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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind Study of the Human Anti-TNF Monoclonal Antibody Adalimumab in Pediatric Subjects With Moderate to Severe Ulcerative Colitis

    Summary
    EudraCT number
    		 2013-003032-77
    Trial protocol
    		 GB   IT   HU   BE   AT   SK   ES   CZ   PL   FR  
    Global end of trial date
    07 Feb 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Aug 2020
    First version publication date
    13 Aug 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    M11-290
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02065557
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AbbVie
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 Feb 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of the study is to demonstrate the efficacy and safety, and to assess the pharmacokinetics of adalimumab administered subcutaneously in pediatric subjects with moderate-to-severe UC.
    Protection of trial subjects
    The study was conducted in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, applicable regulations and guidelines governing clinical study conduct and ethical principles that have their origin in the Declaration of Helsinki. Prior to the initiation of any screening or study-specific procedures, the investigator or his or her representative explained the nature of the study to the subject or his or her representative and answered all questions regarding this study. Pediatric subjects were included in all discussions, and their verbal or written assent was obtained. The informed consent statement was reviewed and signed and dated by the subject's parent or legal guardian, the person who administered the informed consent, and any other signatories according to local requirements. If a subject became of legal age during the study, that subject was reconsented.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Oct 2014
    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
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Japan: 8
    Country: Number of subjects enrolled
    Poland: 66
    Country: Number of subjects enrolled
    Slovakia: 6
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 12
    Worldwide total number of subjects
    101
    EEA total number of subjects
    79
    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)
    19
    Adolescents (12-17 years)
    82
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Prior to Protocol Amendment 4, subjects were randomized 3:2 at baseline to adalimumab induction high dose or adalimumab induction standard dose. At Week 8, those demonstrating a clinical response per Partial Mayo Score (PMS) were randomized 2:2:1 to adalimumab maintenance standard dose, adalimumab maintenance high dose, or maintenance placebo.

    Pre-assignment
    Screening details
    		 After Protocol Amendment 4, subjects received adalimumab induction high dose open-label. At Week 8, those demonstrating a clinical response per PMS were randomized in a 1:1 ratio to adalimumab maintenance standard dose or adalimumab maintenance high dose. "Integrated Study" data includes data from both the Main Study and the Japan Sub-Study.

    Period 1
    Period 1 title
    Induction Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer
    Blinding implementation details
    All AbbVie personnel with direct oversight of the conduct and management of the trial (with the exception of AbbVie Drug Supply Management Team) the Investigator, study site personnel and the subject remained blinded to each subject's treatment throughout the blinded period of the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Integrated Study: Induction Standard Dose (I-SD)
    Arm description
    		 Subjects randomized to receive adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and matching placebo at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6.
    Arm type
    		 Experimental

    Investigational medicinal product name
    adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    subcutaneous injection

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled injector
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    subcutaneous injection

    Arm title
    		 Integrated Study: Induction High Dose (I-HD)
    Arm description
    		 Subjects randomized to receive adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6.
    Arm type
    		 Experimental

    Investigational medicinal product name
    adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    subcutaneous injection

    Arm title
    		 Integrated Study: Induction High Dose Open Label (I-HD-OL)
    Arm description
    		 (After Amendment 4) subjects assigned to open-label adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6.
    Arm type
    		 Experimental

    Investigational medicinal product name
    adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    subcutaneous injection

    Number of subjects in period 1
    		Integrated Study: Induction Standard Dose (I-SD) Integrated Study: Induction High Dose (I-HD) Integrated Study: Induction High Dose Open Label (I-HD-OL)
    Started
    32
    51
    18
    Enrolled in Main Study
    30
    47
    16
    Enrolled in Japan Substudy
    2 [1]
    4 [2]
    2 [3]
    Completed
    22
    43
    16
    Not completed
    10
    8
    2
         Consent withdrawn by subject
    2
    1
    -
         Non-responder at Week 8
    4
    4
    -
         Adverse event
    1
    1
    -
         Requires alternative/prohibited therapy
    1
    1
    1
         Lack of efficacy
    2
    1
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Subjects who were enrolled in the Japan substudy.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Subjects who were enrolled in the Japan substudy.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Subjects who were enrolled in the Japan substudy.
    Period 2
    Period 2 title
    Maintenance Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer
    Blinding implementation details
    All AbbVie personnel with direct oversight of the conduct and management of the trial (with the exception of AbbVie Drug Supply Management Team) the Investigator, study site personnel and the subject remained blinded to each subject's treatment throughout the blinded period of the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Integrated Study: Maintenance Placebo (M-PL)
    Arm description
    		 (Prior to Amendment 4) subjects demonstrating a clinical response per PMS (defined as a decrease in PMS ≥ 2 points and ≥ 30% from Baseline) at Week 8 randomized to maintenance placebo. Subjects were to continue their blinded treatment during the maintenance period until Week 52 unless they had ≥ 2 flares and got open label adalimumab rescue therapy after the second flare.
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled injector
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    subcutaneous injection

    Investigational medicinal product name
    adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    subcutaneous injection

    Arm title
    		 Integrated Study: Maintenance Standard Dose (M-SD)
    Arm description
    		 Subjects demonstrating a clinical response per PMS (defined as a decrease in PMS ≥ 2 points and ≥ 30% from Baseline) at Week 8 randomized to adalimumab maintenance standard dose (0.6 mg/kg [maximum dose of 40 mg] every other week). Subjects were to continue their blinded treatment during the maintenance period until Week 52 unless they had ≥ 2 flares and got open label rescue therapy after second flare.
    Arm type
    		 Experimental

    Investigational medicinal product name
    adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    subcutaneous injection

