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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Upadacitinib in Subjects with Active Ankylosing Spondylitis

    Summary
    EudraCT number
    2017-000431-14
    Trial protocol
    FR   DK   DE   FI   CZ   GB   ES   PT   NL   BE   HU   PL   SE   HR  
    Global end of trial date
    17 Feb 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Feb 2023
    First version publication date
    23 Feb 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M16-098
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03178487
    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, 001 800-633-9110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    Global Medical Services, AbbVie, 001 800-633-9110, abbvieclinicaltrials@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
    17 Feb 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Feb 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the safety and efficacy of upadacitinib in participants with active ankylosing spondylitis (AS) who have had an inadequate response to at least 2 non-steroidal anti-inflammatory drugs (NSAIDs) or intolerance to or a contraindication for NSAIDs, and who are naïve to biologic disease-modifying anti-rheumatic drugs (bDMARD).
    Protection of trial subjects
    Subject read and understood the information provided about the study and gave written permission.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Oct 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Croatia: 1
    Country: Number of subjects enrolled
    Czechia: 36
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Finland: 5
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Hungary: 15
    Country: Number of subjects enrolled
    Japan: 13
    Country: Number of subjects enrolled
    Korea, Republic of: 13
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    New Zealand: 6
    Country: Number of subjects enrolled
    Poland: 18
    Country: Number of subjects enrolled
    Portugal: 11
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    187
    EEA total number of subjects
    128
    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)
    176
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were enrolled between October 24, 2017, and September 10, 2018 at 62 sites in 20 countries in North America, Eastern and Western Europe, Asia, and Oceania. This study consists of a 14-week double-blind treatment period (Period 1) and a 90-week long-term extension period (Period 2) for participants who completed Period 1.

    Pre-assignment
    Screening details
    Eligible participants were randomized in a 1:1 ratio to one of two treatment groups. Randomization was stratified by screening concentrations of high-sensitivity C-reactive protein (hsCRP; ≤ upper limit of normal [ULN] vs > ULN; where the ULN is 2.87 mg/L) and geographical region (USA and Canada, Japan, rest of the world).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants received matching placebo orally once a day for 14 weeks in Period 1.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching tablets taken orally once a day.

    Arm title
    Upadacitinib 15 mg
    Arm description
    Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.
    Arm type
    Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    ABT-494
    Other name
    RINVOQ®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets taken orally once a day.

    Number of subjects in period 1
    Placebo Upadacitinib 15 mg
    Started
    94
    93
    Received Treatment
    94
    93
    Completed
    90
    89
    Not completed
    4
    4
         Consent withdrawn by subject
    2
    1
         Adverse event, non-fatal
    1
    2
         Other
    -
    1
         Lost to follow-up
    1
    -
    Period 2
    Period 2 title
    Period 2
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo / Upadacitinib 15 mg
    Arm description
    Participants randomized to receive placebo in Period 1 received upadacitinib 15 mg orally once a day for 90 weeks in Period 2.
    Arm type
    Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    ABT-494
    Other name
    RINVOQ®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets taken orally once a day.

    Arm title
    Upadacitinib 15 mg / Upadacitinib 15 mg
    Arm description
    Participants randomized to receive upadacitinib in Period 1 continued to receive upadacitinib 15 mg orally once a day for 90 weeks in Period 2.
    Arm type
    Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    ABT-494
    Other name
    RINVOQ®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets taken orally once a day.

    Number of subjects in period 2
    Placebo / Upadacitinib 15 mg Upadacitinib 15 mg / Upadacitinib 15 mg
    Started
    90
    89
    Received Treatment
    89
    89
    Completed
    69
    70
    Not completed
    21
    19
         Consent withdrawn by subject
    6
    6
         Adverse event, non-fatal
    4
    4
         COVID-19 Logistical Restrictions
    1
    -
         Other
    8
    7
         Lost to follow-up
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received matching placebo orally once a day for 14 weeks in Period 1.

    Reporting group title
    Upadacitinib 15 mg
    Reporting group description
    Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.

