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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Study Comparing the Efficacy and Safety of Continuing Versus Withdrawing Adalimumab Therapy in Maintaining Remission in Subjects With Non-Radiographic Axial Spondyloarthritis

    Summary
    EudraCT number
    		 2012-000646-35
    Trial protocol
    		 BE   SK   IT   FI   DE   CZ   DK   SE   GB   IE   NL   NO   ES   PL  
    Global end of trial date
    14 Apr 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    06 Jul 2018
    First version publication date
    04 Mar 2018
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    An update is needed to align the results on clinicaltrials.gov with that of EudraCT.

    Trial information

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    Trial identification
    Sponsor protocol code
    M13-375
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01808118
    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
    AbbVie, Global Medical Services, 001 800-633-9110,
    Scientific contact
    Jaclyn Anderson , AbbVie, jaclyn.anderson@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
    21 Feb 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this multicenter, randomized, double-blind study was to evaluate the efficacy and safety of continuing versus withdrawing therapy with adalimumab 40 mg given every other week (eow) SC in maintaining remission in subjects with moderate to severe non-radiographic axial spondyloarthritis. The study duration included a 42-day Screening Period, a 28-week open-label 40 mg adalimumab eow treatment period (Period 1), a 40-week double-blind placebo controlled eow treatment period (Period 2) with an opportunity to receive at least 12 weeks of rescue therapy with open-label adalimumab (participants that flared at Weeks 60, 64 or 68 were allowed 12 weeks of rescue therapy and final visits were at Weeks 72, 76 or 80 respectively), plus a 70-day follow-up phone call. Participants in sustained Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease were randomized at Week 28 at a 1:1 ratio to receive either blinded adalimumab 40 mg eow or matching placebo.
    Protection of trial subjects
    The investigator or his/her representative explained the nature of the study to the subject, and answered all questions regarding this study. Prior to any study-related screening procedures being performed on the subject, the informed consent statement was reviewed, signed, and dated by the subject.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Apr 2013
    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
    Australia: 62
    Country: Number of subjects enrolled
    Belgium: 36
    Country: Number of subjects enrolled
    Brazil: 2
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Czech Republic: 124
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    Finland: 12
    Country: Number of subjects enrolled
    Germany: 52
    Country: Number of subjects enrolled
    Ireland: 8
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    Mexico: 9
    Country: Number of subjects enrolled
    Netherlands: 33
    Country: Number of subjects enrolled
    New Zealand: 8
    Country: Number of subjects enrolled
    Poland: 93
    Country: Number of subjects enrolled
    Russian Federation: 22
    Country: Number of subjects enrolled
    Slovakia: 5
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    Switzerland: 7
    Country: Number of subjects enrolled
    United Kingdom: 47
    Country: Number of subjects enrolled
    United States: 98
    Worldwide total number of subjects
    673
    EEA total number of subjects
    447
    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)
    663
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were to have had an inadequate response to at least 2 nonsteroidal anti-inflammatory drugs (NSAIDs) over a 4-week period in total at maximum recommended or tolerated doses or an intolerance to or a contraindication for NSAIDs.

    Pre-assignment
    Screening details
    		 Subjects with non-radiographic axial spondyloarthritis fulfilling the Assessment of Spondyloarthritis International Society (ASAS) axial SpA classification criteria, but not fulfilling the radiologic criterion of the modified New York criteria for ankylosing spondylitis enrolled in the study. This study included a 42-day screening period.

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

    Arms
    Arm title
    		 Open-label (OL) Adalimumab (Period 1)
    Arm description
    		 40 mg every other week (eow), Weeks 0-28.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Humira, ABT-D2E7
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    40 mg every other week (eow), Weeks 0-28. If participants flared during the double-blind period, they had an opportunity to receive at least 12 weeks of open-label adalimumab 40 mg eow.

    Number of subjects in period 1
    		Open-label (OL) Adalimumab (Period 1)
    Started
    673
    Completed
    305
    Not completed
    368
         Consent withdrawn by subject
    24
         Did not meet inclusion criteria
    3
         Adverse event, non-fatal
    15
         Noncompliance per sponsor
    1
         Enrolled in error
    7
         Nonconformance with inclusion criteria
    3
         Lost to follow-up
    9
         Did not meet criteria for remission
    303
         Investigator decision: site closure
    2
         Lack of efficacy
    1
    Period 2
    Period 2 title
    Period 2
    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
    Yes

    Arm title
    		 Placebo (Period 2)
    Arm description
    		 Placebo every other week (eow), Weeks 28-68. Placebo was discontinued in participants who met the criteria for flare.
    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
    every other week

    Arm title
    		 Double-blind Adalimumab (Period 2)
    Arm description
    		 Adalimumab 40 mg every other week (eow), Weeks 28-68. Blinded adalimumab was discontinued in participants who met the criteria for flare.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Humira, ABT-D2E7
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    40 mg every other week

    Number of subjects in period 2
    		Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Started
    153
    152
    Completed
    140
    144
    Not completed
    13
    8
         Consent withdrawn by subject
    7
    6
         Adverse event, non-fatal
    4
    -
         Investigator no longer conducting trials
    1
    -
         Switched to other therapy
    1
    -
         Lost to follow-up
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Open-label (OL) Adalimumab (Period 1)
    Reporting group description
    		 40 mg every other week (eow), Weeks 0-28.

    Reporting group values
    		 Open-label (OL) Adalimumab (Period 1) Total
    Number of subjects
    		 673 673
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 663 663
        From 65-84 years
    		 10 10
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.3 ± 11.12 -
    Gender categorical
    Units: Subjects
        Female
    		 343 343
        Male
    		 330 330

    End points

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    End points reporting groups
    Reporting group title
    Open-label (OL) Adalimumab (Period 1)
    Reporting group description
    		 40 mg every other week (eow), Weeks 0-28.
    Reporting group title
    Placebo (Period 2)
    Reporting group description
    		 Placebo every other week (eow), Weeks 28-68. Placebo was discontinued in participants who met the criteria for flare.

