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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled Induction Study of the Efficacy and Safety of Upadacitinib (ABT-494) in Subjects with Moderately to Severely Active Crohn's Disease Who Have Inadequately Responded to or are Intolerant to Conventional and/or Biologic Therapies

    Summary
    EudraCT number
    2017-001240-35
    Trial protocol
    SK   SE   DE   AT   PT   BE   IE   GB   LV   HU   NL   PL   DK   LT   EE   ES   BG   HR   SI   FR   IT   RO  
    Global end of trial date
    13 Jan 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    M14-433
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03345849
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AbbVie Deutschland GmbH & Co. KG
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6 4UB
    Public contact
    Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    Global Medical Services, AbbVie, 001 8006339110, 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
    13 Jan 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jan 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of Study M14-433 was to evaluate the efficacy and safety of upadacitinib compared to placebo as induction therapy in subjects with moderately and severely active Crohn's disease (CD).
    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
    07 Dec 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
    Argentina: 6
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 3
    Country: Number of subjects enrolled
    Brazil: 5
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Canada: 53
    Country: Number of subjects enrolled
    Chile: 3
    Country: Number of subjects enrolled
    China: 66
    Country: Number of subjects enrolled
    Croatia: 5
    Country: Number of subjects enrolled
    Czechia: 5
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    Egypt: 27
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Japan: 23
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Latvia: 7
    Country: Number of subjects enrolled
    Lithuania: 2
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Portugal: 4
    Country: Number of subjects enrolled
    Puerto Rico: 2
    Country: Number of subjects enrolled
    Romania: 5
    Country: Number of subjects enrolled
    Russian Federation: 25
    Country: Number of subjects enrolled
    Serbia: 9
    Country: Number of subjects enrolled
    Slovakia: 2
    Country: Number of subjects enrolled
    South Africa: 20
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    Ukraine: 6
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    United States: 117
    Worldwide total number of subjects
    526
    EEA total number of subjects
    119
    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)
    506
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Eligible participants with moderately to severely active Crohn’s disease (CD) were randomized at 209 sites in 42 countries. The study consisted of a 12-week double-blind induction treatment period, and a 12-week extended treatment period for participants who did not achieve clinical response at the end of the induction treatment period.

    Pre-assignment
    Screening details
    In Part 1 participants were randomly assigned in a 2:1 ratio to receive upadacitinib 45 mg or placebo, with randomization stratified by Baseline corticosteroid use (yes or no), endoscopic disease severity (Simple Endoscopic Score for Crohn's disease [SES-CD] < 15 and ≥ 15), and the number of previously failed biologic therapies (0, 1, and >1).

    Period 1
    Period 1 title
    Induction Period (Baseline - Week 12)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants received placebo once daily for 12 weeks in Part 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
    Taken orally once a day for 12 weeks

    Arm title
    Upadacitinib 45 mg
    Arm description
    Participants received 45 mg upadacitinib once daily for 12 weeks in Part 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
    Taken orally once a day for 12 weeks

    Number of subjects in period 1
    Placebo Upadacitinib 45 mg
    Started
    176
    350
    Received Study Drug
    176
    350
    Completed
    154
    330
    Not completed
    22
    20
         Consent withdrawn by subject
    6
    3
         Adverse event, non-fatal
    8
    12
         Other
    -
    1
         Lost to follow-up
    -
    1
         Lack of efficacy
    8
    3
    Period 2
    Period 2 title
    Extended Treatment (Weeks 12-24)
    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 / Upadacitinib 45 mg
    Arm description
    Participants who received placebo during Part 1 and did not achieve clinical response at Week 12 received induction treatment with 45 mg upadacitinib once daily from Week 12 to Week 24.
    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
    Taken orally once a day for 12 weeks

    Arm title
    Upadacitinib 45 mg / Upadacitinib 30 mg
    Arm description
    Participants who received upadacitinib during Part 1 and did not achieve clinical response at Week 12 received 30 mg upadacitinib once daily from Week 12 to Week 24.
    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
    Taken orally once a day for 12 weeks

    Number of subjects in period 2 [1]
    Placebo / Upadacitinib 45 mg Upadacitinib 45 mg / Upadacitinib 30 mg
    Started
    57
    59
    Completed
    49
    49
    Not completed
    8
    10
         Consent withdrawn by subject
    3
    1
         Adverse event, non-fatal
    2
    2
         COVID-19 Logistical Restrictions
    1
    -
         Other
    1
    1
         Coronavirus Disease-2019 (COVID-19) Infection
    -
    1
         Lack of efficacy
    1
    5
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Participants who were clinical non-responders at the end of the induction period (Week 12) could enter Part 2.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo once daily for 12 weeks in Part 1.

    Reporting group title
    Upadacitinib 45 mg
    Reporting group description
    Participants received 45 mg upadacitinib once daily for 12 weeks in Part 1.

