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    Clinical Trial Results:
    An Open-Label, Multicenter, Efficacy and Safety Study to Evaluate Two Treatment Algorithms in Subjects with Moderate to Severe Crohn's Disease

    Summary
    EudraCT number
    2010-020137-10
    Trial protocol
    GB   DE   SE   CZ   AT   ES   FR   BE   IT   NL   HU   LT  
    Global end of trial date
    05 Jan 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    31 Dec 2017
    First version publication date
    31 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M11-271
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01235689
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Abbvie Deutschland GmbH & Co.KG
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Maidenhead, Berkshire, United Kingdom, SL6-4UB
    Public contact
    Global Medical Services, AbbVie Ltd., 011 800-633-9110,
    Scientific contact
    Anne Robinson, Pharm.D., AbbVie, anne.robinson@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
    03 Jan 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to demonstrate that tight control of disease activity, using stringent criteria based on Crohn's disease activity Index (CDAI), biomarkers (high sensitivity C-reactive protein [hs-CRP] and fecal calprotectin), and corticosteroid use, improves the rate of mucosal healing 48 weeks after randomization compared with management using less stringent criteria based only on CDAI and corticosteroid use.
    Protection of trial subjects
    All subjects entering the study had to sign an informed consent that was explained to them and questions encouraged.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Nov 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 31
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Sweden: 8
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Belgium: 38
    Country: Number of subjects enrolled
    Czech Republic: 30
    Country: Number of subjects enrolled
    France: 19
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Japan: 3
    Country: Number of subjects enrolled
    Romania: 12
    Country: Number of subjects enrolled
    South Africa: 4
    Country: Number of subjects enrolled
    Switzerland: 8
    Country: Number of subjects enrolled
    Turkey: 14
    Country: Number of subjects enrolled
    Ukraine: 21
    Country: Number of subjects enrolled
    Lithuania: 1
    Country: Number of subjects enrolled
    Russian Federation: 3
    Worldwide total number of subjects
    252
    EEA total number of subjects
    178
    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)
    248
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted at 59 sites in Canada, European Union, Israel, Japan, Russia, South Africa, Switzerland, Turkey, and the Ukraine. The study included a screening period, up to 8 weeks of prednisone run-in treatment, a 48-week postrandomization treatment period, and a 70 day follow-up phone call or clinic visit.

    Pre-assignment
    Screening details
    A total of 252 participants were enrolled and received study treatment, of whom • 165 entered the prednisone run-in ◦ 157 randomized (45 prior to Week 9, 112 at Week 9) ◦ 8 discontinued prior to randomization. • 87 randomized at Baseline. Randomization was stratified by smoking status, weight, and disease duration.

    Pre-assignment period milestones [1]
    Number of subjects started
    252
    Intermediate milestone: Number of subjects
    Entered prednisone run-in: 165
    Intermediate milestone: Number of subjects
    Completed prednisone run-in: 157
    Number of subjects completed
    244

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Consent withdrawn by subject: 1
    Reason: Number of subjects
    Lost to follow-up: 1
    Reason: Number of subjects
    Use of prohibited drug: 1
    Reason: Number of subjects
    Did not meet inclusion/exclusion criteria: 2
    Reason: Number of subjects
    Pregnancy: 1
    Reason: Number of subjects
    Adverse event, non-fatal: 2
    Notes
    [1] - The number of subjects at the milestone is less than the number that completed the pre-assignment period. It is expected the number of subjects at the milestones will be greater than, or equal to the number that completed the pre-assignment period.
    Justification: The Number Started indicates the total number of subjects enrolled in the study and the Number Completed indicates the number of subjects who were randomized. The intermediate milestones represent subjects who entered and completed the prednisone run-in phase prior to randomization.
    Period 1
    Period 1 title
    Post-randomization Treatment Period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Clinically Driven
    Arm description
    Participants randomized to receive management of disease activity using criteria based on Crohn's Disease Activity Index (CDAI) and corticosteroid use. Participants received customized therapy that could include prednisone, adalimumab, and azathioprine. Participants who randomized at Week 9 meeting success criteria started with no therapy; participants who randomized prior to Week 9 or who randomized at Week 9 but did not meet the success criteria began treatment with adalimumab. Therapy was escalated according to pre-specified failure criteria using less stringent criteria: At Key Visit 1 the criteria for management of disease activity were a CDAI decrease ≥ 70 (CR-70) compared to Baseline or CDAI < 200 at 1 week prior to the visit. At Key Visits 3, 4, and 5 (every 12 weeks after Key visit 1), the criteria for a change in treatment were a CDAI decrease of ≥ 100 (CR-100) compared to Baseline or CDAI < 200, and absence of prednisone during the preceding week.
    Arm type
    Experimental

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    ABT-D2E7
    Other name
    Humira
    Pharmaceutical forms
    Suspension for injection in pre-filled injector
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    160 mg induction dose the first week, followed by 80 mg 2 weeks later, followed by 40 mg every other week as a maintenance dose. The dose of adalimumab was increased from 40 mg eow to 40 mg every week in participants with an inadequate response and de-escalated to 40 mg eow in participants who met success criteria.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The suggested regimen for subjects initiating prednisone consists of a maximum dose of prednisone 40 mg/day for 2 weeks, followed by a fixed taper for 6 weeks.

    Investigational medicinal product name
    Azathioprine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with normal thiopurine methyltransferase (TPMT) enzyme activity could receive oral azathioprine 2.5 mg/kg/day. In participants with intermediate TPMT enzyme activity azathioprine was initiated at a dose of 1.25 mg/kg/day. The dose of azathioprine was adjusted according to abnormalities of white blood cell (WBC) count, platelet count, liver function tests (LFTs; i.e. alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase), lipase, blood urea nitrogen (BUN), and serum creatinine.

    Arm title
    Tight Control
    Arm description
    Participants randomized to receive management of disease activity using criteria based on Crohn's Disease Activity Index (CDAI), high sensitivity C-reactive protein (hs-CRP), fecal calprotectin, and corticosteroid use. Participants received customized therapy that could include prednisone, adalimumab, and azathioprine. Participants who randomized at Week 9 meeting success criteria started with no therapy; participants who randomized prior to Week 9 or who randomized at Week 9 but did not meet the success criteria began treatment with adalimumab. Therapy was escalated according to pre-specified tight control criteria: At Key Visit 1 the success criteria were CDAI < 150, hs-CRP, < 5 mg/L, fecal calprotectin < 250 μg/g, and absence of prednisone use. At Key Visits 3, 4, and 5 (every 12 weeks after Key visit 1), the criteria were CDAI < 150, hs-CRP < 5 mg/L, fecal calprotectin < 250 μg/g, and absence of prednisone during the preceding week.
    Arm type
    Experimental

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Suspension for injection in pre-filled injector
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    If adalimumab was initiated, it was administered subcutaneously as a 160 mg induction dose the first week, followed by 80 mg 2 weeks later, followed by 40 mg every other week as a maintenance dose. The dose of adalimumab was increased from 40 mg eow to 40 mg every week in participants with an inadequate response and de-escalated to 40 mg eow in participants who met success criteria.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The suggested regimen for participants initiating prednisone consisted of a maximum dose of prednisone 40 mg/day for 2 weeks, followed by a fixed taper for 6 weeks.