    Reporting group title
    Double-blind Adalimumab (Period 2)
    Reporting group description
    		 Adalimumab 40 mg every other week (eow), Weeks 28-68. Blinded adalimumab was discontinued in participants who met the criteria for flare.

    Primary: Number of Participants Who Did Not Experience a Flare During Period 2 by Week 68

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    End point title
    		 Number of Participants Who Did Not Experience a Flare During Period 2 by Week 68
    End point description
    The Ankylosing Spondylitis Disease Activity Score (ASDAS) tool is a self-administered questionnaire/objective laboratory evaluation. The questionnaire assesses disease activity, back pain, and peripheral pain/swelling on a numeric rating scale (from 0 (normal) to 10 (very severe)) and duration of morning stiffness on a numeric rating scale (from 0 to 10, with 0 being none and 10 representing a duration of ≥2 hours). The laboratory parameter is a measurement of high-sensitivity C-reactive protein (mg/L) (hs-CRP). Data from five variables (disease activity, back pain, duration of morning stiffness, peripheral pain/swelling, and hs-CRP) are combined to yield a score (0 to no defined upper limit). During Period 2 participants visited study sites at Weeks 28, 32, 36, 40, 44, 48, 52, 56, 60, 64 and 68 or if they discontinued early from the study. A flare was defined as having any 2 consecutive study visits with ASDAS ≥ 2.100.
    End point type
    Primary
    End point timeframe
    From Week 28 through 68
    End point values
    		 Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    153 [1]
    152 [2]
    Units: Participants
    72
    107
    Notes
    [1] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    [2] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    Statistical analysis title
    		 2-sided Pearson's chi-square test
    Comparison groups
    Double-blind Adalimumab (Period 2) v Placebo (Period 2)
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Number of Participants With Ankylosing Spondylitis Disease Activity Score (ASDAS) Inactive Disease at 12 Weeks After Initiation of Rescue Therapy

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    End point title
    		 Number of Participants With Ankylosing Spondylitis Disease Activity Score (ASDAS) Inactive Disease at 12 Weeks After Initiation of Rescue Therapy
    End point description
    The Ankylosing Spondylitis Disease Activity Score (ASDAS) tool is a self-administered questionnaire/objective laboratory evaluation. The questionnaire assesses disease activity, back pain, and peripheral pain/swelling on a numeric rating scale (from 0 (normal) to 10 (very severe)) and duration of morning stiffness on a numeric rating scale (from 0 to 10, with 0 being none and 10 representing a duration of ≥2 hours). The laboratory parameter is a measurement of high-sensitivity C-reactive protein (mg/L) (hs-CRP). Data from five variables (disease activity, back pain, duration of morning stiffness, peripheral pain/swelling, and hs-CRP) are combined to yield a score (0 to no defined upper limit). ASDAS Inactive Disease is defined as a score of <1.300.
    End point type
    Secondary
    End point timeframe
    Rescue Therapy Week 12
    End point values
    		 Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    65 [3]
    36 [4]
    Units: Participants
    37
    20
    Notes
    [3] - Rescued Population: subjects w/ available data who rcvd open-label rescue Tx after the DB period
    [4] - Rescued Population: subjects w/ available data who rcvd open-label rescue Tx after the DB period
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving ASDAS Major Improvement at 12 Weeks After Initiation of Rescue Therapy

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    End point title
    		 Number of Participants Achieving ASDAS Major Improvement at 12 Weeks After Initiation of Rescue Therapy
    End point description
    The Ankylosing Spondylitis Disease Activity Score (ASDAS) tool is a self-administered questionnaire/objective laboratory evaluation. The questionnaire assesses disease activity, back pain, and peripheral pain/swelling on a numeric rating scale (from 0 (normal) to 10 (very severe)) and duration of morning stiffness on a numeric rating scale (from 0 to 10, with 0 being none and 10 representing a duration of ≥2 hours). The laboratory parameter is a measurement of high-sensitivity C-reactive protein (mg/L) (hs-CRP). Data from five variables (disease activity, back pain, duration of morning stiffness, peripheral pain/swelling, and hs-CRP) are combined to yield a score (0 to no defined upper limit). ASDAS Major Improvement is defined as a change from baseline ≤ –2.000.
    End point type
    Secondary
    End point timeframe
    Baseline and Rescue Therapy Week 12
    End point values
    		 Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    65 [5]
    36 [6]
    Units: Participants
    21
    8
    Notes
    [5] - Rescued Population: subjects w/ available data who rcvd open-label rescue Tx after the DB period
    [6] - Rescued Population: subjects w/ available data who rcvd open-label rescue Tx after the DB period
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving ASDAS Clinically Important Improvement at 12 Weeks After Initiation of Rescue Therapy

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    End point title
    		 Number of Participants Achieving ASDAS Clinically Important Improvement at 12 Weeks After Initiation of Rescue Therapy
    End point description
    The Ankylosing Spondylitis Disease Activity Score (ASDAS) tool is a self-administered questionnaire/objective laboratory evaluation. The questionnaire assesses disease activity, back pain, and peripheral pain/swelling on a numeric rating scale (from 0 (normal) to 10 (very severe)) and duration of morning stiffness on a numeric rating scale (from 0 to 10, with 0 being none and 10 representing a duration of ≥2 hours). The laboratory parameter is a measurement of high-sensitivity C-reactive protein (mg/L) (hs-CRP). Data from five variables (disease activity, back pain, duration of morning stiffness, peripheral pain/swelling, and hs-CRP) are combined to yield a score (0 to no defined upper limit). ASDAS Clinically Important Improvement is defined as a change from baseline ≤ –1.100.
    End point type
    Secondary
    End point timeframe
    Baseline and Rescue Therapy Week 12
    End point values
    		 Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    65 [7]
    36 [8]
    Units: Participants
    37
    17
    Notes
    [7] - Rescued Population: subjects w/ available data who rcvd open-label rescue Tx after the DB period
    [8] - Rescued Population: subjects w/ available data who rcvd open-label rescue Tx after the DB period
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving an Assessment of Spondyloarthritis International Society (ASAS) 20 Response at 12 Weeks After Initiation of Rescue Therapy