    Reporting group values
    Placebo Upadacitinib 45 mg Total
    Number of subjects
    176 350 526
    Age categorical
    Units: Subjects
        18 years - < 40 years
    91 193 284
        40 years - < 65 years
    80 142 222
        ≥ 65 years
    5 15 20
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    39.3 ± 13.63 39.7 ± 13.71 -
    Gender categorical
    Units: Subjects
        Female
    82 161 243
        Male
    94 189 283
    Race
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    36 73 109
        Black or African American
    4 17 21
        Native Hawaiian or other Pacific Islander
    0 0 0
        White
    130 258 388
        Multiple
    6 2 8
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    8 27 35
        Not Hispanic or Latino
    168 323 491
    Baseline Corticosteroid Use
    Units: Subjects
        Yes
    64 126 190
        No
    112 224 336
    Number of Previously Failed Biologics
    Zero previously failed biologics includes those who never used biologics previously, and/or who have used and stopped due to reasons other than inadequate response and/or intolerance. Failed treatment includes an inadequate response or intolerance to treatment.
    Units: Subjects
        Zero
    98 189 287
        One
    28 58 86
        More than one
    50 103 153
    Endoscopic Disease Severity
    Endoscopic disease severity was scored using the Simplified Endoscopic Score for Crohn's Disease (SES-CD). The SES-CD evaluates 4 endoscopic variables (ulcer size, ulcerated surface, affected surface, and narrowing, each on a scale from 0 (none) to 3 (worst) in 5 segments assessed during ileocolonoscopy (ileum, right colon, transverse colon, sigmoid and left colon, and rectum). The total score is the sum of the 4 endoscopic variable scores and ranges from 0 to 56, where higher scores indicate more severe disease.
    Units: Subjects
        SES-CD < 15
    110 218 328
        SES-CD ≥ 15
    66 132 198
    Duration of Crohn's Disease
    Units: years
        arithmetic mean (standard deviation)
    8.1005 ± 7.9901 9.2993 ± 9.4684 -
    Crohn's Disease Activity Index (CDAI) Score
    The Crohn's Disease Activity Index (CDAI) is a composite instrument that includes participant symptoms evaluated over 7 days (abdominal pain, stool frequency and general well-being), as well as physical and laboratory findings. These items are scored individually, weighted, and do not contribute equally to the overall score. The CDAI is derived from summing up the weighted individual scores of eight items. CDAI approximately ranges from 0 to 600 with higher scores indicating more severe disease. Data were available for 176 subjects in the Placebo arm and 349 subjects in the Upadacitinib arm.
    Units: score on a scale
        arithmetic mean (standard deviation)
    293.85 ± 85.378 292.42 ± 81.250 -
    Average Daily Abdominal Pain Score
    Participants were asked to rate their abdominal pain on a daily basis in an electronic diary using the following scale: 0 = none, 1 = mild, 2 = moderate, 3 = severe. The average daily abdominal pain score was calculated using the 4-7 most recent useable days of patient-report outcomes (i.e., excluding days with missing entries or associated with endoscopy procedures) out of the last 14 days prior to the Baseline visit.
    Units: score on a scale
        arithmetic mean (standard deviation)
    1.9064 ± 0.6942 1.8917 ± 0.6795 -
    Average Daily Very Soft or Liquid Stool Frequency
    Participants were asked to record the number of very soft or liquid stools on a daily basis in an electronic diary. The average daily very soft or liquid stool frequency was calculated using the 4-7 most recent useable days of patient-report outcomes (i.e., excluding days with missing entries or associated with endoscopy procedures) out of the last 14 days prior to the Baseline visit.
    Units: stools/day
        arithmetic mean (standard deviation)
    5.0857 ± 2.8366 5.1864 ± 2.6130 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo once daily for 12 weeks in Part 1.

    Reporting group title
    Upadacitinib 45 mg
    Reporting group description
    Participants received 45 mg upadacitinib once daily for 12 weeks in Part 1.
    Reporting group title
    Placebo / Upadacitinib 45 mg
    Reporting group description
    Participants who received placebo during Part 1 and did not achieve clinical response at Week 12 received induction treatment with 45 mg upadacitinib once daily from Week 12 to Week 24.

    Reporting group title
    Upadacitinib 45 mg / Upadacitinib 30 mg
    Reporting group description
    Participants who received upadacitinib during Part 1 and did not achieve clinical response at Week 12 received 30 mg upadacitinib once daily from Week 12 to Week 24.

    Primary: Percentage of Participants With Clinical Remission Per Patient-Reported Outcomes (PROs) at Week 12

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    End point title
    Percentage of Participants With Clinical Remission Per Patient-Reported Outcomes (PROs) at Week 12
    End point description
    The co-primary endpoint for European Union (EU)/European Medicines Agency (EMA) regulatory purposes was clinical remission based on two patient reported outcomes, average daily SF and average daily APS. Clinical remission per PROs was defined as average daily very soft or liquid SF ≤ 2.8 and average daily APS ≤ 1.0 and neither worse than Baseline. Participants recorded APS and very soft or liquid SF daily in an electronic diary. Abdominal pain was rated on a scale from 0 (none) to 3 (severe). The average daily very soft or liquid SF and APS were calculated using the 4-7 most recent useable days of patient-report outcomes (i.e., excluding days with missing entries or associated with endoscopy procedures) out of the last 14 days prior to the Week 12 visit. Participants with missing data or who withdrew prior to Week 12 were counted as non-responders (non-responder imputation); missing data due to COVID-19 infection or logistical restriction were handled by multiple imputation.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    Placebo Upadacitinib 45 mg
    Number of subjects analysed
    176 [1]
    350 [2]
    Units: percentage of participants
        number (confidence interval 95%)
    22.2 (16.0 to 28.3)
    50.7 (45.5 to 56.0)
    Notes
    [1] - Intention-to-treat (ITT) population includes all randomized subjects who received at least one dose
    [2] - Intention-to-treat population
    Statistical analysis title
    Treatment Difference
    Comparison groups
    Upadacitinib 45 mg v Placebo
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    < 0.0001 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Response Rate Difference
    Point estimate
    28.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    20.9
         upper limit
    36.4
    Notes
    [3] - The overall type I error rate of the co-primary and key secondary endpoints were strongly controlled using a fixed sequence multiple-testing procedure as well as a Holm procedure. The testing utilized the sequence of hypothesis testing for the co-primary endpoints using two-sided α of 0.05 followed by a set of key secondary endpoints, defined separately for United States (US)/Food and Drug Administration (FDA) and EU/EMA regulatory purposes.
    [4] - Cochran Mantel-Haenszel (CMH) test adjusting for stratification factors (baseline steroid use [Yes, No], endoscopic disease severity [SES-CD < 15, ≥ 15] and number of prior biologics with prior inadequate response or intolerance [0, 1, > 1]).