    Investigational medicinal product name
    Azathioprine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with normal thiopurine methyltransferase (TPMT) enzyme activity could receive oral azathioprine 2.5 mg/kg/day. In participants with intermediate TPMT enzyme activity azathioprine was initiated at a dose of 1.25 mg/kg/day. The dose of azathioprine was adjusted according to abnormalities of white blood cell (WBC) count, platelet count, liver function tests (LFTs; i.e. alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase), lipase, blood urea nitrogen (BUN), and serum creatinine.

    Number of subjects in period 1 [2]
    Clinically Driven Tight Control
    Started
    122
    122
    - Early Randomized (Baseline to Week 9)
    63 [3]
    69 [4]
    - Randomized at Week 9
    59 [5]
    53 [6]
    Completed
    93
    90
    Not completed
    29
    32
         Miscellaneous
             1
             5
         Lack of efficacy
             12
             5
         Adverse event, non-fatal
             12
             16
         Consent withdrawn by subject
             3
             4
         Lost to follow-up
             1
             2
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 252 participants were enrolled and received study treatment. Eighty-seven participants randomized prior to Week 9 and 165 participants entered the prednisone run-in, of whom 157 completed and randomized at Week 9 (total 244 randomized) and 8 discontinued.
    [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: Subset of randomized subjects who were randomized from Baseline to Week 9.
    [4] - 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: Subset of randomized subjects who were randomized from Baseline to Week 9.
    [5] - 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: Subset of randomized subjects who randomized at Week 9.
    [6] - 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: Subset of randomized subjects who randomized at Week 9.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Clinically Driven
    Reporting group description
    Participants randomized to receive management of disease activity using criteria based on Crohn's Disease Activity Index (CDAI) and corticosteroid use. Participants received customized therapy that could include prednisone, adalimumab, and azathioprine. Participants who randomized at Week 9 meeting success criteria started with no therapy; participants who randomized prior to Week 9 or who randomized at Week 9 but did not meet the success criteria began treatment with adalimumab. Therapy was escalated according to pre-specified failure criteria using less stringent criteria: At Key Visit 1 the criteria for management of disease activity were a CDAI decrease ≥ 70 (CR-70) compared to Baseline or CDAI < 200 at 1 week prior to the visit. At Key Visits 3, 4, and 5 (every 12 weeks after Key visit 1), the criteria for a change in treatment were a CDAI decrease of ≥ 100 (CR-100) compared to Baseline or CDAI < 200, and absence of prednisone during the preceding week.

    Reporting group title
    Tight Control
    Reporting group description
    Participants randomized to receive management of disease activity using criteria based on Crohn's Disease Activity Index (CDAI), high sensitivity C-reactive protein (hs-CRP), fecal calprotectin, and corticosteroid use. Participants received customized therapy that could include prednisone, adalimumab, and azathioprine. Participants who randomized at Week 9 meeting success criteria started with no therapy; participants who randomized prior to Week 9 or who randomized at Week 9 but did not meet the success criteria began treatment with adalimumab. Therapy was escalated according to pre-specified tight control criteria: At Key Visit 1 the success criteria were CDAI < 150, hs-CRP, < 5 mg/L, fecal calprotectin < 250 μg/g, and absence of prednisone use. At Key Visits 3, 4, and 5 (every 12 weeks after Key visit 1), the criteria were CDAI < 150, hs-CRP < 5 mg/L, fecal calprotectin < 250 μg/g, and absence of prednisone during the preceding week.

    Reporting group values
    Clinically Driven Tight Control Total
    Number of subjects
    122 122 244
    Age categorical
    Units: Subjects
        < 40 years
    97 96 193
        40 to < 65 years
    23 24 47
        ≥ 65 years
    2 2 4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    31.10 ± 11.40 32.10 ± 11.97 -
    Gender categorical
    Units: Subjects
        Female
    69 72 141
        Male
    53 50 103
    Race
    Units: Subjects
        White
    113 113 226
        Black
    2 3 5
        Asian
    3 2 5
        American Indian/Alaska Native
    0 0 0
        Native Hawaiian or other Pacific Islander
    0 0 0
        Multi-race
    1 1 2
        Other
    3 3 6
    Weight
    Units: Subjects
        < 70 kg
    79 81 160
        ≥ 70 kg
    43 41 84
    Current Tobacco Use
    Units: Subjects
        Yes
    33 31 64
        No
    89 91 180
    Disease Duration
    Units: Subjects
        ≤ 2 years
    106 106 212
        > 2 years
    16 16 32
    Crohn's Disease Endoscopy Index of Severity (CDEIS)
    Measure Description: CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon (ileum, ascending colon, transverse colon, descending colon and sigmoid loop, and rectum). The score ranges from 0 to 44 where higher scores indicate more severe endoscopic activity.
    Units: units on a scale
        arithmetic mean (standard deviation)
    14.26 ± 6.925 13.38 ± 6.049 -
    Crohn's Disease Activity Index (CDAI)
    CDAI is a tool used to quantify the symptoms of patients with Crohn's disease. Participants were asked to record the frequency of stools, abdominal pain and general well-being on a daily basis. In addition to the diary data, the investigator assessed the following for the calculation of CDAI: presence of complications, the use of antidiarrheal medicines, presence of an abdominal mass, hematocrit, and body weight. The CDAI is the sum of the products of each item multiplied by a weighting factor and generally ranges from 0 up to 600, where higher scores indicate more severe disease.
    Units: units on a scale
        arithmetic mean (standard deviation)
    267.7 ± 58.35 273.3 ± 59.48 -

    End points

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    End points reporting groups
    Reporting group title
    Clinically Driven
    Reporting group description
    Participants randomized to receive management of disease activity using criteria based on Crohn's Disease Activity Index (CDAI) and corticosteroid use. Participants received customized therapy that could include prednisone, adalimumab, and azathioprine. Participants who randomized at Week 9 meeting success criteria started with no therapy; participants who randomized prior to Week 9 or who randomized at Week 9 but did not meet the success criteria began treatment with adalimumab. Therapy was escalated according to pre-specified failure criteria using less stringent criteria: At Key Visit 1 the criteria for management of disease activity were a CDAI decrease ≥ 70 (CR-70) compared to Baseline or CDAI < 200 at 1 week prior to the visit. At Key Visits 3, 4, and 5 (every 12 weeks after Key visit 1), the criteria for a change in treatment were a CDAI decrease of ≥ 100 (CR-100) compared to Baseline or CDAI < 200, and absence of prednisone during the preceding week.

