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    Clinical Trial Results:
    (OSKIRA-4): A Phase IIB, Multi-Centre, Randomised, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy and Safety of Fostamatinib Disodium Monotherapy Compared with Adalimumab Monotherapy in Patients with Active Rheumatoid Arthritis

    Summary
    EudraCT number
    2010-023692-26
    Trial protocol
    GB   DE   CZ   HU   BG   SK  
    Global end of trial date
    17 Jul 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Feb 2017
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D4300C00004
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01264770
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca Pharmaceuticals
    Sponsor organisation address
    Alderley Park, Macclesfield, United Kingdom,
    Public contact
    Neil Mackillop, AstraZeneca, information.center@astrazeneca.com
    Scientific contact
    Neil Mackillop, AstraZeneca, neil.mackillop@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Nov 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Oct 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jul 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objectives of this study were: • To evaluate the efficacy of 3 oral dosing regimens of fostamatinib compared with placebo when used as monotherapy in patients with active RA by assessment of the signs and symptoms of RA, as measured by Disease Activity Score based on a 28-joint count (DAS28) at Week 6. • To evaluate whether the efficacy of 3 oral dosing regimens of fostamatinib were non-inferior to that of adalimumab when used as monotherapy in patients with active RA by assessment of the signs and symptoms of RA, as measured by DAS28 at Week 24.
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Conference on Harmonisation/Good Clinical Practice (GCP) and applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological Samples. Before enrolment of any patient into the study, the final clinical study protocol, including the final version of the informed consent form, was approved by the national regulatory authority or a notification to the national regulatory authority was done, according to local regulations. The study was approved or given a favourable opinion in writing by an Independent Ethics Committee (IEC) for each study centre. The investigator(s) at each centre ensured that the patient was given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the study. Patients were also notified that they were free to discontinue investigational product (IP) and/or withdraw from the study at any time. The patient was given the opportunity to ask questions and allowed time to consider the information provided.The patient’s signed and dated informed consent was obtained before conducting any procedure specifically for the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Jan 2011
    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
    Russian Federation: 53
    Country: Number of subjects enrolled
    United States: 50
    Country: Number of subjects enrolled
    Bulgaria: 33
    Country: Number of subjects enrolled
    Ukraine: 38
    Country: Number of subjects enrolled
    Poland: 23
    Country: Number of subjects enrolled
    Czech Republic: 33
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    South Africa: 13
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Slovakia: 4
    Worldwide total number of subjects
    265
    EEA total number of subjects
    111
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    241
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    452 patients were enrolled into the main study, 173 patients failed screening, 279 were randomised, 14 did not receive treatment (2, 5 and 2 for the fostamatinib doses, 3 for adalimumab and 2 for placebo). 265 were treated and are reported here as the full analysis set.

    Pre-assignment
    Screening details
    192 patients enrolled into a separate MRI sub-study (644 enrolled in total).

    Period 1
    Period 1 title
    6 week placebo controlled study period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    FOSTA 100 MG BID PO
    Arm description
    Dosing Group A
    Arm type
    Experimental

    Investigational medicinal product name
    Fostamatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100mg twice a day

    Arm title
    FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO
    Arm description
    Dosing Group B
    Arm type
    Experimental

    Investigational medicinal product name
    Fostamatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100mg twice daily for 4 weeks then 150gm once daily

    Arm title
    FOSTA 100 MG BID (4 WKS) THEN 100 MG QD PO
    Arm description
    Dosing Group C
    Arm type
    Experimental

    Investigational medicinal product name
    Fostamatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100mg twice daily for 4 weeks then 100mg once daily

    Arm title
    ADALIMUMAB 40 MG SC
    Arm description
    Dosing Group D
    Arm type
    Active comparator

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    40mg every 2 weeks

    Arm title
    PLACEBO
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Twice daily

    Number of subjects in period 1
    FOSTA 100 MG BID PO FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO FOSTA 100 MG BID (4 WKS) THEN 100 MG QD PO ADALIMUMAB 40 MG SC PLACEBO
    Started
    54
    48
    57
    54
    52
    Completed
    49
    47
    50
    54
    48
    Not completed
    5
    1
    7
    0
    4
         Dev. of study specific discont. criteria
    -
    -
    -
    -
    1
         Randomised, but did not receive study drug
    -
    -
    1
    -
    -
         e.g., change in circumstances
    3
    -
    1
    -
    3
         Severe non-compliance to protocol
    -
    -
    1
    -
    -
         Adverse event, non-fatal
    2
    1
    3
    -
    -
         Lost to follow-up
    -
    -
    1
    -
    -
    Period 2
    Period 2 title
    Week 6 to 24 active controlled period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    FOSTA 100 MG BID PO
    Arm description
    Dosing Group A
    Arm type
    Experimental

    Investigational medicinal product name
    Fostamatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100mg twice a day

    Arm title
    FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO
    Arm description
    Dosing Group B
    Arm type
    Experimental

    Investigational medicinal product name
    Fostamatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100mg twice daily for 4 weeks then 150gm once daily

    Arm title
    FOSTA 100 MG BID (4 WKS) THEN 100 MG QD PO
    Arm description
    Dosing Group C
    Arm type
    Experimental

    Investigational medicinal product name
    Fostamatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100mg twice daily for 4 weeks then 100mg once daily

    Arm title
    ADALIMUMAB 40 MG SC
    Arm description
    Dosing Group D
    Arm type
    Active comparator

