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    Clinical Trial Results:
    A Multicenter Open-label Study of the Human Anti-TNF Monoclonal Antibody Adalimumab to Investigate Efficacy, Safety and Pharmacokinetics after Dose Escalation in Japanese Subjects with Crohn's Disease

    Summary
    EudraCT number
    		 2015-004121-13
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    01 Oct 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Apr 2016
    First version publication date
    09 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M13-687
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01958827
    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
    Morio Ozawa, MS, AbbVie GK, morio.ozawa@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
    01 Oct 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to investigate the efficacy, safety and pharmacokinetics after dose escalation in Japanese subjects with Crohn's Disease.
    Protection of trial subjects
    Subject and/or representative and/or legal guardian (if subject was < 20 years old) read and understood the information provided about the study and gave written permission.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Sep 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 28
    Worldwide total number of subjects
    28
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    27
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This study included a 21-day screening period. A total of 28 subjects were enrolled and were included in the Full Analysis Set (FAS: All enrolled subjects who received at least one dose of study drug and had at least one post-treatment efficacy assessment).

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

    Arms
    Arm title
    		 Adalimumab 80 mg
    Arm description
    		 All subjects were to receive subcutaneous injections of open-label adalimumab 80 mg every other week from Week 0 to Week 50.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Humira, ABT-D2E7
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Adalimumab pre-filled syringe, administered by subcutaneous injection.

    Number of subjects in period 1
    		Adalimumab 80 mg
    Started
    28
    Completed
    18
    Not completed
    10
         Concomitant prohibited medicine for AE
    1
         Adverse event
    3
         Lack of efficacy
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Adalimumab 80 mg
    Reporting group description
    		 All subjects were to receive subcutaneous injections of open-label adalimumab 80 mg every other week from Week 0 to Week 50.

    Reporting group values
    		 Adalimumab 80 mg Total
    Number of subjects
    		 28 28
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 33.6 ( 10.09 ) -
    Gender categorical
    Units: Subjects
        Female
    		 12 12
        Male
    		 16 16

    End points

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    End points reporting groups
    Reporting group title
    Adalimumab 80 mg
    Reporting group description
    		 All subjects were to receive subcutaneous injections of open-label adalimumab 80 mg every other week from Week 0 to Week 50.

    Primary: Percentage of Subjects Who Achieved Clinical Response 50 (CR50; Crohn's Disease Activity Index [CDAI] Decrease ≥ 50 From Week 0) at Week 8

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    End point title
    		 Percentage of Subjects Who Achieved Clinical Response 50 (CR50; Crohn's Disease Activity Index [CDAI] Decrease ≥ 50 From Week 0) at Week 8 [1]
    End point description
    CDAI is used to quantify the signs and symptoms of patients with Crohn's Disease. A score below 150 indicates remission and a score above 450 indicates severe disease. Non-responder imputation (NRI) for missing CDAI observations was used.
    End point type
    Primary
    End point timeframe
    Week 8
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive data are summarized for this end point per protocol.
    End point values
    		 Adalimumab 80 mg
    Number of subjects analysed
    28 [2]
    Units: percentage of subjects
        number (confidence interval 95%)
    75 (55.1 to 89.3)
    Notes
    [2] - FAS
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved Clinical Remission (CDAI < 150) Every 4 Weeks up to Week 52