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    End point title
    		 Number of Participants Achieving an Assessment of Spondyloarthritis International Society (ASAS) 20 Response at 12 Weeks After Initiation of Rescue Therapy
    End point description
    ASAS20 response was defined as improvement of ≥ 20% relative to baseline and absolute improvement of ≥ 1 unit (on a scale from 0 to 10) in ≥ 3 of the following 4 domains with no deterioration (defined as a worsening of ≥ 20% and a net worsening of ≥ 1 unit) in the potential remaining domain: • Patient's Global Assessment of disease activity, measured on a numeric rating scale (NRS) from 0 (none) to 10 (severe); • Pain, measured by the total back pain NRS from 0 (no pain) to 10 (most severe); • Function, measured by the Bath Ankylosing Spondylitis Functional Index (BASFI) which consists of 10 items assessing participants' ability to perform activities on an NRS ranging from 0 (easy) to 10 (impossible); • Inflammation, measured by the mean of the 2 morning stiffness-related Bath AS Disease Activity Index (BASDAI) NRS scores (items 5 [level of stiffness] and 6 [duration of stiffness]) each on a scale from 0 (none/0 hours) to 10 (very severe/2 hours or more duration).
    End point type
    Secondary
    End point timeframe
    Baseline and Rescue Therapy Week 12
    End point values
    		 Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    65 [9]
    36 [10]
    Units: Participants
    46
    19
    Notes
    [9] - Rescued Population: subjects w/ available data who rcvd open-label rescue Tx after the DB period
    [10] - Rescued Population: subjects w/ available data who rcvd open-label rescue Tx after the DB period
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving an Assessment of Spondyloarthritis International Society (ASAS) 40 Response at 12 Weeks After Initiation of Rescue Therapy

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    End point title
    		 Number of Participants Achieving an Assessment of Spondyloarthritis International Society (ASAS) 40 Response at 12 Weeks After Initiation of Rescue Therapy
    End point description
    ASAS40 response was defined as improvement of ≥ 40% relative to baseline and absolute improvement of ≥ 2 units (on a scale from 0 to 10) in ≥ 3 of the following 4 domains with no deterioration in the potential remaining domain: • Patient's Global Assessment of disease activity, measured on a numeric rating scale (NRS) from 0 (none) to 10 (severe); • Pain, measured by the total back pain NRS from 0 (no pain) to 10 (most severe); • Function, measured by the Bath Ankylosing Spondylitis Functional Index (BASFI) which consists of 10 items assessing participants' ability to perform activities on an NRS ranging from 0 (easy) to 10 (impossible); • Inflammation, measured by the mean of the 2 morning stiffness-related Bath AS Disease Activity Index (BASDAI) NRS scores (items 5 [level of stiffness] and 6 [duration of stiffness]) each on a scale from 0 (none/0 hours) to 10 (very severe/2 hours or more duration).
    End point type
    Secondary
    End point timeframe
    Baseline and Rescue Therapy Week 12
    End point values
    		 Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    65 [11]
    36 [12]
    Units: Participants
    35
    16
    Notes
    [11] - Rescued Population: subjects w/ available data who rcvd open-label rescue Tx after the DB period
    [12] - Rescued Population: subjects w/ available data who rcvd open-label rescue Tx after the DB period
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving an ASAS 5/6 Response at 12 Weeks After Initiation of Rescue Therapy

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    End point title
    		 Number of Participants Achieving an ASAS 5/6 Response at 12 Weeks After Initiation of Rescue Therapy
    End point description
    An Assessment of Spondyloarthritis International Society (ASAS) 5/6 response is a 20% improvement in 5 out of the following 6 domains: Patient's Global Assessment of disease activity, on a numeric rating scale (NRS) from 0 (none) to 10 (severe); Pain, measured by total back pain NRS from 0 (no pain) to 10 (most severe); Function, measured by the Bath Ankylosing Spondylitis Functional Index (BASFI) which assesses participants' ability to perform activities on an NRS ranging from 0 (easy) to 10 (impossible); Inflammation: the mean of the 2 morning stiffness-related Bath AS Disease Activity Index (BASDAI) NRS scores (items 5 [level of stiffness] and 6 [duration of stiffness]) each on a scale from 0 (none) to 10 (very severe/2 hrs or more duration); Spinal mobility: the lateral lumbar flexion score of the Bath AS Metrology Index (BASMI) on a scale from 0 (best mobility) to 10 (worst mobility); High-sensitivity C-reactive protein level (lower levels = less inflammation).
    End point type
    Secondary
    End point timeframe
    Baseline and Rescue Therapy Week 12
    End point values
    		 Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    63 [13]
    33 [14]
    Units: Participants
    25
    9
    Notes
    [13] - Rescued Population: subjects w/ available data who rcvd open-label rescue Tx after the DB period
    [14] - Rescued Population: subjects w/ available data who rcvd open-label rescue Tx after the DB period
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving ASAS Partial Remission at 12 Weeks After Initiation of Rescue Therapy

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    End point title
    		 Number of Participants Achieving ASAS Partial Remission at 12 Weeks After Initiation of Rescue Therapy
    End point description
    Assessment in SpondyloArthritis International Society (ASAS) partial remission is defined as an absolute score of < 2 units on a 0 to 10 scale for each of the four following domains: • Patient's Global Assessment of disease activity, measured on a numeric rating scale (NRS) from 0 (none) to 10 (severe); • Pain, measured by the total back pain NRS from 0 (no pain) to 10 (most severe); • Function, measured by the Bath Ankylosing Spondylitis Functional Index (BASFI) which consists of 10 items assessing participants' ability to perform activities on an NRS ranging from 0 (easy) to 10 (impossible); • Inflammation, measured by the mean of the 2 morning stiffness-related Bath AS Disease Activity Index (BASDAI) NRS scores (items 5 [level of stiffness] and 6 [duration of stiffness]) each on a scale from 0 (none/0 hours) to 10 (very severe/2 hours or more duration).
    End point type
    Secondary
    End point timeframe
    Rescue Therapy Week 12
    End point values
    		 Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    65 [15]
    36 [16]
    Units: Participants
    26
    15
    Notes
    [15] - Rescued Population: subjects w/ available data who rcvd open-label rescue Tx after the DB period
    [16] - Rescued Population: subjects w/ available data who rcvd open-label rescue Tx after the DB period
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 Response at 12 Weeks After Initiation of Rescue Therapy