    Arm title
    		 Integrated Study: Maintenance High Dose (M-HD)
    Arm description
    		 Subjects demonstrating a clinical response per PMS (defined as a decrease in PMS ≥ 2 points and ≥ 30% from Baseline) at Week 8 randomized to adalimumab maintenance high dose (0.6 mg/kg [maximum dose of 40 mg] every week). Subjects were to continue their blinded treatment during the maintenance period until Week 52 unless they had ≥ 2 flares and got open label rescue therapy after second flare.
    Arm type
    		 Experimental

    Investigational medicinal product name
    adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    subcutaneous injection

    Number of subjects in period 2
    		Integrated Study: Maintenance Placebo (M-PL) Integrated Study: Maintenance Standard Dose (M-SD) Integrated Study: Maintenance High Dose (M-HD)
    Started
    12
    33
    36
    Completed
    11
    25
    32
    Not completed
    1
    8
    4
         Consent withdrawn by subject
    -
    2
    1
         Subject non-compliance
    -
    -
    1
         Requires alternative/prohibited therapy
    1
    1
    -
         Lack of efficacy
    -
    5
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Integrated Study: Induction Standard Dose (I-SD)
    Reporting group description
    		 Subjects randomized to receive adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and matching placebo at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6.

    Reporting group title
    Integrated Study: Induction High Dose (I-HD)
    Reporting group description
    		 Subjects randomized to receive adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6.

    Reporting group title
    Integrated Study: Induction High Dose Open Label (I-HD-OL)
    Reporting group description
    		 (After Amendment 4) subjects assigned to open-label adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6.

    Reporting group values
    		 Integrated Study: Induction Standard Dose (I-SD) Integrated Study: Induction High Dose (I-HD) Integrated Study: Induction High Dose Open Label (I-HD-OL) Total
    Number of subjects
    		 32 51 18 101
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 14.7 ( 2.66 ) 13.8 ( 3.06 ) 13.8 ( 2.82 ) -
    Gender categorical
    Units: Subjects
        Female
    		 15 23 13 51
        Male
    		 17 28 5 50
    Race
    Units: Subjects
        White
    		 28 45 15 88
        Black
    		 1 2 0 3
        Asian
    		 3 4 2 9
        Multiple
    		 0 0 1 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 2 1 4
        Japanese
    		 2 4 2 8
        No ethnicity
    		 29 45 15 89
    Full Mayo Score (FMS)
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease).
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 7.8 ( 1.22 ) 7.7 ( 1.25 ) 7.7 ( 1.09 ) -
    Partial Mayo Score (PMS)
    The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease).
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 5.7 ( 1.14 ) 5.5 ( 1.24 ) 5.5 ( 1.06 ) -
    Endoscopy Subscore
    The endoscopy subscore of the FMS ranges from 0 (normal) to 3 (severe disease).
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 2.1 ( 0.34 ) 2.2 ( 0.40 ) 2.2 ( 0.43 ) -
    Rectal Bleeding Subscore
    The rectal bleeding subscore of the FMS ranges from 0 (normal) to 3 (severe disease).
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 1.4 ( 0.93 ) 1.5 ( 0.88 ) 1.4 ( 0.97 ) -
    Physicians Global Assessment Subscore
    The physicians global assessment subscore of the FMS ranges from 0 (normal) to 3 (severe disease).
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 2.2 ( 0.40 ) 2.2 ( 0.43 ) 2.2 ( 0.38 ) -
    Stool Frequency Subscore
    The stool frequency subscore of the FMS ranges from 0 (normal) to 3 (severe disease).
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 2.1 ( 0.78 ) 1.8 ( 0.88 ) 1.9 ( 0.73 ) -

    End points

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    End points reporting groups
    Reporting group title
    Integrated Study: Induction Standard Dose (I-SD)
    Reporting group description
    		 Subjects randomized to receive adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and matching placebo at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6.

    Reporting group title
    Integrated Study: Induction High Dose (I-HD)
    Reporting group description
    		 Subjects randomized to receive adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6.

    Reporting group title
    Integrated Study: Induction High Dose Open Label (I-HD-OL)
    Reporting group description
    		 (After Amendment 4) subjects assigned to open-label adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6.
    Reporting group title
    Integrated Study: Maintenance Placebo (M-PL)
    Reporting group description
    		 (Prior to Amendment 4) subjects demonstrating a clinical response per PMS (defined as a decrease in PMS ≥ 2 points and ≥ 30% from Baseline) at Week 8 randomized to maintenance placebo. Subjects were to continue their blinded treatment during the maintenance period until Week 52 unless they had ≥ 2 flares and got open label adalimumab rescue therapy after the second flare.

    Reporting group title
    Integrated Study: Maintenance Standard Dose (M-SD)
    Reporting group description
    		 Subjects demonstrating a clinical response per PMS (defined as a decrease in PMS ≥ 2 points and ≥ 30% from Baseline) at Week 8 randomized to adalimumab maintenance standard dose (0.6 mg/kg [maximum dose of 40 mg] every other week). Subjects were to continue their blinded treatment during the maintenance period until Week 52 unless they had ≥ 2 flares and got open label rescue therapy after second flare.

    Reporting group title
    Integrated Study: Maintenance High Dose (M-HD)
    Reporting group description
    		 Subjects demonstrating a clinical response per PMS (defined as a decrease in PMS ≥ 2 points and ≥ 30% from Baseline) at Week 8 randomized to adalimumab maintenance high dose (0.6 mg/kg [maximum dose of 40 mg] every week). Subjects were to continue their blinded treatment during the maintenance period until Week 52 unless they had ≥ 2 flares and got open label rescue therapy after second flare.

    Subject analysis set title
    Main Study: I-SD
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects randomized to receive adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and matching placebo at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6. Intent-to-Treat (ITT): all subjects who received at least 1 dose of study drug during the Induction period; analyzed as enrolled/randomized.

    Subject analysis set title
    Main Study: I-HD
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects randomized to receive adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6. Intent-to-Treat (ITT): all subjects who received at least 1 dose of study drug during the Induction period; analyzed as enrolled/randomized.