    Primary: Percentage of Participants With Clinical Remission Per Crohn's Disease Activity Index (CDAI) at Week 12

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    End point title
    Percentage of Participants With Clinical Remission Per Crohn's Disease Activity Index (CDAI) at Week 12
    End point description
    The co-primary endpoint for United States (US)/Food and Drug Administration (FDA) regulatory purposes was clinical remission based on CDAI at Week 12. CDAI is a composite instrument that includes participant symptoms evaluated over 7 days (abdominal pain, stool frequency and general well-being), as well as presence of complications (arthritis/arthralgia, iritis/uveitis, erythema nodosum/pyoderma gangrenosum/aphthous stomatitis, anal fissure/fistula/abscess, other fistula, and fever), the use of antidiarrheal medicines, presence of an abdominal mass, hematocrit, and body weight. The CDAI is derived from summing up the weighted individual scores of eight items and ranges approximately from 0 to 600 with higher scores indicating more severe disease. Clinical remission is defined as a CDAI score less than 150. Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 infection or logistical restriction was used in the analysis.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    Placebo Upadacitinib 45 mg
    Number of subjects analysed
    176 [5]
    350 [6]
    Units: percentage of participats
        number (confidence interval 95%)
    29.1 (22.4 to 35.8)
    49.5 (44.2 to 54.8)
    Notes
    [5] - Intention-to-treat population
    [6] - Intention-to-treat population
    Statistical analysis title
    Treatment Difference
    Comparison groups
    Placebo v Upadacitinib 45 mg
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    < 0.0001 [8]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Response Rate Difference
    Point estimate
    20.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    12.7
         upper limit
    28.8
    Notes
    [7] - The overall type I error rate of the co-primary and key secondary endpoints were strongly controlled using a fixed sequence multiple-testing procedure as well as a Holm procedure. The testing utilized the sequence of hypothesis testing for the co-primary endpoints using two-sided α of 0.05 followed by a set of key secondary endpoints, defined separately for US/FDA and EU/EMA regulatory purposes.
    [8] - Cochran Mantel-Haenszel test adjusting for stratification factors (baseline steroid use [Yes, No], endoscopic disease severity [SES-CD < 15, ≥ 15] and number of prior biologics with prior inadequate response or intolerance [0, 1, > 1]).

    Primary: Percentage of Participants With Endoscopic Response at Week 12

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    End point title
    Percentage of Participants With Endoscopic Response at Week 12
    End point description
    Endoscopic response at Week 12 was a co-primary endpoint for both the US/FDA and EU/EMA regulatory purposes. Endoscopic response was defined as greater than 50% decrease in Simple Endoscopic Score for Crohn's Disease (SES-CD) from Baseline of the induction study (or for participants with an SES-CD of 4 at Baseline, at least a 2-point reduction from Baseline), as scored by independent external and blinded central readers. The SES-CD evaluates 4 endoscopic variables (ulcer size, ulcerated surface, affected surface, and narrowing, each on a scale from 0 (none) to 3 in 5 segments assessed during ileocolonoscopy (ileum, right colon, transverse colon, sigmoid and left colon, and rectum). The total score is the sum of the 4 endoscopic variable scores and ranges from 0 to 56, where higher scores indicate more severe disease. Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 infection or logistical restriction was used in the analysis.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    End point values
    Placebo Upadacitinib 45 mg
    Number of subjects analysed
    176 [9]
    350 [10]
    Units: percentage of participants
        number (confidence interval 95%)
    13.1 (8.1 to 18.0)
    45.5 (40.3 to 50.8)
    Notes
    [9] - Intention-to-treat population
    [10] - Intention-to-treat population
    Statistical analysis title
    Treatment Difference
    Comparison groups
    Placebo v Upadacitinib 45 mg
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    < 0.0001 [12]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Response Rate Difference
    Point estimate
    33.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    26.2
         upper limit
    39.9
    Notes
    [11] - The overall type I error rate of the co-primary and key secondary endpoints were strongly controlled using a fixed sequence multiple-testing procedure as well as a Holm procedure. The testing utilized the sequence of hypothesis testing for the co-primary endpoints using two-sided α of 0.05 followed by a set of key secondary endpoints, defined separately for US/FDA and EU/EMA regulatory purposes.
    [12] - Cochran Mantel-Haenszel test adjusting for stratification factors (baseline steroid use [Yes, No], endoscopic disease severity [SES-CD < 15, ≥ 15] and number of prior biologics with prior inadequate response or intolerance [0, 1, > 1]).