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    End point title
    		 Percentage of Subjects Who Achieved Clinical Remission (CDAI < 150) Every 4 Weeks up to Week 52
    End point description
    CDAI is used to quantify the signs and symptoms of patients with Crohn's Disease. A score below 150 indicates remission and a score above 450 indicates severe disease. Non-responder imputation (NRI) for missing CDAI observations was used.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    		 Adalimumab 80 mg
    Number of subjects analysed
    28 [3]
    Units: percentage of subjects
    number (confidence interval 95%)
        Week 4
    14.3 (4 to 32.7)
        Week 8
    25 (10.7 to 44.9)
        Week 12
    28.6 (13.2 to 48.7)
        Week 16
    32.1 (15.9 to 52.4)
        Week 20
    35.7 (18.6 to 55.9)
        Week 24
    42.9 (24.5 to 62.8)
        Week 28
    35.7 (18.6 to 55.9)
        Week 32
    42.9 (24.5 to 62.8)
        Week 36
    39.3 (21.5 to 59.4)
        Week 40
    39.3 (21.5 to 59.4)
        Week 44
    42.9 (24.5 to 62.8)
        Week 48
    39.3 (21.5 to 59.4)
        Week 52
    35.7 (18.6 to 55.9)
    Notes
    [3] - FAS
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved Clinical Response 50 (CR50; Crohn's Disease Activity Index [CDAI] Decrease ≥ 50 From Week 0) Every 4 Weeks up to Week 52

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    End point title
    		 Percentage of Subjects Who Achieved Clinical Response 50 (CR50; Crohn's Disease Activity Index [CDAI] Decrease ≥ 50 From Week 0) Every 4 Weeks up to Week 52
    End point description
    CDAI is used to quantify the signs and symptoms of patients with Crohn's Disease. A score below 150 indicates remission and a score above 450 indicates severe disease. Non-responder imputation (NRI) for missing CDAI observations was used. Week 8 was the primary outcome measure.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    		 Adalimumab 80 mg
    Number of subjects analysed
    28 [4]
    Units: percentage of subjects
    number (confidence interval 95%)
        Week 4
    67.9 (47.6 to 84.1)
        Week 12
    67.9 (47.6 to 84.1)
        Week 16
    67.9 (47.6 to 84.1)
        Week 20
    67.9 (47.6 to 84.1)
        Week 24
    71.4 (51.3 to 86.8)
        Week 28
    64.3 (44.1 to 81.4)
        Week 32
    71.4 (51.3 to 86.8)
        Week 36
    67.9 (47.6 to 84.1)
        Week 40
    64.3 (44.1 to 81.4)
        Week 44
    60.7 (40.6 to 78.5)
        Week 48
    64.3 (44.1 to 81.4)
        Week 52
    57.1 (37.2 to 75.5)
    Notes
    [4] - FAS
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved Clinical Response 70 (CR70; Crohn's Disease Activity Index [CDAI] Decrease ≥ 70 From Week 0) Every 4 Weeks up to Week 52

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    End point title
    		 Percentage of Subjects Who Achieved Clinical Response 70 (CR70; Crohn's Disease Activity Index [CDAI] Decrease ≥ 70 From Week 0) Every 4 Weeks up to Week 52
    End point description
    CDAI is used to quantify the signs and symptoms of patients with Crohn's Disease. A score below 150 indicates remission and a score above 450 indicates severe disease. Non-responder imputation (NRI) for missing CDAI observations was used.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    		 Adalimumab 80 mg
    Number of subjects analysed
    28 [5]
    Units: percentage of subjects
    number (confidence interval 95%)
        Week 4
    46.4 (27.5 to 66.1)
        Week 8
    57.1 (37.2 to 75.5)
        Week 12
    64.3 (44.1 to 81.4)
        Week 16
    64.3 (44.1 to 81.4)
        Week 20
    64.3 (44.1 to 81.4)
        Week 24
    67.9 (47.6 to 84.1)
        Week 28
    64.3 (44.1 to 81.4)
        Week 32
    67.9 (47.6 to 84.1)
        Week 36
    64.3 (44.1 to 81.4)
        Week 40
    60.7 (40.6 to 78.5)
        Week 44
    57.1 (37.2 to 75.5)
        Week 48
    60.7 (40.6 to 78.5)
        Week 52
    57.1 (37.2 to 75.5)
    Notes
    [5] - FAS
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved Clinical Response 100 (CR100; Crohn's Disease Activity Index [CDAI] Decrease of 100 From Week 0) Every 4 Weeks up to Week 52