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    40mg every 2 weeks

    Arm title
    PLACEBO (6 WKS) THEN FOSTA
    Arm description
    Dosing Group E
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo for 6 weeks then fostamatinib 100mg twice daily

    Number of subjects in period 2
    FOSTA 100 MG BID PO FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO FOSTA 100 MG BID (4 WKS) THEN 100 MG QD PO ADALIMUMAB 40 MG SC PLACEBO (6 WKS) THEN FOSTA
    Started
    49
    47
    50
    54
    48
    Completed
    36
    38
    41
    48
    38
    Not completed
    13
    9
    9
    6
    10
         Dev. of study specific discont. criteria
    2
    -
    -
    -
    1
         e.g., change in circumstances
    5
    3
    2
    3
    5
         Lack of therapeutic response
    1
    -
    2
    1
    1
         Severe non-compliance to protocol
    -
    -
    -
    1
    -
         Adverse event, non-fatal
    5
    6
    5
    -
    3
         Lost to follow-up
    -
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    FOSTA 100 MG BID PO
    Reporting group description
    Dosing Group A

    Reporting group title
    FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO
    Reporting group description
    Dosing Group B

    Reporting group title
    FOSTA 100 MG BID (4 WKS) THEN 100 MG QD PO
    Reporting group description
    Dosing Group C

    Reporting group title
    ADALIMUMAB 40 MG SC
    Reporting group description
    Dosing Group D

    Reporting group title
    PLACEBO
    Reporting group description
    -

    Reporting group values
    FOSTA 100 MG BID PO FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO FOSTA 100 MG BID (4 WKS) THEN 100 MG QD PO ADALIMUMAB 40 MG SC PLACEBO Total
    Number of subjects
    54 48 57 54 52 265
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0 0
        Adults (18-64 years)
    50 42 53 51 45 241
        From 65-84 years
    4 6 4 3 7 24
        85 years and over
    0 0 0 0 0 0
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    50 ± 11.5 50 ± 12.6 50 ± 11 48 ± 12.4 50 ± 12.7 -
    Gender, Male/Female
    Units: Participants
        Female
    38 39 48 45 40 210
        Male
    16 9 9 9 12 55
    Race/Ethnicity, Customized
    Units: Subjects
        White
    48 47 48 51 46 240
        Black or African American
    5 0 6 1 4 16
        Asian
    1 1 0 1 1 4
        American Indian or Alaska Native
    0 0 1 0 0 1
        Indian or Pakistani
    0 0 1 1 0 2
        Other
    0 0 1 0 1 2
    Subject analysis sets

    Subject analysis set title
    Dosing Group B
    Subject analysis set type
    Full analysis
    Subject analysis set description
    FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO

    Subject analysis set title
    Dosing Group C
    Subject analysis set type
    Full analysis
    Subject analysis set description
    FOSTA 100 MG BID (4 WKS) THEN 100 MG QD PO

    Subject analysis set title
    Dosing Group A
    Subject analysis set type
    Full analysis
    Subject analysis set description
    FOSTA 100 MG BID PO

    Subject analysis set title
    Dosing Group D
    Subject analysis set type
    Full analysis
    Subject analysis set description
    ADALIMUMAB 40 MG SC

    Subject analysis set title
    Dosing Group E
    Subject analysis set type
    Full analysis
    Subject analysis set description
    PLACEBO (COMBINED)

    Subject analysis sets values
    Dosing Group B Dosing Group C Dosing Group A Dosing Group D Dosing Group E
    Number of subjects
    48
    57
    54
    54
    52
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
    0
        Adults (18-64 years)
    42
    53
    50
    51
    45
        From 65-84 years
    6
    4
    4
    3
    7
        85 years and over
    0
    0
    0
    0
    0
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    50 ± 12.6
    50 ± 11
    50 ± 11.5
    48 ± 12.4
    51 ± 11.6
    Gender, Male/Female
    Units: Participants
        Female
    39
    48
    38
    45
    40
        Male
    9
    9
    16
    9
    12
    Race/Ethnicity, Customized
    Units: Subjects
        White
    47
    48
    48
    51
    46
        Black or African American
    0
    6
    5
    1
    4
        Asian
    1
    0
    1
    1
    1
        American Indian or Alaska Native
    0
    1
    0
    0
    0
        Indian or Pakistani
    0
    1
    0
    1
    0
        Other
    0
    1
    0
    0
    1

    End points

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    End points reporting groups
    Reporting group title
    FOSTA 100 MG BID PO
    Reporting group description
    Dosing Group A

    Reporting group title
    FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO
    Reporting group description
    Dosing Group B

    Reporting group title
    FOSTA 100 MG BID (4 WKS) THEN 100 MG QD PO
    Reporting group description
    Dosing Group C

    Reporting group title
    ADALIMUMAB 40 MG SC
    Reporting group description
    Dosing Group D

    Reporting group title
    PLACEBO
    Reporting group description
    -
    Reporting group title
    FOSTA 100 MG BID PO
    Reporting group description
    Dosing Group A

    Reporting group title
    FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO
    Reporting group description
    Dosing Group B

    Reporting group title
    FOSTA 100 MG BID (4 WKS) THEN 100 MG QD PO
    Reporting group description
    Dosing Group C

    Reporting group title
    ADALIMUMAB 40 MG SC
    Reporting group description
    Dosing Group D

    Reporting group title
    PLACEBO (6 WKS) THEN FOSTA
    Reporting group description
    Dosing Group E

    Subject analysis set title
    Dosing Group B
    Subject analysis set type
    Full analysis
    Subject analysis set description
    FOSTA 100 MG BID (4 WKS) THEN 150 MG QD PO