    Subject analysis set title
    Main Study: I-SD + I-HD
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Combined I-SD + I-HD arms (see above). Intent-to-Treat (ITT): all subjects who received at least 1 dose of study drug during the Induction period; analyzed as enrolled/randomized.

    Subject analysis set title
    Main Study: I-HD-OL
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    (After Amendment 4) subjects assigned to open-label adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6. Intent-to-Treat (ITT): all subjects who received at least 1 dose of study drug during the Induction period; analyzed as enrolled/randomized.

    Subject analysis set title
    Integrated Study (Main + Japan Sub- Study): I-SD
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects randomized to receive adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and matching placebo at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6. Intent-to-Treat (ITT): all subjects who received at least 1 dose of study drug during the Induction period; analyzed as enrolled/randomized.

    Subject analysis set title
    Integrated Study (Main + Japan Sub- Study): I-HD
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects randomized to receive adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6. Intent-to-Treat (ITT): all subjects who received at least 1 dose of study drug during the Induction period; analyzed as enrolled/randomized.

    Subject analysis set title
    Integrated Study (Main + Japan Sub- Study): I-SD + I-HD
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Combined I-SD + I-HD arms (see above). Intent-to-Treat (ITT): all subjects who received at least 1 dose of study drug during the Induction period; analyzed as enrolled/randomized.

    Subject analysis set title
    Integrated Study (Main + Japan Sub- Study): I-HD-OL
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    (After Amendment 4) subjects assigned to open-label adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6. Intent-to-Treat (ITT): all subjects who received at least 1 dose of study drug during the Induction period; analyzed as enrolled/randomized.

    Subject analysis set title
    Main Study: M-PL
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    (Prior to Amendment 4) subjects demonstrating a clinical response per PMS (defined as a decrease in PMS ≥ 2 points and ≥ 30% from Baseline) at Week 8 randomized to maintenance placebo. Subjects were to continue their blinded treatment during the maintenance period until Week 52 unless they had ≥ 2 flares and got open label rescue therapy after the second flare. Modified intent-to-treat (mITT): all Week 8 PMS responders who were re-randomized at Week 8 and received at least 1 dose of study drug during the Maintenance period; analyzed as randomized/enrolled at the beginning of the Maintenance phase.

    Subject analysis set title
    Main Study: M-SD
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subjects demonstrating a clinical response per PMS (defined as a decrease in PMS ≥ 2 points and ≥ 30% from Baseline) at Week 8 randomized to adalimumab maintenance standard dose (0.6 mg/kg [maximum dose of 40 mg] eow). Subjects were to continue their blinded treatment during the maintenance period until Week 52 unless they had ≥ 2 flares and got open label rescue therapy after the second flare. Modified intent-to-treat (mITT): all Week 8 PMS responders who were re-randomized at Week 8 and received at least 1 dose of study drug during the Maintenance period; analyzed as randomized/enrolled at the beginning of the Maintenance phase.

    Subject analysis set title
    Main Study: M-HD
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subjects demonstrating a clinical response per PMS (defined as a decrease in PMS ≥ 2 points and ≥ 30% from Baseline) at Week 8 randomized to adalimumab maintenance high dose (0.6 mg/kg [maximum dose of 40 mg] ew). Subjects were to continue their blinded treatment during the maintenance period until Week 52 unless they had ≥ 2 flares and got open label rescue therapy after the second flare. Modified intent-to-treat (mITT): all Week 8 PMS responders who were re-randomized at Week 8 and received at least 1 dose of study drug during the Maintenance period; analyzed as randomized/enrolled at the beginning of the Maintenance phase.

    Subject analysis set title
    Main Study: M-SD + M-HD
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Combined M-SD + M-HD arms (see above). Modified intent-to-treat (mITT): all Week 8 PMS responders who were re-randomized at Week 8 and received at least 1 dose of study drug during the Maintenance period; analyzed as randomized/enrolled at the beginning of the Maintenance phase.

    Subject analysis set title
    Integrated Study (Main + Japan Sub- Study): M-PL
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    (Prior to Amendment 4) subjects demonstrating a clinical response per PMS (defined as a decrease in PMS ≥ 2 points and ≥ 30% from Baseline) at Week 8 randomized to maintenance placebo. Subjects were to continue their blinded treatment during the maintenance period until Week 52 unless they had ≥ 2 flares and got open label rescue therapy after the second flare. Modified intent-to-treat (mITT): all Week 8 PMS responders who were re-randomized at Week 8 and received at least 1 dose of study drug during the Maintenance period; analyzed as randomized/enrolled at the beginning of the Maintenance phase.

    Subject analysis set title
    Integrated Study (Main + Japan Sub- Study): M-SD
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subjects demonstrating a clinical response per PMS (defined as a decrease in PMS ≥ 2 points and ≥ 30% from Baseline) at Week 8 randomized to adalimumab maintenance standard dose (0.6 mg/kg [maximum dose of 40 mg] eow). Subjects were to continue their blinded treatment during the maintenance period until Week 52 unless they had ≥ 2 flares and got open label rescue therapy after the second flare. Modified intent-to-treat (mITT): all Week 8 PMS responders who were re-randomized at Week 8 and received at least 1 dose of study drug during the Maintenance period; analyzed as randomized/enrolled at the beginning of the Maintenance phase.

    Subject analysis set title
    Integrated Study (Main + Japan Sub- Study): M-HD
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subjects demonstrating a clinical response per PMS (defined as a decrease in PMS ≥ 2 points and ≥ 30% from Baseline) at Week 8 randomized to adalimumab maintenance high dose (0.6 mg/kg [maximum dose of 40 mg] ew). Subjects were to continue their blinded treatment during the maintenance period until Week 52 unless they had ≥ 2 flares and got open label rescue therapy after the second flare. Modified intent-to-treat (mITT): all Week 8 PMS responders who were re-randomized at Week 8 and received at least 1 dose of study drug during the Maintenance period; analyzed as randomized/enrolled at the beginning of the Maintenance phase.