    Reporting group title
    Tight Control
    Reporting group description
    Participants randomized to receive management of disease activity using criteria based on Crohn's Disease Activity Index (CDAI), high sensitivity C-reactive protein (hs-CRP), fecal calprotectin, and corticosteroid use. Participants received customized therapy that could include prednisone, adalimumab, and azathioprine. Participants who randomized at Week 9 meeting success criteria started with no therapy; participants who randomized prior to Week 9 or who randomized at Week 9 but did not meet the success criteria began treatment with adalimumab. Therapy was escalated according to pre-specified tight control criteria: At Key Visit 1 the success criteria were CDAI < 150, hs-CRP, < 5 mg/L, fecal calprotectin < 250 μg/g, and absence of prednisone use. At Key Visits 3, 4, and 5 (every 12 weeks after Key visit 1), the criteria were CDAI < 150, hs-CRP < 5 mg/L, fecal calprotectin < 250 μg/g, and absence of prednisone during the preceding week.

    Primary: Percentage of Participants With Mucosal Healing and No Deep Ulcerations

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    End point title
    Percentage of Participants With Mucosal Healing and No Deep Ulcerations
    End point description
    Percentage of participants with mucosal healing (defined as Crohn's disease endoscopy Index of severity [CDEIS] < 4) and no deep ulcerations on ileocolonoscopy (defined as the absence of all deep ulcerations in all segments explored in CDEIS) at 48 weeks after randomization (48 weeks after the 1st Key visit). The ileocolonoscopies were evaluated by the site. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon (ileum, ascending colon, transverse colon, descending colon and sigmoid loop, and rectum). The score ranges from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing data 48 weeks after Randomization were counted as non-responders.
    End point type
    Primary
    End point timeframe
    48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: percentage of participants
        number (not applicable)
    30.3
    45.9
    Statistical analysis title
    Analysis of Mucosal Healing and No Deep Ulceration
    Comparison groups
    Tight Control v Clinically Driven
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.01 [1]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [1] - Cochran-Mantel-Haenszel (CMH) test stratified by Screening smoking status (yes or no) and weight (< 70 kg or ≥ 70 kg).

    Secondary: Percentage of Participants in Deep Remission 48 Weeks After Randomization

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    End point title
    Percentage of Participants in Deep Remission 48 Weeks After Randomization
    End point description
    Deep remission was defined as CDAI < 150, discontinuation from steroids for at least 8 weeks, absence of draining fistula, CDEIS < 4 and no deep ulcerations. CDAI is a tool used to quantify the symptoms of patients with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI generally ranges from 0 to 600 where higher scores indicate more severe disease. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing data 48 weeks after randomization were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: percentage of participants
        number (not applicable)
    23.0
    36.9
    Statistical analysis title
    Analysis of Deep Remission
    Comparison groups
    Clinically Driven v Tight Control
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.014 [2]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [2] - CMH test stratified by screening smoking status (yes or no) and weight (< 70 kg, ≥ 70 kg).

    Secondary: Percentage of Participants in Biologic Remission 48 Weeks After Randomization

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    End point title
    Percentage of Participants in Biologic Remission 48 Weeks After Randomization
    End point description
    Biologic remission was defined as high sensitivity C-reactive protein (hs-CRP) < 5 mg/L, fecal Calprotectin < 250 μg/g, and CDEIS < 4 at 48 weeks after randomization. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing values 48 weeks after Randomization were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: percentage of participants
        number (not applicable)
    15.6
    29.5
    Statistical analysis title
    Analysis of Biologic Remission
    Comparison groups
    Clinically Driven v Tight Control
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.006 [3]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [3] - CMH test stratified by screening smoking status (yes or no) and weight (< 70 kg, ≥ 70 kg).

    Secondary: Percentage of Participants With Mucosal Healing 48 Weeks After Randomization

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    End point title
    Percentage of Participants With Mucosal Healing 48 Weeks After Randomization
    End point description
    Percentage of participants with mucosal healing (defined as a CDEIS < 4) at 48 weeks after randomization (48 weeks after the 1st Key visit). The ileocolonoscopies were evaluated by the site. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing values 48 weeks after Randomization were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: percentage of participants
        number (not applicable)
    30.3
    45.9
    Statistical analysis title
    Analysis of Mucosal Healing
    Comparison groups
    Clinically Driven v Tight Control
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.01 [4]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [4] - CMH test stratified by screening smoking status (yes or no) and weight (< 70 kg, ≥ 70 kg).

    Secondary: Percentage of Participants With Mucosal Healing and CDEIS < 4 in Every Segment 48 Weeks After Randomization

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    End point title
    Percentage of Participants With Mucosal Healing and CDEIS < 4 in Every Segment 48 Weeks After Randomization
    End point description
    Percentage of participants with mucosal healing (defined as CDEIS < 4) and CDEIS < 4 in every segment on ileocolonoscopy at 48 weeks after randomization. The ileocolonoscopies were evaluated by the site. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing values 48 weeks after randomization were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: percentage of participants
        number (not applicable)
    23.8
    29.5
    Statistical analysis title
    Analysis of Mucosal Healing and CDEIS < 4
    Comparison groups
    Clinically Driven v Tight Control
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.299 [5]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [5] - CMH test stratified by screening smoking status (yes or no) and weight (< 70 kg, ≥ 70 kg).

    Secondary: Percentage of Participants With Complete Mucosal Healing 48 Weeks After Randomization

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    End point title
    Percentage of Participants With Complete Mucosal Healing 48 Weeks After Randomization
    End point description
    Complete mucosal healing was defined as CDEIS = 0. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing values 48 weeks after randomization were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: percentage of participants
        number (not applicable)
    16.4
    18.0
    Statistical analysis title
    Analysis of Complete Mucosal Healing
    Comparison groups
    Clinically Driven v Tight Control
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.728 [6]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [6] - CMH test stratified by screening smoking status (yes or no) and weight (< 70 kg, ≥ 70 kg).

    Secondary: Percentage of Participants With Endoscopic Response 48 Weeks After Randomization

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    End point title
    Percentage of Participants With Endoscopic Response 48 Weeks After Randomization
    End point description
    Endoscopic response was defined as a decrease CDEIS > 5 points. CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon. The range of the score is from 0 to 44 where higher scores indicate more severe endoscopic activity. Participants with missing values 48 weeks after Randomization were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: percentage of participants
        number (not applicable)
    40.2
    50.8
    Statistical analysis title
    Analysis of Endoscopic Response
    Comparison groups
    Clinically Driven v Tight Control
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.067 [7]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [7] - CMH test stratified by screening smoking status (yes or no) and weight (< 70 kg, ≥ 70 kg).

