering (n=29;0)
    11.0 ± 17.39
    999 ± 999
        Activity Impairment Flare Wk 16-Withdrawal (n=8;0)
    8.8 ± 11.26
    999 ± 999
    Notes
    [69] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [70] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Short-Form 36 Version 2 Health Survey (SF-36v2) Physical Component Summary (PCS) Score

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    End point title
    Mean Change From Double-blind Baseline in Short-Form 36 Version 2 Health Survey (SF-36v2) Physical Component Summary (PCS) Score
    End point description
    The SF-36v2 is a non-disease specific Health Related Quality of Life (HRQoL) instrument. The SF-36v2 comprises 36 total items (questions) targeting a subject's functional health and well-being in 8 domains (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health) with a recall period of four weeks. Domain scores are aggregated into a Physical Component Summary (PCS) score and a Mental Component Summary (MCS) score. SF-36v2 scores for each domain and PCS/MCS range from 0-100: higher scores indicate a better state of health and a decrease from baseline represents worsening. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data; 9999= not calculable/estimable due to an insufficient number of subjects with an observation
    End point type
    Secondary
    End point timeframe
    At Weeks 4, 28, and 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    45 [71]
    74 [72]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Double Blind Week 28- Tapering Arm (n=13;60)
    -2.9 ± 7.53
    -1.1 ± 4.18
        Double Blind Week 28- Withdrawal Arm (n=3;11)
    -1.9 ± 7.39
    -2.4 ± 3.97
        Double Blind Week 40- Tapering Arm (n=6;60)
    -5.5 ± 6.42
    -0.4 ± 5.53
        Double Blind Week 40- Withdrawal Arm (n=1;11)
    -1.6 ± 9999
    -2.1 ± 5.22
        Flare Week 0- Tapering Arm (n=22;0)
    -10.8 ± 10.85
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=5;0)
    -2.4 ± 10.81
    999 ± 999
        Flare Week 4- Tapering Arm (n=24;0)
    -5.2 ± 8.37
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=6;0)
    -8.0 ± 7.35
    999 ± 999
        Flare Week 10- Tapering Arm (n=25;0)
    -4.0 ± 7.22
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=7;0)
    -4.0 ± 4.57
    999 ± 999
        Flare Week 16- Tapering Arm (n=28;0)
    -3.8 ± 7.38
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=7;0)
    -2.5 ± 2.80
    999 ± 999
    Notes
    [71] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [72] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Short-Form 36 Version 2 Health Survey (SF-36v2) Mental Component Summary (MCS) Score

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    End point title
    Mean Change From Double-blind Baseline in Short-Form 36 Version 2 Health Survey (SF-36v2) Mental Component Summary (MCS) Score
    End point description
    The SF-36v2 is a non-disease specific Health Related Quality of Life (HRQoL) instrument. The SF-36v2 comprises 36 total items (questions) targeting a subject's functional health and well-being in 8 domains (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health) with a recall period of four weeks. Domain scores are aggregated into a Physical Component Summary (PCS) score and a Mental Component Summary (MCS) score. SF-36v2 scores for each domain and PCS/MCS range from 0-100: higher scores indicate a better state of health and a decrease from baseline represents worsening. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data; 9999= not calculable/estimable due to an insufficient number of subjects with an observation
    End point type
    Secondary
    End point timeframe
    At Weeks 4, 28, and 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    45 [73]
    74 [74]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Double Blind Week 28- Tapering Arm (n=13;60)
    -5.5 ± 11.31
    -0.8 ± 6.02
        Double Blind Week 28- Withdrawal Arm (n=3;11)
    -5.2 ± 5.90
    -0.1 ± 7.20
        Double Blind Week 40- Tapering Arm (n=6;60)
    -3.5 ± 11.14
    -0.8 ± 5.89
        Double Blind Week 40- Withdrawal Arm (n=1;11)
    -8.5 ± 9999
    -0.4 ± 6.71
        Flare Week 0- Tapering Arm (n=22;0)
    -4.1 ± 11.43
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=5;0)
    0.4 ± 4.59
    999 ± 999
        Flare Week 4- Tapering Arm (n=24;0)
    -2.0 ± 5.95
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=6;0)
    -0.5 ± 2.51
    999 ± 999
        Flare Week 10- Tapering Arm (n=25;0)
    -1.1 ± 10.14
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=7;0)
    -0.4 ± 3.06
    999 ± 999
        Flare Week 16- Tapering Arm (n=28;0)
    -4.0 ± 11.01
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=7;0)
    0.1 ± 2.55
    999 ± 999
    Notes
    [73] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [74] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale

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    End point title
    Mean Change From Double-blind Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale
    End point description
    The FACIT-Fatigue questionnaire is a participant questionnaire that consists of 13 questions designed to measure the degree of fatigue experienced by participants in the previous 7 days. Participants respond to the questions on a scale from 'not at all' (0) to 'very much' (4). The scale score is computed by summing the item scores, after reversing those items that are worded in the negative direction. The FACIT-Fatigue subscale score ranges from 0 to 52, where higher scores represent less fatigue. A negative change from baseline indicates worsening. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data
    End point type
    Secondary
    End point timeframe
    At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [75]
    74 [76]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Double Blind Week 16- Tapering Arm (n=35;61)
    -6.0 ± 9.80
    -1.5 ± 5.42
        Double Blind Week 16- Withdrawal Arm (n=9;11)
    -2.3 ± 3.39
    -1.9 ± 3.27
        Double Blind Week 28- Tapering Arm (n=16;61)
    -3.5 ± 7.58
    -1.6 ± 5.60
        Double Blind Week 28- Withdrawal Arm (n=4;11)
    -4.3 ± 7.23
    -2.2 ± 4.67
        Double Blind Week 40- Tapering Arm (n=11;61)
    -6.4 ± 8.44
    -0.4 ± 4.00
        Double Blind Week 40- Withdrawal Arm (n=2;11)
    -2.5 ± 6.36
    -1.5 ± 4.78
        Flare Week 0- Tapering Arm (n=28;0)
    -7.4 ± 11.17
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=8;0)
    -3.6 ± 4.75
    999 ± 999
        Flare Week 4- Tapering Arm (n=25;0)
    -3.8 ± 9.19
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=6;0)
    -4.7 ± 5.43
    999 ± 999
        Flare Week 10- Tapering Arm (n=27;0)
    -3.9 ± 8.44
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=7;0)
    -2.4 ± 4.47
    999 ± 999
        Flare Week 16- Tapering Arm (n=28;0)
    -4.5 ± 9.01
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=7;0)
    -1.7 ± 1.89
    999 ± 999
    Notes
    [75] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [76] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Serum Levels of C-reactive Protein (CRP)

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    End point title
    Mean Change From Double-blind Baseline in Serum Levels of C-reactive Protein (CRP)
    End point description
    C-Reactive Protein (CRP; mg/L) was measured from blood samples as a marker for inflammation. Higher levels are indicative of more inflammation. Negative values indicate improvement from baseline. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [77]
    76 [78]
    Units: mg/L
    arithmetic mean (standard deviation)
        Double Blind Week 10- Tapering Arm (n=36;64)
    -7.9 ± 48.87
    1.7 ± 12.92
        Double Blind Week 10- Withdrawal Arm (n=9;11)
    -0.2 ± 3.55
    -0.6 ± 2.53
        Double Blind Week 16- Tapering Arm (n=35;63)
    -7.4 ± 49.77
    -0.4 ± 4.26
        Double Blind Week 16- Withdrawal Arm (n=9;11)
    6.6 ± 12.26
    -0.1 ± 3.67
        Double Blind Week 22- Tapering Arm (n=19;63)
    3.6 ± 9.69
    -0.0 ± 5.43
        Double Blind Week 22- Withdrawal Arm (n=4;11)
    0.6 ± 0.37
    -0.9 ± 3.38
        Double Blind Week 28- Tapering Arm (n=16;63)
    0.5 ± 3.85
    -0.4 ± 4.65
        Double Blind Week 28- Withdrawal Arm (n=4;11)
    1.1 ± 1.34
    2.5 ± 11.60
        Double Blind Week 34- Tapering Arm (n=12;63)
    3.2 ± 10.13
    -0.4 ± 4.41
        Double Blind Week 34- Withdrawal Arm (n=2;11)
    1.8 ± 1.89
    0.3 ± 5.98
        Double Blind Week 40- Tapering Arm (n=11;63)
    1.0 ± 5.69
    -0.3 ± 4.18
        Double Blind Week 40- Withdrawal Arm (n=2;11)
    8.3 ± 11.60
    -0.1 ± 3.43
        Flare Week 0- Tapering Arm (n=30;0)
    -7.4 ± 54.12
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=8;0)
    5.4 ± 12.67
    999 ± 999
        Flare Week 4- Tapering Arm (n=30;0)
    -8.5 ± 55.47
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=8;0)
    -1.3 ± 4.01
    999 ± 999
        Flare Week 10- Tapering Arm (n=30;0)
    -9.5 ± 55.61
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=8;0)
    -0.6 ± 0.97
    999 ± 999
        Flare Week 16- Tapering Arm (n=30;0)
    -9.1 ± 53.70
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=8;0)
    -0.8 ± 2.74
    999 ± 999
    Notes
    [77] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [78] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Secondary: Mean Change From Double-blind Baseline in Serum Levels of Erythrocyte Sedimentation Rate (ESR)

