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    Clinical Trial Results:
    Clinical effectiveness of standard step up care (methotrexate) compared to early combination DMARD therapy with standard step up care compared to early use of TNF inhibitors with standard step up care for the treatment of moderate to Severe Psoriatic arthritis: a 3-arm parallel group randomised controlled trial.

    Summary
    EudraCT number
    		 2017-004542-24
    Trial protocol
    		 GB  
    Global end of trial date
    31 Oct 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Jun 2026
    First version publication date
    17 Jun 2026
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    N/A
    Additional study identifiers
    ISRCTN number
    		 ISRCTN70603700
    US NCT number
    		 NCT03739853
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Research Governance, Ethics and Assurance Team, Boundary Brook House, Churchill Drive, Headington, Oxford, United Kingdom, OX3 7LQ
    Public contact
    Clinical Trials and Research Govern, University of Oxford, 44 1865616480, ctrg@admin.ox.ac.uk
    Scientific contact
    Clinical Trials and Research Govern, University of Oxford, 44 1865616480, ctrg@admin.ox.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
    18 Dec 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Oct 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Oct 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the initial effectiveness of early combination DMARD therapy (arm 2) and early use of TNF inhibitors (arm 3) with standard step up care (received in the TWiCs cohort; arm 1).
    Protection of trial subjects
    All patients received active treatment and it was open label so that they could interpret any side effects or issues. No sensitive questionnaires included.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 The optimal treatment strategy, and how to personalise this in a heterogeneous condition such as psoriatic arthritis remains unknown as highlighted in recent international treatment recommendations. Current guidance suggests more intensive therapy for those with poor prognostic factors, but this is not evidence-based. Since the systematic literature reviews informing these treatment recommendations have been published, one Dutch study comparing combination DMARDs (methotrexate plus leflunomide) to methotrexate alone, showed improved clinical response on the combination but with a higher risk of side effects. Two recent studies have compared early biologics (golimumab in GolMePsA and secukinumab in STAMP) with methotrexate and steroids in early PsA. These studies did not show any significant difference after 24 weeks of treatment when including all newly diagnosed PsA patients with at least 2 active peripheral joints. All medications used in the study were routinely used in PsA treatment in the UK and internationally.
    Actual start date of recruitment
    31 Jul 2019
    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
    United Kingdom: 192
    Worldwide total number of subjects
    192
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    192
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment at 9 UK sites from 2018-2023.

    Pre-assignment
    Screening details
    		 Eligible patients were recruited from participants in the MONITOR-PsA cohort. 310 patients across 9 sites were screened for eligibility. 118 patients were excluded (41 not poor prognosis, 11 no consent for RCTs, 10 axial disease, 20 safety issues, 9 COVID pause, 1 pregnancy, 11 declined, 15 other)

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard care
    Arm description
    		 Patient randomised to arm 1 received standard ‘step-up’ therapy in line with the cohort. While physician discretion is used, the most common initial therapy is methotrexate alone, involving monotherapy methotrexate (15mg/week rising to 25mg/week as tolerated by week 8 of therapy either oral or subcutaneous) unless contraindicated. In cases of inefficacy or intolerance to the provided medication, treatment could be escalated following a step-up approach and the National Institute for Health and Clinical Excellence (NICE) recommendations14 for the use of biologics. This was classified as rescue therapy.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Solution for injection
    Routes of administration
    Oral use, Subcutaneous use
    Dosage and administration details
    the most common initial therapy is methotrexate alone, involving monotherapy methotrexate (15mg/week rising to 25mg/week as tolerated by week 8 of therapy either oral or subcutaneous) unless contraindicated.

    Arm title
    		 Combo DMARD
    Arm description
    		 Arm 2 was the combination DMARD arm. All participants were prescribed methotrexate with an additional csDMARD (either sulfasalazine increasing to 2g, potentially up to 3g daily or leflunomide 10-20mg daily) at baseline, staggering the start of these therapies by one week. In cases of inefficacy or intolerance to the provided medication, treatment could be escalated following a step-up approach and the National Institute for Health and Clinical Excellence (NICE) recommendations14 for the use of biologics. This was classified as rescue therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection, Tablet
    Routes of administration
    Oral use, Subcutaneous use
    Dosage and administration details
    the most common initial therapy is methotrexate alone, involving monotherapy methotrexate (15mg/week rising to 25mg/week as tolerated by week 8 of therapy either oral or subcutaneous) unless contraindicated.

