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    Clinical Trial Results:
    A Multi-center, Open-label Study of the Human Anti−TNF Monoclonal Antibody Adalimumab to Evaluate the Efficacy and the Long-term Safety and Tolerability of Repeated Administration of Adalimumab in Pediatric Subjects with Crohn's Disease Who Have Demonstrated a Clinical Response in the M06-806 Study

    Summary
    EudraCT number
    2007-006494-90
    Trial protocol
    BE   CZ   GB   Outside EU/EEA  
    Global end of trial date
    04 Apr 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Oct 2017
    First version publication date
    14 Oct 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M06-807
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00686374
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AbbVie
    Sponsor organisation address
    1 North Waukegan Road, North Chicago, IL, United States, 60064
    Public contact
    Global Medical Services, AbbVie, 001 800-633-9110,
    Scientific contact
    Andreas Lazar, AbbVie, andreas.lazar@abbvie.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Apr 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the long-term maintenance of clinical response, safety and tolerability of repeated administration of adalimumab in pediatric subjects with Crohn's disease who participated in, and successfully completed, Protocol M06-806 through Week 52 and who met all the inclusion and none of the exclusion criteria of Protocol M06-807.
    Protection of trial subjects
    Prior to any study-related screening procedures being performed, the investigator or his/her representative explained the nature of the study to the parent or guardian of the pediatric subject and answered all questions regarding the study. Subjects were included in all discussions. The informed consent form was reviewed, signed, and dated by the subject's parent or legal guardian, and by the person who administered the informed consent. If a subject became of legal age in the state of residence during the course of the study, another informed consent was to be obtained at that time. Additionally, in keeping with each institution's Institutional Review Board requirements, an informed assent was also to be obtained from the subject, as required. Subjects were to be included in all discussions in order to obtain their signature on an assent form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Feb 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    United States: 47
    Country: Number of subjects enrolled
    Canada: 14
    Worldwide total number of subjects
    100
    EEA total number of subjects
    39
    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)
    20
    Adolescents (12-17 years)
    80
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects enrolled in and completed Study M06-806 through Week 52 who were responders at any time point during Study M06-806 (defined as having achieved at least a 15-point reduction in Pediatric Crohn's Disease Activity Index from Baseline).

    Pre-assignment
    Screening details
    36 subjects discontinued study drug when adalimumab became commercially available (received regulatory approval for pediatric Crohn’s disease) in their country. These subjects were considered to have completed the study, and are included as study completers in the subject disposition.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Any adalimumab
    Arm description
    Adalimumab was administered via subcutaneous injection. Dosage was based on body weight and clinical status, and ranged from 10, 20, or 40 mg every other week to 20 or 40 mg every week.
    Arm type
    Experimental

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    ABT-D2E7, Humira
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects who enrolled into the study from blinded therapy in Protocol M06-806 received open-label (OL) therapy at a dose dependent on their body weight. Subjects who weighed ≥ 40 kg received 40 mg of adalimumab every other week (eow), while those who weighed < 40 kg received 20 mg of adalimumab eow. Beginning with Week 8, subjects who had a disease flare may have been switched to every week (ew) treatment at the same dose of adalimumab received while on eow treatment. Subjects who enrolled into the study from OL therapy in Protocol M06-806 continued to receive the same dose they were receiving (i.e., 40 mg ew or 20 mg ew) at the Week 52 visit of Procotol M06-806. Adalimumab dose could have been decreased to the next lower treatment level for those with body weight changes. Subjects who responded to treatment may have also had their dosage frequency decreased from ew to eow dosing, as well as a decrease in dosage.

    Number of subjects in period 1
    Any adalimumab
    Started
    100
    Completed
    39
    Not completed
    61
         Other, not specified
    4
         Lack of efficacy
    10
         Missing reason
    33
         Adverse event, non-fatal
    8
         Consent withdrawn by subject
    5
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Any adalimumab
    Reporting group description
    Adalimumab was administered via subcutaneous injection. Dosage was based on body weight and clinical status, and ranged from 10, 20, or 40 mg every other week to 20 or 40 mg every week.

    Reporting group values
    Any adalimumab Total
    Number of subjects
    100 100
    Age categorical
    Age at Protocol M06-806 Baseline
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    20 20
        Adolescents (12-17 years)
    80 80
        Adults (18-64 years)
    0 0
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Age at Protocol M06-806 Baseline
    Units: years
        arithmetic mean (standard deviation)
    13.5 ± 2.5 -
    Gender categorical
    Units: Subjects
        Female
    48 48
        Male
    52 52
    Body weight
    Body weight at Protocol M06-806 Baseline
    Units: Subjects
        < 40 kg
    38 38
        ≥ 40 kg
    62 62

    End points

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    End points reporting groups
    Reporting group title
    Any adalimumab
    Reporting group description
    Adalimumab was administered via subcutaneous injection. Dosage was based on body weight and clinical status, and ranged from 10, 20, or 40 mg every other week to 20 or 40 mg every week.