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    End point title
    Mean Change From Double-blind Baseline in Serum Levels of Erythrocyte Sedimentation Rate (ESR)
    End point description
    Erythrocyte sedimentation rate (ESR; mm/hour) indirectly measures how much inflammation is in the body. A higher ESR is indicative of increased inflammation. Negative values indicate improvement from baseline. For Double-blind period data, missing values were only imputed up to the time when the participant entered the Open-label rescue period. 999= subjects did not experience flare and do not have Flare Week data
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
    End point values
    Flared Participants Non-Flared Participants
    Number of subjects analysed
    46 [79]
    76 [80]
    Units: mm/hour
    arithmetic mean (standard deviation)
        Double Blind Week 10- Tapering Arm (n=37;64)
    4.1 ± 11.25
    0.7 ± 5.22
        Double Blind Week 10- Withdrawal Arm (n=9;11)
    0.9 ± 9.24
    -1.5 ± 5.43
        Double Blind Week 16- Tapering Arm (n=35;63)
    4.6 ± 10.73
    0.5 ± 5.82
        Double Blind Week 16- Withdrawal Arm (n=9;11)
    5.2 ± 15.23
    -0.3 ± 5.31
        Double Blind Week 22- Tapering Arm (n=19;63)
    3.5 ± 10.73
    -0.5 ± 7.38
        Double Blind Week 22- Withdrawal Arm (n=4;11)
    2.8 ± 9.22
    -0.3 ± 4.22
        Double Blind Week 28- Tapering Arm (n=16;63)
    3.4 ± 8.18
    0.4 ± 6.93
        Double Blind Week 28- Withdrawal Arm (n=4;11)
    6.0 ± 10.10
    1.0 ± 5.04
        Double Blind Week 34- Tapering Arm (n=12;63)
    4.8 ± 7.28
    0.3 ± 7.57
        Double Blind Week 34- Withdrawal Arm (n=2;11)
    -5.0 ± 1.41
    -0.5 ± 5.94
        Double Blind Week 40- Tapering Arm (n=11;63)
    10.2 ± 13.22
    1.4 ± 7.19
        Double Blind Week 40- Withdrawal Arm (n=2;11)
    -2.0 ± 5.66
    4.7 ± 8.89
        Flare Week 0- Tapering Arm (n=30;0)
    10.4 ± 12.50
    999 ± 999
        Flare Week 0- Withdrawal Arm (n=8;0)
    13.0 ± 11.90
    999 ± 999
        Flare Week 4- Tapering Arm (n=30;0)
    7.2 ± 9.82
    999 ± 999
        Flare Week 4- Withdrawal Arm (n=8;0)
    8.5 ± 9.52
    999 ± 999
        Flare Week 10- Tapering Arm (n=30;0)
    5.8 ± 10.16
    999 ± 999
        Flare Week 10- Withdrawal Arm (n=8;0)
    4.4 ± 6.91
    999 ± 999
        Flare Week 16- Tapering Arm (n=30;0)
    8.0 ± 10.95
    999 ± 999
        Flare Week 16- Withdrawal Arm (n=8;0)
    7.0 ± 14.40
    999 ± 999
    Notes
    [79] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    [80] - Subjects rcvd ≥ 1 dose of study drug during Double-blind period (DB) & had at least DB Baseline data
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs) reported from time of study drug administration until 70 d after last dose (up to 50 wks for Double-blind); up to 66 wks for subjects who experienced flare during Double-blind
    Adverse event reporting additional description
    TEAEs and TESAEs are defined as any adverse event (AE) with an onset date that is on or after the first dose of study drug until 70 days after the last dose of study drug and were collected whether elicited or spontaneously reported by the participant.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Adalimumab 40 mg Eow
    Reporting group description
    40 mg adalimumab administered subcutaneously every other week (eow) from Week 0 to Week 4