    Secondary: Change From Baseline in CDEIS at 48 Weeks After Randomization

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    End point title
    Change From Baseline in CDEIS at 48 Weeks After Randomization
    End point description
    CDEIS is an index for determining the severity of Crohn's disease. The CDEIS considers deep ulcerations, superficial ulcerations, ulcerated and non-ulcerated surface, and the presence of ulcerated/non-ulcerated stenosis evaluated in 5 pre-defined segments of the colon (ileum, ascending colon, transverse colon, descending colon and sigmoid loop, and rectum). The score ranges from 0 to 44 where higher scores indicate more severe endoscopic activity. A negative change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    96 [8]
    105 [9]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -6.4 ± 7.69
    -7.7 ± 7.25
    Notes
    [8] - Randomized participants with non-missing data at Baseline and 48 weeks after Randomization
    [9] - Randomized participants with non-missing data at Baseline and 48 weeks after Randomization
    Statistical analysis title
    Analysis of Change From Baseline in CDEIS
    Comparison groups
    Clinically Driven v Tight Control
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.116 [10]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.2
         upper limit
    0.4
    Notes
    [10] - Model included factors for treatment group, screening smoking status (yes or no), and weight (< 70 kg, ≥ 70 kg), and Baseline values as covariate.

    Secondary: Change From Baseline in CDAI Over Time

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    End point title
    Change From Baseline in CDAI Over Time
    End point description
    CDAI is used to quantify the symptoms of patients with Crohn's disease. Participants were asked to record the frequency of stools, abdominal pain and general well-being on a daily basis. In addition to the diary data, the investigator assessed the following for the calculation of CDAI: 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 the sum of the products of each item multiplied by a weighting factor and generally ranges from 0 up to 600, where remission of Crohn's disease is defined as CDAI < 150, and severe disease is defined as CDAI > 450. A negative change from Baseline indicates improvement. CDAI was only measured at 14, 18, 26, 30, 38 and 42 weeks after randomization if a participant had initiated a change in treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 and 8 weeks during the prednisone run-in, and 2, 6, 11, 14, 18, 23, 26, 30, 35, 38, 42, and 48 weeks after Randomization.
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122 [11]
    122 [12]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Week 4 of Prednisone Run-in (N = 79, 76)
    -78.3 ± 80.02
    -90.9 ± 81.53
        Week 8 of Prednisone Run-in (N = 62, 54)
    -64.2 ± 90.48
    -105.5 ± 88.40
        2 Weeks After Randomization (N = 95, 110)
    -80.2 ± 82.27
    -110.1 ± 85.06
        6 Weeks After Randomization (N = 100, 110)
    -93.1 ± 100.81
    -130.8 ± 89.40
        11 Weeks After Randomization (N = 114, 115)
    -103.5 ± 98.65
    -141.0 ± 97.82
        14 Weeks After Randomization (N = 26, 16)
    -71.1 ± 89.18
    -101.2 ± 115.90
        18 Weeks After Randomization (N = 27, 16)
    -69.9 ± 78.95
    -112.0 ± 115.01
        23 Weeks After Randomization (N = 97, 107)
    -143.3 ± 97.83
    -154.1 ± 101.63
        26 Weeks After Randomization (N = 20, 42)
    -71.8 ± 129.09
    -135.7 ± 112.43
        30 Weeks After Randomization (N = 20, 42)
    -47.9 ± 143.75
    -143.8 ± 103.54
        35 Weeks After Randomization (N = 92, 95)
    -140.4 ± 104.83
    -166.4 ± 93.12
        38 Weeks After Randomization (N = 15, 19)
    -60.8 ± 83.51
    -132.8 ± 103.15
        42 Weeks After Randomization (N = 11, 16)
    -76.8 ± 78.53
    -107.4 ± 99.19
        48 Weeks After Randomization (N = 82, 90)
    -146.2 ± 102.87
    -175.8 ± 97.69
    Notes
    [11] - Randomized participants with non-missing data at each time point.
    [12] - Randomized participants with non-missing data at each time point.
    No statistical analyses for this end point

    Secondary: Time to Crohn's Disease Flare

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    End point title
    Time to Crohn's Disease Flare
    End point description
    Time to Crohn's disease flare, where flare is defined as an increase in CDAI ≥ 70 points compared to Week 8 or Early Randomization CDAI, and a CDAI > 220. "99999" indicates data that could not be estimated due to the low number of events.
    End point type
    Secondary
    End point timeframe
    From Randomization to 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: days
        median (inter-quartile range (Q1-Q3))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Analysis of Time to Crohn's Disease Flare
    Comparison groups
    Clinically Driven v Tight Control
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.012
    Method
    Regression, Cox
    Parameter type
    Cox proportional hazard
    Point estimate
    0.442
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.2
         upper limit
    0.8

    Secondary: Time to Clinical Remission

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    End point title
    Time to Clinical Remission
    End point description
    Clinical remission was defined as CDAI < 150. CDAI is a tool used to quantify the symptoms of patients with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI scores generally range from 0 to 600 where higher scores indicate more severe disease.
    End point type
    Secondary
    End point timeframe
    From Randomization through 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: days
        median (inter-quartile range (Q1-Q3))
    78 (28 to 163)
    43 (15 to 101)
    Statistical analysis title
    Analysis of Time to Clinical Remission
    Comparison groups
    Clinically Driven v Tight Control
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.008
    Method
    Regression, Cox
    Parameter type
    Cox proportional hazard
    Point estimate
    1.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.1
         upper limit
    1.9

    Secondary: Time to Steroid-free Remission

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    End point title
    Time to Steroid-free Remission
    End point description
    Steroid-free remission was defined as CDAI < 150 and discontinuation from steroids for at least 8 weeks. CDAI is a tool used to quantify the symptoms of patients with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI generally ranges from 0 to 600 where higher scores indicate more severe disease.
    End point type
    Secondary
    End point timeframe
    From Randomization through 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: days
        median (inter-quartile range (Q1-Q3))
    162 (80 to 255)
    159 (78 to 168)
    Statistical analysis title
    Analysis of Time to Steroid-free Remission
    Comparison groups
    Clinically Driven v Tight Control
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.052
    Method
    Regression, Cox
    Parameter type
    Cox proportional hazard
    Point estimate
    1.337
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1
         upper limit
    1.8

