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    Clinical Trial Results:
    A Multicenter, Double-Blind Study to Evaluate the Safety, Efficacy and Pharmacokinetics of the Human Anti-TNF Monoclonal Antibody Adalimumab in Pediatric Subjects with Moderate to Severe Crohn's Disease

    Summary
    EudraCT number
    		 2006-004814-41
    Trial protocol
    		 FR   CZ   BE   NL   GB   IT   Outside EU/EEA  
    Global end of trial date
    29 Jul 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Apr 2016
    First version publication date
    07 Jun 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    M06-806
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00409682
    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 Information, AbbVie, 001 800-633-9110,
    Scientific contact
    Roopal Thakkar, MD, AbbVie, roopal.thakkar@abbvie.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000036-PIP01-08
    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
    29 Jul 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jul 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to determine Efficacy, Pharmacokinetics, and Safety of Adalimumab in Pediatric Subjects with Moderate to Severe Crohn's Disease.
    Protection of trial subjects
    The subject and/or parent or legal guardian read and understood information provided about the study and signed an informed consent form. Additionally, a written informed assent was obtained from all children in accordance with individual IRB recommendations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 May 2007
    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
    Netherlands: 7
    Country: Number of subjects enrolled
    Poland: 25
    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
    France: 3
    Country: Number of subjects enrolled
    Canada: 34
    Country: Number of subjects enrolled
    United States: 103
    Worldwide total number of subjects
    192
    EEA total number of subjects
    55
    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)
    37
    Adolescents (12-17 years)
    155
    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 were enrolled at 45 investigative sites in Belgium, Canada, Czech Republic, France, Italy, Netherlands, Poland, the United Kingdom, and the United States.

    Pre-assignment
    Screening details
    		 Paediatric subjects (6-17 years of age) with moderate to severe Crohn's disease (CD) (defined by Pediatric Crohn's Disease Activity Index [PCDAI > 30]) who had either failed conventional therapy for CD or previously received infliximab and lost response/had intolerance to infliximab. Screening occurred 1-3 weeks prior to open-label induction phase.

    Period 1
    Period 1 title
    Open-label Induction Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Open-label Adalimumab (Week 0 to Week 4)
    Arm description
    		 All subjects received an open-label adalimumab induction regimen. Subjects weighing greater than or equal to 40 kg at Baseline received 160 mg at Week 0 and 80 mg at Week 2. Subjects weighing less than 40 kg at Baseline received 80 mg at Week 0 and 40mg at Week 2.
    Arm type
    		 Active comparator

    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
    All subjects received an open-label adalimumab induction regimen. Subjects weighing greater than or equal to 40 kg at Baseline received 160 mg at Week 0 and 80 mg at Week 2. Subjects weighing less than 40 kg at Baseline received 80 mg at Week 0 and 40mg at Week 2.

    Number of subjects in period 1 [1]
    		Open-label Adalimumab (Week 0 to Week 4)
    Started
    188
    Completed
    188
    Notes
    [1] - 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 192 subjects received at least one dose of adalimumab and participated in the the 4- week Open-label induction period of the study. Of these, 4 discontinued and 188 subjects participated in the DB Maintenance period and are included in the analysis (intent-to-treat population was defined as all randomized subjects who received at least one dose of double-blind study medication).
    Period 2
    Period 2 title
    EOW Double-blind Maintenance Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Low-Dose Adalimumab: 20 mg or 10 mg eow (Week 4 to Week 52)
    Arm description
    		 Subjects randomized to the Low-Dose treatment group received either 20 mg adalimumab every other week (eow) (if Week 4 body weight [BW] was greater than or equal to 40 kg) or 10 mg adalimumab eow (if Week 4 BW less than 40 kg). Starting at the Week 12 study visit, subjects who experienced a disease flare or were non-responders could be switched from blinded eow dosing to blinded every week (ew) dosing, continuing with the same blinded dose. If a subject continued to experience a flare or met the definition of non-response following an 8-week course of double-blind (DB) ew therapy they could be switched to open-label ew therapy.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    ABT-D2E7, Humira
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects randomized to the Low-Dose treatment group received either 20 mg adalimumab every other week (eow) (if Week 4 body weight [BW] was greater than or equal to 40 kg) or 10 mg adalimumab eow (if Week 4 BW less than 40 kg). Starting at the Week 12 study visit, subjects who experienced a disease flare or were non-responders could be switched from blinded eow dosing to blinded every week (ew) dosing, continuing with the same blinded dose. If a subject continued to experience a flare or met the definition of non-response following an 8-week course of double-blind (DB) ew therapy they could be switched to open-label ew therapy.

