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    Clinical Trial Results:
    Targeted Ultrasound in Rheumatoid Arthritis (TURA)

    Summary
    EudraCT number
    2013-002777-22
    Trial protocol
    GB   DE   HU   ES   IT   DK  
    Global end of trial date
    30 Jul 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Jul 2020
    First version publication date
    01 Jul 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HG/1096
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02056184
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Leeds
    Sponsor organisation address
    2nd Floor, Chapel Allerton Hospital, Chapeltown Road, Leeds, United Kingdom, LS7 4SA
    Public contact
    Prof. Paul Emery, Leeds Institute of Rheumatic & Musculoskeletal Medicine, University of Leeds, +44 1133924884, p.emery@leeds.ac.uk
    Scientific contact
    Prof. Paul Emery, Leeds Institute of Rheumatic & Musculoskeletal Medicine, University of Leeds, +44 1133924884, p.emery@leeds.ac.uk
    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
    30 Jul 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jul 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine whether therapy modifications (including addition of Ultrasound-guided treatment change) can change Power Doppler (PD) in patients with early Rheumatoid arthritis in a stable clinical disease activity state (clinical remission/LDAS/other physician deemed acceptable state).
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines, the general principles indicated in the Declaration of Helsinki, and all applicable regulatory requirements. Prior to initiation at each study center, the study protocol was reviewed by an Institutional Review Board (IRB) or Independent Ethics Committee (IEC). All subjects were to provide written informed consent prior to entering the study and before initiation of any study-related procedure (including administration of investigational product). The investigator was responsible for explaining the benefits and risks of participation in the study to each subject or the subject’s legally acceptable representative and for obtaining written informed consent.
    Background therapy
    All participants were required to be on an acceptable (maximal tolerated) dose of methotrexate up to 25 mg weekly prior to the screening visit as a monotherapy or in combination with prednisolone up to a maximum 5 mg daily. Participants were expected to continue on this therapy for the duration of the study. Interruption of dose was permitted in case of intolerance to methotrexate. Additionally, it was permitted for steroid injection of methylprednisolone to be administered post-randomisation up to a maximum total dose of 160 mg if clinically indicated.
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Jan 2014
    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
    Spain: 17
    Country: Number of subjects enrolled
    United Kingdom: 85
    Country: Number of subjects enrolled
    Denmark: 14
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Japan: 42
    Worldwide total number of subjects
    185
    EEA total number of subjects
    143
    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)
    122
    From 65 to 84 years
    61
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    Patients were enrolled at 13 centers in Denmark, France, Germany, Italy, Japan, Spain and the UK. Of the 260 patients screened for this study, 185 met all of the inclusion and none of the exclusion criteria and were randomly assigned to treatment into this study.

    Pre-assignment
    Screening details
    Adults diagnosed with rheumatoid arthritis within 5 years of screening, having started methotrexate within 2 years of screening and in a stable clinical disease activity state for at least 8 successive weeks before screening

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind [1]
    Roles blinded
    Subject, Investigator, Assessor
    Blinding implementation details
    This was an open label study with regards to the study medication and hence a pertinent blinding procedure was not applicable. Moreover, according to the study design, patients were aware of which arm they were randomised to, as was the physician. However, the physician (and patient) were blinded to US findings in the Clinical arm. The ultrasonographer in both arms was blinded to the patient’s study arm and treatment details.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Clinical Arm
    Arm description
    Current gold standard clinical Treat to Target (T2T) approach for management of rheumatoid arthritis
    Arm type
    Experimental

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Cutaneous solution
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Adalimumab 40 mg/0.8 ml solution administered every other week as a single dose via subcutaneous injection

    Arm title
    Imaging Arm
    Arm description
    Modified treatment approach based on Ultrasound (US) findings as an additional competent to the current gold-standard clinical T2T approach
    Arm type
    Experimental

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Cutaneous solution
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Adalimumab 40 mg/0.8 ml solution administered every other week as a single dose via subcutaneous injection