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    End point title
    		 Percentage of Subjects Who Achieved Clinical Response 100 (CR100; Crohn's Disease Activity Index [CDAI] Decrease of 100 From Week 0) Every 4 Weeks up to Week 52
    End point description
    CDAI is used to quantify the signs and symptoms of patients with Crohn's Disease. A score below 150 indicates remission and a score above 450 indicates severe disease. Non-responder imputation (NRI) for missing CDAI observations was used.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    		 Adalimumab 80 mg
    Number of subjects analysed
    28 [6]
    Units: percentage of subjects
    number (confidence interval 95%)
        Week 4
    32.1 (15.9 to 52.4)
        Week 8
    35.7 (18.6 to 55.9)
        Week 12
    39.3 (21.5 to 59.4)
        Week 16
    46.4 (27.5 to 66.1)
        Week 20
    50 (30.6 to 69.4)
        Week 24
    50 (30.6 to 69.4)
        Week 28
    42.9 (24.5 to 62.8)
        Week 32
    50 (30.6 to 69.4)
        Week 36
    50 (30.6 to 69.4)
        Week 40
    57.1 (37.2 to 75.5)
        Week 44
    46.4 (27.5 to 66.1)
        Week 48
    50 (30.6 to 69.4)
        Week 52
    46.4 (27.5 to 66.1)
    Notes
    [6] - FAS
    No statistical analyses for this end point

    Secondary: C-reactive Protein (CRP): Mean Change From Baseline (Week 0) to Week 52

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    End point title
    		 C-reactive Protein (CRP): Mean Change From Baseline (Week 0) to Week 52
    End point description
    C-reactive protein (CRP) was measured from blood samples as a marker for inflammation. Higher levels are indicative of more inflammation. Normal concentration in healthy human serum is usually lower than 0.3 mg/dL, slightly increasing with age. Last Observation Carried Forward (LOCF) was used for missing data.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    		 Adalimumab 80 mg
    Number of subjects analysed
    28 [7]
    Units: mg/dL
    arithmetic mean (standard deviation)
        Week 4
    -0.57 ( 1.4902 )
        Week 8
    -0.426 ( 1.6072 )
        Week 12
    -0.71 ( 1.6769 )
        Week 16
    -0.923 ( 1.6981 )
        Week 20
    -0.907 ( 1.7532 )
        Week 24
    -0.813 ( 1.7924 )
        Week 28
    -0.833 ( 1.882 )
        Week 32
    -0.853 ( 2.0507 )
        Week 36
    -0.586 ( 2.3271 )
        Week 40
    -1.008 ( 2.0471 )
        Week 44
    -0.915 ( 2.2324 )
        Week 48
    -0.649 ( 2.5734 )
        Week 52
    -0.57 ( 2.7635 )
    Notes
    [7] - FAS
    No statistical analyses for this end point

    Secondary: Number of Subjects With Potentially Significant Hematology Parameters

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    End point title
    		 Number of Subjects With Potentially Significant Hematology Parameters
    End point description
    Blood was collected for analysis at designated study visits; hematology results were provided by each site laboratory. The number of subjects with an abnormal laboratory result (higher than upper limit of normal [ULN] or lower than lower limit of normal [LLN]) meeting Common Toxicity Criteria (CTC) of Grade 3 or higher is summarized. Increase is signified by ↑. n=the number of participants with CTC Grade <3 at baseline and a post-baseline value for each parameter.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Adalimumab 80 mg
    Number of subjects analysed
    28 [8]
    Units: subjects
        Haemoglobin <8 g/dL (n=27)
    1
        Haemoglobin ↑ >4.0 g/dL (n=28)
    0
        Platelet Count <5.0x10^4/mcL (n=28)
    0
        White Blood Cells <2.0x10^3/mcL (n=28)
    0
        Neutrophils <1.0x10^3/mcL(n=28)
    0
        Lymphocytes <0.5x10^3/mcL (n=28)
    4
    Notes
    [8] - Safety Analysis Set: All enrolled subjects who received at least one dose of study drug
    No statistical analyses for this end point

    Secondary: Number of Subjects With Potentially Significant Clinical Chemistry Parameters