    Arm title
    		 High-Dose Adalimumab: 40 mg or 20 mg eow (Week 4 to Week 52)
    Arm description
    		 Subjects randomized to the High-Dose treatment group received either 40 mg adalimumab every other week (eow) (if Week 4 body weight [BW] was greater than or equal to 40 kg) or 20 mg adalimumab eow (if Week 4 BW less than 40 kg). Starting at the Week 12 study visit, subjects who experienced a disease flare or were non-responders could be switched from blinded eow dosing to blinded every week (ew) dosing, continuing with the same blinded dose. If a subject continued to experience a flare or met the definition of non-response following an 8-week course of double-blinded (DB) ew therapy they could be switched to open-label ew therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    ABT-D2E7, Humira
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects randomized to the High-Dose treatment group received either 40 mg adalimumab every other week (eow) (if Week 4 body weight [BW] was greater than or equal to 40 kg) or 20 mg adalimumab eow (if Week 4 BW less than 40 kg). Starting at the Week 12 study visit, subjects who experienced a disease flare or were non-responders could be switched from blinded eow dosing to blinded every week (ew) dosing, continuing with the same blinded dose. If a subject continued to experience a flare or met the definition of non-response following an 8-week course of double-blinded (DB) ew therapy they could be switched to open-label ew therapy.

    Number of subjects in period 2
    		Low-Dose Adalimumab: 20 mg or 10 mg eow (Week 4 to Week 52) High-Dose Adalimumab: 40 mg or 20 mg eow (Week 4 to Week 52)
    Started
    95
    93
    Completed
    58
    66
    Not completed
    37
    27
         Consent withdrawn by subject
    4
    2
         Adverse event, non-fatal
    10
    12
         Non-compliance
    -
    1
         Lost to follow-up
    1
    -
         Protocol deviation
    4
    1
         Lack of efficacy
    18
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Open-label Adalimumab (Week 0 to Week 4)
    Reporting group description
    		 All subjects received an open-label adalimumab induction regimen. Subjects weighing greater than or equal to 40 kg at Baseline received 160 mg at Week 0 and 80 mg at Week 2. Subjects weighing less than 40 kg at Baseline received 80 mg at Week 0 and 40mg at Week 2.

    Reporting group values
    		 Open-label Adalimumab (Week 0 to Week 4) Total
    Number of subjects
    		 188 188
    Age categorical
    Units: Subjects
        < 13
    		 66 66
        >= 13
    		 122 122
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 13.6 ± 2.49 -
    Gender categorical
    Units: Subjects
        Female
    		 83 83
        Male
    		 105 105
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 166 166
        Black
    		 11 11
        Asian
    		 3 3
        American Indian/Alaska Native
    		 0 0
        Native Hawaiian or other Pacific Islander
    		 0 0
        Multi-race
    		 3 3
        Other
    		 5 5
    Weight (kg)
    Units: Subjects
        < 40
    		 67 67
        >= 40
    		 121 121
    Subject analysis sets

    Subject analysis set title
    Low-Dose Adalimumab: 20 mg or 10 mg (Week 4 to Week 52)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects randomized to the Low-Dose treatment group received either 20 mg adalimumab every other week (eow) (if Week 4 body weight [BW] was greater than or equal to 40 kg) or 10 mg adalimumab eow (if Week 4 BW less than 40 kg). Starting at the Week 12 study visit, subjects who experienced a disease flare or were non-responders could be switched from blinded eow dosing to blinded every week (ew) dosing, continuing with the same blinded dose. If a subject continued to experience a flare or met the definition of non-response following an 8-week course of double-blind (DB) ew therapy they could be switched to open-label ew therapy. The intent-to-treat (ITT) population included all randomized subjects who received at least one dose of double-blind study medication.