    Investigational medicinal product name
    Sulfasalazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    sulfasalazine increasing to 2g, potentially up to 3g daily

    Investigational medicinal product name
    Leflunomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    leflunomide 10-20mg daily

    Arm title
    		 early TNFi
    Arm description
    		 Arm 3 was the early biologic arm. All participants were prescribed weekly methotrexate with a TNF inhibitor (adalimumab 40mg given every two weeks) at baseline staggering the start of these therapies by one week. Treatment with adalimumab at standard dosing was continued until week 24 then tapered by extending the dose interval to week 28 and week 32. Adalimumab was stopped completely after week 32 and participants continued methotrexate as standard care. In cases of inefficacy or intolerance to the provided medication, treatment could be escalated following a step-up approach and the National Institute for Health and Clinical Excellence (NICE) recommendations14 for the use of biologics. This was classified as rescue therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection, Tablet
    Routes of administration
    Oral use, Subcutaneous use
    Dosage and administration details
    the most common initial therapy is methotrexate alone, involving monotherapy methotrexate (15mg/week rising to 25mg/week as tolerated by week 8 of therapy either oral or subcutaneous) unless contraindicated.

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Adalimumab 40mg given every two weeks at baseline staggering the start of these therapies by one week. Treatment with adalimumab at standard dosing was continued until week 24 then tapered by extending the dose interval to week 28 and 32. Adalimumab was stopped completely after week 32

    Number of subjects in period 1
    		Standard care Combo DMARD early TNFi
    Started
    64
    63
    65
    Completed
    57
    55
    58
    Not completed
    7
    8
    7
         Consent withdrawn by subject
    6
    3
    3
         Declined treatment offered
    1
    5
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard care
    Reporting group description
    		 Patient randomised to arm 1 received standard ‘step-up’ therapy in line with the cohort. While physician discretion is used, the most common initial therapy is methotrexate alone, involving monotherapy methotrexate (15mg/week rising to 25mg/week as tolerated by week 8 of therapy either oral or subcutaneous) unless contraindicated. In cases of inefficacy or intolerance to the provided medication, treatment could be escalated following a step-up approach and the National Institute for Health and Clinical Excellence (NICE) recommendations14 for the use of biologics. This was classified as rescue therapy.

    Reporting group title
    Combo DMARD
    Reporting group description
    		 Arm 2 was the combination DMARD arm. All participants were prescribed methotrexate with an additional csDMARD (either sulfasalazine increasing to 2g, potentially up to 3g daily or leflunomide 10-20mg daily) at baseline, staggering the start of these therapies by one week. In cases of inefficacy or intolerance to the provided medication, treatment could be escalated following a step-up approach and the National Institute for Health and Clinical Excellence (NICE) recommendations14 for the use of biologics. This was classified as rescue therapy.

    Reporting group title
    early TNFi
    Reporting group description
    		 Arm 3 was the early biologic arm. All participants were prescribed weekly methotrexate with a TNF inhibitor (adalimumab 40mg given every two weeks) at baseline staggering the start of these therapies by one week. Treatment with adalimumab at standard dosing was continued until week 24 then tapered by extending the dose interval to week 28 and week 32. Adalimumab was stopped completely after week 32 and participants continued methotrexate as standard care. In cases of inefficacy or intolerance to the provided medication, treatment could be escalated following a step-up approach and the National Institute for Health and Clinical Excellence (NICE) recommendations14 for the use of biologics. This was classified as rescue therapy.

