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    Clinical Trial Results:
    SWITCH: Randomised-controlled trial of switching to alternative tumour-necrosis factor (TNF)-blocking drugs or abatacept or rituximab in patients with rheumatoid arthritis who have failed an initial TNF-blocking drug.

    Summary
    EudraCT number
    2010-023880-17
    Trial protocol
    GB  
    Global end of trial date
    23 Nov 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    07 Jul 2018
    First version publication date
    07 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RR10/9589
    Additional study identifiers
    ISRCTN number
    ISRCTN89222125
    US NCT number
    NCT01295151
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Leeds
    Sponsor organisation address
    Hyde Terrace, Leeds, United Kingdom, LS2 9LN
    Public contact
    Regulatory Affairs and Governance Manager, CTRU QA Department, Leeds Institute of Clinical Trials Research, ctruq@leeds.ac.uk
    Scientific contact
    Regulatory Affairs and Governance Manager, CTRU QA Department, Leeds Institute of Clinical Trials Research, ctruq@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
    15 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Nov 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Nov 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare alternative-mechanism-TNF-inhibitor and abatacept to rituximab in terms of disease response, quality of life, cost-effectiveness, and toxicity and safety over a 12 month period.
    Protection of trial subjects
    The randomised treatments in the study are all licensed having demonstrated health benefits with well characterised safety profiles. In addition, in order to be eligible for the trial patients must have already have been established on a biological therapy. Patients were monitored closely throughout the trial and were asked to attend regular outpatient appointments. CTRU prepared annual safety reports containing anonymised data to the MHRA, main REC and sponsor. The Data Monitoring and Ethics Committee reviewed un-blinded periodic safety data to determine patterns and trends of events or to identify safety issues which would not be apparent on an individual case basis. Trial data was collected on paper CRFs and was sent to CTRU where it was entered into a trial database application - MACRO. The database is stored on a private network protected by a firewall. Access is restricted to staff working on the trial by login and password. The trial data was then filed in locked filing cabinets. CTRU comply with all aspects of the Data Protection Act 1998. All information collected during the trial has been kept strictly confidential. Patient names were collected on the Consent Form and sent to CTRU and patients were informed in the Patient Information Sheet that their names were processed this way. For all other data collection forms that were transferred to or from CTRU, the data was coded with a trial number, the patients initials and date of birth.
    Background therapy
    All participants were required to be on a stable dose of methotrexate for 4 weeks prior to the screening visit and were expected to continue on this therapy for the duration of the study. Interruption of dose was permitted however. The protocol indicated participants would receive standard folic acid as per local policy. In addition, methylprednisolone was administered intravenously at a dose of 100mg prior to each rituximab infusion.
    Evidence for comparator
    -
    Actual start date of recruitment
    31 Jul 2012
    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: 122
    Worldwide total number of subjects
    122
    EEA total number of subjects
    122
    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)
    90
    From 65 to 84 years
    32
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Between July 2012 and December 2014, 678 patients were pre-screened for the trial across 35 centres. Of these, 149/678 patients appeared suitable for and consented to pre-randomisation tests to confirm eligibility. Of these, 122/149 patients were confirmed eligible, maintained their consent, and proceeded to randomisation.

    Pre-assignment
    Screening details
    Of the 678 patients screened 529 patients were excluded pre-registration. 417 failed to meet the eligibility criteria. The main reasons were: had not failed an initial TNFi agent (95 patients), were not on a stable dose of methotrexate over the over the previous 28 days (92) and had received more than one TNFi drug or other biological agent (72)

    Pre-assignment period milestones
    Number of subjects started
    678 [1]
    Number of subjects completed
    122

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Declined to consent (pre-consent): 90
    Reason: Number of subjects
    Other reason for non-registration (pre-consent): 22
    Reason: Number of subjects
    Ineligible to be randomised (pre-consent): 417
    Reason: Number of subjects
    Ineligible to be randomised (post-consent): 19
    Reason: Number of subjects
    Other reason for non-randomisation (post consent): 6
    Reason: Number of subjects
    Withdrew consent (post-consent): 2
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: "Numbers started pre-assignment period" is the total number considered for enrolment, including those that were not approached due to being clearly ineligible, those that did not consent to trial specific tests, those that consented to tests, but were not randomised, and those that were randomised. "Worldwide number enrolled" is the number of patients randomised and took part in the SWITCH trial.
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    N/A

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Alternative mechanism TNFi
    Arm description
    a. Etanercept if initial failure to a monoclonal antibody: infliximab, adalimumab, certolizumab or golimumab OR b. Infliximab, adalimumab, certolizumab or golimumab if initial failure to the receptor fusion protein, etanercept (choice of TNFi at investigator’s discretion)
    Arm type
    Experimental

    Investigational medicinal product name
    Etanercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen, Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Etanercept was administered at either a dose of 50mg by subcutaneous injection per week or as two 25mg injections per week for a minimum of 24 weeks (unless not tolerated). For participants who were responding to treatment at week 24, treatment was continued following the same regimen until week 48. Following week 48 treatment was at the discretion of the treating clinician.