    Subject analysis set title
    Integrated Study (Main + Japan Sub- Study): M-SD + M-HD
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Combined M-SD + M-HD arms (see above). Modified intent-to-treat (mITT): all Week 8 PMS responders who were re-randomized at Week 8 and received at least 1 dose of study drug during the Maintenance period; analyzed as randomized/enrolled at the beginning of the Maintenance phase.

    Primary: Co-Primary Endpoint 1: Percentage of Subjects Who Achieved Clinical Remission as Measured by Partial Mayo Score (PMS) at Week 8 - Induction Period

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    End point title
    		 Co-Primary Endpoint 1: Percentage of Subjects Who Achieved Clinical Remission as Measured by Partial Mayo Score (PMS) at Week 8 - Induction Period [1]
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). A negative change in PMS indicates improvement. Clinical remission was defined as a PMS ≤ 2 and no individual subscore > 1. Non-responder imputation: missing data imputed as not having met the endpoint.
    End point type
    Primary
    End point timeframe
    Week 8
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses for this endpoint are presented in the attached document.
    End point values
    		 Main Study: I-SD Main Study: I-HD Main Study: I-SD + I-HD Main Study: I-HD-OL Integrated Study (Main + Japan Sub- Study): I-SD Integrated Study (Main + Japan Sub- Study): I-HD Integrated Study (Main + Japan Sub- Study): I-SD + I-HD Integrated Study (Main + Japan Sub- Study): I-HD-OL
    Number of subjects analysed
    30
    47
    77
    16
    32
    51
    83
    18
    Units: percentage of subjects
        number (confidence interval 95%)
    43.3 (25.46 to 62.57)
    59.6 (44.27 to 73.63)
    53.2 (41.52 to 64.71)
    68.8 (41.34 to 88.98)
    40.6 (23.70 to 59.36)
    58.8 (44.17 to 72.42)
    51.8 (40.56 to 62.92)
    66.7 (40.99 to 86.66)
    Attachments
    		 Untitled (Filename: Statistical Analysis for Co-Primary Endpoint 1.docx)
    No statistical analyses for this end point

    Primary: Co-Primary Endpoint 2: Percentage of Subjects With Clinical Remission Per Full Mayo Score (FMS) at Week 52 in Week 8 Responders Per PMS - Maintenance Period

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    End point title
    		 Co-Primary Endpoint 2: Percentage of Subjects With Clinical Remission Per Full Mayo Score (FMS) at Week 52 in Week 8 Responders Per PMS - Maintenance Period [2]
    End point description
    The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment). Negative changes indicate improvement. PMS responders are defined as those with a decrease in PMS ≥ 2 points and ≥ 30% from Baseline. Clinical remission per FMS is defined as Mayo Score ≤ 2 and no individual subscore > 1. Non-responder imputation: missing data imputed as not having met the endpoint.
    End point type
    Primary
    End point timeframe
    Week 52
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses for this endpoint are presented in the attached document.
    End point values
    		 Main Study: M-PL Main Study: M-SD Main Study: M-HD Main Study: M-SD + M-HD Integrated Study (Main + Japan Sub- Study): M-PL Integrated Study (Main + Japan Sub- Study): M-SD Integrated Study (Main + Japan Sub- Study): M-HD Integrated Study (Main + Japan Sub- Study): M-SD + M-HD
    Number of subjects analysed
    12
    31
    31
    62
    12
    33
    35
    68
    Units: percentage of subjects
        number (confidence interval 95%)
    33.3 (9.92 to 65.11)
    29.0 (14.22 to 48.04)
    45.2 (27.32 to 63.97)
    37.1 (25.16 to 50.31)
    33.3 (9.92 to 65.11)
    27.3 (13.30 to 45.52)
    42.9 (26.32 to 60.65)
    35.3 (24.08 to 47.83)
    Attachments
    		 Untitled (Filename: Statistical Analysis for Co-Primary Endpoint 2.docx)
    No statistical analyses for this end point

    Secondary: Ranked Secondary Endpoint 1: Percentage of Subjects With Clinical Response Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period

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    End point title
    		 Ranked Secondary Endpoint 1: Percentage of Subjects With Clinical Response Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period
    End point description
    The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment). Negative changes indicate improvement. PMS responders are defined as those with a decrease in PMS ≥ 2 points and ≥ 30% from Baseline. Clinical response per FMS is defined as a decrease in FMS ≥ 3 points and ≥ 30% from Baseline. Non-responder imputation: missing data imputed as not having met the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Main Study: M-PL Main Study: M-SD Main Study: M-HD Main Study: M-SD + M-HD Integrated Study (Main + Japan Sub- Study): M-PL Integrated Study (Main + Japan Sub- Study): M-SD Integrated Study (Main + Japan Sub- Study): M-HD Integrated Study (Main + Japan Sub- Study): M-SD + M-HD
    Number of subjects analysed
    12
    31
    31
    62
    12
    33
    35
    68
    Units: percentage of participants
        number (confidence interval 95%)
    33.3 (9.92 to 65.11)
    61.3 (42.19 to 78.15)
    67.7 (48.63 to 83.32)
    64.5 (51.34 to 76.26)
    33.3 (9.92 to 65.11)
    57.6 (39.22 to 74.52)
    65.7 (47.79 to 80.87)
    61.8 (49.18 to 73.29)
    Attachments
    		 Untitled (Filename: Statistical Analysis for Ranked Secondary Endpoint 1.docx)
    No statistical analyses for this end point

    Secondary: Ranked Secondary Endpoint 2: Percentage of Subjects With Mucosal Healing at Week 52 in Week 8 Responders Per PMS - Maintenance Period