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    End point title
    		 Number of Participants Achieving a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 Response at 12 Weeks After Initiation of Rescue Therapy
    End point description
    The Bath Ankylosing Spondylitis (AS) Disease Activity Index assesses disease activity by asking the participant to answer 6 questions (each on a 10 point numeric rating scale [NRS]) pertaining to symptoms experienced for the past week. For 5 questions (level of fatigue/tiredness, level of AS neck, back or hip pain, level of pain/swelling in joints, other than neck, back or hips, level of discomfort from any areas tender to touch or pressure, and level of morning stiffness), the response is from 0 (none) to 10 (very severe); for Question 6 (duration of morning stiffness), the response is from 0 (0 hours) to 10 (≥ 2 hours). The overall BASDAI score ranges from 0 to 10. Lower scores indicate less disease activity. BASDAI50 is a 50% improvement from baseline in BASDAI score.
    End point type
    Secondary
    End point timeframe
    Baseline and Rescue Therapy Week 12
    End point values
    		 Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    64 [17]
    34 [18]
    Units: Participants
    41
    18
    Notes
    [17] - Rescued Population: subjects w/ available data who rcvd open-label rescue Tx after the DB period
    [18] - Rescued Population: subjects w/ available data who rcvd open-label rescue Tx after the DB period
    No statistical analyses for this end point

    Secondary: Change From Baseline in Disability Index of Health Assessment Questionnaire Modified for the Spondyloarthropathies (HAQ-S) at 12 Weeks After Initiation of Rescue Therapy

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    End point title
    		 Change From Baseline in Disability Index of Health Assessment Questionnaire Modified for the Spondyloarthropathies (HAQ-S) at 12 Weeks After Initiation of Rescue Therapy
    End point description
    Health Assessment Questionnaire modified for spondyloarthropathies (HAQ-S) is a self-reported measure to assess the physical function and health-related quality of life. The Disability Index (DI) of HAQ-S is calculated as the mean of the following 8 category scores (range: 0 [without any difficulty] to 3 [unable to do]): Dressing and Grooming, Rising, Eating, Walking, Hygiene, Reach, Grip, and Activities. Five additional items in the functional status measure were included in the HAQ-S, including carrying heavy packages, sitting for long periods, able to work at a flat topped table, and (if the participant had a driver's license or a car) able to look in the rear view mirror and able to turn head to drive in reverse. The overall score ranges from 0 (no disability) to 3 (very severe, high-dependency disability). Negative mean changes from baseline in the overall score indicate improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Rescue Therapy Week 12
    End point values
    		 Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    31 [19]
    17 [20]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.3 ± 0.55
    -0.4 ± 0.60
    Notes
    [19] - Rescued Population: subjects w/ available data who rcvd open-label rescue Tx after the DB period
    [20] - Rescued Population: subjects w/ available data who rcvd open-label rescue Tx after the DB period
    No statistical analyses for this end point

    Secondary: Number of Participants With Ankylosing Spondylitis Disease Activity Score (ASDAS) Inactive Disease at Weeks 28 and 68

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    End point title
    		 Number of Participants With Ankylosing Spondylitis Disease Activity Score (ASDAS) Inactive Disease at Weeks 28 and 68
    End point description
    The Ankylosing Spondylitis Disease Activity Score (ASDAS) tool is a self-administered questionnaire/objective laboratory evaluation. The questionnaire assesses disease activity, back pain, and peripheral pain/swelling on a numeric rating scale (from 0 (normal) to 10 (very severe)) and duration of morning stiffness on a numeric rating scale (from 0 to 10, with 0 being none and 10 representing a duration of ≥2 hours). The laboratory parameter is a measurement of high-sensitivity C-reactive protein (mg/L) (hs-CRP). Data from five variables (disease activity, back pain, duration of morning stiffness, peripheral pain/swelling, and hs-CRP) are combined to yield a score (0 to no defined upper limit). ASDAS Inactive Disease is defined as a score of <1.300.
    End point type
    Secondary
    End point timeframe
    Weeks 28 and 68
    End point values
    		 Open-label (OL) Adalimumab (Period 1) Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    323 [21]
    153 [22]
    152 [23]
    Units: Participants
        Week 28
    295
    0
    0
        Week 68
    0
    51
    87
    Notes
    [21] - Period 1: all enrolled subjects who received at least 1 dose of adalimumab
    [22] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    [23] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving ASDAS Major Improvement at Weeks 28 and 68

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    End point title
    		 Number of Participants Achieving ASDAS Major Improvement at Weeks 28 and 68
    End point description
    The Ankylosing Spondylitis Disease Activity Score (ASDAS) tool is a self-administered questionnaire/objective laboratory evaluation. The questionnaire assesses disease activity, back pain, and peripheral pain/swelling on a numeric rating scale (from 0 (normal) to 10 (very severe)) and duration of morning stiffness on a numeric rating scale (from 0 to 10, with 0 being none and 10 representing a duration of ≥2 hours). The laboratory parameter is a measurement of high-sensitivity C-reactive protein (mg/L) (hs-CRP). Data from five variables (disease activity, back pain, duration of morning stiffness, peripheral pain/swelling, and hs-CRP) are combined to yield a score (0 to no defined upper limit). ASDAS Major Improvement is defined as a change from baseline ≤ –2.000.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 28 and 68
    End point values
    		 Open-label (OL) Adalimumab (Period 1) Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    323 [24]
    153 [25]
    152 [26]
    Units: Participants
        Week 28
    266
    0
    0
        Week 68
    0
    49
    89
    Notes
    [24] - Period 1: all enrolled participants who received at least 1 dose of adalimumab
    [25] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    [26] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving ASDAS Clinically Important Improvement at Weeks 28 and 68