    Subject analysis set title
    High-Dose Adalimumab: 40 mg or 20 mg Eow (Week 4 to Week 52)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects randomized to the High-Dose treatment group received either 40 mg adalimumab every other week (eow) (if Week 4 body weight [BW] was greater than or equal to 40 kg) or 20 mg adalimumab eow (if Week 4 BW less than 40 kg). Starting at the Week 12study visit, subjects who experienced a disease flare or were non-responders could be switched from blinded eow dosing to blinded every week (ew) dosing, continuing with the same blinded dose. If a subject continued to experience a flare or met the definition of non-response following an 8-week course of double-blinded (DB) ew therapy they could be switched to open-label ew therapy. The intent-to-treat (ITT) population included all randomized subjects who received at least one dose of double-blind study medication.

    Subject analysis sets values
    		 Low-Dose Adalimumab: 20 mg or 10 mg (Week 4 to Week 52) High-Dose Adalimumab: 40 mg or 20 mg Eow (Week 4 to Week 52)
    Number of subjects
    95
    93
    Age categorical
    Units: Subjects
        < 13
    35
    31
        >= 13
    60
    62
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    13.5 ± 2.47
    13.7 ± 2.52
    Gender categorical
    Units: Subjects
        Female
    41
    42
        Male
    54
    51
    Race/Ethnicity, Customized
    Units: Subjects
        White
    85
    81
        Black
    6
    5
        Asian
    0
    3
        American Indian/Alaska Native
    0
    0
        Native Hawaiian or other Pacific Islander
    0
    0
        Multi-race
    2
    1
        Other
    2
    3
    Weight (kg)
    Units: Subjects
        < 40
    35
    32
        >= 40
    60
    61

    End points

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    End points reporting groups
    Reporting group title
    Open-label Adalimumab (Week 0 to Week 4)
    Reporting group description
    		 All subjects received an open-label adalimumab induction regimen. Subjects weighing greater than or equal to 40 kg at Baseline received 160 mg at Week 0 and 80 mg at Week 2. Subjects weighing less than 40 kg at Baseline received 80 mg at Week 0 and 40mg at Week 2.
    Reporting group title
    Low-Dose Adalimumab: 20 mg or 10 mg eow (Week 4 to Week 52)
    Reporting group description
    		 Subjects randomized to the Low-Dose treatment group received either 20 mg adalimumab every other week (eow) (if Week 4 body weight [BW] was greater than or equal to 40 kg) or 10 mg adalimumab eow (if Week 4 BW less than 40 kg). Starting at the Week 12 study visit, subjects who experienced a disease flare or were non-responders could be switched from blinded eow dosing to blinded every week (ew) dosing, continuing with the same blinded dose. If a subject continued to experience a flare or met the definition of non-response following an 8-week course of double-blind (DB) ew therapy they could be switched to open-label ew therapy.

    Reporting group title
    High-Dose Adalimumab: 40 mg or 20 mg eow (Week 4 to Week 52)
    Reporting group description
    		 Subjects randomized to the High-Dose treatment group received either 40 mg adalimumab every other week (eow) (if Week 4 body weight [BW] was greater than or equal to 40 kg) or 20 mg adalimumab eow (if Week 4 BW less than 40 kg). Starting at the Week 12 study visit, subjects who experienced a disease flare or were non-responders could be switched from blinded eow dosing to blinded every week (ew) dosing, continuing with the same blinded dose. If a subject continued to experience a flare or met the definition of non-response following an 8-week course of double-blinded (DB) ew therapy they could be switched to open-label ew therapy.

    Subject analysis set title
    Low-Dose Adalimumab: 20 mg or 10 mg (Week 4 to Week 52)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects randomized to the Low-Dose treatment group received either 20 mg adalimumab every other week (eow) (if Week 4 body weight [BW] was greater than or equal to 40 kg) or 10 mg adalimumab eow (if Week 4 BW less than 40 kg). Starting at the Week 12 study visit, subjects who experienced a disease flare or were non-responders could be switched from blinded eow dosing to blinded every week (ew) dosing, continuing with the same blinded dose. If a subject continued to experience a flare or met the definition of non-response following an 8-week course of double-blind (DB) ew therapy they could be switched to open-label ew therapy. The intent-to-treat (ITT) population included all randomized subjects who received at least one dose of double-blind study medication.