    Reporting group values
    Placebo Upadacitinib 15 mg Total
    Number of subjects
    94 93 187
    Age categorical
    Units: Subjects
        < 40 years
    39 28 67
        40 - 64 years
    53 56 109
        ≥ 65 years
    2 9 11
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    43.7 ( 12.07 ) 47.0 ( 12.78 ) -
    Gender categorical
    Units: Subjects
        Female
    25 30 55
        Male
    69 63 132
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    5 4 9
        Not Hispanic or Latino
    89 89 178
    Race
    Units: Subjects
        White
    76 79 155
        Black or African American
    2 1 3
        Asian
    16 13 29
    Region
    Units: Subjects
        USA and Canada
    10 9 19
        Western Europe
    33 30 63
        Eastern Europe
    34 36 70
        Japan
    7 6 13
        South Korea
    7 6 13
        Australia and New Zealand
    3 6 9
    High-sensitivity C-reactive Protein (hsCRP) Level at Screening
    The Screening level of hsCRP was a randomization stratification factor. The hsCRP upper limit of normal (ULN) = 2.87 mg/L.
    Units: Subjects
        > upper limit of normal
    68 67 135
        ≤ upper limit of normal
    26 26 52
    Duration Since Ankylosing Spondylitis Diagnosis
    Units: years
        arithmetic mean (standard deviation)
    6.0 ( 6.79 ) 7.8 ( 10.64 ) -
    Duration of Ankylosing Spondylitis Symptoms
    Units: years
        arithmetic mean (standard deviation)
    14.0 ( 9.86 ) 14.8 ( 11.64 ) -
    Patient's Global Assessment of Disease Activity (PtGA)
    Assessed by the participant using a numeric rating scale (NRS) ranging from 0 (No activity) to 10 (Severe activity). 94 and 91 participants had available data in each treatment group, respectively.
    Units: units on a scale
        arithmetic mean (standard deviation)
    6.8 ( 1.66 ) 6.6 ( 1.81 ) -
    Patient's Assessment of Total Back Pain
    Total back pain was assessed by the participant on a NRS from 0 (no pain) to 10 (most severe pain). 94 and 92 participants had available data in each treatment group, respectively.
    Units: units on a scale
        arithmetic mean (standard deviation)
    6.7 ( 1.78 ) 6.8 ( 1.77 ) -
    Bath Ankylosing Spondylitis Functional Index
    The Bath Ankylosing Spondylitis Functional Index (BASFI) is used to determine the degree of functional limitation in patients with AS. BASFI consists of 10 questions assessing participants' ability to perform activities, each scored on a NRS ranging from 0 (easy to perform activity) to 10 (impossible to perform activity). The overall score is the mean of the 10 items and ranges from 0 to 10 with higher score indicating more functional limitations. 94 and 91 participants had available data in each treatment group, respectively.
    Units: units on a scale
        arithmetic mean (standard deviation)
    5.5 ( 2.17 ) 5.4 ( 2.36 ) -
    Inflammation
    Inflammation was measured by the mean of the two 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). 94 and 92 particiapnts had available data in each treatment group, respectively.
    Units: units on a scale
        arithmetic mean (standard deviation)
    6.7 ( 1.90 ) 6.5 ( 1.99 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received matching placebo orally once a day for 14 weeks in Period 1.

    Reporting group title
    Upadacitinib 15 mg
    Reporting group description
    Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.
    Reporting group title
    Placebo / Upadacitinib 15 mg
    Reporting group description
    Participants randomized to receive placebo in Period 1 received upadacitinib 15 mg orally once a day for 90 weeks in Period 2.

    Reporting group title
    Upadacitinib 15 mg / Upadacitinib 15 mg
    Reporting group description
    Participants randomized to receive upadacitinib in Period 1 continued to receive upadacitinib 15 mg orally once a day for 90 weeks in Period 2.

    Primary: Percentage of Participants With Assessment of SpondyloArthritis International Society (ASAS) 40 Response at Week 14

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    End point title
    Percentage of Participants With Assessment of SpondyloArthritis International Society (ASAS) 40 Response at Week 14
    End point description
    ASAS 40 response was defined as improvement of ≥ 40% relative to Baseline and absolute improvement of ≥ 2 units in ≥ 3 of the following 4 domains with no deterioration (a net worsening of > 0 units) in the potential remaining domain: 1) Patient's global assessment of disease activity, measured on a NRS from 0 - 10 (severe activity); 2) Pain, measured by the total back pain NRS from 0 - 10 (most severe pain); 3) Function, measured by the Bath Ankylosing Spondylitis Functional Index (BASFI), consisting of 10 items assessing participants' ability to perform activities each on an NRS from 0 (easy) - 10 (impossible); 4) 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 duration). Participants with missing data or who discontinued study drug prior to Week 14 were counted as non-responders.
    End point type
    Primary
    End point timeframe
    Baseline and Week 14
    End point values
    Placebo Upadacitinib 15 mg
    Number of subjects analysed
    94 [1]
    93 [2]
    Units: percentage of participants
        number (confidence interval 95%)
    25.5 (16.7 to 34.3)
    51.6 (41.5 to 61.8)
    Notes
    [1] - Full analysis set (all randomized participants who received at least one dose of study drug)
    [2] - Full analysis set
    Statistical analysis title
    Primary Analysis
    Comparison groups
    Placebo v Upadacitinib 15 mg
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    < 0.001 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Response Rate Difference
    Point estimate
    26.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    12.6
         upper limit
    39.5
    Notes
    [3] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint.
    [4] - Cochran-Mantel-Haenszel (CMH) test adjusting for stratification factor of Screening hsCRP level.

    Secondary: Change From Baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS) at Week 14