    Primary: Number of subjects who achieved Pediatric Crohn's Disease Activity Index (PCDAI) clinical remission over time

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    End point title
    Number of subjects who achieved Pediatric Crohn's Disease Activity Index (PCDAI) clinical remission over time [1]
    End point description
    Pediatric Crohn's Disease Activity Index (PCDAI) is an index used to measure disease activity of pediatric patients with Crohn's disease assessing abdominal pain, stool frequency, patient functioning, hematocrit, erythrocyte sedimentation rate, albumin, weight, height, abdomen, perirectal disease, and extraintestinal manifestations. It ranges from 0 to 100; higher scores indicate more active disease. Clinical remission was defined as PCDAI ≤ 10.
    End point type
    Primary
    End point timeframe
    Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics are presented, per protocol.
    End point values
    Any adalimumab
    Number of subjects analysed
    100 [2]
    Units: Subjects
        Week 0 (n=100)
    67
        Week 4 (n=98)
    65
        Week 8 (n=97)
    67
        Week 12 (n=96)
    60
        Week 24 (n=94)
    59
        Week 36 (n=87)
    60
        Week 48 (n=82)
    54
        Week 60 (n=79)
    60
        Week 72 (n=76)
    49
        Week 84 (n=74)
    54
        Week 96 (n=77)
    54
        Week 108 (n=72)
    54
        Week 120 (n=67)
    52
        Week 144 (n=64)
    51
        Week 168 (n=58)
    44
        Week 192 (n=55)
    44
        Week 216 (n=50)
    36
        Week 240 (n=46)
    37
        Week 264 (n=37)
    31
        Week 288 (n=29)
    24
        Week 312 (n=18)
    14
        Week 336 (n=11)
    8
        Week 360 (n=8)
    7
        Week 384 (n=2)
    2
        Week 408 (n=0)
    0
    Notes
    [2] - ITT population:subjects who rcvd ≥ 1 dose of adalimumab and had ≥ 1 non-missing efficacy measurement
    No statistical analyses for this end point

    Primary: Number of subjects with clinical response as defined by Pediatric Crohn's Disease Activity Index (PCDAI) score over time

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    End point title
    Number of subjects with clinical response as defined by Pediatric Crohn's Disease Activity Index (PCDAI) score over time [3]
    End point description
    Pediatric Crohn's Disease Activity Index (PCDAI) is an index used to measure disease activity of pediatric patients with Crohn's disease assessing abdominal pain, stool frequency, patient functioning, hematocrit, erythrocyte sedimentation rate, albumin, weight, height, abdomen, perirectal disease, and extraintestinal manifestations. It ranges from 0 to 100; higher scores indicate more active disease. The baseline PCDAI value was defined as the last non-missing value on or before the date of the first dose of study drug during Protocol M06-806. Clinical response was defined as a PCDAI ≥ 15 points lower than the Protocol M06-806 baseline PCDAI value.
    End point type
    Primary
    End point timeframe
    Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics are presented, per protocol.
    End point values
    Any adalimumab
    Number of subjects analysed
    100 [4]
    Units: subjects
        Week 0 (n=100)
    95
        Week 4 (n=98)
    90
        Week 8 (n=97)
    92
        Week 12 (n=96)
    87
        Week 24 (n=94)
    88
        Week 36 (n=87)
    82
        Week 48 (n=82)
    74
        Week 60 (n=79)
    76
        Week 72 (n=76)
    72
        Week 84 (n=74)
    69
        Week 96 (n=77)
    72
        Week 108 (n=72)
    70
        Week 120 (n=67)
    65
        Week 144 (n=64)
    64
        Week 168 (n=58)
    53
        Week 192 (n=55)
    52
        Week 216 (n=50)
    46
        Week 240 (n=46)
    43
        Week 264 (n=37)
    35
        Week 288 (n=29)
    28
        Week 312 (n=18)
    15
        Week 336 (n=11)
    10
        Week 360 (n=8)
    8
        Week 384 (n=2)
    2
        Week 408 (n=0)
    0
    Notes
    [4] - ITT population:subjects who rcvd ≥ 1 dose of adalimumab and had ≥ 1 non-missing efficacy measurement
    No statistical analyses for this end point

    Secondary: Number of subjects who were in Crohn’s Disease Activity Index (CDAI) clinical remission over time