    Secondary: Percentage of Participants With Clinical Remission Per PROs at Week 4

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    End point title
    Percentage of Participants With Clinical Remission Per PROs at Week 4
    End point description
    Clinical remission per PROs was defined as average daily very soft or liquid SF ≤ 2.8 and average daily APS ≤ 1.0 and neither worse than Baseline. Participants recorded APS and very soft or liquid SF daily in an electronic diary. Abdominal pain was rated on a scale from 0 (none) to 3 (severe). The average daily very soft or liquid SF and APS were calculated using the 4-7 most recent useable days of patient-reported outcomes (i.e., excluding days with missing entries or associated with endoscopy procedures) out of the last 14 days prior to the Week 4 visit. Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 infection or logistical restriction was used in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    Placebo Upadacitinib 45 mg
    Number of subjects analysed
    176 [13]
    350 [14]
    Units: percentage of participants
        number (confidence interval 95%)
    14.8 (9.5 to 20.0)
    35.7 (30.7 to 40.7)
    Notes
    [13] - Intention-to-treat population
    [14] - Intention-to-treat population
    Statistical analysis title
    Treatment Difference
    Comparison groups
    Placebo v Upadacitinib 45 mg
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    < 0.0001 [16]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Response Rate Difference
    Point estimate
    21.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    14.3
         upper limit
    28.2
    Notes
    [15] - The overall type I error rate of the co-primary and key secondary endpoints were strongly controlled using a fixed sequence multiple-testing procedure as well as a Holm procedure. The testing utilized the sequence of hypothesis testing for the co-primary endpoints using two-sided α of 0.05 followed by a set of key secondary endpoints. This endpoint was a key secondary endpoint for EU/EMA regulatory purposes.
    [16] - Cochran Mantel-Haenszel test adjusted for stratification factors.

    Secondary: Percentage of Participants With Endoscopic Remission at Week 12

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    End point title
    Percentage of Participants With Endoscopic Remission at Week 12
    End point description
    Endoscopic remission is defined as an SES-CD ≤ 4 and at least 2 point reduction from Baseline and no subscore > 1 in any individual variable,as scored by independent external and blinded central readers. The SES-CD evaluates 4 endoscopic variables (ulcer size, ulcerated surface, affected surface, and narrowing, each on a scale from 0 (none) to 3 in 5 segments assessed during ileocolonoscopy (ileum, right colon, transverse colon, sigmoid and left colon, and rectum). The total score is the sum of the 4 endoscopic variable scores and ranges from 0 to 56, where higher scores indicate more severe disease. Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 infection or logistical restriction was used in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    Placebo Upadacitinib 45 mg
    Number of subjects analysed
    176 [17]
    350 [18]
    Units: percentage of participants
        number (confidence interval 95%)
    7.4 (3.5 to 11.3)
    28.9 (24.2 to 33.7)
    Notes
    [17] - Intention-to-treat population
    [18] - Intention-to-treat population
    Statistical analysis title
    Treatment Difference
    Comparison groups
    Upadacitinib 45 mg v Placebo
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    < 0.0001 [20]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Response Rate Difference
    Point estimate
    21.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    15.8
         upper limit
    27.8
    Notes
    [19] - The overall type I error rate of the co-primary and key secondary endpoints were strongly controlled using a fixed sequence multiple-testing procedure as well as a Holm procedure. The testing utilized the sequence of hypothesis testing for the co-primary endpoints using two-sided α of 0.05 followed by a set of key secondary endpoints, defined separately for US/FDA and EU/EMA regulatory purposes.
    [20] - Cochran Mantel-Haenszel test adjusted for stratification factors.

    Secondary: Percentage of Participants Who Discontinued Corticosteroid Use for Crohn's Disease and Achieved Clinical Remission Per PROs at Week 12

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    End point title
    Percentage of Participants Who Discontinued Corticosteroid Use for Crohn's Disease and Achieved Clinical Remission Per PROs at Week 12
    End point description
    Corticosteroid-free clinical remission is defined as participants who discontinued corticosteroid use for CD and achieved clinical remission per PROs at Week 12, assessed for participants taking corticosteroids for CD at Baseline. Clinical remission per PROs was defined as average daily very soft or liquid stool frequency (SF) ≤ 2.8 and average daily APS ≤ 1.0 and neither worse than Baseline. Participants recorded APS and liquid or very soft SF daily in an electronic diary. Abdominal pain was rated on a scale from 0 (none) to 3 (severe). The average daily liquid or very soft SF and APS were calculated using the 4-7 most recent useable days of patient-reported outcomes (i.e., excluding days with missing entries or associated with endoscopy procedures) out of the last 14 days prior to the Week 12 visit. Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 infection or logistical restriction was used in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo Upadacitinib 45 mg
    Number of subjects analysed
    64 [21]
    126 [22]
    Units: percentage of participants
        number (confidence interval 95%)
    12.5 (4.4 to 20.6)
    44.4 (35.8 to 53.1)
    Notes
    [21] - Intention-to-treat population; subjects taking corticosteroids for Crohn's disease at Baseline.
    [22] - Intention-to-treat population; subjects taking corticosteroids for Crohn's disease at Baseline.
    Statistical analysis title
    Treatment Difference
    Comparison groups
    Placebo v Upadacitinib 45 mg
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    superiority [23]
    P-value
    < 0.0001 [24]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Response Rate Difference
    Point estimate
    32.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    21.5
         upper limit
    43.7
    Notes
    [23] - The overall type I error rate of the co-primary and key secondary endpoints were strongly controlled using a fixed sequence multiple-testing procedure as well as a Holm procedure. The testing utilized the sequence of hypothesis testing for the co-primary endpoints using two-sided α of 0.05 followed by a set of key secondary endpoints. This endpoint was a key secondary endpoint for EU/EMA regulatory purposes.
    [24] - Cochran Mantel-Haenszel test adjusted for stratification factors.

    Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) at Week 12

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    End point title
    Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) at Week 12
    End point description
    The FACIT-Fatigue questionnaire is a self-administered patient questionnaire that consists of 13 questions designed to measure the degree of fatigue experienced by participants in the previous 7 days, including physical fatigue (e.g., I feel tired), functional fatigue (e.g., trouble finishing things), emotional fatigue (e.g., frustration), and social consequences of fatigue (e.g., limits social activity). Participants respond to the questions on a scale from 0 (not at all) to 4 (very much). The FACIT-Fatigue score is computed by summing the item scores, after reversing those items that are worded in the negative direction. The FACIT-Fatigue score ranges from 0 to 52, where higher scores represent less fatigue. A positive change from Baseline indicates improvement. Missing data were handled using a mixed-effect model with repeated measurements (MMRM).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    Placebo Upadacitinib 45 mg
    Number of subjects analysed
    133 [25]
    304 [26]
    Units: score on a scale
        least squares mean (confidence interval 95%)
    5.0 (3.2 to 6.8)
    11.3 (10.0 to 12.5)
    Notes
    [25] - Intention-to-treat population; subjects with non-missing Baseline and Week 12 values.
    [26] - Intention-to-treat population; subjects with non-missing Baseline and Week 12 values.
    Statistical analysis title
    Treatment Difference
    Comparison groups
    Placebo v Upadacitinib 45 mg
    Number of subjects included in analysis
    437
    Analysis specification
    Pre-specified
    Analysis type
    superiority [27]
    P-value
    < 0.0001 [28]
    Method
    Mixed-effect Model Repeated Measurement
    Parameter type
    Least Squares (LS) Mean Difference
    Point estimate
    6.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.2
         upper limit
    8.3
    Notes
    [27] - The overall type I error rate of the co-primary and key secondary endpoints were strongly controlled using a fixed sequence multiple-testing procedure as well as a Holm procedure. The testing utilized the sequence of hypothesis testing for the co-primary endpoints using two-sided α of 0.05 followed by a set of key secondary endpoints, defined separately for US/FDA and EU/EMA regulatory purposes.
    [28] - MMRM model with fixed effects of treatment, visit, and treatment-by-visit interaction, stratification factors, and Baseline value as covariate.

    Secondary: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 12

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    End point title
    Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 12
    End point description
    The Inflammatory Bowel Disease Questionnaire (IBDQ) is used to assess health-related quality of life (HRQoL) in patients with inflammatory bowel disease. It consists of 32 questions evaluating bowel and systemic symptoms, as well as emotional and social functions. Each question is answered on a scale from 1 (worst) to 7 (best). The total score ranges from 32 to 224 with higher scores indicating better health-related quality of life. A positive change from Baseline indicates improvement. Missing data were handled using a mixed-effect model with repeated measurements (MMRM).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    Placebo Upadacitinib 45 mg
    Number of subjects analysed
    134 [29]
    304 [30]
    Units: score on a scale
        least squares mean (confidence interval 95%)
    24.423 (19.007 to 29.840)
    46.265 (42.495 to 50.035)
    Notes
    [29] - Intention-to-treat population; participants with non-missing Baseline and Week 12 values.
    [30] - Intention-to-treat population; participants with non-missing Baseline and Week 12 values.
    Statistical analysis title
    Treatment Difference
    Comparison groups
    Placebo v Upadacitinib 45 mg
    Number of subjects included in analysis
    438
    Analysis specification
    Pre-specified
    Analysis type
    superiority [31]
    P-value
    < 0.0001 [32]
    Method
    Mixed-effect Model Repeated Measurement
    Parameter type
    LS Mean Difference
    Point estimate
    21.842
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    15.566
         upper limit
    28.118
    Notes
    [31] - The overall type I error rate of the co-primary and key secondary endpoints were strongly controlled using a fixed sequence multiple-testing procedure as well as a Holm procedure. The testing utilized the sequence of hypothesis testing for the co-primary endpoints using two-sided α of 0.05 followed by a set of key secondary endpoints, defined separately for US/FDA and EU/EMA regulatory purposes.
    [32] - MMRM model with fixed effects of treatment, visit, and treatment-by-visit interaction, stratification factors, and Baseline value as covariate.

    Secondary: Percentage of Participants Achieving Clinical Response 100 (CR-100) at Week 2

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    End point title
    Percentage of Participants Achieving Clinical Response 100 (CR-100) at Week 2
    End point description
    Clinical response 100 (CR-100) is defined as a decrease of at least 100 points in CDAI from Baseline. CDAI is a composite instrument that includes participant symptoms evaluated over 7 days (abdominal pain, stool frequency and general well-being), as well as presence of complications (arthritis/arthralgia, iritis/uveitis, erythema nodosum/pyoderma gangrenosum/aphthous stomatitis, anal fissure/fistula/abscess, other fistula, and fever), the use of antidiarrheal medicines, presence of an abdominal mass, hematocrit, and body weight. The CDAI is derived from summing up the weighted individual scores of eight items and ranges approximately from 0 to 600 with higher scores indicating more severe disease. Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 infection or logistical restriction was used in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 2
    End point values
    Placebo Upadacitinib 45 mg
    Number of subjects analysed
    176 [33]
    350 [34]
    Units: percentage of participants
        number (confidence interval 95%)
    20.4 (14.4 to 26.5)
    32.2 (27.3 to 37.1)
    Notes
    [33] - Intention-to-treat population
    [34] - Intention-to-treat population
    Statistical analysis title
    Treatment Difference
    Comparison groups
    Upadacitinib 45 mg v Placebo
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    superiority [35]
    P-value
    = 0.0022 [36]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Response Rate Difference
    Point estimate
    11.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.2
         upper limit
    19.2
    Notes
    [35] - The overall type I error rate of the co-primary and key secondary endpoints were strongly controlled using a fixed sequence multiple-testing procedure as well as a Holm procedure. The testing utilized the sequence of hypothesis testing for the co-primary endpoints using two-sided α of 0.05 followed by a set of key secondary endpoints, defined separately for US/FDA and EU/EMA regulatory purposes.
    [36] - Cochran Mantel-Haenszel test adjusted for stratification factors.