    Reporting group values
    		 Standard care Combo DMARD early TNFi Total
    Number of subjects
    		 64 63 65 192
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 50 (34 to 57) 51 (37 to 60) 48 (34 to 57) -
    Gender categorical
    Gender
    Units: Subjects
        Female
    		 31 33 28 92
        Male
    		 33 30 37 100
    BMI
    BMI categorites
    Units: Subjects
        Underweight/Normal
    		 13 9 15 37
        Overweight
    		 21 28 22 71
        Obese
    		 30 25 26 81
        Not recorded
    		 0 1 2 3
    Enthesitis
    Presence of enthesitis
    Units: Subjects
        Yes
    		 33 30 33 96
        No
    		 31 33 30 94
        Not recorded
    		 0 0 2 2
    Tender joint count
    Tender joint count
    Units: Joints
        median (inter-quartile range (Q1-Q3))
    		 9 (5 to 21.5) 10 (5 to 17) 10 (6 to 18) -
    Swollen joint count
    Swollen joint count
    Units: Joints
        median (inter-quartile range (Q1-Q3))
    		 5 (2 to 8.5) 5 (3 to 9) 5 (3 to 9) -
    PASDAS
    PsA disease activity score
    Units: units
        arithmetic mean (standard deviation)
    		 5.6 ( 1.2 ) 5.5 ( 1.3 ) 5.7 ( 1.1 ) -
    PsAID
    PsA impact of disease questionnaire
    Units: units
        arithmetic mean (standard deviation)
    		 5.4 ( 2.1 ) 5.3 ( 2.2 ) 5.5 ( 2.0 ) -
    Subject analysis sets

    Subject analysis set title
    ITT analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention to treat

    Subject analysis sets values
    		 ITT analysis
    Number of subjects
    192
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    49 (34 to 58)
    Gender categorical
    Gender
    Units: Subjects
        Female
    92
        Male
    100
    BMI
    BMI categorites
    Units: Subjects
        Underweight/Normal
    37
        Overweight
    71
        Obese
    81
        Not recorded
    3
    Enthesitis
    Presence of enthesitis
    Units: Subjects
        Yes
    96
        No
    94
        Not recorded
    2
    Tender joint count
    Tender joint count
    Units: Joints
        median (inter-quartile range (Q1-Q3))
    10 (5 to 18)
    Swollen joint count
    Swollen joint count
    Units: Joints
        median (inter-quartile range (Q1-Q3))
    5 (3 to 9)
    PASDAS
    PsA disease activity score
    Units: units
        arithmetic mean (standard deviation)
    5.6 ( 1.2 )
    PsAID
    PsA impact of disease questionnaire
    Units: units
        arithmetic mean (standard deviation)
    5.4 ( 2.1 )

    End points

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    End points reporting groups
    Reporting group title
    Standard care
    Reporting group description
    		 Patient randomised to arm 1 received standard ‘step-up’ therapy in line with the cohort. While physician discretion is used, the most common initial therapy is methotrexate alone, involving monotherapy methotrexate (15mg/week rising to 25mg/week as tolerated by week 8 of therapy either oral or subcutaneous) unless contraindicated. In cases of inefficacy or intolerance to the provided medication, treatment could be escalated following a step-up approach and the National Institute for Health and Clinical Excellence (NICE) recommendations14 for the use of biologics. This was classified as rescue therapy.

    Reporting group title
    Combo DMARD
    Reporting group description
    		 Arm 2 was the combination DMARD arm. All participants were prescribed methotrexate with an additional csDMARD (either sulfasalazine increasing to 2g, potentially up to 3g daily or leflunomide 10-20mg daily) at baseline, staggering the start of these therapies by one week. In cases of inefficacy or intolerance to the provided medication, treatment could be escalated following a step-up approach and the National Institute for Health and Clinical Excellence (NICE) recommendations14 for the use of biologics. This was classified as rescue therapy.

    Reporting group title
    early TNFi
    Reporting group description
    		 Arm 3 was the early biologic arm. All participants were prescribed weekly methotrexate with a TNF inhibitor (adalimumab 40mg given every two weeks) at baseline staggering the start of these therapies by one week. Treatment with adalimumab at standard dosing was continued until week 24 then tapered by extending the dose interval to week 28 and week 32. Adalimumab was stopped completely after week 32 and participants continued methotrexate as standard care. In cases of inefficacy or intolerance to the provided medication, treatment could be escalated following a step-up approach and the National Institute for Health and Clinical Excellence (NICE) recommendations14 for the use of biologics. This was classified as rescue therapy.