    Subject analysis set title
    High-Dose Adalimumab: 40 mg or 20 mg Eow (Week 4 to Week 52)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects randomized to the High-Dose treatment group received either 40 mg adalimumab every other week (eow) (if Week 4 body weight [BW] was greater than or equal to 40 kg) or 20 mg adalimumab eow (if Week 4 BW less than 40 kg). Starting at the Week 12study visit, subjects who experienced a disease flare or were non-responders could be switched from blinded eow dosing to blinded every week (ew) dosing, continuing with the same blinded dose. If a subject continued to experience a flare or met the definition of non-response following an 8-week course of double-blinded (DB) ew therapy they could be switched to open-label ew therapy. The intent-to-treat (ITT) population included all randomized subjects who received at least one dose of double-blind study medication.

    Primary: Percent of Participants With Clinical Remission as Defined by Pediatric Crohn's Disease Activity Index (PCDAI) Score ≤ 10 at Week 26

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    End point title
    		 Percent of Participants With Clinical Remission as Defined by Pediatric Crohn's Disease Activity Index (PCDAI) Score ≤ 10 at Week 26
    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 primary endpoint was clinical remission as defined by PCDAI score ≤ 10. The comparison was between High-Dose adalimumab versus Low-Dose adalimumab in the intent-to-treat population.
    End point type
    Primary
    End point timeframe
    Week 26
    End point values
    		 Low-Dose Adalimumab: 20 mg or 10 mg eow (Week 4 to Week 52) High-Dose Adalimumab: 40 mg or 20 mg eow (Week 4 to Week 52)
    Number of subjects analysed
    95
    93
    Units: percent of participants
        number (not applicable)
    28.4
    38.7
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The point estimates for the number of subjects who achieved PCDAI clinical remission in each treatment group and the difference in number between the groups were provided. The P value and 95% confidence intervals (CIs) for the difference were provided. The P value is from the CMH test adjusted for infliximab use and response status at Week 4. The primary analysis was performed for the intent-to-treat (ITT) population using the non-responder (NRI) imputation method.
    Comparison groups
    High-Dose Adalimumab: 40 mg or 20 mg eow (Week 4 to Week 52) v Low-Dose Adalimumab: 20 mg or 10 mg eow (Week 4 to Week 52)
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.075 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (net)
    Point estimate
    10.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.14
         upper limit
    		 23.71
    Notes
    [1] - There is no adjustment for multiple comparison on the primary outcome measure.

    Secondary: Percent of Participants With Clinical Remission as Defined by Pediatric Crohn's Disease Activity Index (PCDAI) Score ≤ 10 at Week 52

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    End point title
    		 Percent of Participants With Clinical Remission as Defined by Pediatric Crohn's Disease Activity Index (PCDAI) Score ≤ 10 at Week 52
    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, examination of abdomen, perirectal disease, and extraintestinal manifestations. It ranges from 0 to 100 with higher scores indicating more active disease. Clinical remission was defined as PCDAI score of ≤ 10. The comparison was between High-Dose adalimumab versus Low-Dose adalimumab in the intent-to treat population. Non-responder imputation (NRI)was used.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Low-Dose Adalimumab: 20 mg or 10 mg eow (Week 4 to Week 52) High-Dose Adalimumab: 40 mg or 20 mg eow (Week 4 to Week 52)
    Number of subjects analysed
    95
    93
    Units: percent of participants
        number (not applicable)
    23.2
    33.3
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The point estimates for the number of subjects who achieved PCDAI clinical remission in each arm, the difference in number between the arms, and the P value and 95% CI for the difference were provided. The analysis was performed for the ITT population using the NRI method. A significance test for any individual major secondary efficacy endpoint in the hierarchy was to be inferential only if the hypothesis tests of all preceding major secondary endpoints were statistically significant at 0.050.
    Comparison groups
    Low-Dose Adalimumab: 20 mg or 10 mg eow (Week 4 to Week 52) v High-Dose Adalimumab: 40 mg or 20 mg eow (Week 4 to Week 52)
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (net)
    Point estimate
    10.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.62
         upper limit
    		 22.97
    Notes
    [2] - The hierarchical stepwise closed testing procedure was implemented to control the overall significance level at 0.05 in the ITT population.