    Secondary: Percentage of Participants Achieving Clinical Response 100 (CR-100) at Week 12

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    End point title
    Percentage of Participants Achieving Clinical Response 100 (CR-100) at Week 12
    End point description
    Clinical response 100 (CR-100) is defined as a decrease of at least 100 points in CDAI from Baseline. CDAI is a composite instrument that includes participant symptoms evaluated over 7 days (abdominal pain, stool frequency and general well-being), as well as presence of complications (arthritis/arthralgia, iritis/uveitis, erythema nodosum/pyoderma gangrenosum/aphthous stomatitis, anal fissure/fistula/abscess, other fistula, and fever), the use of antidiarrheal medicines, presence of an abdominal mass, hematocrit, and body weight. The CDAI is derived from summing up the weighted individual scores of eight items and ranges approximately from 0 to 600 with higher scores indicating more severe disease. Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 infection or logistical restriction was used in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    Placebo Upadacitinib 45 mg
    Number of subjects analysed
    176 [37]
    350 [38]
    Units: percentage of participants
        number (confidence interval 95%)
    37.3 (30.1 to 44.5)
    56.6 (51.4 to 61.8)
    Notes
    [37] - Intention-to-treat population
    [38] - Intention-to-treat population
    Statistical analysis title
    Treatment Difference
    Comparison groups
    Placebo v Upadacitinib 45 mg
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    superiority [39]
    P-value
    < 0.0001 [40]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Response Rate Difference
    Point estimate
    19.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.3
         upper limit
    28.4
    Notes
    [39] - The overall type I error rate of the co-primary and key secondary endpoints were strongly controlled using a fixed sequence multiple-testing procedure as well as a Holm procedure. The testing utilized the sequence of hypothesis testing for the co-primary endpoints using two-sided α of 0.05 followed by a set of key secondary endpoints, defined separately for US/FDA and EU/EMA regulatory purposes.
    [40] - Cochran Mantel-Haenszel test adjusted for stratification factors.

    Secondary: Percentage of Participants With Hospitalizations Due to Crohn's Disease (CD) During the 12-Week Induction Period

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    End point title
    Percentage of Participants With Hospitalizations Due to Crohn's Disease (CD) During the 12-Week Induction Period
    End point description
    This was assessed by reviewing participant's hospitalization data.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    Placebo Upadacitinib 45 mg
    Number of subjects analysed
    176 [41]
    350 [42]
    Units: percentage of participants
        number (confidence interval 95%)
    5.1 (1.9 to 8.4)
    3.7 (1.7 to 5.7)
    Notes
    [41] - Intention-to-treat population
    [42] - Intention-to-treat population
    Statistical analysis title
    Treatment Difference
    Comparison groups
    Placebo v Upadacitinib 45 mg
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    superiority [43]
    P-value
    = 0.4494
    Method
    Chi-squared
    Parameter type
    Response Rate Difference
    Point estimate
    -1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.2
         upper limit
    2.4
    Notes
    [43] - The overall type I error rate of the co-primary and key secondary endpoints were strongly controlled using a fixed sequence multiple-testing procedure as well as a Holm procedure. The testing utilized the sequence of hypothesis testing for the co-primary endpoints using two-sided α of 0.05 followed by a set of key secondary endpoints, defined separately for US/FDA and EU/EMA regulatory purposes.

    Secondary: Percentage of Participants With Resolution of Extra-Intestinal Manifestation (EIMs) at Week 12

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    End point title
    Percentage of Participants With Resolution of Extra-Intestinal Manifestation (EIMs) at Week 12
    End point description
    EIMs are defined as manifestations of Crohn's disease in areas of the body other than the digestive tract, including eyes, skin, joints, mouth, and liver. Only participants with any EIM present at Baseline were included in the analysis of resolution of EIMs. Resolution of EIMs was defined as absence of all EIMs at the Week 12 visit.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo Upadacitinib 45 mg
    Number of subjects analysed
    78 [44]
    151 [45]
    Units: percentage of participants
        number (confidence interval 95%)
    20.9 (11.8 to 30.1)
    28.5 (21.3 to 35.7)
    Notes
    [44] - Intention-to-treat population; participants with any EIM at Baseline
    [45] - Intention-to-treat population; participants with any EIM at Baseline
    Statistical analysis title
    Treatment Difference
    Comparison groups
    Placebo v Upadacitinib 45 mg
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    superiority [46]
    P-value
    = 0.1044 [47]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Response Rate Difference
    Point estimate
    9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.9
         upper limit
    19.9
    Notes
    [46] - The overall type I error rate of the co-primary and key secondary endpoints were strongly controlled using a fixed sequence multiple-testing procedure as well as a Holm procedure. The testing utilized the sequence of hypothesis testing for the co-primary endpoints using two-sided α of 0.05 followed by a set of key secondary endpoints, defined separately for US/FDA and EU/EMA regulatory purposes.
    [47] - Cochran Mantel-Haenszel test adjusted for stratification factors.

    Secondary: Percentage of Participants Who Discontinued Corticosteroid Use for Crohn's Disease and Achieved Clinical Remission Per CDAI at Week 12