    Subject analysis set title
    ITT analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention to treat

    Primary: PASDAS at week 24

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    End point title
    		 PASDAS at week 24
    End point description
    PASDAS at 24 weeks
    End point type
    Primary
    End point timeframe
    24 weeks
    End point values
    		 Standard care Combo DMARD early TNFi ITT analysis
    Number of subjects analysed
    39
    47
    53
    139
    Units: units
        arithmetic mean (standard deviation)
    4.7 ( 1.5 )
    4.0 ( 1.5 )
    3.6 ( 1.9 )
    4.03 ( 1.7 )
    Statistical analysis title
    		 PASDAS at week 24
    Statistical analysis description
    Primary outcome - ANOVA across all 3 groups
    Comparison groups
    Standard care v Combo DMARD v early TNFi
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Combo DMARD vs standard care
    Comparison groups
    Standard care v Combo DMARD
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0096
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 -0.19
    Statistical analysis title
    		 TNF vs Standard Care
    Comparison groups
    early TNFi v Standard care
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.78
         upper limit
    		 -0.49
    Statistical analysis title
    		 TNF vs Combo DMARD
    Comparison groups
    Combo DMARD v early TNFi
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1952
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 0.22

    Secondary: PASDAS at week 48

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    End point title
    		 PASDAS at week 48
    End point description
    PASDAS at week 48
    End point type
    Secondary
    End point timeframe
    48 week
    End point values
    		 Standard care Combo DMARD early TNFi ITT analysis
    Number of subjects analysed
    45
    45
    49
    139
    Units: units
        arithmetic mean (standard deviation)
    4.1 ( 1.8 )
    3.8 ( 1.5 )
    3.5 ( 1.7 )
    0 ( 0 )
    Statistical analysis title
    		 Combo DMARD vs standard care
    Comparison groups
    Combo DMARD v Standard care
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1444
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.11
         upper limit
    		 0.16
    Statistical analysis title
    		 TNF vs Standard Care
    Comparison groups
    Standard care v early TNFi
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0298
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.31
         upper limit
    		 -0.07

    Secondary: MDA at week 24

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    End point title
    		 MDA at week 24
    End point description
    End point type
    Secondary
    End point timeframe
    24 week
    End point values
    		 Standard care Combo DMARD early TNFi ITT analysis
    Number of subjects analysed
    42
    51
    54
    147
    Units: Individual
        Achieved
    4
    15
    18
    37
        Not achieved
    38
    36
    36
    110
    No statistical analyses for this end point

    Secondary: MDA at week 48

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    End point title
    		 MDA at week 48
    End point description
    MDA at week 48
    End point type
    Secondary
    End point timeframe
    week 48
    End point values
    		 Standard care Combo DMARD early TNFi ITT analysis
    Number of subjects analysed
    44
    45
    51
    140
    Units: Individual
        Not achieved
    33
    33
    35
    101
        Achieved
    11
    12
    16
    39
    No statistical analyses for this end point

    Secondary: PSAID at week 24

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    End point title
    		 PSAID at week 24
    End point description
    PSAID at week 24
    End point type
    Secondary
    End point timeframe
    24 week
    End point values
    		 Standard care Combo DMARD early TNFi ITT analysis
    Number of subjects analysed
    43
    51
    54
    148
    Units: units
        arithmetic mean (standard deviation)
    3.8 ( 2.1 )
    3.5 ( 2.4 )
    3.1 ( 2.5 )
    0 ( 0 )
    Statistical analysis title
    		 Combo DMARD vs Standard Care
    Comparison groups
    Combo DMARD v Standard care
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5187
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.07
         upper limit
    		 0.54
    Statistical analysis title
    		 TNF vs Standard Care
    Comparison groups
    Standard care v early TNFi
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0795
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.53
         upper limit
    		 0.09

    Secondary: PSAID at week 48

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    End point title
    		 PSAID at week 48
    End point description
    PSAID at week 48
    End point type
    Secondary
    End point timeframe
    48 week
    End point values
    		 Standard care Combo DMARD early TNFi ITT analysis
    Number of subjects analysed
    45
    46
    51
    142
    Units: units
        arithmetic mean (standard deviation)
    3.4 ( 2.5 )
    3.3 ( 2.6 )
    3.0 ( 2.5 )
    0 ( 0 )
    Statistical analysis title
    		 Combination DMARD vs Standard Care
    Comparison groups
    Standard care v Combo DMARD
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4229
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.15
         upper limit
    		 0.48
    Statistical analysis title
    		 TNF vs Standard Care
    Comparison groups
    Standard care v early TNFi
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2058
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.33
         upper limit
    		 0.29