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    End point title
    		 Number of Participants Achieving ASDAS Clinically Important Improvement at Weeks 28 and 68
    End point description
    The Ankylosing Spondylitis Disease Activity Score (ASDAS) tool is a self-administered questionnaire/objective laboratory evaluation. The questionnaire assesses disease activity, back pain, and peripheral pain/swelling on a numeric rating scale (from 0 (normal) to 10 (very severe)) and duration of morning stiffness on a numeric rating scale (from 0 to 10, with 0 being none and 10 representing a duration of ≥2 hours). The laboratory parameter is a measurement of high-sensitivity C-reactive protein (mg/L) (hs-CRP). Data from five variables (disease activity, back pain, duration of morning stiffness, peripheral pain/swelling, and hs-CRP) are combined to yield a score (0 to no defined upper limit). ASDAS Clinically Important Improvement is defined as a change from baseline ≤ –1.100.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 28 and 68
    End point values
    		 Open-label (OL) Adalimumab (Period 1) Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    323 [27]
    153 [28]
    152 [29]
    Units: Participants
        Week 28
    316
    0
    0
        Week 68
    0
    69
    102
    Notes
    [27] - Period 1: all enrolled participants who received at least 1 dose of adalimumab
    [28] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    [29] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving an Assessment of Spondyloarthritis International Society (ASAS) 20 Response at Weeks 28 and 68

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    End point title
    		 Number of Participants Achieving an Assessment of Spondyloarthritis International Society (ASAS) 20 Response at Weeks 28 and 68
    End point description
    ASAS20 response was defined as improvement of ≥ 20% relative to baseline and absolute improvement of ≥ 1 unit (on a scale from 0 to 10) in ≥ 3 of the following 4 domains with no deterioration (defined as a worsening of ≥ 20% and a net worsening of ≥ 1 unit) in the potential remaining domain: • Patient's Global Assessment of disease activity, measured on a numeric rating scale (NRS) from 0 (none) to 10 (severe); • Pain, measured by the total back pain NRS from 0 (no pain) to 10 (most severe); • Function, measured by the Bath Ankylosing Spondylitis Functional Index (BASFI) which consists of 10 items assessing participants' ability to perform activities on an NRS ranging from 0 (easy) to 10 (impossible); • Inflammation, measured by the mean of the 2 morning stiffness-related Bath AS Disease Activity Index (BASDAI) NRS scores (items 5 [level of stiffness] and 6 [duration of stiffness]) each on a scale from 0 (none/0 hours) to 10 (very severe/2 hours or more duration).
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 28 and 68
    End point values
    		 Open-label (OL) Adalimumab (Period 1) Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    324 [30]
    153 [31]
    152 [32]
    Units: Participants
        Week 28
    315
    0
    0
        Week 68
    0
    72
    107
    Notes
    [30] - Period 1: all enrolled participants who received at least 1 dose of adalimumab
    [31] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    [32] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving an Assessment of Spondyloarthritis International Society (ASAS) 40 Response at Weeks 28 and 68

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    End point title
    		 Number of Participants Achieving an Assessment of Spondyloarthritis International Society (ASAS) 40 Response at Weeks 28 and 68
    End point description
    ASAS40 response was defined as improvement of ≥ 40% relative to baseline and absolute improvement of ≥ 2 units (on a scale from 0 to 10) in ≥ 3 of the following 4 domains with no deterioration in the potential remaining domain: • Patient's Global Assessment of disease activity, measured on a numeric rating scale (NRS) from 0 (none) to 10 (severe); • Pain, measured by the total back pain NRS from 0 (no pain) to 10 (most severe); • Function, measured by the Bath Ankylosing Spondylitis Functional Index (BASFI) which consists of 10 items assessing participants' ability to perform activities on an NRS ranging from 0 (easy) to 10 (impossible); • Inflammation, measured by the mean of the 2 morning stiffness-related Bath AS Disease Activity Index (BASDAI) NRS scores (items 5 [level of stiffness] and 6 [duration of stiffness]) each on a scale from 0 (none/0 hours) to 10 (very severe/2 hours or more duration).
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 28 and 68
    End point values
    		 Open-label (OL) Adalimumab (Period 1) Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    324 [33]
    153 [34]
    152 [35]
    Units: Participants
        Week 28
    302
    0
    0
        Week 68
    0
    70
    100
    Notes
    [33] - Period 1: all enrolled participants who received at least 1 dose of adalimumab
    [34] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    [35] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving an ASAS 5/6 Response at Weeks 28 and 68

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    End point title
    		 Number of Participants Achieving an ASAS 5/6 Response at Weeks 28 and 68
    End point description
    An Assessment of Spondyloarthritis International Society (ASAS) 5/6 response is a 20% improvement in 5 out of the following 6 domains: Patient's Global Assessment of disease activity, on a numeric rating scale (NRS) from 0 (none) to 10 (severe); Pain, measured by total back pain NRS from 0 (no pain) to 10 (most severe); Function, measured by the Bath Ankylosing Spondylitis Functional Index (BASFI) which assesses participants' ability to perform activities on an NRS ranging from 0 (easy) to 10 (impossible); Inflammation: the mean of the 2 morning stiffness-related Bath AS Disease Activity Index (BASDAI) NRS scores (items 5 [level of stiffness] and 6 [duration of stiffness]) each on a scale from 0 (none) to 10 (very severe/2 hrs or more duration); Spinal mobility: the lateral lumbar flexion score of the Bath AS Metrology Index (BASMI) on a scale from 0 (best mobility) to 10 (worst mobility); High-sensitivity C-reactive protein level (lower levels = less inflammation).
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 28 and 68
    End point values
    		 Open-label (OL) Adalimumab (Period 1) Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    324 [36]
    153 [37]
    152 [38]
    Units: Participants
        Week 28
    253
    0
    0
        Week 68
    0
    49
    87
    Notes
    [36] - Period 1: all enrolled participants who received at least 1 dose of adalimumab
    [37] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    [38] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving ASAS Partial Remission at Weeks 28 and 68