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    End point title
    Change From Baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS) at Week 14
    End point description
    ASDAS is a composite index to assess disease activity in Ankylosing Spondylitis. ASDAS combines the following 5 disease activity variables using a weighted formula: 1. Patient's assessment of total back pain (BASDAI Question 2; NRS from 0 - 10 [very severe]) 2. Patient global assessment of disease activity (NRS from 0 [no activity] - 10 [severe activity]) 3. Peripheral pain/swelling (BASDAI Question 3; NRS from 0 - 10 [very severe]) 4. Duration of morning stiffness (BASDAI Question 6; NRS from 0 [0 hours] - 10 [2 or more hours]) 5. hs-CRP in mg/L. The overall score ranges from 0 with no defined upper score; published ranges for disease activity states as defined by the ASDAS include Inactive disease (ASDAS < 1.3) and very high disease (ASDAS > 3.5). A negative change from Baseline score indicates improvement in disease activity. A mixed effect model repeat measurement (MMRM) analysis with longitudinal data from observed cases up to Week 14 was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 14
    End point values
    Placebo Upadacitinib 15 mg
    Number of subjects analysed
    84 [5]
    84 [6]
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -0.54 (-0.71 to -0.37)
    -1.45 (-1.62 to -1.28)
    Notes
    [5] - Full analysis set; MMRM including all observed longitudinal data up to Week 14
    [6] - Full analysis set; MMRM including all observed longitudinal data up to Week 14
    Statistical analysis title
    Analysis of Change from Baseline in ASDAS
    Comparison groups
    Placebo v Upadacitinib 15 mg
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    < 0.001 [8]
    Method
    Mixed Effect Model Repeated Measurement
    Parameter type
    Least Squares (LS) Mean Difference
    Point estimate
    -0.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.14
         upper limit
    -0.68
    Notes
    [7] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint.
    [8] - MMRM model includes treatment, visit, treatment-by-visit interaction as fixed effects and Screening hsCRP level and Baseline value as covariates.

    Secondary: Change From Baseline in Spondyloarthritis Research Consortium of Canada (SPARCC) Magnetic Resonance Imaging (MRI) Score for the Spine at Week 14

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    End point title
    Change From Baseline in Spondyloarthritis Research Consortium of Canada (SPARCC) Magnetic Resonance Imaging (MRI) Score for the Spine at Week 14
    End point description
    The entire spine was evaluated for active inflammation (bone marrow edema) and 6 discovertebral units (DVU) representing the most abnormal DVUs were selected to calculate the SPARCC MRI Spine score. For each of the 6 DVUs, 3 consecutive sagittal slices were assessed in 4 quadrants to evaluate the extent of inflammation in three dimensions. Each quadrant was scored for the presence (1) or absence (0) of edema. If edema was present in at least 1 quadrant of a DVU slice, it was also scored for intensity and depth of the edema representing that slice: An additional score of 1 was assigned if an intense signal was seen in any quadrant on a DVU slice. Slices that included a lesion demonstrating continuous increased signal of depth ≥ 1 cm extending from the endplate were scored as an additional 1 per slice. The maximum (worst) overall score for all 6 DVUs is 108. MRI data up to 3 days post first dose (for Baseline) and up to first dose of period 2 for Week 14 were included in the anlaysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 14
    End point values
    Placebo Upadacitinib 15 mg
    Number of subjects analysed
    60 [9]
    68 [10]
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -0.22 (-2.01 to 1.57)
    -6.93 (-8.58 to -5.28)
    Notes
    [9] - Full analysis set with available MRI data during pre-specified time window
    [10] - Full analysis set with available MRI data during pre-specified time window
    Statistical analysis title
    Analysis of Change in SPARCC MRI Spine Score
    Comparison groups
    Placebo v Upadacitinib 15 mg
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    < 0.001 [12]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -6.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.01
         upper limit
    -4.41
    Notes
    [11] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint.
    [12] - ANCOVA model including treatment and Screening hsCRP level as fixed factors and Baseline value as covariate.

    Secondary: Percentage of Participants With Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 Response at Week 14

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    End point title
    Percentage of Participants With Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 Response at Week 14
    End point description
    The BASDAI assesses disease activity by asking the participant to answer 6 questions (each on an 11 point numeric rating scale [NRS]) pertaining to symptoms experienced for the past week. For Questions 1 to 5 (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. A BASDAI 50 response is defined as improvement of 50% or more from Baseline in BASDAI score. Participants with missing data or who discontinued study drug prior to Week 14 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 14
    End point values
    Placebo Upadacitinib 15 mg
    Number of subjects analysed
    94 [13]
    93 [14]
    Units: percentage of participants
        number (confidence interval 95%)
    23.4 (14.8 to 32.0)
    45.2 (35.0 to 55.3)
    Notes
    [13] - Full analysis set
    [14] - Full analysis set
    Statistical analysis title
    Analyis of BASDAI 50 Response
    Comparison groups
    Placebo v Upadacitinib 15 mg
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    = 0.002 [16]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Response Rate Difference
    Point estimate
    21.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.5
         upper limit
    35
    Notes
    [15] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint. The testing sequence included a group of endpoints tested by the Hochberg procedure, including BASDAI 50; within the group, the allocated α was adjusted based on the magnitude of p values.
    [16] - Cochran-Mantel-Haenszel test adjusting for stratification factor of Screening hsCRP level.