    Subject analysis set title
    Dosing Group C
    Subject analysis set type
    Full analysis
    Subject analysis set description
    FOSTA 100 MG BID (4 WKS) THEN 100 MG QD PO

    Subject analysis set title
    Dosing Group A
    Subject analysis set type
    Full analysis
    Subject analysis set description
    FOSTA 100 MG BID PO

    Subject analysis set title
    Dosing Group D
    Subject analysis set type
    Full analysis
    Subject analysis set description
    ADALIMUMAB 40 MG SC

    Subject analysis set title
    Dosing Group E
    Subject analysis set type
    Full analysis
    Subject analysis set description
    PLACEBO (COMBINED)

    Primary: DAS28-CRP score - change from baseline to Week 6 compared to placebo

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    End point title
    DAS28-CRP score - change from baseline to Week 6 compared to placebo
    End point description
    DAS28-CRP: Disease Activity Score based on a count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (CRP) and the patient's own assessment. Scores can take any positive value with a lower value indicating a better clinical condition. Mean changes from baseline in DAS28-CRP score are shown at each visit and are presented as decreases from baseline (defined as baseline minus post-baseline) with larger changes indicative of a better clinical condition. ANCOVA = analysis of covariance, BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, LS = least squares, n/a = not applicable, PO = orally, QD = once a day, SC = subcutaneous.
    End point type
    Primary
    End point timeframe
    Baseline and 6 weeks
    End point values
    Dosing Group A Dosing Group B Dosing Group C Dosing Group E
    Number of subjects analysed
    54
    48
    57
    52
    Units: Units on a scale
        arithmetic mean (standard deviation)
    1.1 ± 0.92
    1.1 ± 1.01
    0.8 ± 0.96
    0.6 ± 1.14
    Statistical analysis title
    DAS28 ANCOVA vs placebo
    Statistical analysis description
    Change from baseline at Week 6. Non-responder imputation applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group A v Dosing Group E
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.006
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    0.56
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.23
         upper limit
    0.9
    Statistical analysis title
    DAS28 ANCOVA vs placebo
    Statistical analysis description
    Change from baseline at Week 6. Non-responder imputation applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group C v Dosing Group E
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.28
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    0.22
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.12
         upper limit
    0.56
    Statistical analysis title
    DAS28 ANCOVA vs placebo
    Statistical analysis description
    Change from baseline at Week 6. Non-responder imputation applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group B v Dosing Group E
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.022
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    0.49
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.14
         upper limit
    0.84

    Primary: DAS28-CRP score - change from baseline to Week 24 compared to adalimumab

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    End point title
    DAS28-CRP score - change from baseline to Week 24 compared to adalimumab
    End point description
    DAS28-CRP: Disease Activity Score based on a count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (CRP) and the patient's own assessment. Scores can take any positive value with a lower value indicating a better clinical condition. Mean changes from baseline in DAS28-CRP score are shown at each visit and are presented as decreases from baseline (defined as baseline minus post-baseline) with larger changes indicative of a better clinical condition. Non-responder imputation has been applied by carrying the baseline observation forward. ANCOVA = analysis of covariance, BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, LS = least squares, n/a = not applicable, PO = orally, QD = once a day, SC = subcutaneous.
    End point type
    Primary
    End point timeframe
    Baseline and 24 weeks
    End point values
    Dosing Group A Dosing Group B Dosing Group C Dosing Group D
    Number of subjects analysed
    54
    48
    57
    54
    Units: Units on a scale
        arithmetic mean (standard deviation)
    1 ± 1.31
    1.1 ± 1.22
    1 ± 1.25
    1.8 ± 1.45
    Statistical analysis title
    DAS28 ANCOVA vs adalimumab
    Statistical analysis description
    Change from baseline at Week 24. Non-responder imputation applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group A v Dosing Group D
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    P-value
    = 0.005
    Method
    ANCOVA
    Parameter type
    Median difference (net)
    Point estimate
    -0.72
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.04
         upper limit
    -0.4
    Notes
    [1] - For the comparison with adalimumab a non-inferiority margin of -0.6 in the mean change from baseline in DAS28-CRP at Week 24 was defined. The lower 80% confidence interval for treatment difference was below this value so non-inferiority could not be concluded. A p-value is also provided for a 2-sided test of superiority.
    Statistical analysis title
    DAS28 ANCOVA vs adalimumab
    Statistical analysis description
    Change from baseline at Week 24. Non-responder imputation applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group B v Dosing Group D
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    P-value
    = 0.02
    Method
    ANCOVA
    Parameter type
    Median difference (net)
    Point estimate
    -0.61
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.94
         upper limit
    -0.27
    Notes
    [2] - For the comparison with adalimumab a non-inferiority margin of -0.6 in the mean change from baseline in DAS28-CRP at Week 24 was defined. The lower 80% confidence interval for treatment difference was below this value so non-inferiority could not be concluded. A p-value is also provided for a 2-sided test of superiority.
    Statistical analysis title
    DAS28 ANCOVA vs adalimumab
    Statistical analysis description
    Change from baseline at Week 24. Non-responder imputation applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group C v Dosing Group D
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [3]
    P-value
    = 0.004
    Method
    ANCOVA
    Parameter type
    Median difference (net)
    Point estimate
    -0.72
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.04
         upper limit
    -0.4
    Notes
    [3] - For the comparison with adalimumab a non-inferiority margin of -0.6 in the mean change from baseline in DAS28-CRP at Week 24 was defined. The lower 80% confidence interval for treatment difference was below this value so non-inferiority could not be concluded. A p-value is also provided for a 2-sided test of superiority.