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    End point title
    Number of subjects who were in Crohn’s Disease Activity Index (CDAI) clinical remission over time
    End point description
    The CDAI includes 8 variables encompassing both subject-reported (symptoms, general well-being) and objective (medication usage, laboratory variables, presence of abdominal mass or complications, and weight) variables. For symptoms scores, subjects kept track of daily symptoms on a diary card, and the daily symptom scores were summed for the week. Each item in the CDAI is assigned a specific weight, and the weighted values of the items are totaled to produce the CDAI score. Higher CDAI scores indicate greater disease activity; 0 is the lower limit with no set upper limit. The scale for the score is as follows: < 150 to indicate remission, 150 - 219 to define mildly active disease, 220 - 450 to define moderately active disease, and > 450 to define severely active disease. A CDAI was calculated at each visit for subjects who were age 13 or older at Protocol M06-806 entry. The Protocol M06-806 Week 52 visit served as the baseline visit for this study.
    End point type
    Secondary
    End point timeframe
    Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408
    End point values
    Any adalimumab
    Number of subjects analysed
    65 [5]
    Units: subjects
        Week 0 (n=65)
    58
        Week 4 (n=63)
    55
        Week 8 (n=62)
    58
        Week 12 (n=61)
    53
        Week 24 (n=59)
    54
        Week 36 (n=55)
    52
        Week 48 (n=53)
    48
        Week 60 (n=52)
    49
        Week 72 (n=50)
    47
        Week 84 (n=50)
    46
        Week 96 (n=50)
    45
        Week 108 (n=49)
    45
        Week 120 (n=43)
    42
        Week 144 (n=41)
    40
        Week 168 (n=35)
    35
        Week 192 (n=33)
    31
        Week 216 (n=30)
    27
        Week 240 (n=29)
    26
        Week 264 (n=24)
    23
        Week 288 (n=18)
    17
        Week 312 (n=15)
    15
        Week 336 (n=9)
    8
        Week 360 (n=7)
    7
        Week 384 (n=1)
    1
        Week 408 (n=0)
    0
    Notes
    [5] - Subjects ≥ 13 years old at M06-806 entry;rcvd ≥ 1 dose adalimumab;had ≥ 1 non-missing efficacy meas
    No statistical analyses for this end point

    Secondary: Number of subjects who were in Crohn’s Disease Activity Index (CDAI) clinical response over time

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    End point title
    Number of subjects who were in Crohn’s Disease Activity Index (CDAI) clinical response over time
    End point description
    The CDAI includes 8 variables: subject-reported (symptoms, general well-being) and objective (medication usage, laboratory variables, presence of abdominal mass or complications, and weight). Subjects kept track of symptoms on a diary card, and scores were summed for the week. Each item is assigned a specific weight, and the weighted values of the items are totaled to produce the CDAI score. Higher CDAI scores indicate greater disease activity; 0 is the lower limit with no set upper limit. Scale: < 150 (remission), 150 - 219 (mildly active disease), 220 - 450 (moderately active disease), and > 450 (severely active disease). A CDAI was calculated at each visit for subjects ≥ 13 yrs old at M06-806 entry. Clinical response was defined as a decrease from M06-806 Baseline CDAI value of ≥ 70 pts. The M06-806 Baseline value was defined as the last non-missing value on or before the date of the 1st dose of study drug in M06-806.
    End point type
    Secondary
    End point timeframe
    Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408
    End point values
    Any adalimumab
    Number of subjects analysed
    64 [6]
    Units: subjects
        Week 0 (n=64)
    55
        Week 4 (n=63)
    56
        Week 8 (n=62)
    56
        Week 12 (n=61)
    51
        Week 24 (n=59)
    52
        Week 36 (n=55)
    53
        Week 48 (n=53)
    48
        Week 60 (n=52)
    48
        Week 72 (n=50)
    45
        Week 84 (n=50)
    47
        Week 96 (n=50)
    45
        Week 108 (n=49)
    47
        Week 120 (n=43)
    40
        Week 144 (n=41)
    41
        Week 168 (n=35)
    34
        Week 192 (n=33)
    33
        Week 216 (n=30)
    28
        Week 240 (n=29)
    28
        Week 264 (n=24)
    24
        Week 288 (n=18)
    18
        Week 312 (n=15)
    15
        Week 336 (n=9)
    9
        Week 360 (n=7)
    7
        Week 384 (n=1)
    1
        Week 408 (n=0)
    0
    Notes
    [6] - Subjects ≥ 13 years old at M06-806 entry;rcvd ≥ 1 dose adalimumab;had ≥ 1 non-missing efficacy meas
    No statistical analyses for this end point

    Secondary: Number of subjects in Steroid-free Pediatric Crohn's Disease Activity Index (PCDAI) remission over time