    Secondary: Percent of Participants With Clinical Response as Defined by Pediatric Crohn's Disease Activity Index (PCDAI) Score at Week 26

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    End point title
    		 Percent of Participants With Clinical Response as Defined by Pediatric Crohn's Disease Activity Index (PCDAI) Score at Week 26
    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, examination of abdomen, perirectal disease, and extraintestinal manifestations. It ranges from 0 to 100; higher scores indicate more active disease. Clinical response was defined as a decrease from Baseline in the PCDAI score of at least 15 points. The comparison was High-Dose adalimumab versus Low-Dose in the ITT population. Non-responder imputation (NRI) was used.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Low-Dose Adalimumab: 20 mg or 10 mg eow (Week 4 to Week 52) High-Dose Adalimumab: 40 mg or 20 mg eow (Week 4 to Week 52)
    Number of subjects analysed
    95
    93
    Units: percent of participants
        number (not applicable)
    48.4
    59.1
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The point estimates for the number of subjects who achieved PCDAI clinical remission in each arm, the difference in number between the arms, and the P value and 95% CI for the difference were provided. The analysis was performed for the ITT population using the NRI method. A significance test for any individual major secondary efficacy endpoint in the hierarchy was to be inferential only if the hypothesis tests of all preceding major secondary endpoints were statistically significant at 0.050
    Comparison groups
    Low-Dose Adalimumab: 20 mg or 10 mg eow (Week 4 to Week 52) v High-Dose Adalimumab: 40 mg or 20 mg eow (Week 4 to Week 52)
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.073 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (net)
    Point estimate
    10.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.45
         upper limit
    		 24.89
    Notes
    [3] - The hierarchical stepwise closed testing procedure was implemented to control the overall significance level at 0.05 in the ITT population

    Secondary: Percent of Participants With Clinical Response as Defined by Pediatric Crohn's Disease Activity Index (PCDAI) Score at Week 52

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    End point title
    		 Percent of Participants With Clinical Response as Defined by Pediatric Crohn's Disease Activity Index (PCDAI) Score at Week 52
    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, examination of abdomen, perirectal disease, and extraintestinal manifestations. It ranges from 0 to 100; higher scores indicate more active disease. Clinical response was defined as a decrease from Baseline in the PCDAI score of at least 15 points. The comparison was High-Dose adalimumab versus Low-Dose in the ITT population. Non-responder imputation (NRI) was used.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Low-Dose Adalimumab: 20 mg or 10 mg eow (Week 4 to Week 52) High-Dose Adalimumab: 40 mg or 20 mg eow (Week 4 to Week 52)
    Number of subjects analysed
    95
    93
    Units: percent of participants
        number (not applicable)
    28.4
    41.9
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The point estimates for the number of subjects who achieved PCDAI clinical remission in each arm, the difference in number between the arms, and the P value and 95% CI for the difference were provided. The analysis was performed for the ITT population using the NRI method. A significance test for any individual major secondary efficacy endpoint in the hierarchy was to be inferential only if the hypothesis tests of all preceding major secondary endpoints were statistically significant at 0.050
    Comparison groups
    Low-Dose Adalimumab: 20 mg or 10 mg eow (Week 4 to Week 52) v High-Dose Adalimumab: 40 mg or 20 mg eow (Week 4 to Week 52)
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.038 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (net)
    Point estimate
    13.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 27.04
    Notes
    [4] - The hierarchical stepwise closed testing procedure was implemented to control the overall significance level at 0.05 in the ITT population

    Secondary: Change From Baseline IMPACT III Scores at Week 26 (Observed Case)