    Secondary: Percentage of Participants in Clinical Remission Over Time

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    End point title
    Percentage of Participants in Clinical Remission Over Time
    End point description
    Clinical remission was defined as CDAI < 150. CDAI is a tool used to quantify the symptoms of patients with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI generally ranges from 0 to 600 where higher scores indicate more severe disease. Participants with missing data at each time point were counted as non-responders. CDAI was only measured at 14, 18, 26, 30, 38 and 42 weeks after randomization if a participant had initiated a change in treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 and 8 weeks during the prednisone run-in, and 2, 6, 11, 14, 18, 23, 26, 30, 35, 38, 42, and 48 weeks after Randomization.
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: percentage of particiapnts
    number (not applicable)
        Week 4 of Prednisone Run-in
    24.6
    30.3
        Week 8 of Prednisone Run-in
    14.8
    22.1
        2 Weeks After Randomization
    23.8
    41.0
        6 Weeks After Randomization
    32.8
    47.5
        11 Weeks After Randomization
    41.8
    62.3
        14 Weeks After Randomization
    8.2
    6.6
        18 Weeks After Randomization
    9.0
    8.2
        23 Weeks After Randomization
    50.8
    65.6
        26 Weeks After Randomization
    4.1
    20.5
        30 Weeks After Randomization
    3.3
    23.0
        35 Weeks After Randomization
    45.1
    59.8
        38 Weeks After Randomization
    4.1
    9.0
        42 Weeks After Randomization
    4.1
    7.4
        48 Weeks After Randomization
    43.4
    59.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants in Steroid-free Remission Over Time

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    End point title
    Percentage of Participants in Steroid-free Remission Over Time
    End point description
    Steroid-free remission was defined as CDAI < 150 and discontinuation from steroids for at least 8 weeks. CDAI is a tool used to quantify the symptoms of patients with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI generally ranges from 0 to 600 where higher scores indicate more severe disease. Participants with missing data at each time point were counted as non-responders. CDAI was only measured at 14, 18, 26, 30, 38 and 42 weeks after randomization if a participant had initiated a change in treatment.
    End point type
    Secondary
    End point timeframe
    11, 14, 18, 23, 26, 30, 35, 38, 42, and 48 weeks after Randomization.
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: percentage of participants
    number (not applicable)
        11 Weeks After Randomization
    23.8
    39.3
        14 Weeks After Randomization
    4.1
    4.9
        18 Weeks After Randomization
    3.3
    7.4
        23 Weeks After Randomization
    45.1
    63.1
        26 Weeks After Randomization
    2.5
    18.9
        30 Weeks After Randomization
    0.8
    21.3
        35 Weeks After Randomization
    42.6
    59.0
        38 Weeks After Randomization
    4.1
    9.0
        42 Weeks After Randomization
    4.1
    7.4
        48 Weeks After Randomization
    39.3
    59.8
    No statistical analyses for this end point

    Secondary: Time to All-cause Hospitalization

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    End point title
    Time to All-cause Hospitalization
    End point description
    Hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic. "99999" indicates values that could not be estimated due to the low number of hospitalization events.
    End point type
    Secondary
    End point timeframe
    From Randomization through 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: days
        median (inter-quartile range (Q1-Q3))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Analysis of Time to All-cause Hospitalization
    Comparison groups
    Tight Control v Clinically Driven
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.501
    Method
    Regression, Cox
    Parameter type
    Cox proportional hazard
    Point estimate
    0.823
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    1.5

    Secondary: Time to Crohn's Disease-related Hospitalization or Hospitalization Due to Adverse Event Relating to Study Medication

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    End point title
    Time to Crohn's Disease-related Hospitalization or Hospitalization Due to Adverse Event Relating to Study Medication
    End point description
    Crohn's disease-related hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic for reasons related to Crohn's disease (CD). Hospitalization for adverse events relating to study medication, i.e., prednisone, azathioprine or adalimumab, were according to Investigator's clinical judgment. "99999" indicates values that could not be estimated due to the low number of hospitalization events.
    End point type
    Secondary
    End point timeframe
    From Randomization through 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: days
        median (inter-quartile range (Q1-Q3))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Analysis of Time to Hospitalization
    Comparison groups
    Clinically Driven v Tight Control
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.459
    Method
    Regression, Cox
    Parameter type
    Cox proportional hazard
    Point estimate
    0.785
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    1.5

    Secondary: Number of Major Crohn's Disease-related Surgeries After Randomization

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    End point title
    Number of Major Crohn's Disease-related Surgeries After Randomization
    End point description
    Major Crohn's disease-related intra-abdominal surgery included: • bowel resection • ostomy • by-pass • strictureplasty • drainage of abdominal or pelvic abscess (surgical drainage or percutaneous drainage by interventional radiology). The following were excluded: • debridement • exploration laparotomy • abdominal surgery for other reason • perineal related surgery • abscess drainage • placement of setons • fistulotomy • Total parental nutrition (TPN) use
    End point type
    Secondary
    End point timeframe
    From Randomization through 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: surgeries
    3
    6
    No statistical analyses for this end point

    Secondary: Number of Crohn's Disease-related Hospitalizations After Randomization

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    End point title
    Number of Crohn's Disease-related Hospitalizations After Randomization
    End point description
    Any hospitalization with an overnight stay in hospital/clinic related to Crohn's disease.
    End point type
    Secondary
    End point timeframe
    From Randomization through 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: hospitalizations
    29
    14
    No statistical analyses for this end point

    Secondary: Number of All-cause Hospitalizations After Randomization

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    End point title
    Number of All-cause Hospitalizations After Randomization
    End point description
    Hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic.
    End point type
    Secondary
    End point timeframe
    From Randomization through 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: hospitalizations
    37
    25
    No statistical analyses for this end point

    Secondary: Total Length of Stay in Hospital for All-cause Hospitalizations

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    End point title
    Total Length of Stay in Hospital for All-cause Hospitalizations
    End point description
    End point type
    Secondary
    End point timeframe
    From Randomization through 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    26 [13]
    22 [14]
    Units: days
        arithmetic mean (standard deviation)
    40.2 ± 45.72
    50.1 ± 85.69
    Notes
    [13] - Randomized participants with all-cause hospitalizations
    [14] - Randomized participants with all-cause hospitalizations
    No statistical analyses for this end point

    Secondary: Total Length of Stay in Hospital for Crohn's Disease-related Hospitalizations

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    End point title
    Total Length of Stay in Hospital for Crohn's Disease-related Hospitalizations
    End point description
    End point type
    Secondary
    End point timeframe
    From Randomization through 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    21 [15]
    13 [16]
    Units: days
        arithmetic mean (standard deviation)
    9.8 ± 7.21
    15.8 ± 20.39
    Notes
    [15] - Randomized participants with Crohn's disease-related hospitalizations
    [16] - Randomized participants with Crohn's disease-related hospitalizations
    No statistical analyses for this end point

    Secondary: Number of Crohn's Disease-related Surgical Procedures After Randomization

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    End point title
    Number of Crohn's Disease-related Surgical Procedures After Randomization
    End point description
    The total number of CD-related surgical procedures included major CD-related surgery, debridement, perineal related surgery - abscess drainage, seton placement, fistulotomy, and TPN.
    End point type
    Secondary
    End point timeframe
    From Randomization through 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: surgical procedures
    9
    7
    No statistical analyses for this end point