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    End point title
    Percentage of Participants Who Discontinued Corticosteroid Use for Crohn's Disease and Achieved Clinical Remission Per CDAI at Week 12
    End point description
    Corticosteroid-free clinical remission is defined as participants who discontinued corticosteroid use for CD and achieved clinical remission per CDAI, assessed in participants taking corticosteroids for CD at Baseline. Clinical remission is defined as CDAI score < 150. Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 infection or logistical restriction was used in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo Upadacitinib 45 mg
    Number of subjects analysed
    64 [48]
    126 [49]
    Units: percentage of participants
        number (confidence interval 95%)
    15.7 (6.8 to 24.7)
    42.9 (34.2 to 51.5)
    Notes
    [48] - Intention-to-treat population; subjects taking corticosteroids for Crohn's disease at Baseline
    [49] - Intention-to-treat population; subjects taking corticosteroids for Crohn's disease at Baseline
    Statistical analysis title
    Treatment Difference
    Comparison groups
    Placebo v Upadacitinib 45 mg
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    superiority [50]
    P-value
    < 0.0001 [51]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Response Rate Difference
    Point estimate
    27.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    15.7
         upper limit
    39.8
    Notes
    [50] - The overall type I error rate of the co-primary and key secondary endpoints were strongly controlled using a fixed sequence multiple-testing procedure as well as a Holm procedure. The testing utilized the sequence of hypothesis testing for the co-primary endpoints using two-sided α of 0.05 followed by a set of key secondary endpoints. This endpoint was a key secondary endpoint for US/FDA regulatory purposes.
    [51] - Cochran Mantel-Haenszel test adjusted for stratification factors.

    Secondary: Percentage of Participants With Clinical Remission Per CDAI at Week 4

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    End point title
    Percentage of Participants With Clinical Remission Per CDAI at Week 4
    End point description
    CDAI is a composite instrument that includes participant symptoms evaluated over 7 days (abdominal pain, stool frequency and general well-being), as well as presence of complications (arthritis/arthralgia, iritis/uveitis, erythema nodosum/pyoderma gangrenosum/aphthous stomatitis, anal fissure/fistula/abscess, other fistula, and fever), the use of antidiarrheal medicines, presence of an abdominal mass, hematocrit, and body weight. The CDAI is derived from summing up the weighted individual scores of eight items and ranges from approximately 0 to 600 with higher scores indicating more severe disease. Clinical remission is defined as CDAI score less than 150. Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 infection or logistical restriction was used in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    Placebo Upadacitinib 45 mg
    Number of subjects analysed
    176 [52]
    350 [53]
    Units: percentage of participants
        number (confidence interval 95%)
    26.7 (20.2 to 33.3)
    37.1 (32.1 to 42.2)
    Notes
    [52] - Intention-to-treat population
    [53] - Intention-to-treat population
    Statistical analysis title
    Treatment Difference
    Comparison groups
    Placebo v Upadacitinib 45 mg
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    superiority [54]
    P-value
    = 0.0071 [55]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Response Rate Difference
    Point estimate
    10.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.9
         upper limit
    18.6
    Notes
    [54] - The overall type I error rate of the co-primary and key secondary endpoints were strongly controlled using a fixed sequence multiple-testing procedure as well as a Holm procedure. The testing utilized the sequence of hypothesis testing for the co-primary endpoints using two-sided α of 0.05 followed by a set of key secondary endpoints. This endpoint was a key secondary endpoint for US/FDA regulatory purposes.
    [55] - Cochran Mantel-Haenszel test adjusted for stratification factors.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Part 1: 12 weeks; Part 2: 12 weeks
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Part 1: Placebo
    Reporting group description
    Participants received placebo once daily for 12 weeks in Part 1.

    Reporting group title
    Part 1: Upadacitinib 45 mg
    Reporting group description
    Participants received 45 mg upadacitinib once daily for 12 weeks in Part 1.

    Reporting group title
    Part 2: Placebo / Upadacitinib 45 mg
    Reporting group description
    Participants who received placebo during Part 1 and did not achieve clinical response at Week 12 received induction treatment with 45 mg upadacitinib once daily from Week 12 to Week 24.

    Reporting group title
    Part 2: Upadacitinib 45 mg / Upadacitinib 30 mg
    Reporting group description
    Participants who received upadacitinib during Part 1 and did not achieve clinical response at Week 12 received 30 mg upadacitinib once daily from Week 12 to Week 24.