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    End point title
    Number of subjects in Steroid-free Pediatric Crohn's Disease Activity Index (PCDAI) remission over time
    End point description
    Pediatric Crohn's Disease Activity Index (PCDAI) is an index used to measure disease activity of pediatric patients with Crohn's disease assessing abdominal pain, stool frequency, patient functioning, hematocrit, erythrocyte sedimentation rate, albumin, weight, height, abdomen, perirectal disease, and extraintestinal manifestations. It ranges from 0 to 100; higher scores indicate more active disease. PCDAI corticosteroid-free remission was defined as discontinued corticosteroid use at least 90 consecutive days prior to the respective visit, with a PCDAI ≤ 10 at that visit.
    End point type
    Secondary
    End point timeframe
    Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384
    End point values
    Any adalimumab
    Number of subjects analysed
    37 [7]
    Units: subjects
        Week 0 (n=37)
    23
        Week 4 (n=37)
    23
        Week 8 (n=37)
    23
        Week 12 (n=37)
    20
        Week 24 (n=37)
    21
        Week 36 (n=33)
    19
        Week 48 (n=32)
    19
        Week 60 (n=30)
    24
        Week 72 (n=28)
    17
        Week 84 (n=29)
    19
        Week 96 (n=29)
    20
        Week 108 (n=27)
    18
        Week 120 (n=25)
    19
        Week 144 (n=24)
    17
        Week 168 (n=22)
    16
        Week 192 (n=19)
    15
        Week 216 (n=19)
    13
        Week 240 (n=16)
    13
        Week 264 (n=13)
    11
        Week 288 (n=10)
    9
        Week 312 (n=5)
    5
        Week 336 (n=3)
    2
        Week 360 (n=2)
    1
        Week 384 (n=0)
    0
    Notes
    [7] - Corticosteroid use at M06-806 entry; rcvd ≥ 1 dose adalimumab; ≥ 1 non-missing efficacy measurement
    No statistical analyses for this end point

    Secondary: Number of subjects in Steroid-free Crohn's Disease Activity Index (CDAI) remission over time

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    End point title
    Number of subjects in Steroid-free Crohn's Disease Activity Index (CDAI) remission over time
    End point description
    The CDAI includes 8 variables encompassing subject-reported (symptoms, general well-being) and objective (medication usage, laboratory variables, presence of abdominal mass or complications, and weight) variables. Subjects kept track of daily symptoms on a diary card, and the scores were summed for the week. Each item in the CDAI is assigned a specific weight, and the items are totaled to produce the CDAI score. Higher CDAI scores indicate greater disease activity; 0 is the lower limit with no set upper limit. The scale for the score is as follows: < 150 (remission), 150 - 219 (mildly active disease), 220 - 450 (moderately active disease), and > 450 (severely active disease). A CDAI was calculated at each visit for subjects ≥ 13 years old at M06-806 entry. CDAI corticosteroid-free remission was defined as discontinued use at least 90 consecutive days prior to the respective visit and a CDAI < 150 at that visit.
    End point type
    Secondary
    End point timeframe
    Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384
    End point values
    Any adalimumab
    Number of subjects analysed
    26 [8]
    Units: subjects
        Week 0 (n=26)
    21
        Week 4 (n=26)
    22
        Week 8 (n=26)
    22
        Week 12 (n=26)
    20
        Week 24 (n=26)
    21
        Week 36 (n=24)
    22
        Week 48 (n=24)
    22
        Week 60 (n=23)
    21
        Week 72 (n=21)
    19
        Week 84 (n=22)
    20
        Week 96 (n=22)
    20
        Week 108 (n=21)
    18
        Week 120 (n=18)
    16
        Week 144 (n=17)
    15
        Week 168 (n=14)
    13
        Week 192 (n=12)
    11
        Week 216 (n=13)
    10
        Week 240 (n=11)
    10
        Week 264 (n=8)
    8
        Week 288 (n=6)
    6
        Week 312 (n=4)
    4
        Week 336 (n=3)
    2
        Week 360 (n=2)
    1
        Week 384 (n=0)
    0
    Notes
    [8] - ≥ 13 yrs, corticosteroid use at M06-806 entry;rcvd ≥ 1 dose adalimumab;≥ 1 non-missing efficacy meas
    No statistical analyses for this end point

    Secondary: Mean change from baseline in Pediatric Crohn's Disease Activity Index (PCDAI) over time