    Reporting group title
    Adalimumab Withdrawal Arm
    Reporting group description
    Placebo administered subcutaneously every three weeks from Week 4 to Week 40 (Double-blind Period)

    Reporting group title
    Adalimumab 40 mg Eow Rescue Arm
    Reporting group description
    40 mg adalimumab administered subcutaneously every other week from Flare Week 0 to Flare Week 16 (Open-label Rescue Period)

    Reporting group title
    Adalimumab Tapering
    Reporting group description
    40 mg adalimumab administered subcutaneously every three weeks from Week 4 to Week 40 (Double-blind Period)

    Serious adverse events
    Adalimumab 40 mg Eow Adalimumab Withdrawal Arm Adalimumab 40 mg Eow Rescue Arm Adalimumab Tapering
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 146 (2.74%)
    0 / 20 (0.00%)
    3 / 39 (7.69%)
    1 / 102 (0.98%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    COMMINUTED FRACTURE
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 20 (0.00%)
    0 / 39 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BREAST CANCER
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 20 (0.00%)
    0 / 39 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 20 (0.00%)
    0 / 39 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    PLEURAL EFFUSION
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 20 (0.00%)
    1 / 39 (2.56%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 20 (0.00%)
    0 / 39 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    RETINAL VEIN OCCLUSION
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 20 (0.00%)
    1 / 39 (2.56%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    OSTEOARTHRITIS
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 20 (0.00%)
    1 / 39 (2.56%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    PNEUMONIA
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 20 (0.00%)
    0 / 39 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Adalimumab 40 mg Eow Adalimumab Withdrawal Arm Adalimumab 40 mg Eow Rescue Arm Adalimumab Tapering
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 146 (7.53%)
    12 / 20 (60.00%)
    13 / 39 (33.33%)
    33 / 102 (32.35%)
    Injury, poisoning and procedural complications
    MUSCLE STRAIN
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 20 (5.00%)
    0 / 39 (0.00%)
    0 / 102 (0.00%)
         occurrences all number
    0
    1
    0
    0
    LIMB INJURY
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 20 (10.00%)
    1 / 39 (2.56%)
    0 / 102 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Investigations
    C-REACTIVE PROTEIN INCREASED
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 20 (5.00%)
    0 / 39 (0.00%)
    1 / 102 (0.98%)
         occurrences all number
    0
    1
    0
    1
    HEPATIC ENZYME INCREASED
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 20 (0.00%)
    2 / 39 (5.13%)
    0 / 102 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    4 / 146 (2.74%)
    1 / 20 (5.00%)
    0 / 39 (0.00%)
    4 / 102 (3.92%)
         occurrences all number
    4
    1
    0
    4
    General disorders and administration site conditions
    OEDEMA PERIPHERAL
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 20 (5.00%)
    1 / 39 (2.56%)
    0 / 102 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Renal and urinary disorders
    URINARY RETENTION
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 20 (5.00%)
    0 / 39 (0.00%)
    0 / 102 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 20 (0.00%)
    1 / 39 (2.56%)
    6 / 102 (5.88%)
         occurrences all number
    0
    0
    1
    10
    BACK PAIN
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 20 (5.00%)
    0 / 39 (0.00%)
    1 / 102 (0.98%)
         occurrences all number
    0
    1
    0
    1
    MUSCULOSKELETAL STIFFNESS
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 20 (5.00%)
    0 / 39 (0.00%)
    1 / 102 (0.98%)
         occurrences all number
    0
    1
    0
    1
    NECK PAIN
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 20 (5.00%)
    0 / 39 (0.00%)
    0 / 102 (0.00%)
         occurrences all number
    0
    1
    0