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    End point title
    		 Ranked Secondary Endpoint 2: Percentage of Subjects With Mucosal Healing at Week 52 in Week 8 Responders Per PMS - Maintenance Period
    End point description
    The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment). Negative changes indicate improvement. PMS responders are defined as those subjects with a decrease in PMS ≥ 2 points and ≥ 30% from Baseline. Mucosal healing per Mayo endoscopy subscore is defined as a subscore of ≤ 1. Non-responder imputation: missing data imputed as not having met the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Main Study: M-PL Main Study: M-SD Main Study: M-HD Main Study: M-SD + M-HD Integrated Study (Main + Japan Sub- Study): M-PL Integrated Study (Main + Japan Sub- Study): M-SD Integrated Study (Main + Japan Sub- Study): M-HD Integrated Study (Main + Japan Sub- Study): M-SD + M-HD
    Number of subjects analysed
    12
    31
    31
    62
    12
    33
    35
    68
    Units: percentage of subjects
        number (confidence interval 95%)
    33.3 (9.92 to 65.11)
    38.7 (21.85 to 57.81)
    51.6 (33.06 to 69.85)
    45.2 (32.48 to 58.32)
    33.3 (9.92 to 65.11)
    36.4 (20.40 to 54.88)
    48.6 (31.38 to 66.01)
    42.6 (30.72 to 55.23)
    Attachments
    		 Untitled (Filename: Statistical Analysis for Ranked Secondary Endpoint 2.docx)
    No statistical analyses for this end point

    Secondary: Ranked Secondary Endpoint 3: Percentage of Subjects With Clinical Remission Per FMS at Week 52 in Week 8 Remitters Per PMS - Maintenance Period

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    End point title
    		 Ranked Secondary Endpoint 3: Percentage of Subjects With Clinical Remission Per FMS at Week 52 in Week 8 Remitters Per PMS - Maintenance Period
    End point description
    The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment). Negative changes indicate improvement. PMS remitters are defined as those subjects with a PMS ≤ 2 and no individual subscore > 1. Clinical remission per FMS is defined as Mayo Score ≤ 2 and no individual subscore > 1. Non-responder imputation: missing data imputed as not having met the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Main Study: M-PL Main Study: M-SD Main Study: M-HD Main Study: M-SD + M-HD Integrated Study (Main + Japan Sub- Study): M-PL Integrated Study (Main + Japan Sub- Study): M-SD Integrated Study (Main + Japan Sub- Study): M-HD Integrated Study (Main + Japan Sub- Study): M-SD + M-HD
    Number of subjects analysed
    8 [3]
    21 [4]
    22 [5]
    43 [6]
    8 [7]
    21 [8]
    25 [9]
    46 [10]
    Units: percentage of subjects
        number (confidence interval 95%)
    37.5 (8.52 to 75.51)
    42.9 (21.82 to 65.98)
    45.5 (24.39 to 67.79)
    44.2 (29.08 to 60.12)
    37.5 (8.52 to 75.51)
    42.9 (21.82 to 65.98)
    44.0 (24.40 to 65.07)
    43.5 (28.93 to 58.89)
    Attachments
    		 Untitled (Filename: Statistical Analysis for Ranked Secondary Endpoint 3.docx)
    Notes
    [3] - mITT subjects who were also Week 8 remitters
    [4] - mITT subjects who were also Week 8 remitters
    [5] - mITT subjects who were also Week 8 remitters
    [6] - mITT subjects who were also Week 8 remitters
    [7] - mITT subjects who were also Week 8 remitters
    [8] - mITT subjects who were also Week 8 remitters
    [9] - mITT subjects who were also Week 8 remitters
    [10] - mITT subjects who were also Week 8 remitters
    No statistical analyses for this end point

    Secondary: Ranked Secondary Endpoint 4: Percentage of Subjects With Corticosteroid-Free Clinical Remission Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period

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    End point title
    		 Ranked Secondary Endpoint 4: Percentage of Subjects With Corticosteroid-Free Clinical Remission Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period
    End point description
    The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment). Negative changes indicate improvement. PMS responders are defined as those with a decrease in PMS ≥ 2 points and ≥ 30% from baseline. Among subjects receiving systemic corticosteroids at Baseline, corticosteroid-free clinical remission per FMS at Week 52 is defined as having discontinued systemic corticosteroids prior to Week 52 and being in FMS clinical remission at Week 52 (defined as Mayo Score ≤ 2 and no individual subscore > 1). Non-responder imputation: missing data imputed as not having met the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Main Study: M-PL Main Study: M-SD Main Study: M-HD Main Study: M-SD + M-HD Integrated Study (Main + Japan Sub- Study): M-PL Integrated Study (Main + Japan Sub- Study): M-SD Integrated Study (Main + Japan Sub- Study): M-HD Integrated Study (Main + Japan Sub- Study): M-SD + M-HD
    Number of subjects analysed
    5 [11]
    13 [12]
    16 [13]
    29 [14]
    5 [15]
    15 [16]
    17 [17]
    32 [18]
    Units: percentage of stubjects
        number (confidence interval 95%)
    40.0 (5.27 to 85.34)
    30.8 (9.09 to 61.43)
    31.3 (11.02 to 58.66)
    31.0 (15.28 to 50.83)
    40.0 (5.27 to 85.34)
    26.7 (7.79 to 55.10)
    35.3 (14.21 to 61.67)
    31.3 (16.12 to 50.01)
    Attachments
    		 Untitled (Filename: Statistical Analysis for Ranked Secondary Endpoint 4.docx)
    Notes
    [11] - mITT subjects receiving systemic corticosteroids at baseline.
    [12] - mITT subjects receiving systemic corticosteroids at baseline.
    [13] - mITT subjects receiving systemic corticosteroids at baseline.
    [14] - mITT subjects receiving systemic corticosteroids at baseline.
    [15] - mITT subjects receiving systemic corticosteroids at baseline.
    [16] - mITT subjects receiving systemic corticosteroids at baseline.
    [17] - mITT subjects receiving systemic corticosteroids at baseline.
    [18] - mITT subjects receiving systemic corticosteroids at baseline.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    See time frame specifics detailed for each reporting group in their respective descriptions below.
    Adverse event reporting additional description
    Treatment-emergent adverse events (TEAEs) are presented.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Integrated Study (Main + Japan Sub- Study): I-SD
    Reporting group description
    		 Subjects randomized to receive adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and matching placebo at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6. TEAEs during induction period: events with an onset date on or after first dose date of study drug in induction period and up to 70 days after last dose date of the study drug in induction period and prior to first dose date of study drug in maintenance period. Mean duration of treatment was 52.8 days.