    Secondary: DAS28 EULAR response at Week 6

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    End point title
    DAS28 EULAR response at Week 6
    End point description
    Change in DAS28 was derived for each post baseline scheduled assessment and categorised using the European League Against Rheumatism (EULAR) response criteria. Non-responder imputation has been applied by carrying the baseline observation forward. bid = twice daily, DAS28 = Disease Activity Score based on a 28-joint count, DMARD = disease-modifying anti-rheumatic drug, OR = odds ratio, PO = orally, qd = once a day, SC = subcutaneous.
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    Dosing Group A Dosing Group B Dosing Group C Dosing Group E
    Number of subjects analysed
    54
    48
    57
    52
    Units: Percentage of responders
    number (not applicable)
        No response
    37
    33.3
    57.9
    67.3
        Moderate response
    53.7
    47.9
    35.1
    25
        Good response
    9.3
    18.8
    7
    7.7
    Statistical analysis title
    DAS28 EULAR response vs placebo
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group A v Dosing Group E
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005
    Method
    Proportional odds model
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.05
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    1.59
         upper limit
    5.86
    Statistical analysis title
    DAS28 EULAR response vs placebo
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group B v Dosing Group E
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Proportional odds model
    Parameter type
    Odds ratio (OR)
    Point estimate
    4.11
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    2.1
         upper limit
    8.05
    Statistical analysis title
    DAS28 EULAR response vs placebo
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group C v Dosing Group E
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.335
    Method
    Proportional odds model
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.47
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.76
         upper limit
    2.83

    Secondary: DAS28 EULAR response at Week 24

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    End point title
    DAS28 EULAR response at Week 24
    End point description
    Change in DAS28 was derived for each post baseline scheduled assessment and categorised using the European League Against Rheumatism (EULAR) response criteria. Non-responder imputation has been applied by carrying the baseline observation forward. bid = twice daily, DAS28 = Disease Activity Score based on a 28-joint count, DMARD = disease-modifying anti-rheumatic drug, OR = odds ratio, PO = orally, qd = once a day, SC = subcutaneous.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    Dosing Group A Dosing Group B Dosing Group C Dosing Group D
    Number of subjects analysed
    54
    48
    57
    54
    Units: Percentage of responders
    number (not applicable)
        No response
    51.9
    41.7
    52.6
    31.5
        Moderate response
    29.6
    39.6
    29.8
    27.8
        Good response
    18.5
    18.8
    17.5
    40.7
    Statistical analysis title
    DAS28 EULAR response vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group A v Dosing Group D
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.007
    Method
    Proportional odds model
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.37
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.2
         upper limit
    0.68
    Statistical analysis title
    DAS28 EULAR response vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group B v Dosing Group D
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.051
    Method
    Proportional odds model
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.48
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.26
         upper limit
    0.89
    Statistical analysis title
    DAS28 EULAR response vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group C v Dosing Group D
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004
    Method
    Proportional odds model
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.36
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.2
         upper limit
    0.65

    Secondary: Proportion of patients achieving ACR20 up to Week 24

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    End point title
    Proportion of patients achieving ACR20 up to Week 24
    End point description
    ACR20: American College of Rheumatology 20% response criteria, based on count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (such as CRP) and the physician and patient's own assessments of disease activity, pain and physical function. Non-responder imputation has been applied by carrying the baseline observation forward. BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous.
    End point type
    Secondary
    End point timeframe
    6 and 24 weeks
    End point values
    Dosing Group A Dosing Group B Dosing Group C Dosing Group D Dosing Group E
    Number of subjects analysed
    54
    48
    57
    54
    52 [4]
    Units: Percentage of responders
    number (not applicable)
        Week 6
    48.1
    47.9
    38.6
    53.7
    19.2
        Week 24
    40.7
    56.3
    35.1
    59.3
    44.2
    Notes
    [4] - Week 24 placebo data is after switch to fostamatinib (doses combined)
    Statistical analysis title
    ACR20 vs placebo
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group A v Dosing Group E
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [5]
    Method
    Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    0.29
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.17
         upper limit
    0.4
    Notes
    [5] - Week 6
    Statistical analysis title
    ACR20 vs placebo
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group B v Dosing Group E
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [6]
    Method
    Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    0.3
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.18
         upper limit
    0.43
    Notes
    [6] - Week 6
    Statistical analysis title
    ACR20 vs placebo
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group C v Dosing Group E
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.007 [7]
    Method
    Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    0.19
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.07
         upper limit
    0.31
    Notes
    [7] - Week 6
    Statistical analysis title
    ACR20 vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group A v Dosing Group D
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.049 [8]
    Method
    Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.16
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    -0.03
    Notes
    [8] - Week 24
    Statistical analysis title
    ACR20 vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group B v Dosing Group D
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.803 [9]
    Method
    Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.02
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.16
         upper limit
    0.12
    Notes
    [9] - Week 24
    Statistical analysis title
    ACR20 vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group C v Dosing Group D
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003 [10]
    Method
    Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.24
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.37
         upper limit
    -0.1
    Notes
    [10] - Week 24