    Secondary: Change From Baseline in Ankylosing Spondylitis Quality of Life (ASQoL) Score

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    End point title
    Change From Baseline in Ankylosing Spondylitis Quality of Life (ASQoL) Score
    End point description
    The ASQoL consists of 18 items related to quality of life, including the impact of pain on sleep, mood, motivation, ability to cope, activities of daily living, independence, relationships, and social life. Each item is answered as yes (scored as 1) or no (scored as 0). Scores are summed to obtain the overall score which ranges from 0 to 18, where higher scores indicate a worse quality of life. A negative change from Baseline in ASQoL indicates improvement in quality of life. A mixed effect model repeat measurement (MMRM) analysis with longitudinal data from observed cases up to Week 14 was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 14
    End point values
    Placebo Upadacitinib 15 mg
    Number of subjects analysed
    88 [17]
    88 [18]
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -2.67 (-3.58 to -1.75)
    -4.20 (-5.12 to -3.29)
    Notes
    [17] - Full analysis set; MMRM including all observed longitudinal data up to Week 14
    [18] - Full analysis set; MMRM including all observed longitudinal data up to Week 14
    Statistical analysis title
    Analysis of Change from Baseline in ASQoL Score
    Comparison groups
    Upadacitinib 15 mg v Placebo
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    = 0.16 [20]
    Method
    Mixed Effect Model Repeated Measurement
    Parameter type
    LS Mean Difference
    Point estimate
    -1.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.78
         upper limit
    -0.3
    Notes
    [19] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint. The testing sequence included a group of endpoints tested by the Hochberg procedure, including ASQoL; within the group, the allocated α was adjusted based on the magnitude of p values.
    [20] - MMRM model includes treatment, visit, treatment-by-visit interaction as fixed effects and Screening hsCRP level and Baseline value as covariates.

    Secondary: Percentage of Participants Achieving an Assessment of Spondyloarthritis International Society (ASAS) Partial Remission

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    End point title
    Percentage of Participants Achieving an Assessment of Spondyloarthritis International Society (ASAS) Partial Remission
    End point description
    ASAS partial remission (PR) is defined as an absolute score of ≤ 2 units on a 0 to 10 scale for each of the four following domains: 1) Patient's global assessment of disease activity, measured on a numeric rating scale (NRS) from 0 (no activity) to 10 (severe activity); 2) Pain, measured by the total back pain NRS from 0 (no pain) to 10 (most severe pain); 3) 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); 4) 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). Participants with missing data or who discontinued study drug prior to Week 14 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Week 14
    End point values
    Placebo Upadacitinib 15 mg
    Number of subjects analysed
    94 [21]
    93 [22]
    Units: percentage of participants
        number (confidence interval 95%)
    1.1 (0.0 to 3.1)
    19.4 (11.3 to 27.4)
    Notes
    [21] - Full analysis set
    [22] - Full analysis set
    Statistical analysis title
    Analysis of ASAS Partial Remission
    Comparison groups
    Placebo v Upadacitinib 15 mg
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    superiority [23]
    P-value
    < 0.001 [24]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Response Rate Difference
    Point estimate
    18.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    10
         upper limit
    26.6
    Notes
    [23] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint. The testing sequence included a group of endpoints tested by the Hochberg procedure, including ASAS PR; within the group, the allocated α was adjusted based on the magnitude of p values.
    [24] - Cochran-Mantel-Haenszel test adjusting for stratification factor of Screening hsCRP level.

    Secondary: Change From Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 14

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    End point title
    Change From Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 14
    End point description
    The Bath Ankylosing Spondylitis Functional Index is a validated index to determine the degree of functional limitation in patients with AS. BASFI consists of 10 questions assessing participants' ability to perform activities such as putting on socks, bending, reaching, getting up from the floor or an armless chair, standing, climbing and other physical activities. Each item is scored on a NRS ranging from 0 (easy to perform an activity) to 10 (impossible to perform an activity). The overall score is the mean of the 10 items and ranges from 0 to 10 with higher scores indicating more functional limitations. A negative change from Baseline in BASFI indicates improvement. A mixed effect model repeat measurement (MMRM) analysis with longitudinal data from observed cases up to Week 14 was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 14
    End point values
    Placebo Upadacitinib 15 mg
    Number of subjects analysed
    86 [25]
    86 [26]
    Units: score n a scale
        least squares mean (confidence interval 5%)
    -1.30 (-1.74 to -0.86)
    -2.29 (-2.73 to -1.85)
    Notes
    [25] - Full analysis set; MMRM including all observed longitudinal data up to Week 14
    [26] - Full analysis set; MMRM including all observed longitudinal data up to Week 14
    Statistical analysis title
    Analysis of Change from Baseline in BASFI
    Comparison groups
    Placebo v Upadacitinib 15 mg
    Number of subjects included in analysis
    172
    Analysis specification
    Post-hoc
    Analysis type
    superiority [27]
    P-value
    = 0.001 [28]
    Method
    Mixed Effect Model Repeated Measurement
    Parameter type
    LS Mean Difference
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    -0.39
    Notes
    [27] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint. The testing sequence included a group of endpoints tested by the Hochberg procedure, including BASFI; within the group, the allocated α was adjusted based on the magnitude of p values.
    [28] - MMRM model includes treatment, visit, treatment-by-visit interaction as fixed effects and Screening hsCRP level and Baseline value as covariates.