    Secondary: Time to Crohn's Disease-related Hospitalization Due to Emergency

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    End point title
    Time to Crohn's Disease-related Hospitalization Due to Emergency
    End point description
    Hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic. Hospitalization due to emergency was defined as a hospitalization admitted through the emergency department. "99999" indicates values that could not be estimated due to the low number of emergency hospitalizations.
    End point type
    Secondary
    End point timeframe
    From Randomization through 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: days
        median (inter-quartile range (Q1-Q3))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Time to Crohn's Emergency Hospitalization
    Comparison groups
    Clinically Driven v Tight Control
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.212
    Method
    Regression, Cox
    Parameter type
    Cox proportional hazard
    Point estimate
    0.423
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.1
         upper limit
    1.6

    Secondary: Number of Crohn's Disease-related Hospitalizations Due to Emergency

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    End point title
    Number of Crohn's Disease-related Hospitalizations Due to Emergency
    End point description
    Hospitalization was defined as a visit to hospital/clinic resulting in admission and overnight stay in hospital/clinic. Hospitalization due to emergency was defined as a hospitalization admitted through the emergency department.
    End point type
    Secondary
    End point timeframe
    From Randomization through 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: emergency hospitalizations
    11
    4
    No statistical analyses for this end point

    Secondary: Change in Crohn's Disease Behavior According to Montreal Classification

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    End point title
    Change in Crohn's Disease Behavior According to Montreal Classification
    End point description
    Participants' Crohn's Disease was classified according to the Montreal Classification which classifies CD according to its predominant phenotypic elements (age at diagnosis, location, and disease behavior) based on the results of clinical examination and endoscopy. Disease behavior was classified according to the following: B1 = non-stricturing, non-penetrating; B2 = structuring; B3 = penetrating; P = perianal disease modifier. The change in Montreal Classification is presented in three categories: no change, deterioration, and improvement. Deterioration was defined as an increase in behavior index between 1 and 3, or development of perianal disease. Participants with missing data at Week 48 were classified as deterioration.
    End point type
    Secondary
    End point timeframe
    From Baseline to 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: participants
        Deterioration
    54
    35
        No Change
    64
    79
        Improvement
    4
    8
    No statistical analyses for this end point

    Secondary: Change From Baseline in High Sensitivity C-Reactive Protein (hs-CRP) Over Time

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    End point title
    Change From Baseline in High Sensitivity C-Reactive Protein (hs-CRP) Over Time
    End point description
    High sensitivity C-reactive protein was analyzed by a central laboratory. For participants with missing data after randomization last observation carried forward (LOCF) imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline and 8 weeks during the prednisone run-in, and 11, 23, 35, and 48 weeks after Randomization.
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    122
    Units: mg/L
    arithmetic mean (standard deviation)
        Week 8 of Prednisone Run-in (N = 77, 73)
    -10.3 ± 40.04
    -9.2 ± 33.67
        11 Weeks After Randomization (N = 120, 121)
    -14.6 ± 31.87
    -15.9 ± 26.38
        23 Weeks After Randomization (N = 121, 122)
    -15.1 ± 31.59
    -14.7 ± 28.94
        35 Weeks After Randomization (N = 121, 122)
    -11.0 ± 31.22
    -14.0 ± 28.85
        48 Weeks After Randomization (N = 121, 122)
    -12.3 ± 28.97
    -13.2 ± 28.93
    No statistical analyses for this end point

    Secondary: Change in Fecal Calprotectin From Baseline to 48 Weeks After Randomization

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    End point title
    Change in Fecal Calprotectin From Baseline to 48 Weeks After Randomization
    End point description
    Stool samples were analyzed by a central laboratory for fecal calprotectin qualitative measurement (< 250 or ≥ 250 μg/g). Results are reported for participants in each category at Baseline and 48 weeks after Randomization. Participants with missing data 48 weeks after Randomization were counted as having fecal calprotectin ≥ 250µg/g.
    End point type
    Secondary
    End point timeframe
    Baseline and 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    122
    120 [17]
    Units: participants
        Baseline < 250µg/g and Week 48 < 250µg/g
    8
    14
        Baseline < 250µg/g and Week 48 ≥ 250µg/g
    9
    10
        Baseline ≥ 250µg/g and Week 48 < 250µg/g
    37
    44
        Baseline ≥ 250µg/g and Week 48 ≥ 250µg/g
    68
    52
    Notes
    [17] - Randomized participants with Baseline data
    No statistical analyses for this end point

    Secondary: Total Dose of Prednisone

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    End point title
    Total Dose of Prednisone
    End point description
    The total dose of prednisone each participant received during both the run-in phase and post-randomization treatment phase.
    End point type
    Secondary
    End point timeframe
    From Baseline through 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    102 [18]
    104 [19]
    Units: mg
        arithmetic mean (standard deviation)
    1505.7 ± 1029.83
    1369.8 ± 1137.65
    Notes
    [18] - Participants who received prednisone
    [19] - Participants who received prednisone
    No statistical analyses for this end point

    Secondary: Change From Baseline in Quality of Life in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score

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    End point title
    Change From Baseline in Quality of Life in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score
    End point description
    The IBDQ measures the effects of inflammatory bowel disease on daily function and quality of life. The IBDQ consists of 32 questions which address symptoms as a result of Crohn's disease, feeling in general, and mood. Each question is answered on a scale from 1 (all of the time) to 7 ( none of the time); the total score ranges from 7 (worst) to 224 (best). A positive change from baseline indicates improvement. Last observation carried forward imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline and 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    111 [20]
    111 [21]
    Units: units on a scale
        arithmetic mean (standard deviation)
    31.2 ± 39.33
    41.9 ± 36.90
    Notes
    [20] - Randomized participants with baseline and at least one post-baseline value
    [21] - Randomized participants with baseline and at least one post-baseline value
    No statistical analyses for this end point

    Secondary: Change From Baseline in Work Productivity Activity Index - Crohn's Disease (WPAI:CD)