    Secondary: Proportion of patients achieving ACR50 up to Week 24

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    End point title
    Proportion of patients achieving ACR50 up to Week 24
    End point description
    ACR50: American College of Rheumatology 50% response criteria, based on count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (such as CRP) and the physician and patient's own assessments of disease activity, pain and physical function. Non-responder imputation has been applied by carrying the baseline observation forward. BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous.
    End point type
    Secondary
    End point timeframe
    6 and 24 weeks
    End point values
    Dosing Group A Dosing Group B Dosing Group C Dosing Group D Dosing Group E
    Number of subjects analysed
    54
    48
    57
    54
    52 [11]
    Units: Percentage of responders
    number (not applicable)
        Week 6
    13
    12.5
    7
    25.9
    3.8
        Week 24
    20.4
    18.8
    12.3
    31.5
    23.1
    Notes
    [11] - Week 24 placebo data is after switch to fostamatinib (doses combined)
    Statistical analysis title
    ACR50 vs placebo
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group A v Dosing Group E
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.059 [12]
    Method
    Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    0.09
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.01
         upper limit
    0.18
    Notes
    [12] - Week 6
    Statistical analysis title
    ACR50 vs placebo
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group B v Dosing Group E
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.071 [13]
    Method
    Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    0.09
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.01
         upper limit
    0.17
    Notes
    [13] - Week 6
    Statistical analysis title
    ACR50 vs placebo
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group C v Dosing Group E
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.758 [14]
    Method
    Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    0.01
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.05
         upper limit
    0.07
    Notes
    [14] - Week 6
    Statistical analysis title
    ACR50 vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group A v Dosing Group D
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.114 [15]
    Method
    Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.12
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.24
         upper limit
    0
    Notes
    [15] - Week 24
    Statistical analysis title
    ACR50 vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group B v Dosing Group D
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.078 [16]
    Method
    Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.14
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.26
         upper limit
    -0.01
    Notes
    [16] - Week 24
    Statistical analysis title
    ACR50 vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group C v Dosing Group D
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003 [17]
    Method
    Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.21
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.32
         upper limit
    -0.09
    Notes
    [17] - Week 24

    Secondary: Proportion of patients achieving ACR70 up to Week 24

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    End point title
    Proportion of patients achieving ACR70 up to Week 24
    End point description
    ACR70: American College of Rheumatology 70% response criteria, based on count of swollen and tender joints (out of 28 joints), blood test measures of inflammation (such as CRP) and the physician and patient's own assessments of disease activity, pain and physical function. Non-responder imputation has been applied by carrying the baseline observation forward. BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous.
    End point type
    Secondary
    End point timeframe
    6 and 24 weeks
    End point values
    Dosing Group A Dosing Group B Dosing Group C Dosing Group D Dosing Group E
    Number of subjects analysed
    54
    48
    57
    54
    52 [18]
    Units: Percentage of responders
    number (not applicable)
        Week 6
    1.9
    4.2
    1.8
    7.4
    3.8
        Week 24
    9.3
    10.4
    3.5
    20.4
    5.8
    Notes
    [18] - Week 24 placebo data is after switch to fostamatinib (doses combined)
    Statistical analysis title
    ACR70 vs placebo
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group A v Dosing Group E
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.46 [19]
    Method
    Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.02
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.07
         upper limit
    0.03
    Notes
    [19] - Week 6
    Statistical analysis title
    ACR70 vs placebo
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group B v Dosing Group E
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.903 [20]
    Method
    Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    0
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.05
         upper limit
    0.06
    Notes
    [20] - Week 6
    Statistical analysis title
    ACR70 vs placebo
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group C v Dosing Group E
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.172 [21]
    Method
    Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.03
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.08
         upper limit
    0.01
    Notes
    [21] - Week 6
    Statistical analysis title
    ACR70 vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group A v Dosing Group D
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.082 [22]
    Method
    Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.11
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.21
         upper limit
    -0.01
    Notes
    [22] - Week 24
    Statistical analysis title
    ACR70 vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group B v Dosing Group D
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.092 [23]
    Method
    Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.11
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.21
         upper limit
    0
    Notes
    [23] - Week 24
    Statistical analysis title
    ACR70 vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group C v Dosing Group D
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002 [24]
    Method
    Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.17
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.27
         upper limit
    -0.08
    Notes
    [24] - Week 24

    Secondary: ACRn - comparison between fostamatinib and placebo at Week 6

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    End point title
    ACRn - comparison between fostamatinib and placebo at Week 6
    End point description
    ACRn: American College of Rheumatology Index of RA improvement, based on smallest percentage improvement in the count of swollen joints (out of 28 joints), count of tender joints (out of 28 joints) or in blood test measures of inflammation (such as CRP) or the physician and patient's own asessment of disease activity, pain and physical function. Scores are reported as a percentage improvement on a scale of -100 to +100, with larger values representing a better clinical outcome and negative values a worsening of clinical condition. Non-responder imputation has been applied by carrying the baseline observation forward. BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous. Mean refers to change at Week 6. Treatment difference: difference between fostamatinib and placebo groups.
    End point type
    Secondary
    End point timeframe
    Baseline and 6 weeks
    End point values
    Dosing Group A Dosing Group B Dosing Group C Dosing Group E
    Number of subjects analysed
    54
    48
    57
    52
    Units: Percentage change from baseline
        arithmetic mean (standard deviation)
    16.6 ± 30.682
    15.07 ± 33.334
    6.48 ± 32.237
    -6.49 ± 35.159
    Statistical analysis title
    ACRn vs placebo
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group A v Dosing Group E
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Van Elteren
    Parameter type
    Treatment difference
    Point estimate
    23.39
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    9.57
         upper limit
    40
    Statistical analysis title
    ACRn vs placebo
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group C v Dosing Group E
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.234
    Method
    Van Elteren
    Parameter type
    Treatment difference
    Point estimate
    5.72
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -3.2
         upper limit
    21.68
    Statistical analysis title
    ACRn vs placebo
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group B v Dosing Group E
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.006
    Method
    Van Elteren
    Parameter type
    Treatment difference
    Point estimate
    22.97
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    7.84
         upper limit
    38.34