    0
    OSTEOPOROSIS
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 20 (5.00%)
    0 / 39 (0.00%)
    0 / 102 (0.00%)
         occurrences all number
    0
    1
    0
    0
    PAIN IN EXTREMITY
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 20 (5.00%)
    0 / 39 (0.00%)
    1 / 102 (0.98%)
         occurrences all number
    0
    1
    0
    1
    RHEUMATOID ARTHRITIS
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 20 (5.00%)
    0 / 39 (0.00%)
    5 / 102 (4.90%)
         occurrences all number
    0
    1
    0
    5
    Infections and infestations
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 146 (0.68%)
    1 / 20 (5.00%)
    1 / 39 (2.56%)
    3 / 102 (2.94%)
         occurrences all number
    1
    1
    1
    3
    INFLUENZA
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 20 (10.00%)
    0 / 39 (0.00%)
    5 / 102 (4.90%)
         occurrences all number
    0
    2
    0
    6
    NASOPHARYNGITIS
         subjects affected / exposed
    4 / 146 (2.74%)
    4 / 20 (20.00%)
    4 / 39 (10.26%)
    16 / 102 (15.69%)
         occurrences all number
    4
    5
    4
    17
    PHARYNGOTONSILLITIS
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 20 (5.00%)
    0 / 39 (0.00%)
    0 / 102 (0.00%)
         occurrences all number
    0
    1
    0
    0
    TONSILLITIS
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 20 (5.00%)
    0 / 39 (0.00%)
    0 / 102 (0.00%)
         occurrences all number
    0
    1
    0
    0
    TOOTH INFECTION
         subjects affected / exposed
    1 / 146 (0.68%)
    1 / 20 (5.00%)
    1 / 39 (2.56%)
    0 / 102 (0.00%)
         occurrences all number
    1
    1
    1
    0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 20 (0.00%)
    3 / 39 (7.69%)
    1 / 102 (0.98%)
         occurrences all number
    0
    0
    3
    1
    URINARY TRACT INFECTION
         subjects affected / exposed
    2 / 146 (1.37%)
    0 / 20 (0.00%)
    2 / 39 (5.13%)
    0 / 102 (0.00%)
         occurrences all number
    2
    0
    2
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Feb 2016
    ● Reduced sample size from 334 to ~200 ● Allowed for 3 variables of the DAS28 (CRP or ESR) to satisfy inclusion criteria of patients in stable remission ● Added that 3 variable DAS28 (ESR) score can be used for evaluation of flare when the physician's global assessment score not available ● Changed time for required stable medications to ensure medication that affects risk of flare is stable ● Clarified that once the limit of 20% of enrolled subjects on other csDMARDs or no csDMARDs is met, only subjects on concomitant MTX allowed into trial ● Clarified language regarding MRI scans: scan dominant hand if both hands/wrists are affected ● Clarified concomitant therapies (e.g. intra-muscular MTX, equivalent opioids to Tramadol, dose decrease related to MTX or other csDMARDs, folic acid dosage) ● Removed azathioprine from exclusion criteria to allow for subjects previously treated ● Clarified allowed dose interruption of adalimumab prior to the study ● Clarified importance of stopping commercial adalimumab at enrollment ● Ensured subject safety (e.g. MRI report for non-RA findings, csDMARD use while on rescue therapy, 70-day follow-up for AEs) ● Increased number of sites and countries planned ● Extended Screening and Lead-In time to ensure enough time for procedures, increased dosing window during the DB period, added option for shortened Early Termination Visit ● Provided clarification re: urine pregnancy testing/timing, CDAI and SDAI calculation as part of statistical analysis, ESR testing, and tuberculosis (TB) screening; updated 24-hour medical surveillance contact information; added information regarding electronic PROs ● Updated Complaint and Product Complaint definition and reporting requirements ● Revised injection instructions to correct error regarding how many syringes the subject will take home ● Revised timing of first dose of OL Rescue arm ● Revised language regarding duration of treatment ● Removed TB language re: Czech Republic

    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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