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    End point title
    Change From Baseline in Work Productivity Activity Index - Crohn's Disease (WPAI:CD)
    End point description
    The WPAI:CD questionnaire was used to assess impairments in paid work and unpaid work due to symptoms of Crohn's Disease. The self-administered questionnaire consisted of 6 questions. Work time missed is defined as the percentage of time absent from work due to Crohn's disease in the past week. Impairment while working is the degree to which Crohn's disease affected productivity while working in the past 7 days. Total work productivity impairment takes into account both hours missed due to Crohn's disease symptoms and the degree to which Crohn's disease affected productivity while working. Total activity impairment is the percent impairment of non-work related activities due to Crohn's disease. WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity. A negative change from Baseline indicates improvement. LOCF imputation was used. The first 3 scores were only calculated for participants who were employed.
    End point type
    Secondary
    End point timeframe
    Baseline and 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    119 [22]
    118 [23]
    Units: percent impairment
    arithmetic mean (standard deviation)
        Work time missed (N = 67, 62)
    -12.8 ± 30.17
    -17.6 ± 41.33
        Impairment while working (N = 64, 52)
    -17.5 ± 23.37
    -25.8 ± 34.32
        Overall work impairment (n = 67, 62)
    -21.7 ± 29.68
    -29.2 ± 39.53
        Activity impairment (N = 118, 118)
    -19.2 ± 27.16
    -27.7 ± 33.22
    Notes
    [22] - Randomized participants with baseline and at least one post-baseline value
    [23] - Randomized participants with baseline and at least one post-baseline value
    No statistical analyses for this end point

    Secondary: Change From Baseline in Patient Health Questionnaire - 9 (PHQ9)

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    End point title
    Change From Baseline in Patient Health Questionnaire - 9 (PHQ9)
    End point description
    The PHQ-9 is a 9-item questionnaire for assessing the severity of depression. Each question is answered on a scale from 0 (not at all) to 3 (nearly every day). The total score ranges from 0 to 27, where higher scores indicate more severe depression. A negative change from Baseline score indicates improvement. LOCF imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline and 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    120 [24]
    120 [25]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -3.6 ± 5.65
    -5.6 ± 5.95
    Notes
    [24] - Randomized participants with Baseline and at least one post-baseline value
    [25] - Randomized participants with Baseline and at least one post-baseline value
    No statistical analyses for this end point

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

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    End point title
    Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score
    End point description
    The FACIT-Fatigue scale is a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, from 0 (not at all) to 4 (very much). The FACIT-Fatigue score ranges from 0 to 52, with higher scores denoting lower levels of fatigue. A positive change from Baseline score indicates an improvement. LOCF imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline and 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    120 [26]
    119 [27]
    Units: units on a scale
        arithmetic mean (standard deviation)
    7.6 ± 10.85
    13.0 ± 13.19
    Notes
    [26] - Randomized participants with Baseline and at least 1 post-baseline value
    [27] - Randomized participants with Baseline and at least 1 post-baseline value
    No statistical analyses for this end point

    Secondary: Change From Baseline in Short-Form 36 (SF-36) Physical Component Summary and Mental Component Summary Scores

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    End point title
    Change From Baseline in Short-Form 36 (SF-36) Physical Component Summary and Mental Component Summary Scores
    End point description
    The Medical Outcome Study Short Form 36-Item Health Survey (SF-36), Version 2 is a self-administered instrument that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The physical component summary (PCS) score summarizes the subscales physical functioning, role-physical, bodily pain, and general health. The mental component summary (MCS) score summarizes the subscales vitality, social functioning, role-emotional, and mental health. Each score ranges from 0 to 100 where higher scores indicate a better quality of life. A positive change from Baseline score indicates an improvement. LOCF imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline and 48 weeks after Randomization
    End point values
    Clinically Driven Tight Control
    Number of subjects analysed
    119 [28]
    118 [29]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Physical Component Summary Score
    6.3 ± 8.34
    9.2 ± 10.22
        Mental Component Summary Score
    5.8 ± 12.24
    9.3 ± 12.40
    Notes
    [28] - Randomized participants with Baseline and at least one post-baseline value
    [29] - Randomized participants with Baseline and at least one post-baseline value
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs) were collected from randomization until 70 days after the last dose of study drug (up to 58 weeks).
    Adverse event reporting additional description
    TEAEs and TESAEs are defined as any adverse event or serious adverse event that begins or worsens in severity on or after randomization until 70 days after the last dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Clinically Driven
    Reporting group description
    Participants randomized to receive management of disease activity using criteria based on Crohn's Disease Activity Index (CDAI) and corticosteroid use. Participants received customized therapy that could include prednisone, adalimumab, and azathioprine.

    Reporting group title
    Tight Control
    Reporting group description
    Participants randomized to receive management of disease activity using criteria based on Crohn's Disease Activity Index (CDAI), high sensitivity C-reactive protein (hs-CRP), fecal calprotectin, and corticosteroid use. Participants received customized therapy that could include prednisone, adalimumab, and azathioprine.

    Serious adverse events
    Clinically Driven Tight Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 122 (20.49%)
    22 / 122 (18.03%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Cartilage Injury
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus Injury
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    C-Reactive Protein Increased
         subjects affected / exposed
    2 / 122 (1.64%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cholesteatoma
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal Septum Disorder
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Guillain-Barre Syndrome
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial Venous Sinus Thrombosis
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Drug Intolerance
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    2 / 122 (1.64%)
    2 / 122 (1.64%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal Fistula
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's Disease
         subjects affected / exposed
    12 / 122 (9.84%)
    6 / 122 (4.92%)
         occurrences causally related to treatment / all
    1 / 13
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula of Small Intestine
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal Stenosis
         subjects affected / exposed
    0 / 122 (0.00%)
    2 / 122 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malocclusion
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal Perforation
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    1 / 122 (0.82%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema Nodosum
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Retrognathia
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator Cuff Syndrome
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal Abscess
         subjects affected / exposed
    0 / 122 (0.00%)
    2 / 122 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    1 / 122 (0.82%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal Abscess
         subjects affected / exposed
    4 / 122 (3.28%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium Difficile Infection
         subjects affected / exposed
    0 / 122 (0.00%)
    2 / 122 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis Salmonella
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis Viral
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal Vestibulitis
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Tuberculosis
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotavirus Infection
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viraemia
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Clinically Driven Tight Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    78 / 122 (63.93%)
    76 / 122 (62.30%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 122 (5.74%)
    7 / 122 (5.74%)
         occurrences all number
    7
    9
    Oropharyngeal Pain
         subjects affected / exposed
    10 / 122 (8.20%)
    4 / 122 (3.28%)
         occurrences all number
    11
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 122 (5.74%)
    8 / 122 (6.56%)
         occurrences all number
    8
    8
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 122 (5.74%)
    7 / 122 (5.74%)
         occurrences all number
    7
    9
    Headache
         subjects affected / exposed
    15 / 122 (12.30%)
    18 / 122 (14.75%)
         occurrences all number
    24
    23
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    11 / 122 (9.02%)
    11 / 122 (9.02%)
         occurrences all number
    13
    14
    Injection Site Erythema
         subjects affected / exposed
    0 / 122 (0.00%)
    8 / 122 (6.56%)
         occurrences all number
    0
    10
    Pyrexia
         subjects affected / exposed
    12 / 122 (9.84%)
    9 / 122 (7.38%)
         occurrences all number
    16
    12
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    15 / 122 (12.30%)
    13 / 122 (10.66%)
         occurrences all number
    18
    20
    Abdominal Pain Upper
         subjects affected / exposed
    4 / 122 (3.28%)
    8 / 122 (6.56%)
         occurrences all number
    4
    9
    Crohn'S Disease
         subjects affected / exposed
    23 / 122 (18.85%)
    11 / 122 (9.02%)
         occurrences all number
    26
    15
    Diarrhoea
         subjects affected / exposed
    2 / 122 (1.64%)
    10 / 122 (8.20%)
         occurrences all number
    2
    12
    Nausea
         subjects affected / exposed
    7 / 122 (5.74%)
    21 / 122 (17.21%)
         occurrences all number
    10
    23
    Vomiting
         subjects affected / exposed
    4 / 122 (3.28%)
    13 / 122 (10.66%)
         occurrences all number
    6
    14
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    8 / 122 (6.56%)
    5 / 122 (4.10%)
         occurrences all number
    8
    6
    Rash
         subjects affected / exposed
    9 / 122 (7.38%)
    4 / 122 (3.28%)
         occurrences all number
    12
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    19 / 122 (15.57%)
    17 / 122 (13.93%)
         occurrences all number
    20
    20
    Infections and infestations
    Influenza
         subjects affected / exposed
    8 / 122 (6.56%)
    7 / 122 (5.74%)
         occurrences all number
    10
    8
    Nasopharyngitis
         subjects affected / exposed
    18 / 122 (14.75%)
    18 / 122 (14.75%)
         occurrences all number
    24
    22
    Tonsillitis
         subjects affected / exposed
    1 / 122 (0.82%)
    7 / 122 (5.74%)
         occurrences all number
    1
    7