    Secondary: Change From Baseline in Linear Bath Ankylosing Spondylitis Metrology Index (BASMI[Lin]) at Week 14

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    End point title
    Change From Baseline in Linear Bath Ankylosing Spondylitis Metrology Index (BASMI[Lin]) at Week 14
    End point description
    The BASMI is a composite score based on 5 direct measurements of spinal mobility: 1) cervical rotation (measured in degrees), 2) tragus to wall distance (in centimeters [cm]), 3) lumbar side flexion (in cm), 4) lumbar flexion (modified Schober's) (in cm), and 5) intermalleolar distance (in cm). Each measurement is converted to a linear score between 0 and 10. The total BASMI score is the average of the 5 scores and ranges from 0 to 10; the higher the BASMI score the more severe the patient's limitation of movement due to their ankylosing spondylitis. A negative change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 14
    End point values
    Placebo Upadacitinib 15 mg
    Number of subjects analysed
    89 [29]
    89 [30]
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -0.14 (-0.29 to 0.01)
    -0.37 (-0.52 to -0.21)
    Notes
    [29] - Full analysis set participants with available data
    [30] - Full analysis set participants with available data
    Statistical analysis title
    Analysis of Change from Baseline in BASMI(lin)
    Comparison groups
    Placebo v Upadacitinib 15 mg
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    superiority [31]
    P-value
    = 0.03 [32]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.43
         upper limit
    -0.02
    Notes
    [31] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint. The testing sequence included a group of endpoints tested by the Hochberg procedure, including BASMI(lin); within the group, the allocated α was adjusted based on the magnitude of p values.
    [32] - ANCOVA model including treatment and Screening hsCRP level as fixed factors and Baseline value as covariate.

    Secondary: Change From Baseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) at Week 14

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    End point title
    Change From Baseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) at Week 14
    End point description
    The MASES evaluation was conducted to assess the presence or absence of enthesitis (inflammation of the entheses, or sites where tendons or ligaments insert into the bone) at 13 different sites (first costochondral joint left/right, seventh costochondral joint left/right, posterior superior iliac spine left/right, anterior superior iliac spine left/right, iliac crest left/right, fifth lumbar spinous process, and proximal insertion of Achilles tendon left/right. Each site was scored for presence (1) or absence (0) of enthesitis. The MASES is the sum of the 13 site scores, and ranges from 0 to 13, with higher scores indicating more inflammation of the entheses. A mixed effect model repeat measurement (MMRM) analysis with longitudinal data from observed cases up to Week 14 was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 14
    End point values
    Placebo Upadacitinib 15 mg
    Number of subjects analysed
    51 [33]
    50 [34]
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -1.41 (-2.02 to -0.80)
    -2.25 (-2.86 to -1.64)
    Notes
    [33] - Full analysis set participants with Baseline enthesitis; MMRM including all observed data to Week 14
    [34] - Full analysis set participants with Baseline enthesitis; MMRM including all observed data to Week 14
    Statistical analysis title
    Analysis of Change from Baseline in MASES
    Comparison groups
    Placebo v Upadacitinib 15 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    superiority [35]
    P-value
    = 0.049 [36]
    Method
    Mixed Effect Model Repeated Measurement
    Parameter type
    LS Mean Difference
    Point estimate
    -0.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.68
         upper limit
    0
    Notes
    [35] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint. The testing sequence included a group of endpoints tested by the Hochberg procedure, including MASES; within the group, the allocated α was adjusted based on the magnitude of p values.
    [36] - MMRM model includes treatment, visit, treatment-by-visit interaction as fixed effects and Screening hsCRP level and Baseline value as covariates.

    Secondary: Change From Baseline in Work Productivity and Activity Impairment (WPAI) Overall Work Impairment at Week 14

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    End point title
    Change From Baseline in Work Productivity and Activity Impairment (WPAI) Overall Work Impairment at Week 14
    End point description
    The Work Productivity and Activity Impairment Questionnaire: Axial Spondyloarthritis, Version 2.0 (WPAI-Axial Spondyloarthritis) measures the effect of overall health and specific symptoms on productivity at work and outside of work. It consists of 6 questions. Respondents were asked about time missed from work and time while at work during which productivity was impaired in the past seven days. Results of WPAI are expressed as a percentage of impairment from 0 to 100, with higher percentages indicating greater impairment and less productivity. Overall Work Impairment indicates the percentage of overall work impairment due to health problems. A negative change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 14
    End point values
    Placebo Upadacitinib 15 mg
    Number of subjects analysed
    53 [37]
    55 [38]
    Units: percent impairment
        least squares mean (confidence interval 95%)
    -12.60 (-19.04 to -6.15)
    -18.11 (-24.73 to -11.50)
    Notes
    [37] - Full analysis participants who were employed and with available data
    [38] - Full analysis participants who were employed and with available data
    Statistical analysis title
    Analysis of Change in WPAI Overall Work Impairment
    Comparison groups
    Placebo v Upadacitinib 15 mg
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    superiority [39]
    P-value
    = 0.19 [40]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -5.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.82
         upper limit
    2.78
    Notes
    [39] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint. The testing sequence included a group of endpoints tested by the Hochberg procedure, including WPAI; within the group, the allocated α was adjusted based on the magnitude of p values.
    [40] - ANCOVA model including treatment and Screening hsCRP level as fixed factors and Baseline value as covariate.