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    End point title
    		 Number of Participants Achieving ASAS Partial Remission at Weeks 28 and 68
    End point description
    Assessment in SpondyloArthritis International Society (ASAS) partial remission is defined as an absolute score of < 2 units on a 0 to 10 scale for each of the four following domains: • Patient's Global Assessment of disease activity, measured on a numeric rating scale (NRS) from 0 (none) to 10 (severe); • Pain, measured by the total back pain NRS from 0 (no pain) to 10 (most severe); • Function, measured by the Bath Ankylosing Spondylitis Functional Index (BASFI) which consists of 10 items assessing participants' ability to perform activities on an NRS ranging from 0 (easy) to 10 (impossible); • Inflammation, measured by the mean of the 2 morning stiffness-related Bath AS Disease Activity Index (BASDAI) NRS scores (items 5 [level of stiffness] and 6 [duration of stiffness]) each on a scale from 0 (none/0 hours) to 10 (very severe/2 hours or more duration).
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 28 and 68
    End point values
    		 Open-label (OL) Adalimumab (Period 1) Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    324 [39]
    153 [40]
    152 [41]
    Units: Participants
        Week 28
    224
    0
    0
        Week 68
    0
    41
    64
    Notes
    [39] - Period 1: all enrolled participants who received at least 1 dose of adalimumab
    [40] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    [41] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 Response at Weeks 28 and 68

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    End point title
    		 Number of Participants Achieving a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 Response at Weeks 28 and 68
    End point description
    The Bath Ankylosing Spondylitis (AS) Disease Activity Index assesses disease activity by asking the participant to answer 6 questions (each on a 10 point numeric rating scale [NRS]) pertaining to symptoms experienced for the past week. For 5 questions (level of fatigue/tiredness, level of AS neck, back or hip pain, level of pain/swelling in joints, other than neck, back or hips, level of discomfort from any areas tender to touch or pressure, and level of morning stiffness), the response is from 0 (none) to 10 (very severe); for Question 6 (duration of morning stiffness), the response is from 0 (0 hours) to 10 (≥ 2 hours). The overall BASDAI score ranges from 0 to 10. Lower scores indicate less disease activity. BASDAI50 is a 50% improvement from baseline in BASDAI score.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 28 and 68
    End point values
    		 Open-label (OL) Adalimumab (Period 1) Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    324 [42]
    153 [43]
    152 [44]
    Units: Participants
        Week 28
    317
    0
    0
        Week 68
    0
    72
    103
    Notes
    [42] - Period 1: all enrolled participants who received at least 1 dose of adalimumab
    [43] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    [44] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    No statistical analyses for this end point

    Secondary: Change From Baseline in Disability Index of Health Assessment Questionnaire Modified for the Spondyloarthropathies (HAQ-S) at Weeks 28 and 68

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    End point title
    		 Change From Baseline in Disability Index of Health Assessment Questionnaire Modified for the Spondyloarthropathies (HAQ-S) at Weeks 28 and 68
    End point description
    Health Assessment Questionnaire modified for spondyloarthropathies (HAQ-S) is a self-reported measure to assess the physical function and health-related quality of life. The Disability Index (DI) of HAQ-S is calculated as the mean of the following 8 category scores (range: 0 [without any difficulty] to 3 [unable to do]): Dressing and Grooming, Rising, Eating, Walking, Hygiene, Reach, Grip, and Activities. Five additional items in the functional status measure were included in the HAQ-S, including carrying heavy packages, sitting for long periods, able to work at a flat topped table, and (if the participant had a driver's license or a car) able to look in the rear view mirror and able to turn head to drive in reverse. The overall score ranges from 0 (no disability) to 3 (very severe, high-dependency disability). Negative mean changes from baseline in the overall score indicate improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 28 and 68
    End point values
    		 Open-label (OL) Adalimumab (Period 1) Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    324 [45]
    79 [46]
    112 [47]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Week 28
    -0.8 ± 0.58
    0 ± 0
    0 ± 0
        Week 68
    0 ± 0
    -0.8 ± 0.59
    -0.8 ± 0.63
    Notes
    [45] - Period 1: all enrolled participants who received at least 1 dose of adalimumab
    [46] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    [47] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    No statistical analyses for this end point

    Secondary: Time to Flare at Week 68

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    End point title
    		 Time to Flare at Week 68
    End point description
    The Ankylosing Spondylitis Disease Activity Score (ASDAS) tool is a self-administered questionnaire/objective laboratory evaluation. The questionnaire assesses disease activity, back pain, and peripheral pain/swelling on a numeric rating scale (from 0 (normal) to 10 (very severe)) and duration of morning stiffness on a numeric rating scale (from 0 to 10, with 0 being none and 10 representing a duration of ≥2 hours). The laboratory parameter is a measurement of high-sensitivity C-reactive protein (mg/L) (hs-CRP). Data from five variables (disease activity, back pain, duration of morning stiffness, peripheral pain/swelling, and hs-CRP) are combined to yield a score (0 to no defined upper limit). During Period 2 participants visited study sites at Weeks 28, 32, 36, 40, 44, 48, 52, 56, 60, 64 and 68 or if they discontinued early from the study. A flare was defined as having any 2 consecutive study visits with ASDAS ≥ 2.100.
    End point type
    Secondary
    End point timeframe
    From Week 28 through 68
    End point values
    		 Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    153 [48]
    152 [49]
    Units: weeks
        median (confidence interval 95%)
    999 (41 to 999)
    999 (999 to 999)
    Notes
    [48] - 999= survival function >50%; median time to flare and upper 95% CI limit not estimable
    [49] - 999= survival function >50%; median time to flare and lower/upper 95% CI limit not estimable
    Statistical analysis title
    		 Time to Flare at Week 68
    Statistical analysis description
    The statistical test was performed at a 2-sided significance level of 0.05. Time to flare analysis showed statistically significant lower risk of flare in the adalimumab group than in the placebo group.
    Comparison groups
    Placebo (Period 2) v Double-blind Adalimumab (Period 2)
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Logrank
    Confidence interval