    Secondary: ACRn - comparison between fostamatinib and adalimumab at Week 24

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    End point title
    ACRn - comparison between fostamatinib and adalimumab at Week 24
    End point description
    ACRn: American College of Rheumatology Index of RA improvement, based on smallest percentage improvement in the count of swollen joints (out of 28 joints), count of tender joints (out of 28 joints) or in blood test measures of inflammation (such as CRP) or the physician and patient's own asessment of disease activity, pain and physical function. Scores are reported as a percentage improvement on a scale of -100 to +100, with larger values representing a better clinical outcome and negative values a worsening of clinical condition. Non-responder imputation has been applied by carrying the baseline observation forward. BID = twice daily, CRP = C-reactive protein, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous. Mean refers to change at Week 24. Treatment difference: difference between fostamatinib and adalimumab groups.
    End point type
    Secondary
    End point timeframe
    Baseline and 24 weeks
    End point values
    Dosing Group A Dosing Group B Dosing Group C Dosing Group D
    Number of subjects analysed
    54
    48
    57
    54
    Units: Percentage change from baseline
        arithmetic mean (standard deviation)
    18.35 ± 34.355
    22.03 ± 32.361
    11.49 ± 26.916
    31.21 ± 39.187
    Statistical analysis title
    ACRn vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group A v Dosing Group D
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.03
    Method
    Van Elteren
    Parameter type
    Treatment difference
    Point estimate
    -13.72
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -25.01
         upper limit
    0
    Statistical analysis title
    ACRn vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group B v Dosing Group D
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.207
    Method
    Van Elteren
    Parameter type
    Treatment difference
    Point estimate
    -9.49
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -25
         upper limit
    6.96
    Statistical analysis title
    ACRn vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group C v Dosing Group D
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002
    Method
    Van Elteren
    Parameter type
    Treatment difference
    Point estimate
    -19.53
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -30.01
         upper limit
    -6.25

    Secondary: HAQ-DI - comparison of the change from baseline between fostamatinib and placebo at Week 6

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    End point title
    HAQ-DI - comparison of the change from baseline between fostamatinib and placebo at Week 6
    End point description
    HAQ-DI: Health Assessment Questionnaire - Disability Index, a measure of physical function. The HAQ-DI score is calculated by summing the category scores from 8 sub-categories (ie, scores for patient ability in dressing and grooming, rising, eating, walking, hygiene, reach, grip and common daily activities) and dividing by the number of categories completed. The HAQ-DI score takes values between 0 and 3, with a higher score indicating greater disability. Non-responder imputation has been applied by carrying the baseline observation forward. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, LS = least squares, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous.
    End point type
    Secondary
    End point timeframe
    Baseline and 6 weeks
    End point values
    Dosing Group A Dosing Group B Dosing Group C Dosing Group E
    Number of subjects analysed
    54
    48
    57
    52
    Units: Units on a scale
        arithmetic mean (standard deviation)
    0.3 ± 0.35
    0.3 ± 0.54
    0.2 ± 0.43
    0.1 ± 0.52
    Statistical analysis title
    HAQ-DI vs placebo
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group A v Dosing Group E
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.007
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    0.24
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.09
         upper limit
    0.38
    Statistical analysis title
    HAQ-DI vs placebo
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group B v Dosing Group E
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.016
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    0.22
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.07
         upper limit
    0.37
    Statistical analysis title
    HAQ-DI vs placebo
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group C v Dosing Group E
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.094
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    0.14
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0
         upper limit
    0.29

    Secondary: HAQ-DI - comparison of the change from baseline between fostamatinib and adalimumab at Week 24

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    End point title
    HAQ-DI - comparison of the change from baseline between fostamatinib and adalimumab at Week 24
    End point description
    HAQ-DI: Health Assessment Questionnaire - Disability Index, a measure of physical function. The HAQ-DI score is calculated by summing the category scores from 8 sub-categories (ie, scores for patient ability in dressing and grooming, rising, eating, walking, hygiene, reach, grip and common daily activities) and dividing by the number of categories completed. The HAQ-DI score takes values between 0 and 3, with a higher score indicating greater disability. Non-responder imputation has been applied by carrying the baseline observation forward. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, LS = least squares, n/a = not applicable, PO = orally, qd = once a day, SC = subcutaneous.
    End point type
    Secondary
    End point timeframe
    Baseline and 24 weeks
    End point values
    Dosing Group A Dosing Group B Dosing Group C Dosing Group D
    Number of subjects analysed
    54
    48
    57
    54
    Units: Units on a scale
        arithmetic mean (standard deviation)
    0.3 ± 0.57
    0.4 ± 0.56
    0.2 ± 0.45
    0.5 ± 0.53
    Statistical analysis title
    HAQ-DI vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group A v Dosing Group D
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.043
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.2
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.36
         upper limit
    -0.04
    Statistical analysis title
    HAQ-DI vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group B v Dosing Group D
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.158
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.14
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.31
         upper limit
    0.02
    Statistical analysis title
    HAQ-DI vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group C v Dosing Group D
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.32
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.47
         upper limit
    -0.16

    Secondary: SF-36 - comparison of the change in PCS from baseline between fostamatinib and adalimumab at Week 24