    Secondary: Change From Baseline in ASAS Health Index (HI) at Week 14

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    End point title
    Change From Baseline in ASAS Health Index (HI) at Week 14
    End point description
    The ASAS HI measures functioning and health across 17 aspects of health in patients with AS, including pain, emotional functions, sleep, sexual function, mobility, self care, and community life. Each of the 17 questions is answered by the participant as "I agree" (score = 1) or "I disagree" (score = 0). The responses to the 17 dichotomous items are summed up to give a total score ranging from 0 to 17, where a higher score indicates a worse health status. A negative change from Baseline indicates improvement. A mixed effect model repeat measurement (MMRM) analysis with longitudinal data from observed cases up to Week 14 was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 14
    End point values
    Placebo Upadacitinib 15 mg
    Number of subjects analysed
    88 [41]
    88 [42]
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -1.38 (-2.11 to -0.65)
    -2.75 (-3.48 to -2.02)
    Notes
    [41] - Full analysis set; MMRM including all observed longitudinal data up to Week 14
    [42] - Full analysis set; MMRM including all observed longitudinal data up to Week 14
    Statistical analysis title
    Analysis of Change from Baseline in ASAS HI
    Comparison groups
    Placebo v Upadacitinib 15 mg
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    other [43]
    P-value
    = 0.007 [44]
    Method
    Mixed Effect Model Repeated Measurement
    Parameter type
    LS Mean Difference
    Point estimate
    -1.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.37
         upper limit
    -0.37
    Notes
    [43] - To preserve the overall type I error rate at α=0.05 level, a step-down approach was used to test the primary and multiplicity-controlled key secondary endpoints. The testing began with the primary endpoint at α=0.05 and continued conditional on significance of higher-ranked endpoint. ASAS HI was to be evaluated only if the group of endpoints tested by Hochberg procedure were all significant.
    [44] - MMRM model includes treatment, visit, treatment-by-visit interaction as fixed effects and Screening hsCRP level and Baseline value as covariates.

    Secondary: Percentage of Participants Achieving an ASAS 20 Response at Week 14

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    End point title
    Percentage of Participants Achieving an ASAS 20 Response at Week 14
    End point description
    ASAS 20 response was defined as improvement of ≥ 20% and an absolute improvement of ≥ 1 unit from Baseline in ≥ 3 of the following 4 domains, with no deterioration (defined as a worsening of ≥ 20% and a net worsening of ≥ 1 units [on a scale of 0 to 10]) in the remaining domain: 1) Patient's global assessment of disease activity, measured on a NRS from 0 - 10 (severe activity); 2) Pain, measured by the total back pain NRS from 0 - 10 (most severe pain); 3) Function, measured by the BASFI, consisting of 10 items assessing participants' ability to perform activities each on an NRS from 0 (easy) - 10 (impossible); 4) Inflammation, measured by the mean of the 2 morning stiffness-related 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 duration). Participants with missing data or who discontinued study drug prior to Week 14 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 14
    End point values
    Placebo Upadacitinib 15 mg
    Number of subjects analysed
    94 [45]
    93 [46]
    Units: percentage of participants
        number (confidence interval 95%)
    40.4 (30.5 to 50.3)
    64.5 (54.8 to 74.2)
    Notes
    [45] - Full analysis set
    [46] - Full analysis set
    Statistical analysis title
    Analysis of ASAS 20 Response
    Comparison groups
    Placebo v Upadacitinib 15 mg
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    other [47]
    P-value
    = 0.001 [48]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Response Rate Difference
    Point estimate
    24.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    10.2
         upper limit
    38
    Notes
    [47] - This comparison was not part of the pre-specified multiplicity testing sequence.
    [48] - Cochran-Mantel-Haenszel test adjusting for stratification factor of Screening hsCRP level.

    Secondary: Change From Baseline in SPARCC MRI Score for Sacroiliac Joints at Week 14

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    End point title
    Change From Baseline in SPARCC MRI Score for Sacroiliac Joints at Week 14
    End point description
    In the SPARCC MRI assessment of the sacroiliac (SI) joints 6 consecutive sacroiliac joint image coronal slices representing the largest proportion of the synovial compartment of the SI joints were assessed for edema, intensity and depth of edema. Each SI joint (left and right) was divided into quadrants for a total of 8 SI scoring locations. Each quadrant was scored for the presence (1) or absence (0) of edema, intensity of edema (a score of 1 was assigned for each SI joint (left and right) if an intense signal was seen in any quadrant of that joint for each slice), and a lesion was graded as deep (score of 1) if there was homogeneous and unequivocal increase in signal extending over a depth of at least 1 cm from the articular surface of the SI joint in any quadrant. The total maximum score for all SI joints across 6 slices is 72. MRI data up to 3 days post first dose (for Baseline) and up to first dose of period 2 for Week 14 were included in the anlaysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 14
    End point values
    Placebo Upadacitinib 15 mg
    Number of subjects analysed
    59 [49]
    68 [50]
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -0.22 (-1.47 to 1.04)
    -3.91 (-5.05 to -2.77)
    Notes
    [49] - Full analysis set with available MRI data during pre-specified time window
    [50] - Full analysis set with available MRI data during pre-specified time window
    Statistical analysis title
    Analysis of Change in SPARCC MRI SI Joint Score
    Comparison groups
    Placebo v Upadacitinib 15 mg
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    superiority [51]
    P-value
    < 0.001 [52]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -3.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.31
         upper limit
    -2.08
    Notes
    [51] - This comparison was not part of the pre-specified multiplicity testing sequence.
    [52] - ANCOVA model including treatment and Screening hsCRP level as fixed factors and Baseline value as covariate.