    Secondary: PASDAS (Good) at week 24

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    End point title
    		 PASDAS (Good) at week 24
    End point description
    End point type
    Secondary
    End point timeframe
    24 week
    End point values
    		 Standard care Combo DMARD early TNFi ITT analysis
    Number of subjects analysed
    64
    63
    65
    192
    Units: Individual
        Good
    3
    15
    24
    42
    Statistical analysis title
    		 Combination DMARD vs Standard Care
    Comparison groups
    Standard care v Combo DMARD
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0074
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.63
         upper limit
    		 23.67
    Statistical analysis title
    		 TNF vs Standard Care
    Comparison groups
    Standard care v early TNFi
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    11.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.98
         upper limit
    		 40.97
    Statistical analysis title
    		 TNF vs Combo DMARD
    Comparison groups
    Combo DMARD v early TNFi
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1579
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 4.21

    Secondary: PASDAS (Good) at week 48

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    End point title
    		 PASDAS (Good) at week 48
    End point description
    End point type
    Secondary
    End point timeframe
    48 week
    End point values
    		 Standard care Combo DMARD early TNFi ITT analysis
    Number of subjects analysed
    64
    63
    65
    192
    Units: Individual
        Good
    11
    15
    20
    46
    Statistical analysis title
    		 Combo DMARD vs Standard Care
    Comparison groups
    Standard care v Combo DMARD
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2271
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 4.53
    Statistical analysis title
    		 TNF vs Standard Care
    Comparison groups
    Standard care v early TNFi
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.107
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 5.18

    Secondary: PASDAS (Moderate and Good) at week 24

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    End point title
    		 PASDAS (Moderate and Good) at week 24
    End point description
    End point type
    Secondary
    End point timeframe
    24 week
    End point values
    		 Standard care Combo DMARD early TNFi ITT analysis
    Number of subjects analysed
    64
    63
    65
    192
    Units: Individual
        Moderate and Good
    20
    29
    39
    88
    Statistical analysis title
    		 Combination DMARD vs Standard Care
    Comparison groups
    Standard care v Combo DMARD
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2137
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 4.59
    Statistical analysis title
    		 TNF vs Standard Care
    Comparison groups
    Standard care v early TNFi
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0217
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.18
         upper limit
    		 8.45

    Secondary: PASDAS (Moderate and Good) at week 48

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    End point title
    		 PASDAS (Moderate and Good) at week 48
    End point description
    End point type
    Secondary
    End point timeframe
    48 week
    End point values
    		 Standard care Combo DMARD early TNFi ITT analysis
    Number of subjects analysed
    64
    63
    65
    192
    Units: Individual
        Moderate and Good
    25
    31
    37
    93
    Statistical analysis title
    		 Combo DMARD vs Standard Care
    Comparison groups
    Standard care v Combo DMARD
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1281
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 5.38
    Statistical analysis title
    		 TNF vs Standard Care
    Comparison groups
    Standard care v early TNFi
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.105
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 5.8

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to week 48
    Adverse event reporting additional description
    Adverse events of special interest and SAEs
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 DMARD side effects
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Standard care
    Reporting group description
    		 Patient randomised to arm 1 received standard ‘step-up’ therapy in line with the cohort. While physician discretion is used, the most common initial therapy is methotrexate alone, involving monotherapy methotrexate (15mg/week rising to 25mg/week as tolerated by week 8 of therapy either oral or subcutaneous) unless contraindicated. In cases of inefficacy or intolerance to the provided medication, treatment could be escalated following a step-up approach and the National Institute for Health and Clinical Excellence (NICE) recommendations14 for the use of biologics. This was classified as rescue therapy.

    Reporting group title
    Combo DMARD
    Reporting group description
    		 Arm 2 was the combination DMARD arm. All participants were prescribed methotrexate with an additional csDMARD (either sulfasalazine increasing to 2g, potentially up to 3g daily or leflunomide 10-20mg daily) at baseline, staggering the start of these therapies by one week. In cases of inefficacy or intolerance to the provided medication, treatment could be escalated following a step-up approach and the National Institute for Health and Clinical Excellence (NICE) recommendations14 for the use of biologics. This was classified as rescue therapy.