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    End point title
    Mean change from baseline in Pediatric Crohn's Disease Activity Index (PCDAI) over time
    End point description
    Pediatric Crohn's Disease Activity Index (PCDAI) is an index used to measure disease activity of pediatric patients with Crohn's disease assessing abdominal pain, stool frequency, patient functioning, hematocrit, erythrocyte sedimentation rate, albumin, weight, height, abdomen, perirectal disease, and extraintestinal manifestations. It ranges from 0 to 100; higher scores indicate more active disease. The baseline value was defined as the last non-missing value on or before the date of the first dose of study drug in Study M06-806. Negative changes indicate reductions (improvement) in disease activity.
    End point type
    Secondary
    End point timeframe
    Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384
    End point values
    Any adalimumab
    Number of subjects analysed
    100 [9]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Week 0 (n=100)
    -29.95 ± 11.459
        Week 4 (n=98)
    -30.15 ± 11.514
        Week 8 (n=97)
    -30.7 ± 11.415
        Week 12 (n=96)
    -29.19 ± 11.405
        Week 24 (n=94)
    -29.84 ± 11.702
        Week 36 (n=87)
    -30.89 ± 12.354
        Week 48 (n=82)
    -30.73 ± 11.983
        Week 60 (n=79)
    -32.78 ± 10.927
        Week 72 (n=76)
    -31.15 ± 10.404
        Week 84 (n=74)
    -32.94 ± 10.809
        Week 96 (n=77)
    -31.14 ± 11.33
        Week 108 (n=72)
    -33.54 ± 9.538
        Week 120 (n=67)
    -33.36 ± 10.441
        Week 144 (n=64)
    -34.38 ± 9.204
        Week 168 (n=58)
    -32.57 ± 11.273
        Week 192 (n=55)
    -33 ± 13.258
        Week 216 (n=50)
    -31.95 ± 12.344
        Week 240 (n=46)
    -34.18 ± 13.386
        Week 264 (n=37)
    -35 ± 9.242
        Week 288 (n=29)
    -35.95 ± 11.941
        Week 312 (n=18)
    -33.19 ± 14.318
        Week 336 (n=11)
    -35.23 ± 12.013
        Week 360 (n=8)
    -38.75 ± 10.69
        Week 384 (n=2)
    -46.25 ± 22.981
    Notes
    [9] - ITT population:subjects who rcvd ≥ 1 dose of adalimumab and had ≥ 1 non-missing efficacy measurement
    No statistical analyses for this end point

    Secondary: Mean change from baseline in Crohn's Disease Activity Index (CDAI) over time

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    End point title
    Mean change from baseline in Crohn's Disease Activity Index (CDAI) over time
    End point description
    The CDAI includes 8 variables: subject-reported (symptoms, general well-being) and objective (medication usage, laboratory variables, presence of abdominal mass or complications, and weight) variables. For symptoms scores, subjects kept track of daily symptoms on a diary card, and the scores were summed for the week. Each item in the CDAI is assigned a specific weight, and the items are totaled to produce the CDAI score. Higher CDAI scores indicate greater disease activity; 0 is the lower limit with no set upper limit. The scale for the score is as follows: < 150 (remission), 150 - 219 (mildly active disease), 220 - 450 (moderately active disease) and > 450 (severely active disease). A CDAI was calculated at each visit for subjects who were ≥ 13 years old at Protocol M06-806 entry. The baseline value was defined as the last non-missing value on or before the date of the first dose of study drug in Study M06-806. Negative changes indicate reductions (improvement) in disease activity.
    End point type
    Secondary
    End point timeframe
    Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384
    End point values
    Any adalimumab
    Number of subjects analysed
    64 [10]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Week 0 (n=64)
    -160.8 ± 82.543
        Week 4 (n=63)
    -159.9 ± 79.986
        Week 8 (n=62)
    -164.45 ± 79.272
        Week 12 (n=61)
    -151.34 ± 87.157
        Week 24 (n=59)
    -161.51 ± 84.663
        Week 36 (n=55)
    -173.55 ± 77.358
        Week 48 (n=53)
    -162.08 ± 86.292
        Week 60 (n=52)
    -168.27 ± 82.605
        Week 72 (n=50)
    -165.4 ± 80.038
        Week 84 (n=50)
    -172.68 ± 86.223
        Week 96 (n=50)
    -168.3 ± 79.658
        Week 108 (n=49)
    -171.63 ± 85.19
        Week 120 (n=43)
    -179.14 ± 86.93
        Week 144 (n=41)
    -181.53 ± 78.99
        Week 168 (n=35)
    -175.05 ± 80.965
        Week 192 (n=33)
    -172.42 ± 76.381
        Week 216 (n=30)
    -173.13 ± 78.588
        Week 240 (n=29)
    -184.46 ± 94.114
        Week 264 (n=24)
    -186.42 ± 75.396
        Week 288 (n=18)
    -197.11 ± 88.029
        Week 312 (n=15)
    -199 ± 77.184
        Week 336 (n=9)
    -240.33 ± 97.395
        Week 360 (n=7)
    -224.86 ± 89.025
        Week 384 (n=1)
    -458 ± 0
    Notes
    [10] - Subjects ≥ 13 years old at M06-806 entry;rcvd ≥ 1 dose adalimumab;had ≥ 1 non-missing efficacy meas
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs) were collected from the time of study drug administration in Protocol M06-806 until 70 days after the last dose of study drug in Protocol M06-807 (up to 470 weeks).
    Adverse event reporting additional description
    TEAEs and TESAEs are defined as any adverse event (AE) or serious adverse event (SAE) with an onset date that is after the first dose of study drug until 70 days after the last dose of study drug and were collected whether elicited or spontaneously reported by the participant.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Any adalimumab
    Reporting group description
    Adalimumab was administered via subcutaneous injection. Dosage was based on body weight and clinical status, and ranged from 10, 20, or 40 mg every other week to 20 or 40 mg every week.