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    End point title
    		 Number of Subjects With Potentially Significant Clinical Chemistry Parameters
    End point description
    Blood was collected for analysis at designated study visits; chemistry results were provided by a central laboratory. The number of subjects with an abnormal laboratory result (higher than upper limit of normal [ULN] or lower than lower limit of normal [LLN]) meeting Common Toxicity Criteria (CTC) of Grade 3 or higher is summarized. n=the number of participants with CTC Grade <3 at baseline and a post-baseline value for each parameter.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Adalimumab 80 mg
    Number of subjects analysed
    28 [9]
    Units: subjects
        Alanine Aminotransferase >5xULN (n=28)
    0
        Aspartate Aminotransferase >5xULN (n=28)
    0
        Gamma-glutamyl Transpeptidase >5x ULN (n=28)
    0
        Alkaline Phosphatase >5xU/L (n=28)
    0
        Total Bilirubin >3xULN (n=28)
    0
        Creatine Phosphokinase >5x ULN (n=28)
    1
        Creatinine >3xULN or >3xBL (n=28)
    0
        Uric Acid >10.0 mg/dL (n=28)
    0
        Inorganic Phosphate <2.0 mg/dL (n=28)
    3
        Calcium <7.0 mg/dL (n=28)
    1
        Calcium >12.5 mg/dL (n=28)
    0
        Sodium <130 mEq/L (n=28)
    0
        Sodium >155 mEq/L (n=28)
    0
        Potassium <3.0 mEq/L (n=27)
    0
        Potassium >6.0 mEq/L (n=28)
    0
        Non-fasting Glucose <40 mg/dL (n=28)
    0
        Non-fasting Glucose >250 mg/dL (n=28)
    0
        Albumin <2.0 g/dL (n=28)
    0
        Cholesterol >400 mg/dL (n=28)
    0
        Triglycerides >500 mg/dL (n=28)
    0
        Magnesium <0.9 mg/dL (n=28)
    0
        Magnesium >3.0 mg/dL (n=28)
    0
    Notes
    [9] - Safety Analysis Set
    No statistical analyses for this end point

    Secondary: Systolic Blood Pressure: Mean Change From Baseline (Week 0) to Each Visit

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    End point title
    		 Systolic Blood Pressure: Mean Change From Baseline (Week 0) to Each Visit
    End point description
    Blood pressure was measured while the subject was sitting. n=the number of subjects with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    		 Adalimumab 80 mg
    Number of subjects analysed
    28 [10]
    Units: mm Hg
    arithmetic mean (standard deviation)
        Week 2 (n=28)
    -3.9 ( 11.98 )
        Week 4 (n=28)
    -2.5 ( 9.41 )
        Week 8 (n=25)
    -1.1 ( 9.98 )
        Week 12 (n=21)
    -1.3 ( 9.34 )
        Week 16 (n=21)
    -0.2 ( 11.72 )
        Week 20 (n=20)
    1.9 ( 12.64 )
        Week 24 (n=20)
    2 ( 8.89 )
        Week 28 (n=20)
    0.8 ( 8.91 )
        Week 32 (n=20)
    -1.7 ( 7.41 )
        Week 36 (n=20)
    -0.5 ( 10.79 )
        Week 40 (n=20)
    2.3 ( 9.55 )
        Week 44 (n=19)
    1.9 ( 14.12 )
        Week 48 (n=19)
    4.6 ( 11.66 )
        Week 52 (n=18)
    -0.3 ( 9.41 )
    Notes
    [10] - Safety Analysis Set
    No statistical analyses for this end point

    Secondary: Diastolic Blood Pressure: Mean Change From Baseline (Week 0) to Each Visit