    Reporting group title
    Integrated Study (Main + Japan Sub- Study): I-HD
    Reporting group description
    		 Subjects randomized to receive adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6. TEAEs during induction period: events with an onset date on or after first dose date of study drug in induction period and up to 70 days after last dose date of the study drug in induction period and prior to first dose date of study drug in maintenance period. Mean duration of treatment was 55.4 days.

    Reporting group title
    Integrated Study (Main + Japan Sub- Study): I-HD-OL
    Reporting group description
    		 (After Amendment 4) subjects assigned to open-label adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6. TEAEs during induction period: events with an onset date on or after first dose date of study drug in induction period and up to 70 days after last dose date of the study drug in induction period and prior to first dose date of study drug in maintenance period. Mean duration of treatment was 53.8 days.

    Reporting group title
    Integrated Study (Main + Japan Sub- Study): M-SD
    Reporting group description
    		 Subjects demonstrating a clinical response per PMS (defined as a decrease in PMS ≥ 2 points and ≥ 30% from Baseline) at Week 8 randomized to adalimumab maintenance standard dose (0.6 mg/kg [maximum dose of 40 mg] eow). Subjects were to continue their blinded treatment during the maintenance period until Week 52 unless they had ≥ 2 flares and got open label adalimumab rescue therapy after the second flare. TEAEs during maintenance period: events with an onset date on or after first dose date of study drug in maintenance period and prior to re-randomization due to first disease flare if applicable and up to 70 days after the last dose date of the study drug in maintenance period. Events with an onset date on or after the first dose date in long-term follow-up study M10-870 (NCT02632175) are excluded. Mean duration of treatment was 226.8 days.

    Reporting group title
    Integrated Study (Main + Japan Sub- Study): M-HD
    Reporting group description
    		 Subjects demonstrating a clinical response per PMS (defined as a decrease in PMS ≥ 2 points and ≥ 30% from Baseline) at Week 8 randomized to adalimumab maintenance high dose (0.6 mg/kg [maximum dose of 40 mg] ew). Subjects were to continue their blinded treatment during the maintenance period until Week 52 unless they had ≥ 2 flares and got open label adalimumab rescue therapy after the second flare. TEAEs during maintenance period: events with an onset date on or after first dose date of study drug in maintenance period and prior to re-randomization due to first disease flare if applicable and up to 70 days after the last dose date of the study drug in maintenance period. Events with an onset date on or after the first dose date in long-term follow-up study M10-870 (NCT02632175) are excluded. Mean duration of treatment was 241.0 days.

    Reporting group title
    Integrated Study (Main + Japan Sub- Study): M-PL
    Reporting group description
    		 (Prior to Amendment 4) subjects demonstrating a clinical response per PMS (defined as a decrease in PMS ≥ 2 points and ≥ 30% from Baseline) at Week 8 randomized to maintenance placebo. Subjects were to continue their blinded treatment during the maintenance period until Week 52 unless they had ≥ 2 flares and got open label adalimumab rescue therapy after the second flare. TEAEs during maintenance period: events with an onset date on or after first dose date of study drug in maintenance period and prior to re-randomization due to first disease flare if applicable and up to 70 days after the last dose date of the study drug in maintenance period. Events with an onset date on or after the first dose date in long-term follow-up study M10-870 (NCT02632175) are excluded. Mean duration of treatment was 184.2 days.

    Reporting group title
    Integrated Study (Main + Japan Sub- Study): Any Adalimumab
    Reporting group description
    		 Subjects receiving any adalimumab during Induction or Maintenance Phase. Any Adalimumab TEAEs: events with an onset date on or after first dose date of adalimumab and up to 70 days after the last dose date of adalimumab and prior to the first dose date in M10-870 if applicable, whichever comes first. For subjects who received placebo during the maintenance period, TEAE collection period ends 70 days after last induction dose of adalimumab and re-starts with their next adalimumab dose, if applicable. Mean duration of treatment was 256.3 days.