    Serious adverse events
    Any adalimumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    48 / 100 (48.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Bone contusion
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Heart rate irregular
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Schizoaffective disorder
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Somatic symptom disorder
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Crohn's disease
         subjects affected / exposed
    25 / 100 (25.00%)
         occurrences causally related to treatment / all
    0 / 36
         deaths causally related to treatment / all
    0 / 0
    Faecal volume increased
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ileal perforation
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileal stenosis
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Small intestinal stenosis
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Pelvic fluid collection
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Systemic lupus erythematosus
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anal abscess
         subjects affected / exposed
    3 / 100 (3.00%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cystitis viral
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes virus infection
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Impetigo
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Salmonellosis
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal abscess
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    2 / 100 (2.00%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Yersinia infection
         subjects affected / exposed
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Any adalimumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    98 / 100 (98.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    13 / 100 (13.00%)
         occurrences all number
    15
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    5 / 100 (5.00%)
         occurrences all number
    5
    Seasonal allergy
         subjects affected / exposed
    8 / 100 (8.00%)
         occurrences all number
    10
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    18 / 100 (18.00%)
         occurrences all number
    24
    Injection site pain
         subjects affected / exposed
    7 / 100 (7.00%)
         occurrences all number
    23
    Injection site reaction
         subjects affected / exposed
    16 / 100 (16.00%)
         occurrences all number
    34
    Pain
         subjects affected / exposed
    6 / 100 (6.00%)
         occurrences all number
    8
    Pyrexia
         subjects affected / exposed
    20 / 100 (20.00%)
         occurrences all number
    35
    Psychiatric disorders
    Depression
         subjects affected / exposed
    6 / 100 (6.00%)
         occurrences all number
    7
    Insomnia
         subjects affected / exposed
    6 / 100 (6.00%)
         occurrences all number
    6
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    7 / 100 (7.00%)
         occurrences all number
    18
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    6 / 100 (6.00%)
         occurrences all number
    8
    Procedural pain
         subjects affected / exposed
    9 / 100 (9.00%)
         occurrences all number
    9
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 100 (6.00%)
         occurrences all number
    6
    Antinuclear antibody positive
         subjects affected / exposed
    5 / 100 (5.00%)
         occurrences all number
    6
    C-reactive protein increased
         subjects affected / exposed
    15 / 100 (15.00%)
         occurrences all number
    15
    Red blood cell sedimentation rate increased
         subjects affected / exposed
    8 / 100 (8.00%)
         occurrences all number
    9
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    5 / 100 (5.00%)
         occurrences all number
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    20 / 100 (20.00%)
         occurrences all number
    34
    Dyspnoea
         subjects affected / exposed
    5 / 100 (5.00%)
         occurrences all number
    5
    Epistaxis
         subjects affected / exposed
    6 / 100 (6.00%)
         occurrences all number
    12
    Nasal congestion
         subjects affected / exposed
    12 / 100 (12.00%)
         occurrences all number
    17
    Oropharyngeal pain
         subjects affected / exposed
    27 / 100 (27.00%)
         occurrences all number
    48
    Rhinitis allergic
         subjects affected / exposed
    5 / 100 (5.00%)
         occurrences all number
    6
    Rhinorrhoea
         subjects affected / exposed
    7 / 100 (7.00%)
         occurrences all number
    13
    Sinus congestion
         subjects affected / exposed
    7 / 100 (7.00%)
         occurrences all number
    10
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 100 (8.00%)
         occurrences all number
    9
    Leukopenia
         subjects affected / exposed
    5 / 100 (5.00%)
         occurrences all number
    6
    Lymphadenectomy
         subjects affected / exposed
    7 / 100 (7.00%)
         occurrences all number
    10
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 100 (6.00%)
         occurrences all number
    10
    Headache
         subjects affected / exposed
    37 / 100 (37.00%)
         occurrences all number
    100
    Migraine
         subjects affected / exposed
    8 / 100 (8.00%)
         occurrences all number
    13
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    5 / 100 (5.00%)
         occurrences all number
    5
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    24 / 100 (24.00%)
         occurrences all number