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    End point title
    		 Change From Baseline IMPACT III Scores at Week 26 (Observed Case)
    End point description
    The IMPACT III questionnaire is a 35-item assessment of health-related quality of life in patients with inflammatory bowel disease (Crohn's disease [CD] or ulcerative colitis). In this study, subjects greater than or equal 10 years old who had CD at baseline completed an IMPACT III questionnaire at Baseline, Week 26, and Week 52. Subjects marked an option from 1 to 5 for each item left to right with numbers 5 (good 'quality of life' condition) through 1 (bad 'quality of life' condition). The total scores, range from 35 to 175 with higher scores representing a better quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Low-Dose Adalimumab: 20 mg or 10 mg eow (Week 4 to Week 52) High-Dose Adalimumab: 40 mg or 20 mg eow (Week 4 to Week 52)
    Number of subjects analysed
    48
    56
    Units: scores on a scale
        arithmetic mean (standard deviation)
    26.4 ± 15.589
    23.7 ± 18.99
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analyzed as change from Baseline to Week 26, and compared between the 2 treatment arms. The estimated treatment mean difference, P values, and 95% CI for the treatment difference were provided. Analysis was conducted in the ITT population for OC. P value is from the ANCOVA model with treatment as a factor, adjusted for the baseline value, and the strata (response status at Week 4 and prior infliximab experience). Baseline means include subjects with both Baseline and post-Baseline measurements.
    Comparison groups
    Low-Dose Adalimumab: 20 mg or 10 mg eow (Week 4 to Week 52) v High-Dose Adalimumab: 40 mg or 20 mg eow (Week 4 to Week 52)
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.161 [5]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -4.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.86
         upper limit
    		 1.66
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.903
    Notes
    [5] - The hierarchical stepwise closed testing procedure was implemented to control the overall significance level at 0.05 in the ITT population

    Secondary: Change From Baseline IMPACT III Scores at Week 52 (Observed Case)

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    End point title
    		 Change From Baseline IMPACT III Scores at Week 52 (Observed Case)
    End point description
    The IMPACT III questionnaire is a 35-item assessment of health-related quality of life in patients with inflammatory bowel disease (Crohn's disease [CD] or ulcerative colitis). In this study, subjects greater than or equal 10 years old who had CD at baseline completed an IMPACT III questionnaire at Baseline, Week 26, and Week 52. Subjects marked an option from 1 to 5 for each item left to right with numbers 5 (good 'quality of life' condition) through 1 (bad 'quality of life' condition). The total scores, range from 35 to 175 with higher scores representing a better quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Low-Dose Adalimumab: 20 mg or 10 mg eow (Week 4 to Week 52) High-Dose Adalimumab: 40 mg or 20 mg eow (Week 4 to Week 52)
    Number of subjects analysed
    31
    38
    Units: scores on a scale
        arithmetic mean (standard deviation)
    26.49 ± 16.182
    24.25 ± 14.678
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analyzed as change from Baseline to Week 52, and compared between the two treatment arms. The estimated treatment mean difference, P values, and 95% CI for the treatment difference were provided. Analysis was conducted in the ITT population for OC. Difference is between adalimumab High-dose and adalimumab Low-dose groups. Baseline means include subjects who had both Baseline and post-Baseline means. Baseline means include subjects who had both Baseline and post-Baseline measurements.
    Comparison groups
    Low-Dose Adalimumab: 20 mg or 10 mg eow (Week 4 to Week 52) v High-Dose Adalimumab: 40 mg or 20 mg eow (Week 4 to Week 52)
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.735
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.88
         upper limit
    		 4.88
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.941

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events (AEs) reported from the time of study drug administration until 70 days after discontinuation of study drug were collected. Serious AEs were collected from the time the subject or parent/legal guardian signed the informed consent.
    Adverse event reporting additional description
    Open-label (OL) Adalimumab (Wk 0 - Wk 4): AEs from first OL dose to 70 days after last OL induction adalimumab dose or until first double-blind (DB) dose Low-Dose/High-Dose Adalimumab (Wk 4 - Wk 52): AEs from first DB dose to 70 days after last DB every other week (eow) or until switch to every week (ew) dosing or OL extension.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Open-label Adalimumab (Week 0 to Week 4)
    Reporting group description
    		 -

    Reporting group title
    Low-Dose Adalimumab: 20 mg or 10 mg Eow (Week 4 to Week 52)
    Reporting group description
    		 -