    Notes
    [1] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial.
    Justification: This was an open label study with regards to the study medication and hence a pertinent blinding procedure was not applicable. The ultra-sonographer in both arms was blinded to the patient’s study arm and treatment details. Joint counts were performed by a blinded assessor (blinded to all clinical data except joint counts). Patient and Physician were unblinded to study arm and treatment details. In the Clinical arm only, the physician and patient were blinded to ultrasound (US) findings.
    Number of subjects in period 1
    Clinical Arm Imaging Arm
    Started
    92
    93
    Completed
    75
    75
    Not completed
    17
    18
         Death
    1
    -
         Other
    2
    3
         Physician decision
    2
    3
         Adverse event, serious fatal
    -
    1
         Adverse event, non-fatal
    4
    2
         Consent withdrawn by subject
    4
    2
         Did not complete or discontinue
    1
    1
         Lost to follow-up
    -
    1
         Sponsor decision
    3
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Clinical Arm
    Reporting group description
    Current gold standard clinical Treat to Target (T2T) approach for management of rheumatoid arthritis

    Reporting group title
    Imaging Arm
    Reporting group description
    Modified treatment approach based on Ultrasound (US) findings as an additional competent to the current gold-standard clinical T2T approach

    Reporting group values
    Clinical Arm Imaging Arm Total
    Number of subjects
    92 93 185
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55.8 ± 14.43 56.8 ± 14.14 -
    Gender categorical
    Units: Subjects
        Female
    62 67 129
        Male
    30 26 56
    Ethnicity
    Units: Subjects
        Asian
    22 21 43
        White
    70 70 140
        Other
    0 2 2
    Employment Status
    Units: Subjects
        Full time
    30 28 58
        Part time
    7 8 15
        On sick leave
    1 0 1
        Retired
    21 27 48
        Not in paid employment (but not retired)
    5 5 10
        Missing
    28 25 53

    End points

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    End points reporting groups
    Reporting group title
    Clinical Arm
    Reporting group description
    Current gold standard clinical Treat to Target (T2T) approach for management of rheumatoid arthritis

    Reporting group title
    Imaging Arm
    Reporting group description
    Modified treatment approach based on Ultrasound (US) findings as an additional competent to the current gold-standard clinical T2T approach

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All patients from the Randomized Set who have at least one post-randomization primary outcome result recorded

    Subject analysis set title
    Per-Protocol Set (PPS)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All patients in FAS, who have no major protocol deviations

    Subject analysis set title
    Safety Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients in the Randomized Set who received at least one dose of study drug

    Subject analysis set title
    FASPPD
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Primary efficacy analysis was conducted in patients in the FAS who had at least 1 joint showing measurable PD at baseline (denoted as FASPPD)

    Subject analysis set title
    PPSPPD
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Primary efficacy analysis was conducted in patients in the PPS who had at least 1 joint showing measurable PD at baseline (denoted as PPSPPD)

    Primary: PD Response at Week 48 (FASPPD)

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    End point title
    PD Response at Week 48 (FASPPD)
    End point description
    Response rate is defined as proportion of patient whose total PD (Power Doppler) score decreases at Week 48 relative to baseline
    End point type
    Primary
    End point timeframe
    48 weeks
    End point values
    Clinical Arm Imaging Arm FASPPD
    Number of subjects analysed
    59 [1]
    50 [2]
    109 [3]
    Units: Total PD Response
    number (not applicable)
        Yes
    32
    36
    68
        No
    16
    5
    21
    Notes
    [1] - 48/59 Clinical arm participants completed Week 48, responses present for 48 participants only
    [2] - 41/50 Imaging arm participants completed Week 48, responses present for 41 participants only
    [3] - FASPPD set includes participants for whom a response was missing
    Statistical analysis title
    PD Response at Week 48 (FASPPD)
    Comparison groups
    Imaging Arm v Clinical Arm
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.029
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    4.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.17
         upper limit
    17.27

    Primary: PD Response at Week 48 (PPSPPD)