    57
    Abdominal pain upper
         subjects affected / exposed
    15 / 100 (15.00%)
         occurrences all number
    26
    Anal fissure
         subjects affected / exposed
    9 / 100 (9.00%)
         occurrences all number
    10
    Constipation
         subjects affected / exposed
    15 / 100 (15.00%)
         occurrences all number
    25
    Crohn's disease
         subjects affected / exposed
    24 / 100 (24.00%)
         occurrences all number
    48
    Diarrhoea
         subjects affected / exposed
    26 / 100 (26.00%)
         occurrences all number
    41
    Dyspepsia
         subjects affected / exposed
    5 / 100 (5.00%)
         occurrences all number
    6
    Haematochezia
         subjects affected / exposed
    8 / 100 (8.00%)
         occurrences all number
    12
    Malpositioned teeth
         subjects affected / exposed
    6 / 100 (6.00%)
         occurrences all number
    6
    Nausea
         subjects affected / exposed
    19 / 100 (19.00%)
         occurrences all number
    49
    Rectal haemorrhage
         subjects affected / exposed
    5 / 100 (5.00%)
         occurrences all number
    5
    Toothache
         subjects affected / exposed
    5 / 100 (5.00%)
         occurrences all number
    10
    Vomiting
         subjects affected / exposed
    22 / 100 (22.00%)
         occurrences all number
    39
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    7 / 100 (7.00%)
         occurrences all number
    7
    Alopecia
         subjects affected / exposed
    5 / 100 (5.00%)
         occurrences all number
    7
    Dry skin
         subjects affected / exposed
    7 / 100 (7.00%)
         occurrences all number
    10
    Eczema
         subjects affected / exposed
    8 / 100 (8.00%)
         occurrences all number
    11
    Erythema
         subjects affected / exposed
    6 / 100 (6.00%)
         occurrences all number
    8
    Psoriasis
         subjects affected / exposed
    5 / 100 (5.00%)
         occurrences all number
    6
    Rash
         subjects affected / exposed
    15 / 100 (15.00%)
         occurrences all number
    25
    Urticaria
         subjects affected / exposed
    8 / 100 (8.00%)
         occurrences all number
    13
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    21 / 100 (21.00%)
         occurrences all number
    36
    Back pain
         subjects affected / exposed
    14 / 100 (14.00%)
         occurrences all number
    25
    Joint swelling
         subjects affected / exposed
    5 / 100 (5.00%)
         occurrences all number
    6
    Muscle spasms
         subjects affected / exposed
    8 / 100 (8.00%)
         occurrences all number
    11
    Myalgia
         subjects affected / exposed
    9 / 100 (9.00%)
         occurrences all number
    10
    Pain in extremity
         subjects affected / exposed
    9 / 100 (9.00%)
         occurrences all number
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    6 / 100 (6.00%)
         occurrences all number
    6
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    11 / 100 (11.00%)
         occurrences all number
    18
    Conjunctivitis
         subjects affected / exposed
    9 / 100 (9.00%)
         occurrences all number
    11
    Ear infection
         subjects affected / exposed
    10 / 100 (10.00%)
         occurrences all number
    15
    Eye infection
         subjects affected / exposed
    5 / 100 (5.00%)
         occurrences all number
    5
    Gastroenteritis
         subjects affected / exposed
    7 / 100 (7.00%)
         occurrences all number
    9
    Gastroenteritis viral
         subjects affected / exposed
    7 / 100 (7.00%)
         occurrences all number
    7
    Herpes zoster
         subjects affected / exposed
    8 / 100 (8.00%)
         occurrences all number
    9
    Impetigo
         subjects affected / exposed
    7 / 100 (7.00%)
         occurrences all number
    9
    Influenza
         subjects affected / exposed
    15 / 100 (15.00%)
         occurrences all number
    23
    Oral herpes
         subjects affected / exposed
    5 / 100 (5.00%)
         occurrences all number
    6
    Otitis media
         subjects affected / exposed
    8 / 100 (8.00%)
         occurrences all number
    11
    Pharyngitis
         subjects affected / exposed
    20 / 100 (20.00%)
         occurrences all number
    48
    Pharyngitis streptococcal
         subjects affected / exposed
    14 / 100 (14.00%)
         occurrences all number
    20
    Pneumonia
         subjects affected / exposed
    8 / 100 (8.00%)
         occurrences all number
    9
    Respiratory tract infection viral
         subjects affected / exposed
    5 / 100 (5.00%)
         occurrences all number
    5
    Rhinitis
         subjects affected / exposed
    10 / 100 (10.00%)
         occurrences all number
    20
    Sinusitis
         subjects affected / exposed
    17 / 100 (17.00%)
         occurrences all number
    33
    Staphylococcal infection
         subjects affected / exposed
    5 / 100 (5.00%)
         occurrences all number
    7
    Tonsillitis
         subjects affected / exposed
    7 / 100 (7.00%)
         occurrences all number
    8
    Upper respiratory tract infection
         subjects affected / exposed
    31 / 100 (31.00%)
         occurrences all number
    60
    Urinary tract infection
         subjects affected / exposed
    14 / 100 (14.00%)
         occurrences all number
    19
    Viral infection
         subjects affected / exposed
    18 / 100 (18.00%)
         occurrences all number
    21
    Viral upper respiratory tract infection
         subjects affected / exposed
    39 / 100 (39.00%)
         occurrences all number
    88