    Reporting group title
    High-Dose Adalimumab: 40 mg or 20 mg Eow (Week 4 to Week 52)
    Reporting group description
    		 -

    Serious adverse events
    		 Open-label Adalimumab (Week 0 to Week 4) Low-Dose Adalimumab: 20 mg or 10 mg Eow (Week 4 to Week 52) High-Dose Adalimumab: 40 mg or 20 mg Eow (Week 4 to Week 52)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 192 (3.13%)
    19 / 95 (20.00%)
    22 / 93 (23.66%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Heart rate irregular
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 95 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Facial bones fracture
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 95 (1.05%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 192 (0.00%)
    0 / 95 (0.00%)
    4 / 93 (4.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Crohn's disease
         subjects affected / exposed
    2 / 192 (1.04%)
    15 / 95 (15.79%)
    12 / 93 (12.90%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 15
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inflammatory bowel disease
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 95 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 95 (1.05%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 192 (0.00%)
    0 / 95 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychosomatic disease
         subjects affected / exposed
    0 / 192 (0.00%)
    0 / 95 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 192 (0.00%)
    0 / 95 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 192 (0.00%)
    0 / 95 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bartholin's abscess
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 95 (1.05%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 192 (0.00%)
    0 / 95 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 192 (0.00%)
    0 / 95 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Histoplasmosis disseminated
         subjects affected / exposed
    0 / 192 (0.00%)
    0 / 95 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Scarlet fever
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 95 (1.05%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 95 (1.05%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 95 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Yersinia infection
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 95 (0.00%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Open-label Adalimumab (Week 0 to Week 4) Low-Dose Adalimumab: 20 mg or 10 mg Eow (Week 4 to Week 52) High-Dose Adalimumab: 40 mg or 20 mg Eow (Week 4 to Week 52)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    64 / 192 (33.33%)
    62 / 95 (65.26%)
    69 / 93 (74.19%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 192 (0.00%)
    5 / 95 (5.26%)
    2 / 93 (2.15%)
         occurrences all number
    0
    6
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 192 (0.52%)
    3 / 95 (3.16%)
    5 / 93 (5.38%)
         occurrences all number
    1
    4
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 192 (1.04%)
    5 / 95 (5.26%)
    1 / 93 (1.08%)
         occurrences all number
    2
    5
    2
    Headache
         subjects affected / exposed
    9 / 192 (4.69%)
    20 / 95 (21.05%)
    16 / 93 (17.20%)
         occurrences all number
    15
    26
    27
    Blood and lymphatic system disorders
    Lymphadenectomy
         subjects affected / exposed
    0 / 192 (0.00%)
    6 / 95 (6.32%)
    3 / 93 (3.23%)
         occurrences all number
    0
    6
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 192 (1.56%)
    4 / 95 (4.21%)
    5 / 93 (5.38%)
         occurrences all number
    3
    4
    6
    Injection site pain
         subjects affected / exposed
    12 / 192 (6.25%)
    4 / 95 (4.21%)
    2 / 93 (2.15%)
         occurrences all number
    15
    5
    13
    Injection site reaction
         subjects affected / exposed
    10 / 192 (5.21%)
    4 / 95 (4.21%)
    5 / 93 (5.38%)
         occurrences all number
    11
    4
    9
    Pain
         subjects affected / exposed
    2 / 192 (1.04%)
    2 / 95 (2.11%)
    5 / 93 (5.38%)
         occurrences all number
    2
    2
    5
    Pyrexia
         subjects affected / exposed
    1 / 192 (0.52%)
    8 / 95 (8.42%)
    10 / 93 (10.75%)
         occurrences all number
    1
    13
    14
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 192 (2.60%)
    6 / 95 (6.32%)
    9 / 93 (9.68%)
         occurrences all number
    5
    9
    13
    Abdominal pain upper
         subjects affected / exposed
    2 / 192 (1.04%)