    Secondary: Time to Partial Flare at Week 68

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    End point title
    		 Time to Partial Flare at Week 68
    End point description
    The Ankylosing Spondylitis Disease Activity Score (ASDAS) tool is a self-administered questionnaire/objective laboratory evaluation. The questionnaire assesses disease activity, back pain, and peripheral pain/swelling on a numeric rating scale (from 0 (normal) to 10 (very severe)) and duration of morning stiffness on a numeric rating scale (from 0 to 10, with 0 being none and 10 representing a duration of ≥2 hours). The laboratory parameter is a measurement of high-sensitivity C-reactive protein (mg/L) (hs-CRP). Data from five variables (disease activity, back pain, duration of morning stiffness, peripheral pain/swelling, and hs-CRP) are combined to yield a score (0 to no defined upper limit). During Period 2 participants visited study sites at Weeks 28, 32, 36, 40, 44, 48, 52, 56, 60, 64 and 68 or if they discontinued early from the study. A partial flare was defined as having any 2 consecutive study visits with ASDAS ≥ 1.300 but <2.100.
    End point type
    Secondary
    End point timeframe
    From Week 28 through 68
    End point values
    		 Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    153 [50]
    152 [51]
    Units: weeks
        median (confidence interval 95%)
    41 (41 to 999)
    42 (42 to 999)
    Notes
    [50] - The upper 95% CI limit was not estimable due to low no. of subjects with events, indicated by 999.
    [51] - The upper 95% CI limit was not estimable due to low no. of subjects with events, indicated by 999.
    No statistical analyses for this end point

    Secondary: Number of Participants Reaching Flare Definition by Week 68

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    End point title
    		 Number of Participants Reaching Flare Definition by Week 68
    End point description
    The Ankylosing Spondylitis Disease Activity Score (ASDAS) tool is a self-administered questionnaire/objective laboratory evaluation. The questionnaire assesses disease activity, back pain, and peripheral pain/swelling on a numeric rating scale (from 0 (normal) to 10 (very severe)) and duration of morning stiffness on a numeric rating scale (from 0 to 10, with 0 being none and 10 representing a duration of ≥2 hours). The laboratory parameter is a measurement of high-sensitivity C-reactive protein (mg/L) (hs-CRP). Data from five variables (disease activity, back pain, duration of morning stiffness, peripheral pain/swelling, and hs-CRP) are combined to yield a score (0 to no defined upper limit). During Period 2 participants visited study sites at Weeks 28, 32, 36, 40, 44, 48, 52, 56, 60, 64 and 68 or if they discontinued early from the study. A flare was defined as having any 2 consecutive study visits with ASDAS ≥ 2.100.
    End point type
    Secondary
    End point timeframe
    From Week 28 through 68
    End point values
    		 Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    153 [52]
    152 [53]
    Units: Participants
    81
    45
    Notes
    [52] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    [53] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    No statistical analyses for this end point

    Secondary: Number of Participants Reaching Partial Flare Definition by Week 68

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    End point title
    		 Number of Participants Reaching Partial Flare Definition by Week 68
    End point description
    The Ankylosing Spondylitis Disease Activity Score (ASDAS) tool is a self-administered questionnaire/objective laboratory evaluation. The questionnaire assesses disease activity, back pain, and peripheral pain/swelling on a numeric rating scale (from 0 (normal) to 10 (very severe)) and duration of morning stiffness on a numeric rating scale (from 0 to 10, with 0 being none and 10 representing a duration of ≥2 hours). The laboratory parameter is a measurement of high-sensitivity C-reactive protein (mg/L) (hs-CRP). Data from five variables (disease activity, back pain, duration of morning stiffness, peripheral pain/swelling, and hs-CRP) are combined to yield a score (0 to no defined upper limit). During Period 2 participants visited study sites at Weeks 28, 32, 36, 40, 44, 48, 52, 56, 60, 64 and 68 or if they discontinued early from the study. A partial flare was defined as having any 2 consecutive study visits with ASDAS ≥ 1.300 but <2.100.
    End point type
    Secondary
    End point timeframe
    From Week 28 through 68
    End point values
    		 Placebo (Period 2) Double-blind Adalimumab (Period 2)
    Number of subjects analysed
    153 [54]
    152 [55]
    Units: Participants
    98
    62
    Notes
    [54] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    [55] - mITT: randomized and rcvd ≥1 dose of double-blind study meds; missing data imputed as nonresponders
    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) were collected from the time of study drug administration until 70 days after the last dose of study drug (up to 90 weeks).
    Adverse event reporting additional description
    TEAEs and TESAEs are defined as any adverse event (AE) with an onset date that is after the first dose ofstudy 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
    19.1
    Reporting groups
    Reporting group title
    Open-label (OL) Adalimumab (Period 1), Full Analysis Set
    Reporting group description
    		 40 mg every other week (eow), Weeks 0-28. The Full Analysis Set included all participants who enrolled in the open-label period (Period 1) and received at least 1 dose of adalimumab.

    Reporting group title
    Placebo (Period 2)
    Reporting group description
    		 Placebo every other week (eow), Weeks 28-68. Placebo was discontinued in participants who met the criteria for flare.

    Reporting group title
    Double-blind Adalimumab (Period 2)
    Reporting group description
    		 Adalimumab 40 mg every other week (eow), Weeks 28-68. Blinded adalimumab was discontinued in participants who met the criteria for flare.

    Reporting group title
    Any Adalimumab Population
    Reporting group description
    		 The Any Adalimumab Population consisted of all participants who received at least 1 dose of adalimumab any time during the study (including the open-label period, double-blind period and rescue period).