    Post-hoc: Change From Baseline in SPARCC MRI Score for the Spine at Week 14 - Supplementary Analysis

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    End point title
    Change From Baseline in SPARCC MRI Score for the Spine at Week 14 - Supplementary Analysis
    End point description
    The entire spine was evaluated for active inflammation (bone marrow edema). Six DVUs representing the most abnormal DVUs were selected to calculate the SPARCC MRI spine score. For each DVU, 3 consecutive sagittal slices were assessed in 4 quadrants to evaluate the extent of inflammation in all dimensions. Each quadrant was scored for the presence (1) or absence (0) of edema. If edema was present in at least 1 quadrant of a DVU slice, it was also scored for intensity and depth of the edema representing that slice: An additional score of 1 was assigned if an intense signal was seen in any quadrant on a DVU slice. Slices that included a lesion demonstrating continuous increased signal of depth ≥ 1 cm extending from the endplate were scored as an additional 1 per slice. The maximum (worst) overall score for all 6 DVUs is 108. A supplemental post-hoc SPARCC MRI analysis included all MRI data collected at nominal visits at Baseline and Week 14.
    End point type
    Post-hoc
    End point timeframe
    Baseline and Week 14
    End point values
    Placebo Upadacitinib 15 mg
    Number of subjects analysed
    88 [53]
    89 [54]
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -0.65 (-2.20 to 0.90)
    -6.86 (-8.41 to -5.30)
    Notes
    [53] - Full analysis set participants with available MRI data at Baseline and Week 14
    [54] - Full analysis set participants with available MRI data at Baseline and Week 14
    Statistical analysis title
    Supplementary Analysis of SPARCC MRI Spine Score
    Comparison groups
    Placebo v Upadacitinib 15 mg
    Number of subjects included in analysis
    177
    Analysis specification
    Post-hoc
    Analysis type
    other
    P-value
    < 0.001 [55]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -6.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.27
         upper limit
    -4.14
    Notes
    [55] - ANCOVA model including treatment and Screening hsCRP level as fixed factors and Baseline value as covariate.

    Post-hoc: Change From Baseline in SPARCC MRI Score for Sacroiliac Joints at Week 14 - Supplementary Analysis

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    End point title
    Change From Baseline in SPARCC MRI Score for Sacroiliac Joints at Week 14 - Supplementary Analysis
    End point description
    In the SPARCC MRI assessment of the sacroiliac joints 6 consecutive sacroiliac joint image coronal slices representing the largest proportion of the synovial compartment of the SI joints were assessed for edema, intensity and depth of edema. Each SI joint (left and right) was divided into quadrants for a total of 8 SI scoring locations. Each quadrant was scored for the presence (1) or absence (0) of edema, intensity of edema (a score of 1 was assigned for each SI joint (left and right) if an intense signal was seen in any quadrant of that joint for each slice), and a lesion was graded as deep (score of 1) if there was homogeneous and unequivocal increase in signal extending over a depth of at least 1 cm from the articular surface of the SI joint in any quadrant. The total maximum score for all SI joints across 6 slices is 72. A supplemental post-hoc SPARCC MRI analysis was done to include all MRI data collected at nominal visits at Baseline and Week 14.
    End point type
    Post-hoc
    End point timeframe
    Baseline and Week 14
    End point values
    Placebo Upadacitinib 15 mg
    Number of subjects analysed
    87 [56]
    89 [57]
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -0.90 (-2.01 to 0.20)
    -3.45 (-4.54 to -2.36)
    Notes
    [56] - Full analysis set participants with available MRI data at Baseline and Week 14
    [57] - Full analysis set participants with available MRI data at Baseline and Week 14
    Statistical analysis title
    Supplmentary Analysis of SPARCC MRI SI Joint Score
    Comparison groups
    Placebo v Upadacitinib 15 mg
    Number of subjects included in analysis
    176
    Analysis specification
    Post-hoc
    Analysis type
    other
    P-value
    < 0.001 [58]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -2.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.01
         upper limit
    -1.08
    Notes
    [58] - ANCOVA model including treatment and Screening hsCRP level as fixed factors and Baseline value as covariate.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Period 1: From the first dose of study drug to Week 14. Period 1+2: Week 14 to 30 days after last dose (94 weeks) for subjects initially assigned to placebo; Week 1 to 30 days after last dose (108 weeks) for subjects initially assigned to upadacitinib.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Period 1: Placebo
    Reporting group description
    Participants received matching placebo orally once a day for 14 weeks in Period 1.

    Reporting group title
    Period 1: Upadacitinib 15 mg
    Reporting group description
    Participants received 15 mg upadacitinib orally once a day for 14 weeks in Period 1.

    Reporting group title
    Period 1+2: Upadacitinib 15 mg
    Reporting group description
    Participants originally assigned to placebo received upadacitinib 15 mg from Week 14 to Week 104. Participants originally assigned to upadacitinib received upadacitinib 15 mg from Week 0 to Week 104.