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Oct 2008
    Amendment 1 ● Updated Inclusion Criterion #2 to clarify that subject must be responder during Study M06-806. ● Amended the stopping rules as follows: The rate of possibly related SAEs or higher, on a per subject per year basis in excess of 0.45, was changed to the proportion of SAEs, possibly related or higher, on a per subject basis in excess of 0.20. ● Changed overall rate, in excess of 0.09 infectious SAEs on a per subject per year basis to the overall proportion of infectious SAEs in excess of 0.20 on a per subject basis. ● Changed the protocol paragraph with text "If either of these criteria is met, no new enrollment will occur until the Data Monitoring Committee (DMC) or the Sponsor Steering Committee makes their recommendations" to "If either of the above criteria is met, the DMC will meet within 2 weeks to consider whether or not to recommend a temporary suspension of enrollment." ● Removed Section 12.2 re: publication. ● Administrative Changes: ○ Updated approvals from other indications to reflect the most current data available. ○ Updated Safety Hotline address and contact information for AE reporting. ○ Updated to add reference for current guidelines for treatment of latent TB to reference list. ○ Appendix C (Documents Required Prior to Initiation of the Study): updated to reflect current regulatory requirements. ○ Appendix D (Responsibilities of the Clinical investigator): updated to reflect current regulatory requirements. ○ Appendix E (Centers for Disease Control [CDC] Treatment of Tuberculosis Infection [Preventive Therapy]): updated with current guidelines for treatment of latent TB. ○ Appendix H (PCDAI User's Guide and Guideline for Reference Weight and Height): updated to clarify from Wk 48 to Wk 72 and from post Wk 72, using height from Wk 48. ○ Appendix L (Excluded Medications): updated to state any previous anti TNF medication except infliximab before Study M06-806 ○ Appendix M (Day 70 Phone Call): updated faxing contact info.
    26 Aug 2010
    Amendment 2 ● Added blood sample collections for adalimumab concentration and AAA assays. ● Changed the stopping criteria for study based on discussion and recommendation by the DMC members. ● Added subject visits through Week 264 and provided for study to continue until local regulatory approval. ● Incorporated Administrative Changes 3 through 6 into this protocol. ● Added a new required template for protocol signatories (Appendix B).
    14 Dec 2010
    Amendment 3 ● Included an interim analysis. ● Clarified that the x-ray for bone age was not to be performed at the unscheduled visit. ● Added a statement allowing the investigator to omit the x-ray for bone age and the determination of serum bone markers if the subject was no longer growing.
    29 Jun 2011
    Amendment 4 ● Allowed dose and frequency decrease in subjects who responded well to treatment, allowed dose adjustment due to weight loss, and added 10 mg eow dosage.
    03 Jan 2012
    Amendment 5 ● Added in regular TB testing in response to the US Food and Drug Administration required labeling change based on cases of reactivation of TB/occurrence or new TB infections in patients receiving Humira. The US package insert now says retest should be done "periodically" during therapy, without specifying the interval. Based on the actual US package insert and on literature search, annual TB rescreening was implemented as a reasonable interval.
    12 Apr 2013
    Amendment 6 ● Added subject visits through Week 336 to extend the study. ● Section 3.0, Section 5.2.3.1, and Section 6.5 were revised to include additional anti-TNF information per Humira standards, and provided background information about enhanced data collection to understand the risks of malignancy in subjects 30 and younger. ● Section 5.2.3.2 Concomitant Therapy was revised to allow immunosuppressant to be started or restarted during the study. In addition, a sentence regarding the use of therapeutic enemas, suppositories and TPN was added to encourage the investigator to discuss with the Medical Monitor prior to use. ● In Section 5.2.3.4 Prohibited Medication, the use of therapeutic enemas and suppositories was removed. ● Section 5.3.1.1 Study Procedures (Outcomes): A clarification on the completion procedure of the WPAI-CD Caregiver was added. ● Section 5.3.2.1 Collection of samples for analysis: A clarification on collecting samples for subjects who require switching or change dose was added. ● Section 5.5.2.1 Packaging and Labeling was revised. ● Section 6.6 Pregnancy: The verbiage regarding the pregnancy registry was removed, as the registry is closed to Humira subjects and is only enrolling in the comparator (non-Humira) arm. ● Incorporated Administrative Change 7 into this protocol.
    26 May 2015
    Amendment 7 ● Added subject visits through Week 408 (approximately 8 years) to extend the study and provide for study to continue until local regulatory approval. ● Added the Complaint and Product Complaint definition to Sections 6.0, 6.2.1, and 6.2.2 as well as the reporting requirements for Product Complaints. ● Updated Section 8.1.5, Interim Analysis. ● Incorporated Administrative Changes 8 and 9 into this protocol.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/28129288
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