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen, Solution for injection/infusion, Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Adalimumab was given at a dose of 40mg by subcutaneous injection every 2 weeks for a minimum of 24 weeks (unless not tolerated). For participants who were responding to treatment at week 24 treatment was continued following the same regimen until week 48. Following week 48 treatment was at the discretion of the treating clinician.

    Investigational medicinal product name
    Certolizumab Pegol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen, Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Certolizumab pegol was given at a dose of 400mg by subcutaneous injection at weeks 0, 2, 4 and then at a dose of 200mg every 2 weeks thereafter for a minimum of 24 weeks. For participants who were responding to treatment at week 24 treatment was continued at the same 200mg every 2 weeks regimen until week 48. Following week 48 treatment was at the discretion of the treating clinician.

    Investigational medicinal product name
    Golimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection, Solution for injection in pre-filled pen, Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Golimumab will be given at a dose of 50mg by subcutaneous injection every 4 weeks for a minimum of 24 weeks. For participants who were responding to treatment at week 24 treatment was continued following the same regimen until week 48. Following week 48 treatment is at the discretion of the treating clinician.

    Investigational medicinal product name
    Infliximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Infliximab was given at a dose of 3mg/kg per intravenous infusion. The intravenous infusions were administered at week 0, 2 (+/- 2 days), 6 (+/- 2 days) and then 8-weekly thereafter (+/- 7 days) for a minimum of 24 weeks. For participants who were responding to treatment at week 24 treatment was continued at the same 8-weekly regimen until week 48. Following week 48 treatment was at the discretion of the treating clinician.

    Arm title
    Abatacept
    Arm description
    Subcutaneous abatacept. Dose=125mg at week 0 and then once a week thereafter for a minimum of 24 weeks. Trial specific supplies were provided by Bristol Myers Squibb.
    Arm type
    Experimental

    Investigational medicinal product name
    abatacept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Abatacept was given at a dose of 125 mg by subcutaneous injection at week 0 and once weekly thereafter for a minimum of 24 weeks. For participants who are responding to treatment at week 24 treatment will continue following the same regimen until week 48. Following week 48 treatment is at the discretion of the treating clinician.

    Arm title
    Rituximab
    Arm description
    Rituximab IV at weeks 0 and 2, and then at weeks 24 and 26 if necessary.
    Arm type
    Active comparator

    Investigational medicinal product name
    rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab will be given at a dose of 1g; 2 intravenous infusions will be administered at days 0 (week 0) and 15 (week 2; +5 days). In line with standard practice, a participant who loses an initial 6 month (week 24) response as per NICE guidance may receive a further cycle of rituximab after a minimum of 6 months following the first dose. The second cycle of rituximab will be given at a dose of 1g; 2 intravenous infusions will be administered at a 2 week interval (+5 days) e.g. week 24 and 26 (+5 days). Subsequent treatment following week 48 will be at the discretion of the treating clinician. Prior to receiving rituximab, intravenous methylprednisolone 100mg will also be given.

    Number of subjects in period 1
    Alternative mechanism TNFi Abatacept Rituximab
    Started
    41
    41
    40
    Completed
    31
    34
    31
    Not completed
    10
    7
    9
         Death
    -
    1
    1
         Trial termination
    4
    3
    4
         Physician decision
    2
    1
    3
         Consent withdrawn by subject
    2
    1
    -
         Lost to follow-up
    2
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Alternative mechanism TNFi
    Reporting group description
    a. Etanercept if initial failure to a monoclonal antibody: infliximab, adalimumab, certolizumab or golimumab OR b. Infliximab, adalimumab, certolizumab or golimumab if initial failure to the receptor fusion protein, etanercept (choice of TNFi at investigator’s discretion)

    Reporting group title
    Abatacept
    Reporting group description
    Subcutaneous abatacept. Dose=125mg at week 0 and then once a week thereafter for a minimum of 24 weeks. Trial specific supplies were provided by Bristol Myers Squibb.

    Reporting group title
    Rituximab
    Reporting group description
    Rituximab IV at weeks 0 and 2, and then at weeks 24 and 26 if necessary.