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    End point title
    PD Response at Week 48 (PPSPPD)
    End point description
    Response rate is defined as proportion of patient whose total PD (Power Doppler) score decreases at Week 48 relative to baseline
    End point type
    Primary
    End point timeframe
    48 weeks
    End point values
    Clinical Arm Imaging Arm PPSPPD
    Number of subjects analysed
    40 [4]
    27 [5]
    67 [6]
    Units: Total PD Response
    number (not applicable)
        Yes
    18
    15
    33
        No
    14
    3
    17
    Notes
    [4] - 32/40 Clinical arm participants in PPSPPD completed Week 48, responses present for 32 only
    [5] - 18/27 Imaging arm participants in PPSPPD completed Week 48, , responses present for 18 only
    [6] - PPSPPD set includes participants for whom a response was missing
    Statistical analysis title
    PD Response at Week 48 (PPSPPD)
    Comparison groups
    Imaging Arm v Clinical Arm
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0451
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    6.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.04
         upper limit
    40.48

    Secondary: Change from Baseline in Total PD Score at Week 48 (FASPPD Population)

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    End point title
    Change from Baseline in Total PD Score at Week 48 (FASPPD Population)
    End point description
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Clinical Arm Imaging Arm
    Number of subjects analysed
    59
    50
    Units: Median change from baseline
    number (not applicable)
        Total PD response
    -2.0
    -2.0
    Statistical analysis title
    Change from Baseline in Total PD Score at Week 48
    Comparison groups
    Clinical Arm v Imaging Arm
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1665
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from Baseline in Total GS Score at Week 48 (FASPPD Population)

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    End point title
    Change from Baseline in Total GS Score at Week 48 (FASPPD Population)
    End point description
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Clinical Arm Imaging Arm
    Number of subjects analysed
    59
    50
    Units: Median change from baseline
    number (not applicable)
        Total GS response
    -1.5
    -5.0
    Statistical analysis title
    Change from Baseline in Total GS Score at Week 48
    Comparison groups
    Clinical Arm v Imaging Arm
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 1
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from Baseline in Modified Sharp Scores at Week 48 (FASPPD Population)

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    End point title
    Change from Baseline in Modified Sharp Scores at Week 48 (FASPPD Population)
    End point description
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Clinical Arm Imaging Arm
    Number of subjects analysed
    59
    50
    Units: Median change from baseline
    number (not applicable)
        Modified Sharp Score
    1.0
    -1.0
    Statistical analysis title
    Change from Baseline in Modified Sharp Scores
    Comparison groups
    Clinical Arm v Imaging Arm
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.4004
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from Baseline in HAQ-DI Score at Week 48 (FASPPD Population)

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    End point title
    Change from Baseline in HAQ-DI Score at Week 48 (FASPPD Population)
    End point description
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Clinical Arm Imaging Arm
    Number of subjects analysed
    59
    50
    Units: Median change from baseline
    number (not applicable)
        HAQ-DI Score
    0.0000
    0.0000
    Statistical analysis title
    Change from Baseline in HAQ-DI Score
    Comparison groups
    Clinical Arm v Imaging Arm
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.4004
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from Baseline in Bone Densitometry Scores (Hip)(FASPPD Population)

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    End point title
    Change from Baseline in Bone Densitometry Scores (Hip)(FASPPD Population)
    End point description
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Clinical Arm Imaging Arm
    Number of subjects analysed
    59
    50
    Units: Mean change from baseline
    number (not applicable)
        Hip T-score
    -0.20
    0.03
    Statistical analysis title
    Change from Baseline Hip T-score
    Comparison groups
    Clinical Arm v Imaging Arm
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.8016
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.48
         upper limit
    0.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.143

    Secondary: Change from Baseline in Bone Densitometry Scores (Spine)(FASPPD Population)

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    End point title
    Change from Baseline in Bone Densitometry Scores (Spine)(FASPPD Population)
    End point description
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Clinical Arm Imaging Arm
    Number of subjects analysed
    59
    50
    Units: Mean change from baseline
    number (not applicable)
        Spine T-score
    -0.08
    -0.11
    Statistical analysis title
    Change from Baseline Spine T-score
    Comparison groups
    Clinical Arm v Imaging Arm
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 1
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.43
         upper limit
    0.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.219

    Secondary: Change from Baseline in Total RA-WIS Score (FASPPD Population)

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    End point title
    Change from Baseline in Total RA-WIS Score (FASPPD Population)
    End point description
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Clinical Arm Imaging Arm
    Number of subjects analysed
    59
    50
    Units: Median change from baseline
    number (not applicable)
        Total RA-WIS Score
    -1.0
    0.0
    Statistical analysis title
    Change from Baseline in Total RA-WIS Score
    Comparison groups
    Clinical Arm v Imaging Arm
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 1
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change from Baseline in EQ-5D-3L Score (FASPPD Population)