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    End point title
    SF-36 - comparison of the change in PCS from baseline between fostamatinib and adalimumab at Week 24
    End point description
    SF-36: 36 item short form health survey, as a measure of health-related quality of life. Scores for 8 sub-domains (Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Function, Role-Emotional and Mental Health) are derived and normalised to a scale of 0 to 100. The physical and mental component scores (PCS and MCS) are derived by multiplying each of these 8 scores by a constant, summing them and standardising against a population with a mean of 50, standard deviation of 10. A higher score represents a better quality of life. Mean changes from baseline score are presented as increases from baseline (defined as post-baseline minus baseline); larger changes indicate a better clinical condition. Mean refers to change in scores at Week 24. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease-modifying anti-rheumatic drug, IR = inadequate response, LS = least squares, PO = orally, QD = once a day, QoL = quality of life, SC = subcutaneous
    End point type
    Secondary
    End point timeframe
    Baseline and 24 weeks
    End point values
    Dosing Group A Dosing Group B Dosing Group C Dosing Group D
    Number of subjects analysed
    54
    48
    57
    54
    Units: Units on a scale
        arithmetic mean (standard deviation)
    4 ± 7.3
    5 ± 7.2
    4 ± 7.4
    7 ± 8.4
    Statistical analysis title
    SF-36 PCS vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group A v Dosing Group D
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.05
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -2.77
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -5.08
         upper limit
    -0.45
    Statistical analysis title
    SF-36 PCS vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group C v Dosing Group D
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.032
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -2.99
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -5.29
         upper limit
    -0.7
    Statistical analysis title
    SF-36 PCS vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group B v Dosing Group D
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.36
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -1.33
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -3.73
         upper limit
    1.06

    Secondary: SF-36 - comparison of the change in MCS from baseline between fostamatinib and adalimumab at Week 24

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    End point title
    SF-36 - comparison of the change in MCS from baseline between fostamatinib and adalimumab at Week 24
    End point description
    SF-36: 36 item short form health survey, as a measure of health-related quality of life. The SF-36 scores for 8 sub-domains (Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Function, Role-Emotional and Mental Health) are derived and normalised to a scale of 0 to 100. The physical and mental component scores (PCS and MCS) are derived by multiplying each of these 8 scores by a constant, summing them and standardising against a population with a mean of 50, standard deviation of 10. A higher score represents a better quality of life. Mean changes from baseline score are presented as increases from baseline (defined as post-baseline minus baseline); larger changes indicate a better clinical condition. Mean refers to change in score at Week 24. ANCOVA = analysis of covariance, BID = twice daily, DMARD = disease modifying antirheumatic drugs, PO = orally, QD = once daily.
    End point type
    Secondary
    End point timeframe
    Baseline and 24 weeks
    End point values
    Dosing Group A Dosing Group B Dosing Group C Dosing Group D
    Number of subjects analysed
    54
    48
    57
    54
    Units: Units on a scale
        arithmetic mean (standard deviation)
    3 ± 9.3
    3 ± 11.5
    2 ± 10
    4 ± 9.8
    Statistical analysis title
    SF-36 MCS vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group A v Dosing Group D
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.568
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -1.02
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -3.95
         upper limit
    1.92
    Statistical analysis title
    SF-36 MCS vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group B v Dosing Group D
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.368
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -1.66
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -4.69
         upper limit
    1.38
    Statistical analysis title
    SF-36 MCS vs adalimumab
    Statistical analysis description
    Non-responder imputation has been applied following premature withdrawal, or any DMARD initiation, or for 8 weeks following receipt of any parenteral steroids, or for patients with no post baseline data.
    Comparison groups
    Dosing Group C v Dosing Group D
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.16
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -2.48
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -5.38
         upper limit
    0.43

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 weeks
    Adverse event reporting additional description
    For placebo treated patients time frame includes both placebo(6 weeks) and fostamatinib(18 weeks) treatment. 1 SAE occurred in these treatment arms began during the 6 week placebo treated period
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    ADALIMUMAB 40mg SC
    Reporting group description
    Dosing Group D

    Reporting group title
    FOSTA 100mg BID (4WKS) THEN 100mg QD
    Reporting group description
    Dosing Group C

    Reporting group title
    FOSTA 100mg BID
    Reporting group description
    Dosing Group A

    Reporting group title
    FOSTA 100 MG BID (4WKS) THEN 150 MG QD
    Reporting group description
    Dosing Group B

    Reporting group title
    PLACEBO(6WKS) THEN FOSTA 100mgBID THEN 150mgQD- FOSTA period
    Reporting group description
    Dosing Group G

    Reporting group title
    PLACEBO(6WKS) THEN FOSTA 100mgBID THEN 150mgQD- Placebo period
    Reporting group description
    Dosing Group G

    Reporting group title
    PLACEBO(6WKS) THEN FOSTA 100mgBID- FOSTA Period
    Reporting group description
    Dosing Group F

    Reporting group title
    PLACEBO(6WKS) THEN FOSTA 100mgBID- Placebo Period
    Reporting group description
    Dosing Group F