    Serious adverse events
    		 Integrated Study (Main + Japan Sub- Study): I-SD Integrated Study (Main + Japan Sub- Study): I-HD Integrated Study (Main + Japan Sub- Study): I-HD-OL Integrated Study (Main + Japan Sub- Study): M-SD Integrated Study (Main + Japan Sub- Study): M-HD Integrated Study (Main + Japan Sub- Study): M-PL Integrated Study (Main + Japan Sub- Study): Any Adalimumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 32 (15.63%)
    4 / 51 (7.84%)
    1 / 18 (5.56%)
    5 / 33 (15.15%)
    5 / 36 (13.89%)
    1 / 12 (8.33%)
    22 / 101 (21.78%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    HAND FRACTURE
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    1 / 36 (2.78%)
    0 / 12 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WRIST FRACTURE
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 51 (1.96%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    PERICARDITIS
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LOSS OF CONSCIOUSNESS
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    1 / 33 (3.03%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    3 / 101 (2.97%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    COLITIS ULCERATIVE
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 51 (3.92%)
    1 / 18 (5.56%)
    3 / 33 (9.09%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    10 / 101 (9.90%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    1 / 1
    0 / 4
    0 / 0
    0 / 0
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DYSPEPSIA
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    1 / 36 (2.78%)
    0 / 12 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ENTERITIS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    1 / 33 (3.03%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 51 (1.96%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    ERYTHEMA NODOSUM
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    1 / 36 (2.78%)
    0 / 12 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PSORIASIS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    1 / 12 (8.33%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    ENTERITIS INFECTIOUS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    1 / 33 (3.03%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    2 / 33 (6.06%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    2 / 101 (1.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MENINGITIS ASEPTIC
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    1 / 36 (2.78%)
    0 / 12 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PHARYNGITIS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    1 / 36 (2.78%)
    0 / 12 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    1 / 36 (2.78%)
    0 / 12 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Integrated Study (Main + Japan Sub- Study): I-SD Integrated Study (Main + Japan Sub- Study): I-HD Integrated Study (Main + Japan Sub- Study): I-HD-OL Integrated Study (Main + Japan Sub- Study): M-SD Integrated Study (Main + Japan Sub- Study): M-HD Integrated Study (Main + Japan Sub- Study): M-PL Integrated Study (Main + Japan Sub- Study): Any Adalimumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 32 (40.63%)
    16 / 51 (31.37%)
    14 / 18 (77.78%)
    15 / 33 (45.45%)
    20 / 36 (55.56%)
    10 / 12 (83.33%)
    65 / 101 (64.36%)
    Investigations
    C-REACTIVE PROTEIN INCREASED
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 51 (1.96%)
    0 / 18 (0.00%)
    3 / 33 (9.09%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    5 / 101 (4.95%)
         occurrences all number
    0
    1
    0
    3
    0
    0
    5
    HEPATIC ENZYME INCREASED
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    1 / 18 (5.56%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    MONOCYTE COUNT DECREASED
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    1 / 18 (5.56%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    1 / 18 (5.56%)
    1 / 33 (3.03%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    3
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    1 / 18 (5.56%)
    1 / 33 (3.03%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    3
    Injury, poisoning and procedural complications
    JOINT INJURY
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    1 / 12 (8.33%)
    0 / 101 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    4 / 32 (12.50%)
    5 / 51 (9.80%)
    4 / 18 (22.22%)
    6 / 33 (18.18%)
    2 / 36 (5.56%)
    2 / 12 (16.67%)
    19 / 101 (18.81%)
         occurrences all number
    4
    7
    6
    6
    2
    2
    28
    TREMOR
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 51 (1.96%)
    1 / 18 (5.56%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    3
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 32 (3.13%)
    3 / 51 (5.88%)
    1 / 18 (5.56%)
    2 / 33 (6.06%)
    1 / 36 (2.78%)
    1 / 12 (8.33%)
    9 / 101 (8.91%)
         occurrences all number
    1
    3
    1
    2
    1
    1
    9
    NEUTROPENIA
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    1 / 12 (8.33%)
    0 / 101 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    THROMBOCYTOSIS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    1 / 18 (5.56%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    General disorders and administration site conditions
    FATIGUE
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 51 (1.96%)
    0 / 18 (0.00%)
    2 / 33 (6.06%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    3 / 101 (2.97%)
         occurrences all number
    0
    1
    0
    2
    0
    0
    3
    INFLAMMATION
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    1 / 12 (8.33%)
    1 / 101 (0.99%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    PERIPHERAL SWELLING
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 51 (0.00%)
    1 / 18 (5.56%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    2
    PYREXIA
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 51 (1.96%)
    0 / 18 (0.00%)
    1 / 33 (3.03%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    5 / 101 (4.95%)
         occurrences all number
    2
    1
    0
    1
    0
    0
    5
    Eye disorders
    NONINFECTIVE CONJUNCTIVITIS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    1 / 12 (8.33%)
    1 / 101 (0.99%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 51 (3.92%)
    2 / 18 (11.11%)
    1 / 33 (3.03%)
    1 / 36 (2.78%)
    1 / 12 (8.33%)
    6 / 101 (5.94%)
         occurrences all number
    0
    2
    2
    3
    1
    1
    11
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 51 (3.92%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    2 / 36 (5.56%)
    0 / 12 (0.00%)
    4 / 101 (3.96%)
         occurrences all number
    1
    2
    0
    0
    2
    0
    5
    COLITIS ULCERATIVE
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    3 / 33 (9.09%)
    4 / 36 (11.11%)
    2 / 12 (16.67%)
    11 / 101 (10.89%)
         occurrences all number
    2
    0
    0
    3
    4
    2
    14
    CONSTIPATION
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    1 / 18 (5.56%)
    1 / 33 (3.03%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    2
    DIARRHOEA
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    1 / 18 (5.56%)
    0 / 33 (0.00%)
    1 / 36 (2.78%)
    0 / 12 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    2
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 51 (1.96%)
    1 / 18 (5.56%)
    0 / 33 (0.00%)
    1 / 36 (2.78%)
    0 / 12 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    3
    NAUSEA
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 51 (5.88%)
    1 / 18 (5.56%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    4 / 101 (3.96%)
         occurrences all number
    0
    3
    1
    0
    0
    0
    4