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    End point title
    Change from Baseline in EQ-5D-3L Score (FASPPD Population)
    End point description
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Clinical Arm Imaging Arm
    Number of subjects analysed
    59
    50
    Units: Median change from baseline
    number (not applicable)
        EQ-5D-3L Score
    0.0000
    0.0000
    Statistical analysis title
    Change from Baseline in EQ-5D-3L Score
    Comparison groups
    Clinical Arm v Imaging Arm
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.603
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Proportion of Patients Requiring Biologic Therapy at Week 48 (FASPPD Population)

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    End point title
    Proportion of Patients Requiring Biologic Therapy at Week 48 (FASPPD Population)
    End point description
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Clinical Arm Imaging Arm
    Number of subjects analysed
    59
    50
    Units: Biologic Therapy Required?
    number (not applicable)
        Yes
    8
    15
        No
    40
    26
    Statistical analysis title
    Proportion of Patients Requiring Biologic Therapy
    Comparison groups
    Clinical Arm v Imaging Arm
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.34
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.04
         upper limit
    9.65

    Secondary: Total Steroid Exposure Baseline to Week 48 (FASPPD Population)

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    End point title
    Total Steroid Exposure Baseline to Week 48 (FASPPD Population)
    End point description
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Clinical Arm Imaging Arm
    Number of subjects analysed
    59
    50
    Units: Steroid exposure (until week 48)
    number (not applicable)
        Yes
    12
    24
        No
    47
    26
    No statistical analyses for this end point

    Secondary: Total Steroid Exposure Baseline to Week 48 (FASPPD Population)

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    End point title
    Total Steroid Exposure Baseline to Week 48 (FASPPD Population)
    End point description
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Clinical Arm Imaging Arm
    Number of subjects analysed
    12
    24
    Units: Total steroid exposure, days
    arithmetic mean (standard deviation)
        Mean
    93.1 ± 141.14
    101.8 ± 152.63
    No statistical analyses for this end point

    Secondary: Co-morbidity Incidence of Infection (FASPPD Population)

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    End point title
    Co-morbidity Incidence of Infection (FASPPD Population)
    End point description
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Clinical Arm Imaging Arm FASPPD
    Number of subjects analysed
    59
    50
    109
    Units: Incidence of infection
        Yes
    11
    17
    28
        No
    48
    33
    81
    No statistical analyses for this end point

    Secondary: Co-morbidity Systolic blood pressure > 140 mmHg (FASPPD Population)

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    End point title
    Co-morbidity Systolic blood pressure > 140 mmHg (FASPPD Population)
    End point description
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Clinical Arm Imaging Arm FASPPD
    Number of subjects analysed
    59
    50
    109
    Units: Systolic blood pressure > 140 mmHg
        Yes
    24
    19
    43
        No
    35
    31
    66
    No statistical analyses for this end point

    Secondary: Co-morbidity Diastolic blood pressure > 80 mmHg (FASPPD Population)

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    End point title
    Co-morbidity Diastolic blood pressure > 80 mmHg (FASPPD Population)
    End point description
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Clinical Arm Imaging Arm FASPPD
    Number of subjects analysed
    59
    50
    109
    Units: Diastolic blood pressure > 80 mmHg
        Yes
    37
    26
    63
        No
    22
    24
    46
    No statistical analyses for this end point

    Secondary: Change from Baseline in DAS Score (FASPPD Population)

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    End point title
    Change from Baseline in DAS Score (FASPPD Population)
    End point description
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Clinical Arm Imaging Arm
    Number of subjects analysed
    48 [7]
    41 [8]
    Units: Total DAS Score
    arithmetic mean (standard deviation)
        Change from Baseline
    0.003 ± 0.7136
    0.046 ± 0.6949
    Notes
    [7] - 48/59 Clinical arm participants completed Week 48
    [8] - 41/50 Imaging arm participants completed Week 48
    No statistical analyses for this end point

    Secondary: Change from Baseline in DAS28 Score (FASPPD Population)