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    End point title
    		 Diastolic Blood Pressure: Mean Change From Baseline (Week 0) to Each Visit
    End point description
    Blood pressure was measured while the subject was sitting. n=the number of subjects with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    		 Adalimumab 80 mg
    Number of subjects analysed
    28 [11]
    Units: mm Hg
    arithmetic mean (standard deviation)
        Week 2 (n=28)
    -0.6 ( 9.53 )
        Week 4 (n=28)
    0.2 ( 8.56 )
        Week 8 (n=25)
    0.7 ( 8.13 )
        Week 12 (n=21)
    1.1 ( 7.12 )
        Week 16 (n=21)
    0.1 ( 7.78 )
        Week 20 (n=20)
    0.8 ( 9.38 )
        Week 24 (n=20)
    0.8 ( 8.72 )
        Week 28 (n=20)
    -0.5 ( 7.81 )
        Week 32 (n=20)
    -0.8 ( 9.27 )
        Week 36 (n=20)
    -0.4 ( 10.27 )
        Week 40 (n=20)
    0.7 ( 10.66 )
        Week 44 (n=19)
    -1.2 ( 8.57 )
        Week 48 (n=19)
    1.3 ( 8.48 )
        Week 52 (n=18)
    3 ( 11.97 )
    Notes
    [11] - Safety Analysis Set
    No statistical analyses for this end point

    Secondary: Heart Rate: Mean Change From Baseline (Week 0) to Each Visit

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    End point title
    		 Heart Rate: Mean Change From Baseline (Week 0) to Each Visit
    End point description
    Heart rate was measured while the subject was sitting. n=the number of subjects with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    		 Adalimumab 80 mg
    Number of subjects analysed
    28 [12]
    Units: bpm
    arithmetic mean (standard deviation)
        Week 2 (n=28)
    -0.3 ( 11.94 )
        Week 4 (n=28)
    0.7 ( 12.78 )
        Week 8 (n=25)
    -1.1 ( 9.48 )
        Week 12 (n=21)
    -1.1 ( 11.59 )
        Week 16 (n=21)
    -1.9 ( 9.56 )
        Week 20 (n=20)
    -3 ( 8.68 )
        Week 24 (n=20)
    -0.9 ( 13.15 )
        Week 28 (n=20)
    -1.6 ( 11.3 )
        Week 32 (n=20)
    -5.6 ( 11.95 )
        Week 36 (n=20)
    -4.7 ( 12.88 )
        Week 40 (n=20)
    -3.7 ( 13.88 )
        Week 44 (n=19)
    -2 ( 10.78 )
        Week 48 (n=19)
    -1.3 ( 15.53 )
        Week 52 (n=18)
    -2.8 ( 11.8 )
    Notes
    [12] - Safety Analysis Set
    No statistical analyses for this end point

    Secondary: Body Temperature: Mean Change From Baseline (Week 0) to Each Visit

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    End point title
    		 Body Temperature: Mean Change From Baseline (Week 0) to Each Visit
    End point description
    n=the number of subjects with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    		 Adalimumab 80 mg
    Number of subjects analysed
    28 [13]
    Units: degrees Celsius
    arithmetic mean (standard deviation)
        Week 2 (n=28)
    -0.03 ( 0.558 )
        Week 4 (n=28)
    -0.02 ( 0.571 )
        Week 8 (n=25)
    -0.08 ( 0.569 )
        Week 12 (n=21)
    -0.14 ( 0.606 )
        Week 16 (n=21)
    -0.11 ( 0.558 )
        Week 20 (n=20)
    -0.16 ( 0.545 )
        Week 24 (n=20)
    -0.2 ( 0.701 )
        Week 28 (n=20)
    -0.23 ( 0.716 )
        Week 32 (n=20)
    -0.26 ( 0.762 )
        Week 36 (n=20)
    -0.36 ( 0.476 )
        Week 40 (n=20)
    -0.16 ( 0.555 )
        Week 44 (n=19)
    -0.24 ( 0.472 )
        Week 48 (n=19)
    -0.03 ( 0.781 )
        Week 52 (n=18)
    -0.13 ( 0.717 )
    Notes
    [13] - Safety Analysis Set
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events (AEs)