    Serious adverse events
    		 Open-label (OL) Adalimumab (Period 1), Full Analysis Set Placebo (Period 2) Double-blind Adalimumab (Period 2) Any Adalimumab Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 673 (2.82%)
    10 / 153 (6.54%)
    1 / 152 (0.66%)
    28 / 673 (4.16%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    THYROID ADENOMA
         subjects affected / exposed
    0 / 673 (0.00%)
    1 / 153 (0.65%)
    0 / 152 (0.00%)
    0 / 673 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ADENOCARCINOMA GASTRIC
         subjects affected / exposed
    0 / 673 (0.00%)
    1 / 153 (0.65%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UTERINE LEIOMYOMA
         subjects affected / exposed
    2 / 673 (0.30%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    2 / 673 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    PYREXIA
         subjects affected / exposed
    2 / 673 (0.30%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    2 / 673 (0.30%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PAIN
         subjects affected / exposed
    1 / 673 (0.15%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    VAGINAL PROLAPSE
         subjects affected / exposed
    1 / 673 (0.15%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 673 (0.15%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY MASS
         subjects affected / exposed
    0 / 673 (0.00%)
    1 / 153 (0.65%)
    0 / 152 (0.00%)
    0 / 673 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    INTENTIONAL SELF-INJURY
         subjects affected / exposed
    1 / 673 (0.15%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    FOOT FRACTURE
         subjects affected / exposed
    1 / 673 (0.15%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CLAVICLE FRACTURE
         subjects affected / exposed
    0 / 673 (0.00%)
    1 / 153 (0.65%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PROCEDURAL PAIN
         subjects affected / exposed
    1 / 673 (0.15%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 673 (0.00%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CORONARY ARTERY DISEASE
         subjects affected / exposed
    0 / 673 (0.00%)
    1 / 153 (0.65%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CORONARY ARTERY STENOSIS
         subjects affected / exposed
    0 / 673 (0.00%)
    1 / 153 (0.65%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MYOCARDIAL ISCHAEMIA
         subjects affected / exposed
    0 / 673 (0.00%)
    1 / 153 (0.65%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VENTRICULAR FIBRILLATION
         subjects affected / exposed
    0 / 673 (0.00%)
    1 / 153 (0.65%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SINUS TACHYCARDIA
         subjects affected / exposed
    1 / 673 (0.15%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    0 / 673 (0.00%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MIGRAINE
         subjects affected / exposed
    1 / 673 (0.15%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OPTIC NEURITIS
         subjects affected / exposed
    0 / 673 (0.00%)
    1 / 153 (0.65%)
    0 / 152 (0.00%)
    0 / 673 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ILEUS
         subjects affected / exposed
    1 / 673 (0.15%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    1 / 673 (0.15%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    URETEROLITHIASIS
         subjects affected / exposed
    0 / 673 (0.00%)
    1 / 153 (0.65%)
    1 / 152 (0.66%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URETHRAL CYST
         subjects affected / exposed
    0 / 673 (0.00%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    AXIAL SPONDYLOARTHRITIS
         subjects affected / exposed
    1 / 673 (0.15%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BURSITIS
         subjects affected / exposed
    1 / 673 (0.15%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTERVERTEBRAL DISC PROTRUSION
         subjects affected / exposed
    1 / 673 (0.15%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    ATYPICAL PNEUMONIA
         subjects affected / exposed
    1 / 673 (0.15%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    APPENDICITIS
         subjects affected / exposed
    2 / 673 (0.30%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    3 / 673 (0.45%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    1 / 673 (0.15%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    1 / 673 (0.15%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA LEGIONELLA
         subjects affected / exposed
    1 / 673 (0.15%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUBCUTANEOUS ABSCESS
         subjects affected / exposed
    1 / 673 (0.15%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    0 / 673 (0.00%)
    1 / 153 (0.65%)
    0 / 152 (0.00%)
    1 / 673 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VIRAL INFECTION
         subjects affected / exposed
    0 / 673 (0.00%)
    1 / 153 (0.65%)
    0 / 152 (0.00%)
    0 / 673 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    		 Open-label (OL) Adalimumab (Period 1), Full Analysis Set Placebo (Period 2) Double-blind Adalimumab (Period 2) Any Adalimumab Population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    221 / 673 (32.84%)
    51 / 153 (33.33%)
    57 / 152 (37.50%)
    275 / 673 (40.86%)
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    45 / 673 (6.69%)
    5 / 153 (3.27%)
    7 / 152 (4.61%)
    54 / 673 (8.02%)
         occurrences all number
    50
    5
    7
    62
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    36 / 673 (5.35%)
    5 / 153 (3.27%)
    6 / 152 (3.95%)
    42 / 673 (6.24%)
         occurrences all number
    39
    5
    7
    48
    Musculoskeletal and connective tissue disorders
    AXIAL SPONDYLOARTHRITIS
         subjects affected / exposed
    36 / 673 (5.35%)
    21 / 153 (13.73%)
    10 / 152 (6.58%)
    57 / 673 (8.47%)
         occurrences all number
    38
    23
    15
    65
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    90 / 673 (13.37%)
    20 / 153 (13.07%)
    25 / 152 (16.45%)
    117 / 673 (17.38%)
         occurrences all number
    103
    23
    32
    151
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    57 / 673 (8.47%)
    12 / 153 (7.84%)
    20 / 152 (13.16%)
    80 / 673 (11.89%)
         occurrences all number
    70
    14
    25
    114

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Dec 2013
    - Added an assessment of dactylitis - Added a requirement to submit a local pelvic x-ray assessment to the central imaging vendor - Added an interim analysis after all subjects had completed Week 28
    15 Jan 2015
    - Added mercaptopurine (6-MP) in the list of stable Disease modifying anti-rheumatic drugs (DMARDs) within the exclusion criteria - Increased the screening period from less than or equal to 30 days to 6 weeks - Updated the rounding rule in reference to ASDAS calculation - Added the Optional Blood Sample Collection Sub-Study, which gave subjects the option to provide blood samples for future research.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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