    Serious adverse events
    ADALIMUMAB 40mg SC FOSTA 100mg BID (4WKS) THEN 100mg QD FOSTA 100mg BID FOSTA 100 MG BID (4WKS) THEN 150 MG QD PLACEBO(6WKS) THEN FOSTA 100mgBID THEN 150mgQD- FOSTA period PLACEBO(6WKS) THEN FOSTA 100mgBID THEN 150mgQD- Placebo period PLACEBO(6WKS) THEN FOSTA 100mgBID- FOSTA Period PLACEBO(6WKS) THEN FOSTA 100mgBID- Placebo Period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 54 (7.41%)
    4 / 57 (7.02%)
    5 / 54 (9.26%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Essential hypertension
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 57 (0.00%)
    1 / 54 (1.85%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 57 (0.00%)
    1 / 54 (1.85%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ligament injury NOS
    Additional description: Rupture
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 57 (0.00%)
    0 / 54 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion, unspecified
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 57 (0.00%)
    0 / 54 (0.00%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
    Additional description: Lesion
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 57 (0.00%)
    0 / 54 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cardiac myxoma
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 57 (0.00%)
    0 / 54 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple myeloma
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 57 (0.00%)
    0 / 54 (0.00%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 57 (1.75%)
    1 / 54 (1.85%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left Bundle Branch Block
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 57 (1.75%)
    0 / 54 (0.00%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure (NOS)
    Additional description: Congestive
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 57 (1.75%)
    0 / 54 (0.00%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cor Pulmonale Acute
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 57 (1.75%)
    0 / 54 (0.00%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 57 (1.75%)
    0 / 54 (0.00%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma NOS
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 57 (0.00%)
    0 / 54 (0.00%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 57 (1.75%)
    0 / 54 (0.00%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain localized
    Additional description: Upper
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 57 (1.75%)
    0 / 54 (0.00%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia, without mention of obstruction or gangrene
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 57 (0.00%)
    0 / 54 (0.00%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperadrenalism
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 57 (0.00%)
    0 / 54 (0.00%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Chronic sinusitis, unspecified
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 57 (0.00%)
    1 / 54 (1.85%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 57 (0.00%)
    1 / 54 (1.85%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis, unspecified
    Additional description: Chronic
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 57 (0.00%)
    1 / 54 (1.85%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    ADALIMUMAB 40mg SC FOSTA 100mg BID (4WKS) THEN 100mg QD FOSTA 100mg BID FOSTA 100 MG BID (4WKS) THEN 150 MG QD PLACEBO(6WKS) THEN FOSTA 100mgBID THEN 150mgQD- FOSTA period PLACEBO(6WKS) THEN FOSTA 100mgBID THEN 150mgQD- Placebo period PLACEBO(6WKS) THEN FOSTA 100mgBID- FOSTA Period PLACEBO(6WKS) THEN FOSTA 100mgBID- Placebo Period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 54 (27.78%)
    19 / 57 (33.33%)
    30 / 54 (55.56%)
    20 / 48 (41.67%)
    13 / 25 (52.00%)
    1 / 25 (4.00%)
    11 / 27 (40.74%)
    3 / 27 (11.11%)
    Vascular disorders
    Hypertension
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    5 / 54 (9.26%)
    5 / 57 (8.77%)
    7 / 54 (12.96%)
    3 / 48 (6.25%)
    7 / 25 (28.00%)
    0 / 25 (0.00%)
    4 / 27 (14.81%)
    0 / 27 (0.00%)
         occurrences all number
    5
    5
    7
    3
    7
    0
    4
    0
    Investigations
    Alanine aminotransferase increased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 57 (3.51%)
    3 / 54 (5.56%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    2
    3
    1
    0
    1
    0
    0
    Hepatic enzyme increased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 57 (3.51%)
    3 / 54 (5.56%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    2
    3
    1
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Leukopenia NOS
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 57 (0.00%)
    3 / 54 (5.56%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    0
    0
    Neutropenia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 57 (0.00%)
    3 / 54 (5.56%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    2 / 27 (7.41%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    2
    0
    Gastrointestinal disorders
    Diarrhoea NOS
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 54 (1.85%)
    12 / 57 (21.05%)
    9 / 54 (16.67%)
    13 / 48 (27.08%)
    4 / 25 (16.00%)
    0 / 25 (0.00%)
    3 / 27 (11.11%)
    0 / 27 (0.00%)
         occurrences all number
    1
    12
    9
    13
    4
    0
    3
    0
    Dyspepsia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 54 (5.56%)
    1 / 57 (1.75%)
    0 / 54 (0.00%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    3
    1
    0
    0
    0
    0
    0
    0
    Nausea
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 57 (0.00%)
    2 / 54 (3.70%)
    2 / 48 (4.17%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    2 / 27 (7.41%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    2
    2
    0
    0
    2
    0
    Vomiting alone
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 57 (0.00%)
    3 / 54 (5.56%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    1
    0
    Renal and urinary disorders
    Nephrolithiasis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 57 (0.00%)
    3 / 54 (5.56%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 57 (0.00%)
    3 / 54 (5.56%)
    2 / 48 (4.17%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
    4 / 27 (14.81%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    3
    2
    1
    0
    4
    0
    Infections and infestations
    Bronchitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 57 (0.00%)
    1 / 54 (1.85%)
    0 / 48 (0.00%)
    2 / 25 (8.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    0
    0
    Influenza
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 57 (0.00%)
    1 / 54 (1.85%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    2
    Nasopharyngitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    4 / 54 (7.41%)
    1 / 57 (1.75%)
    1 / 54 (1.85%)
    2 / 48 (4.17%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    4
    1
    1
    2
    1
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Mar 2011
    Added an imaging sub-study. This was reported separately. Restrictions for males wishing to father a child or donate sperm were removed.
    28 Sep 2011
    Patient discontinuing treatment were to be contacted every 12 weeks up to week 24 to collect follow-up safety outcomes data. All week 24 assessments were to be completed.

    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
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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