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    End point title
    Change from Baseline in DAS28 Score (FASPPD Population)
    End point description
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    Clinical Arm Imaging Arm
    Number of subjects analysed
    48 [9]
    41 [10]
    Units: Total DAS28 Score
    arithmetic mean (standard deviation)
        Change from Baseline
    -0.279 ± 0.8304
    0.076 ± 0.8642
    Notes
    [9] - 48/59 Clinical arm participants completed Week 48
    [10] - 41/50 Imaging arm participants completed Week 48
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Adverse events were reported from the time of participant consent to 70 days after the end of trial participation
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Clinical Arm
    Reporting group description
    Current gold standard clinical Treat to Target (T2T) approach for management of rheumatoid arthritis

    Reporting group title
    Imaging Arm
    Reporting group description
    Modified treatment approach based on Ultrasound (US) findings as an additional competent to the current gold-standard clinical T2T approach

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Per the Statistical Analysis Plan non-serious AEs were not analysed by frequency due to the early termination of the trial therefore this data is not available. In addition, as this was a standard of care study therefore non-serious AEs that were unrelated to the study medication were not required to be reported.
    Serious adverse events
    Clinical Arm Imaging Arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 12 (16.67%)
    3 / 30 (10.00%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain injury
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral infarction
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Oral infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Clinical Arm Imaging Arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 30 (0.00%)

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Sep 2013
    • Update to Inclusion/exclusion criteria regarding requirement for confirmed participation by Informed Consent, requirement for contraception 5 months after study completion and exclusion of person committed to a psychiatric institution or prison. • Update to SAE reporting requirement within 24 hours of awareness • Clarification on concomitant use adalimumab in year 2 • Clarification on statistical management of missing data and withdrawn participants
    30 Sep 2013
    • Removal of patient questionnaire Rheumatoid Arthritis Quality of Life questionnaire (RAQoL) and update to clarify use of RA-WIS where available per local site practice • Requirement to have TB testing at screening if not done within the previous 24 weeks • Requirement to have X-ray of hands and feet performed at baseline if not done in previous 12 weeks and if not done in the format required for study evaluation • Update to dosage of adalimumab to accommodate global/national guidelines and clarification on maximum dose and escalation of dosage • Inclusion of information on management of Investigational Medicinal Product (IMP)
    23 Jun 2014
    • Clarification – non-MTX DMARDS should be stopped if escalated to ADA • Optimisation of MTX dose prior to treatment escalation • Non- escalation to ADA/MTX if DAS28 increase <0.6 • Revisions to treatment algorithm • Aligning EC country specific feedback
    01 Oct 2015
    • Clarification regarding Tenosynovitis Ultrasound sub- study in the TURA Protocol • Clarification in the numbering of the Exclusion Criteria in the TURA protocol • Clarification for the capture of alcohol data in e-CRF in the TURA Protocol • Clarification on the exclusion criteria: general safety • Clarification regarding Sample size justification • Guidance on blood and Chemistry tests • Clarification regarding the study schedule
    05 May 2017
    • Clarification on the exclusion criteria: general safety • New information regarding study duration, number of sites and countries taking part • New information and clarification regarding Sample size justification • Clarification of the blinding status in the Clinical Arm A • New information regarding the SAE Requirements • Clarification regarding the study schedule • Deletion of weeks 72 and 96 and follow-up year 2 • Clarification of visit 48 final visit or early discontinuation and post safety at 10 weeks

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    30 Jul 2018
    The TURA study was terminated early due to the withdrawal of the original Clinical Research Organisation overseeing the trial (Theorem, which were later acquired by Chiltern) and advice provided by the MHRA GCP Inspectorate. Existing patients were followed up for 10 weeks to allow collection of safety information regarding ongoing SAEs (until resolution or stabilization). Existing patients were also followed up to record any new, initial SAEs that may have occurred after Week 48 (or after early discontinuation). This safety information was not entered into the CRF by the site staff but it was reviewed as per the SAE procedures. The last patient visit occurred on 30 July 2018.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to the study terminating early, analyses related to the Week 72 and Week 96 time points, exploratory analyses, lab values, and a number of safety tables were removed. Data from Week 72 and 96 was not fully monitored or 'cleaned'.
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