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    End point title
    		 Number of Subjects With Adverse Events (AEs)
    End point description
    An AE is any untoward medical occurrence in a subject which does not necessarily have a causal relationship with this treatment. A serious AE (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the subject and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent events (TEAEs or TESAE) are defined as any event that began or worsened in severity after the first dose of study drug. The investigator assessed the relationship of each event to the use of study drug as either Reasonable possibility or No reasonable possibility of being related to study drug. For more details on adverse events please see the AE section below.
    End point type
    Secondary
    End point timeframe
    60 weeks
    End point values
    		 Adalimumab 80 mg
    Number of subjects analysed
    28 [14]
    Units: subjects
        Any TEAE
    24
        TEAEs with reasonable possibility of being related
    5
        Any severe TEAE
    2
        TESAE
    8
        Any TEAE Leading to Discontinuation of Study
    4
        Death
    0
    Notes
    [14] - Safety Analysis Set
    No statistical analyses for this end point

    Other pre-specified: Change in Mean Serum Adalimumab Concentration From Baseline (Week 0) to Week 52

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    End point title
    		 Change in Mean Serum Adalimumab Concentration From Baseline (Week 0) to Week 52
    End point description
    Blood samples were drawn prior to drug administration. Adalimumab concentrations in serum were determined using a validated heterogeneous electrochemiluminescence (ECL)-immunoassay method. The assay captures adalimumab via biotinylated anti-idiotypic antibody, and detects it via sulfo-tagged TNF-alpha. n=the number of subjects with available data at each time point.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Week 0) to Week 52
    End point values
    		 Adalimumab 80 mg
    Number of subjects analysed
    28 [15]
    Units: µg/mL
    arithmetic mean (standard deviation)
        Baseline (Week 0) (n=28)
    3.06 ( 2.19 )
        Week 52 (n=18)
    9.47 ( 5.34 )
    Notes
    [15] - All subjects in the FAS with available data at both time points
    No statistical analyses for this end point

    Other pre-specified: Change in Number of Subjects Positive for Anti-Adalimumab Antibodies (AAA) From Baseline to Week 52

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    End point title
    		 Change in Number of Subjects Positive for Anti-Adalimumab Antibodies (AAA) From Baseline to Week 52
    End point description
    Serum samples with adalimumab concentration below 2 μg/mL were selected for AAA analyses. Samples were considered AAA positive if the measured AAA concentration was above 20 ng/mL. A subject was considered to be AAA positive if the subject had at least one AAA positive sample observed within 30 days following the subject's last adalimumab dose.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Week 0) to Week 52
    End point values
    		 Adalimumab 80 mg
    Number of subjects analysed
    28 [16]
    Units: subjects
        Baseline (Week 0)
    3
        Week 52
    4
    Notes
    [16] - FAS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected from the time of study drug administration until 70 days after last dose of study drug (60 weeks); SAEs were also collected from the time that informed consent was obtained until 70 days after last dose of study drug (up to 63 weeks).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Adalimumab 80 mg
    Reporting group description
    		 All subjects were to receive subcutaneous injections of open-label adalimumab 80 mg every other week from Week 0 to Week 50.

    Serious adverse events
    		 Adalimumab 80 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 28 (28.57%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Allergic transfusion reaction
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Crohn's disease
         subjects affected / exposed
    4 / 28 (14.29%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small intestinal ulcer haemorrhage
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Adalimumab 80 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 28 (75.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Female genital tract fistula
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Blood pressure increased
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    2
    Blood triglycerides increased
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences all number
    3
    Migraine
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Radiculopathy
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Syncope
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Leukopenia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Aphthous stomatitis
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Cheilitis
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Dental caries
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Ileus paralytic
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Stomatitis
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 28 (14.29%)
         occurrences all number
    4
    Urticaria
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Joint swelling
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    2
    Myalgia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Temporomandibular joint syndrome
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Bronchitis
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Candida infection
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    2
    Infection
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Mycoplasma infection
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    13 / 28 (46.43%)
         occurrences all number
    19
    Otitis externa
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Periodontitis
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Postoperative abscess
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Pulpitis dental
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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