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Aug 2010
    ● Removed SES CD and reference to the publication. ● Added subjects who met success criteria at Week 9 Key visit to the list of subjects who went directly to TO2. ● Specified that subjects within the rescue Therapeutic Option 4 could restart prednisone under certain conditions. ● Specified that subjects who re-escalated in TO3 success or Therapeutic Option 4 success were to remain in either TO3 or TO4 of their allocated arm. ● Clarified that the prednisone re initiation based on CDAI > 300 in Therapeutic Option 4 only occurred upon the first entry into TO4. ● Included that budesonide and systemic corticosteroid with CD related corticosteroids that were to be recorded regardless of when they were taken. ● Updated study activities table to clarify situations that required an unscheduled visit; remove retesting fecal calprotectin if elevated for reasons other than CD; clarify that a stool sample was to be obtained at an unscheduled visit for a flare to determine fecal calprotectin levels; clarify that the 70 day follow-up was not required for subjects who continued on adalimumab therapy after the end of study participation. ● Added pleural thickening and signs of active TB for standard evaluations. ● Added that retesting of elevated fecal calprotectin levels was not required and that the investigator may delay success criteria visit for suspected infection.
    16 Mar 2011
    ● Clarified and modified required (onsite and telephone follow-up) versus optional visits. ● Stated that an ET endoscopy was not to be performed if the subject discontinued early prior to randomization. ● Added that QuantiFERON TB Gold test or equivalent was an acceptable alternative to the PPD test for TB screening at the screening visit and at subsequent visits if required by local guidelines, including visits for flare and unsatisfactory response to therapy. ● Modified rules for a subject to move to the Rescue Group after randomization. ● Stated that calculation of CD3S was to be a substudy. Added that ET MRIs were not to be performed if a subject discontinued early prior to randomization. ● Allowed a subject to have either elevated hs CRP or fecal calprotectin to be eligible for the study ● Clarified that subjects must have not been taking immunomodulator(s) for non CD use at Baseline. ● Modified current and previous corticosteroid/budesonide use criteria. ● Removed the exclusion criterion for subjects not on stable doses of aminosalicylates, CD related antibiotics, and topical therapy for CD prior to Baseline. ● Updated dysplasia exclusion criterion to include information for endoscopy performed independent of the study. ● Modified MRI contraindications and impaired renal function to apply only to subjects who consented to participate in the CD3S (MRI) substudy. ● Updated rationale and include prohibition of allopurinol due to interference with AZA. ● Removed active and chronic hepatitis B and added exclusions of viral infections and positive hepatitis B tests. ● Added that subjects were to have an additional visit occurring 4 weeks after initiating AZA as required per local requirements.
    29 Sep 2011
    ● Change references to end of study visit, if not an ET visit, from Week 56 to 48 weeks after randomization. ● Update primary objective timeline to approximately 1 year (56 weeks). ● Modify entry CDAI score based on whether subject was receiving prednisone or equivalent and dose of prednisone received ≥ 7 days prior to Baseline. ● Allow randomization at Baseline in subjects with active disease or for whom prednisone or equivalent had to be tapered according to investigator’s opinion AND who had received corticosteroids for ≥ 4 weeks, including 2 weeks of prednisone or equivalent. ● Modify success criteria in the Clinically Driven group. ● Modify Rescue Group entry from flare or unsatisfactory response. ● Modify CD intestinal locations to include isolated ileal disease, clarify that colonic includes the rectum, and increase disease duration to ≤ 6 years. ● Change total CDEIS score from > 8 to > 6 and timing of entry criteria endoscopy from within 3 weeks prior to Baseline to Screening. ● Modify TPMT enzyme activity cutoff from ≤ 67 mU/L to ≤ 20 mU/L and specify that subjects with intermediate enzyme activity were to undergo weekly laboratory surveillance for ≥ 4 weeks per local guidelines, if initiating TO 4. ● Add stricture exclusion for subjects were with a passable stricture, even if it could be dilated during the screening endoscopy. ● Add exclusion for subjects with recent surgery (< 6 months of screening). ● Delete exclusion for subjects who underwent therapeutic enemas within 2 months of Baseline. ● Allow prescreening endoscopies within 4 weeks of Baseline instead of 3 weeks, also allow documentation with photographs instead of recordings if CDEIS was evaluated during the endoscopy. Allow rescreening subjects to avoid a second endoscopy for an initial screen failure not due to an ineligible CDEIS, if the time period between rescreen and randomization was ≤ 12 weeks. ● Allow subjects with intermediate TPMT to initiate AZA at a lower dose
    21 Mar 2013
    ● Updated requirements and study schedule for Rescue Group entry and for subjects who needed to escalate therapy within the Rescue Group between scheduled visits. ● Included Janus kinase (JAK) and alpha-integrin inhibitors to exclusion criteria.
    28 Jan 2015
    ● Modified TB language to add the possibility of including subjects who had evidence of a latent TB infection under certain circumstances. An annual TB test was to be performed for all subjects who completed the study. ● Clarified for Montreal Classification that imaging needed to be available to consider a stricture as inflammatory. ● Included prohibited new treatments available for CD and cytopheresis therapy (sometimes used in Japan for treatment of CD).

    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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