    Serious adverse events
    Part 1: Placebo Part 1: Upadacitinib 45 mg Part 2: Placebo / Upadacitinib 45 mg Part 2: Upadacitinib 45 mg / Upadacitinib 30 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 176 (6.82%)
    24 / 350 (6.86%)
    4 / 57 (7.02%)
    6 / 59 (10.17%)
         number of deaths (all causes)
    0
    1
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    FALL
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 350 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 350 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 350 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PARAESTHESIA
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 350 (0.29%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SEIZURE
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 350 (0.29%)
    0 / 57 (0.00%)
    0 / 59 (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
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 350 (0.29%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    IRON DEFICIENCY ANAEMIA
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 350 (0.29%)
    0 / 57 (0.00%)
    0 / 59 (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
    General disorders and administration site conditions
    PYREXIA
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 350 (0.29%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 350 (0.29%)
    0 / 57 (0.00%)
    0 / 59 (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
    ANAL FISTULA
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 350 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 350 (0.29%)
    0 / 57 (0.00%)
    0 / 59 (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
    CROHN'S DISEASE
         subjects affected / exposed
    5 / 176 (2.84%)
    7 / 350 (2.00%)
    1 / 57 (1.75%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 8
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ENTERITIS
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 350 (0.00%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ILEAL STENOSIS
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 350 (0.29%)
    0 / 57 (0.00%)
    0 / 59 (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
    ILEUS
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 350 (0.29%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 176 (0.00%)
    2 / 350 (0.57%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTESTINAL PERFORATION
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 350 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LARGE INTESTINAL STENOSIS
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 350 (0.29%)
    0 / 57 (0.00%)
    0 / 59 (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
    LARGE INTESTINE PERFORATION
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 350 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LOWER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 350 (0.29%)
    0 / 57 (0.00%)
    0 / 59 (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
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 350 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 350 (0.29%)
    0 / 57 (0.00%)
    0 / 59 (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
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 350 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    METASTATIC CUTANEOUS CROHN'S DISEASE
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 350 (0.29%)
    0 / 57 (0.00%)
    0 / 59 (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
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 350 (0.00%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         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
    NEPHROLITHIASIS
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 350 (0.29%)
    0 / 57 (0.00%)
    0 / 59 (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
    Musculoskeletal and connective tissue disorders
    FLANK PAIN
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 350 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    ANAL ABSCESS
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 350 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    APPENDICITIS
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 350 (0.29%)
    0 / 57 (0.00%)
    0 / 59 (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
    COVID-19
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 350 (0.00%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         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 / 1
    COVID-19 PNEUMONIA
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 350 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROENTERITIS ROTAVIRUS
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 350 (0.29%)
    0 / 57 (0.00%)
    0 / 59 (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
    GASTROENTERITIS VIRAL
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 350 (0.00%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OSTEOMYELITIS
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 350 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RECTAL ABSCESS
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 350 (0.29%)
    0 / 57 (0.00%)
    0 / 59 (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
    PNEUMONIA
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 350 (0.29%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 350 (0.00%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    HYPOKALAEMIA
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 350 (0.29%)
    0 / 57 (0.00%)
    0 / 59 (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
    Part 1: Placebo Part 1: Upadacitinib 45 mg Part 2: Placebo / Upadacitinib 45 mg Part 2: Upadacitinib 45 mg / Upadacitinib 30 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 176 (21.02%)
    93 / 350 (26.57%)
    14 / 57 (24.56%)
    13 / 59 (22.03%)
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    8 / 176 (4.55%)
    21 / 350 (6.00%)
    3 / 57 (5.26%)
    2 / 59 (3.39%)
         occurrences all number
    8
    23
    3
    2
    General disorders and administration site conditions
    PYREXIA
         subjects affected / exposed
    2 / 176 (1.14%)
    14 / 350 (4.00%)
    1 / 57 (1.75%)
    3 / 59 (5.08%)
         occurrences all number
    2
    15
    1
    3
    Gastrointestinal disorders
    CROHN'S DISEASE
         subjects affected / exposed
    13 / 176 (7.39%)
    6 / 350 (1.71%)
    1 / 57 (1.75%)
    3 / 59 (5.08%)
         occurrences all number
    13
    6
    1
    3
    Skin and subcutaneous tissue disorders
    ACNE
         subjects affected / exposed
    1 / 176 (0.57%)
    24 / 350 (6.86%)
    3 / 57 (5.26%)
    1 / 59 (1.69%)
         occurrences all number
    1
    24
    3
    1
    RASH
         subjects affected / exposed
    4 / 176 (2.27%)
    13 / 350 (3.71%)
    3 / 57 (5.26%)
    1 / 59 (1.69%)
         occurrences all number
    4
    14
    3
    1
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    8 / 176 (4.55%)
    9 / 350 (2.57%)
    3 / 57 (5.26%)
    1 / 59 (1.69%)
         occurrences all number
    9
    10
    3
    1
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 176 (0.00%)
    3 / 350 (0.86%)
    3 / 57 (5.26%)
    1 / 59 (1.69%)
         occurrences all number
    0
    3
    3
    1
    NASOPHARYNGITIS
         subjects affected / exposed
    6 / 176 (3.41%)
    16 / 350 (4.57%)
    2 / 57 (3.51%)
    4 / 59 (6.78%)
         occurrences all number
    6
    16
    2
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Oct 2017
    Major changes to the protocol included: ● Updated eligibility criteria. ● Updated the duration of the maintenance part of Substudy 1 from 48 to 52 weeks. ● Revised ranked secondary and additional secondary efficacy endpoints.
    24 Jan 2018
    Major changes to the protocol included: ● Added vedolizumab as a prohibited biologic therapy during the study. ● Clarified that the primary variables would be analyzed for subjects enrolled in Part 1. ● Clarified that the secondary variables would be analyzed for subjects enrolled in Part 1. ● Clarification on the analysis methods considered for continuous secondary endpoints.
    24 Aug 2018
    Major changes to the protocol included: ● Minimum screening period duration was corrected and rescreening process was clarified. ● Updated eligibility criteria. ● Clarified and provided additional guidance on the use of concomitant corticosteroids. ● Updated and clarified prohibited therapies. ● Corrected and updated contraception recommendations. ● Added the Montreal classification for CD at Screening. ● Revised ranked secondary and additional secondary efficacy endpoints. ● Updated the list of adverse events of special interest (AESIs). ● Removed Section 6.1.3.1. ● Reduced the number of data point collections of the Crohn's Symptom Severity (CSS) during the study.
    08 Apr 2019
    Major chnages to the protocol included: ● Revised study title. ● Updated Section 5.1 and Section 5.3.1.1 for alignment with induction Study M14-431 to include enrollment of Bio-IR subjects which increased the subject population. ● Updated eligibility criteria. ● Corrected and updated contraception recommendations. ● Revised ranked secondary and additional secondary efficacy endpoints.
    29 Apr 2020
    Major changes to the protocol included: ● Removed the number of subjects and the maximum enrollment in the subpopulations. ● Included COVID-19 pandemic provisions for post-baseline endoscopy. ● Updated eligibility criteria. ● Revised prohibited therapy. ● Removed eGFR at Week 12 and Week 24. ● Increased the number of intestinal biopsy samples to be collected. ● Changed co-primary efficacy endpoint to clinical remission based on CDAI for the US/FDA. ● Revised ranked secondary and additional secondary efficacy endpoints. ● Updated the AESIs.
    24 Sep 2020
    Major changes to the protocol included: ● Updated information on the re-evaluation of the benefit and risk to subjects participating in the study, updated wording to allow for changes in visits and procedures affected by COVID-19 pandemic and asocial changes in global/local regulations.

    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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