    Serious adverse events
    Period 1: Placebo Period 1: Upadacitinib 15 mg Period 1+2: Upadacitinib 15 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 93 (1.08%)
    16 / 182 (8.79%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 93 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    SQUAMOUS CELL CARCINOMA OF THE TONGUE
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 93 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    ANKLE FRACTURE
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 93 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FACIAL BONES FRACTURE
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 93 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MULTIPLE FRACTURES
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 93 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RADIUS FRACTURE
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 93 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    AORTIC DILATATION
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 93 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERTENSION
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 93 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERTENSIVE EMERGENCY
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 93 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    CARDIOVASCULAR DISORDER
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 93 (0.00%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    HEMIPARAESTHESIA
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 93 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 93 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    VERTIGO POSITIONAL
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 93 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    APPENDICITIS NONINFECTIVE
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 93 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 93 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    BENIGN PROSTATIC HYPERPLASIA
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 93 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    UTERINE PROLAPSE
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 93 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    PULMONARY EMBOLISM
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 93 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    BLISTER
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 93 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    OSTEOARTHRITIS
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 93 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERIARTHRITIS
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 93 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SPINAL OSTEOARTHRITIS
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Period 1: Placebo Period 1: Upadacitinib 15 mg Period 1+2: Upadacitinib 15 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 94 (22.34%)
    26 / 93 (27.96%)
    104 / 182 (57.14%)
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    2 / 94 (2.13%)
    5 / 93 (5.38%)
    13 / 182 (7.14%)
         occurrences all number
    2
    5
    14
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    2 / 94 (2.13%)
    8 / 93 (8.60%)
    29 / 182 (15.93%)
         occurrences all number
    2
    8
    35
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    2 / 94 (2.13%)
    5 / 93 (5.38%)
    15 / 182 (8.24%)
         occurrences all number
    2
    5
    16
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    5 / 94 (5.32%)
    5 / 93 (5.38%)
    13 / 182 (7.14%)
         occurrences all number
    5
    5
    14
    NAUSEA
         subjects affected / exposed
    5 / 94 (5.32%)
    1 / 93 (1.08%)
    6 / 182 (3.30%)
         occurrences all number
    5
    1
    6
    Musculoskeletal and connective tissue disorders
    ANKYLOSING SPONDYLITIS
         subjects affected / exposed
    4 / 94 (4.26%)
    0 / 93 (0.00%)
    13 / 182 (7.14%)
         occurrences all number
    4
    0
    20
    BACK PAIN
         subjects affected / exposed
    4 / 94 (4.26%)
    1 / 93 (1.08%)
    11 / 182 (6.04%)
         occurrences all number
    5
    1
    11
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    4 / 94 (4.26%)
    5 / 93 (5.38%)
    35 / 182 (19.23%)
         occurrences all number
    4
    6
    48
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    3 / 94 (3.19%)
    2 / 93 (2.15%)
    23 / 182 (12.64%)
         occurrences all number
    3
    2
    30

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Sep 2017
    ●Removed upadacitinib 30 mg QD dose from study plan. ●Updated Phase from 2b/3 to Phase 2/3. ●Clarified definition of inadequate response to NSAIDs required for enrollment. ●Updated number of sites from 120 to 107. ●Updated subject enrollment from 228 to 170. ●Modified Period 2 study design from blinded to open-label with only one dose (15 mg). ●Allowed earlier option of rescue therapy (Week 16 for concomitant pain medications and Week 20 for certain csDMARDs). ●Allowed earlier discontinuation of study drug, and assessment of ASAS 20 from Week 16. ●Updated results from other clinical trials in benefits and risks. ●Updated references to spondyloarthritis to specify axial manifestation. ●Removed statement on subject enrollment after target number reached. ●Updated tuberculosis testing and prophylaxis information. ●Updated schedule for subjects still participating in the study but discontinued study drug. ●Updated contraception requirements for females. ●Updated purpose and assessment of x-ray, MRI, and low-dose computed tomography. ●Updated requirements for local hsCRP testing. ●Updated Hepatitis B infection definition and testing requirements. ●Clarified the impact of corticosteroid injections on swollen joint and dactylitis assessments. ●Added embolic and thrombotic events to the Adverse Events (AE) of Special Interest and added a Supplemental CRF. ●Updated safety assessments to reference Common Terminology Criteria. ●Updated AE collection for subjects continuing in the study but discontinued study drug. ●Updated supplemental information to be collected for certain cardiovascular, herpes zoster, and thrombotic/embolic AEs. ●Updated SUSAR reporting reference. ●Updated pregnancy information to be collected. ●Updated toxicity management guidelines for serum creatinine and creatine phosphokinase and added gastrointestinal perforation. ●Updated the timeframe for product complaint reporting. ●Updated multiplicity control and statistical power.
    20 Dec 2019
    ● Added events of deep vein thrombosis (DVT) and pulmonary embolism (PE) to the adverse events that have been observed in subjects who receive JAK inhibitors, including upadacitinib. ● Added management of thrombosis events. ● Added management of herpes zoster and a recommendation for periodic skin examination for subjects who are at increased risk for skin cancer. ● Amended the wording for subjects who experience a study drug interruption > 7 consecutive days during Weeks 1 through 14 (Period 1) or > 30 consecutive days during Period 2 to allow the Investigator to decide if the drug should be re-started; previous wording required that upadacitinib be permanently discontinued if interruptions of those lengths occurred.

    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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