    3 / 95 (3.16%)
    7 / 93 (7.53%)
         occurrences all number
    3
    4
    8
    Crohn's disease
         subjects affected / exposed
    5 / 192 (2.60%)
    15 / 95 (15.79%)
    11 / 93 (11.83%)
         occurrences all number
    6
    18
    16
    Diarrhoea
         subjects affected / exposed
    3 / 192 (1.56%)
    9 / 95 (9.47%)
    8 / 93 (8.60%)
         occurrences all number
    3
    14
    9
    Nausea
         subjects affected / exposed
    9 / 192 (4.69%)
    6 / 95 (6.32%)
    10 / 93 (10.75%)
         occurrences all number
    10
    9
    14
    Vomiting
         subjects affected / exposed
    3 / 192 (1.56%)
    10 / 95 (10.53%)
    6 / 93 (6.45%)
         occurrences all number
    3
    17
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 192 (0.00%)
    7 / 95 (7.37%)
    9 / 93 (9.68%)
         occurrences all number
    0
    7
    13
    Oropharyngeal pain
         subjects affected / exposed
    3 / 192 (1.56%)
    8 / 95 (8.42%)
    9 / 93 (9.68%)
         occurrences all number
    3
    10
    11
    Rhinorrhoea
         subjects affected / exposed
    1 / 192 (0.52%)
    8 / 95 (8.42%)
    3 / 93 (3.23%)
         occurrences all number
    1
    11
    3
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 192 (0.00%)
    5 / 95 (5.26%)
    5 / 93 (5.38%)
         occurrences all number
    0
    6
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 192 (2.08%)
    4 / 95 (4.21%)
    8 / 93 (8.60%)
         occurrences all number
    4
    4
    11
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 192 (1.56%)
    11 / 95 (11.58%)
    9 / 93 (9.68%)
         occurrences all number
    3
    14
    11
    Pharyngitis
         subjects affected / exposed
    2 / 192 (1.04%)
    2 / 95 (2.11%)
    7 / 93 (7.53%)
         occurrences all number
    2
    6
    10
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 192 (0.00%)
    5 / 95 (5.26%)
    2 / 93 (2.15%)
         occurrences all number
    0
    5
    2
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 192 (2.60%)
    10 / 95 (10.53%)
    10 / 93 (10.75%)
         occurrences all number
    5
    11
    11
    Viral infection
         subjects affected / exposed
    0 / 192 (0.00%)
    6 / 95 (6.32%)
    4 / 93 (4.30%)
         occurrences all number
    0
    6
    4
    Viral upper respiratory tract infection
         subjects affected / exposed
    6 / 192 (3.13%)
    3 / 95 (3.16%)
    5 / 93 (5.38%)
         occurrences all number
    6
    3
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Mar 2007
    To provide procedural and safety clarification; update exclusion criteria based on postmarketing report (subjects with chronic or active hepatitis B will be excluded); update primary efficacy variable (clinical remission at Week 26 irrespective of responder status at Week 4).
    08 Aug 2007
    To include approval of adalimumab for Crohn's Disease in the US; clarify withdrawal criteria for subjects that continue to flare, develop another flare, or continue to have a non-response while receiving open-label weekly therapy; to clarify rescreening of subjects; clarify subject eligibility bases on age (between 6 and 17 years of age, inclusive prior to baseline dosing); clarify eligibility criteria (simplify stable dose of corticosteroids; expand choice of birth control methods; exclude subjects with a history of histoplasmosis, active tuberculosis, moderate to severe heart failure; daily dose of prednisone < 10 mg; certain concomitant medications); clarify that subjects with a positive C.difficile stool assay at Screening were not permitted to re-screen. and to prohibit abatacept and therapeutic enemas and suppositories during the study.
    04 Feb 2008
    To allow subjects with a positive C. difficile stool assay at Screening to re-screen.
    02 Oct 2008
    To revise the stopping rules based on new data available and agreed upon by the Data Monitoring Committee; clarify that assent from the subject may be verbal and/or written; provide clarification regarding permitted medications; allow baseline visits as soon as all screening assessments are complete for subjects < 13 years of age; clarify statistical analyses of primary and secondary endpoints.
    30 Mar 2010
    To analyze the primary endpoint for concomitant immunomodulator use (at baseline) as well as serious infection incidence and rates (patient years); clarify endpoint analyses.

    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.
    Absence of placebo group comparative data.
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