    Reporting group title
    early TNFi
    Reporting group description
    		 Arm 3 was the early biologic arm. All participants were prescribed weekly methotrexate with a TNF inhibitor (adalimumab 40mg given every two weeks) at baseline staggering the start of these therapies by one week. Treatment with adalimumab at standard dosing was continued until week 24 then tapered by extending the dose interval to week 28 and week 32. Adalimumab was stopped completely after week 32 and participants continued methotrexate as standard care. In cases of inefficacy or intolerance to the provided medication, treatment could be escalated following a step-up approach and the National Institute for Health and Clinical Excellence (NICE) recommendations14 for the use of biologics. This was classified as rescue therapy.

    Serious adverse events
    		 Standard care Combo DMARD early TNFi
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 63 (0.00%)
    2 / 65 (3.08%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Nervous system disorders
    Cerebellar haemorrhage
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastroenteritis
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 63 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Perineal abscess
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 63 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 63 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Standard care Combo DMARD early TNFi
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 64 (29.69%)
    20 / 63 (31.75%)
    18 / 65 (27.69%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 64 (14.06%)
    11 / 63 (17.46%)
    5 / 65 (7.69%)
         occurrences all number
    9
    11
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    19 / 64 (29.69%)
    20 / 63 (31.75%)
    15 / 65 (23.08%)
         occurrences all number
    19
    20
    15
    Diarrhoea
         subjects affected / exposed
    6 / 64 (9.38%)
    8 / 63 (12.70%)
    6 / 65 (9.23%)
         occurrences all number
    6
    8
    6
    Hepatobiliary disorders
    Liver function test abnormal
         subjects affected / exposed
    11 / 64 (17.19%)
    19 / 63 (30.16%)
    18 / 65 (27.69%)
         occurrences all number
    11
    19
    18
    Infections and infestations
    Infection
         subjects affected / exposed
    3 / 64 (4.69%)
    3 / 63 (4.76%)
    6 / 65 (9.23%)
         occurrences all number
    3
    3
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Aug 2018
    Change in sample testing to BRS guidelines. Change to sponsor address, LC's phone number, NHS digital added. The title has been changed to include 'moderate' . The PIS has also been submitted in this amendment to remove 'at least 24 hours'
    03 May 2019
    PIS - GDPR added to Arm 2 and Arm 3 of the Patient Information Sheet. Protocol changes to include the two new sites, Removal of BASMI at 12,24,36 and 72 weeks, only to be performed at baseline, 48 weeks and thereafter.
    03 Jul 2019
    Manufacturing documents required by the MHRA.
    08 Mar 2022
    Protocol has been updated to include: addition of information about creation and storage of datasets, clarification of SAE reporting requirements, acceptable methods of contraception added, discontinuation of trial treatment in pregnancy and information added relating to the reporting procedure for pregnancy, reporting obligations to AbbVie, correction to Schedule to match body of protocol and due to SPEED being a pragmatic study, where deviations from this standard national policy on blood monitoring are implemented by the NHS hospitals, this may change in accordance with local guidelines (allowance of blood monitoring to be within 3 months not just 1 month) monitoring will remain in line with local hospital policy. Update to SmPC for Adalimumab and Methotrexate which include changes to the RSI (for which we seek approval) but that do not affect risk/benefit assessment. PIS arm 2 and 3 now have information related to pregnancies. In arm 3 additional information has been added for patients partners who become pregnant, the associated reporting requirement and contraception examples provided. A new combined PIS and ICF has been generated for patients pregnant partners. Addition of importer for compliance with new regulations to import investigational medicinal for clinical research into GB from the EU.
    10 Mar 2023
    Protocol changes: Planned sample size has changed to 192, follow up duration has changed. Planned end date has changed to October 2023. Treatment duration changed to min36-max48 weeks. Primary and secondary outcomes have been clarified with new evidence in mind. Clarification provided that some patients who are recruited late into the trial will only reach the week 36 assessment visit. Statistics section updated to only include information on the primary outcome and updated to include the change to the way the new primary outcome is specified. Following information from new publication the primary outcome has changed to continuous outcome. PIS arm 2 and 3 have been updated to reflect protocol changes.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    20 Mar 2020
    Covid-19 study pause
    29 Jul 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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