    VOMITING
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 51 (1.96%)
    1 / 18 (5.56%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    3 / 101 (2.97%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    3
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 51 (1.96%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    2 / 36 (5.56%)
    0 / 12 (0.00%)
    4 / 101 (3.96%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    6
    EPISTAXIS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    2 / 12 (16.67%)
    2 / 101 (1.98%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    2
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 51 (1.96%)
    2 / 18 (11.11%)
    2 / 33 (6.06%)
    1 / 36 (2.78%)
    0 / 12 (0.00%)
    7 / 101 (6.93%)
         occurrences all number
    1
    1
    2
    2
    1
    0
    8
    RHINITIS ALLERGIC
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    2 / 36 (5.56%)
    0 / 12 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    3
    RHINORRHOEA
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 51 (1.96%)
    1 / 18 (5.56%)
    1 / 33 (3.03%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    3 / 101 (2.97%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    3
    WHEEZING
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    1 / 12 (8.33%)
    1 / 101 (0.99%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Skin and subcutaneous tissue disorders
    DERMATITIS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    1 / 36 (2.78%)
    1 / 12 (8.33%)
    2 / 101 (1.98%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    2
    HANGNAIL
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    1 / 12 (8.33%)
    1 / 101 (0.99%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    RASH
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    1 / 18 (5.56%)
    1 / 33 (3.03%)
    2 / 36 (5.56%)
    0 / 12 (0.00%)
    4 / 101 (3.96%)
         occurrences all number
    0
    0
    1
    1
    2
    0
    4
    Renal and urinary disorders
    GLYCOSURIA
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    1 / 18 (5.56%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 51 (0.00%)
    1 / 18 (5.56%)
    0 / 33 (0.00%)
    1 / 36 (2.78%)
    0 / 12 (0.00%)
    3 / 101 (2.97%)
         occurrences all number
    1
    0
    1
    0
    1
    0
    3
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    1 / 12 (8.33%)
    0 / 101 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    1 / 18 (5.56%)
    1 / 33 (3.03%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    2
    GASTROENTERITIS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    1 / 12 (8.33%)
    1 / 101 (0.99%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    INFLUENZA
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    2 / 36 (5.56%)
    0 / 12 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    2
    NASOPHARYNGITIS
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 51 (3.92%)
    1 / 18 (5.56%)
    3 / 33 (9.09%)
    4 / 36 (11.11%)
    1 / 12 (8.33%)
    12 / 101 (11.88%)
         occurrences all number
    2
    2
    2
    4
    4
    1
    18
    PHARYNGITIS
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 51 (1.96%)
    1 / 18 (5.56%)
    2 / 33 (6.06%)
    1 / 36 (2.78%)
    1 / 12 (8.33%)
    9 / 101 (8.91%)
         occurrences all number
    2
    1
    1
    2
    1
    3
    10
    RESPIRATORY TRACT INFECTION VIRAL
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    1 / 12 (8.33%)
    1 / 101 (0.99%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    STREPTOCOCCAL INFECTION
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    1 / 18 (5.56%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    2
    TOOTH ABSCESS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    0 / 18 (0.00%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    1 / 12 (8.33%)
    1 / 101 (0.99%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 51 (5.88%)
    0 / 18 (0.00%)
    2 / 33 (6.06%)
    4 / 36 (11.11%)
    2 / 12 (16.67%)
    10 / 101 (9.90%)
         occurrences all number
    0
    4
    0
    3
    4
    2
    13
    VIRAL INFECTION
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    1 / 18 (5.56%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    VULVOVAGINAL MYCOTIC INFECTION
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 51 (0.00%)
    1 / 18 (5.56%)
    0 / 33 (0.00%)
    0 / 36 (0.00%)
    0 / 12 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Sep 2013
    Major changes included: revised the time points of blood sampling measurements for adalimumab concentrations and anti-adalimumab antibodies; revised exclusion criteria and prohibited therapy to clarify that rectal medication for bowel preparation prior to endoscopy was permitted; revised exclusion criteria and concomitant therapy in terms of the number of days that subjects needed to be on stable dose of oral aminosalicylates prior to Baseline; revised study procedures to clarify the process of adjudication to evaluate subject's eligibility for the study and to clarify that subjects who prematurely discontinue from the study before or at Week 26 do not have to undergo an endoscopy at the Premature Discontinuation Visit; ePRO and data collection process details were added.
    02 Apr 2014
    Major changes included: added information about a Japan Substudy with inclusion of approximately 20 subjects; revised steroid tapering requirements; replaced inadequate response criteria with disease flare criteria; clarified Inclusion Criterion 2 regarding the diagnosis of ulcerative colitis confirmed by endoscopy; revised Inclusion Criterion 3 regarding methotrexate dosing requirement; added information of antibiotics use in prior therapy and concomitant therapy.
    28 Aug 2015
    Major changes included: revised steroid tapering requirements to allow tapering schedule based on investigator's discretion; revised time point to allow increasing dose of corticosteroid after corticosteroid taper was initiated;revised time point allowing initiation of treatment with corticosteroids, immunosuppressants or aminosalicylates; revised disease flare criteria and time point that rescue therapy based on disease flare could be initiated; updated Inclusion Criterion 2 to clarify the requirement for endoscopy during the Screening period; revised Inclusion Criterion 3 to add guidance on use of 6-Thioguanine nucleotide levels and revised the required timeline for previous treatment with corticosteroids or immunosuppressants; clarified Exclusion Criterion 24 regarding Hepatitis B; added fecal transplantation within 30 days prior to the Baseline visit to Exclusion Criterion 26; added vedolizumab to the list of prohibited medications; removed stool sample collection for fecal calprotectin and microbiota; removed the collection of serum bone markers; added information about the use of NRI.
    02 Nov 2017
    Major changes included: ceased randomization to double-blind induction treatment and enrollment into the standard induction dose group (all subsequent subjects who enter the study were to receive open-label high induction dose); ceased randomization to the internal placebo arm from the maintenance period and modified study endpoints and statistical analyses to reflect said change; reduced the number of planned subjects from approximately 225 (and approximately 20 subjects in the Japan Substudy) to approximately 85 subjects (and up to approximately 20 subjects in the Japan Substudy).
    20 Nov 2018
    Major changes included: modified statistical analyses and ranking of study endpoints; reflected final sample size of 93 subjects (and up to approximately 9 subjects in the Japan Substudy).

    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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