    Reporting group values
    Alternative mechanism TNFi Abatacept Rituximab Total
    Number of subjects
    41 41 40 122
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    36 27 27 90
        From 65-84 years
    5 14 13 32
        85 years and over
    0 0 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    56.9 (45.5 to 59.8) 60.5 (45.2 to 66.9) 57 (52.4 to 67.4) -
    Gender categorical
    Units: Subjects
        Female
    33 39 30 102
        Male
    8 2 10 20
    Disease Duration Category
    Units: Subjects
        < 5 years
    16 15 14 45
        ≥5 years
    25 26 26 77
    Rheumatoid Factor / Anti-citrullinated protein antibody status
    Units: Subjects
        RF seropositive or ACPA positive
    36 31 33 100
        Both RF seronegative and ACPA negative
    5 10 7 22
    Non-Response category
    Units: Subjects
        Primary
    15 15 15 45
        Secondary
    26 26 25 77
    Smoking status
    Units: Subjects
        Non-smoking (Never smoked)
    12 17 21 50
        Past smoker
    18 13 11 42
        Current smoker
    11 11 8 30
    Previous TNFi agent
    Units: Subjects
        Adalimumab
    10 10 8 28
        Certolizumab pegol
    11 9 5 25
        Etanercept
    16 18 18 52
        Golimumab
    2 0 4 6
        Infliximab
    2 4 5 11
    Disease Duration
    Years between Rheumatoid Arthritis diagnosis and randomisation.
    Units: Years
        median (inter-quartile range (Q1-Q3))
    5.9 (3.9 to 12.3) 6.9 (4 to 15.4) 7 (3.9 to 15.6) -
    Body Mass Index
    Units: Kg/m2
        median (inter-quartile range (Q1-Q3))
    28.7 (25 to 34) 28.4 (24.3 to 34.5) 29 (25.4 to 33.5) -
    Subject analysis sets

    Subject analysis set title
    Intention-to-treat
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All patients randomised

    Subject analysis set title
    Per-protocol population
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Patients who deviated from the protocol or failed to comply with the required treatment regimen were excluded from the per-protocol population. Analysis was conducted by treatment received

    Subject analysis sets values
    Intention-to-treat Per-protocol population
    Number of subjects
    122
    41
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    90
    31
        From 65-84 years
    32
    10
        85 years and over
    0
    0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    57.3 (46.7 to 65.4)
    57.7 (45.6 to 64.7)
    Gender categorical
    Units: Subjects
        Female
    20
    30
        Male
    102
    11
    Disease Duration Category
    Units: Subjects
        < 5 years
    45
    11
        ≥5 years
    77
    30
    Rheumatoid Factor / Anti-citrullinated protein antibody status
    Units: Subjects
        RF seropositive or ACPA positive
    100
    33
        Both RF seronegative and ACPA negative
    22
    8
    Non-Response category
    Units: Subjects
        Primary
    45
    18
        Secondary
    77
    23
    Smoking status
    Units: Subjects
        Non-smoking (Never smoked)
    50
    16
        Past smoker
    42
    15
        Current smoker
    30
    10
    Previous TNFi agent
    Units: Subjects
        Adalimumab
    28
    9
        Certolizumab pegol
    25
    9
        Etanercept
    52
    16
        Golimumab
    6
    2
        Infliximab
    11
    5
    Disease Duration
    Years between Rheumatoid Arthritis diagnosis and randomisation.
    Units: Years
        median (inter-quartile range (Q1-Q3))
    6.7 (3.9 to 14.2)
    8 (4.4 to 14.3)
    Body Mass Index
    Units: Kg/m2
        median (inter-quartile range (Q1-Q3))
    29 (24.9 to 34.1)
    29 (25.3 to 34.9)

    End points

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    End points reporting groups
    Reporting group title
    Alternative mechanism TNFi
    Reporting group description
    a. Etanercept if initial failure to a monoclonal antibody: infliximab, adalimumab, certolizumab or golimumab OR b. Infliximab, adalimumab, certolizumab or golimumab if initial failure to the receptor fusion protein, etanercept (choice of TNFi at investigator’s discretion)

    Reporting group title
    Abatacept
    Reporting group description
    Subcutaneous abatacept. Dose=125mg at week 0 and then once a week thereafter for a minimum of 24 weeks. Trial specific supplies were provided by Bristol Myers Squibb.

    Reporting group title
    Rituximab
    Reporting group description
    Rituximab IV at weeks 0 and 2, and then at weeks 24 and 26 if necessary.

    Subject analysis set title
    Intention-to-treat
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All patients randomised

    Subject analysis set title
    Per-protocol population
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Patients who deviated from the protocol or failed to comply with the required treatment regimen were excluded from the per-protocol population. Analysis was conducted by treatment received

    Primary: Absolute reduction in DAS28 at 24 weeks post randomisation

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    End point title
    Absolute reduction in DAS28 at 24 weeks post randomisation
    End point description
    Endpoint description: DAS28 is a measure of disease activity in RA. The composite score is calculated as a function of the number of tender and swollen joints (total 28 joints), the erythrocyte sedimentation rate (ESR) and the patient’s global assessment of their arthritis measured - Tender Joint Count (TJC: Range 0-28) - Swollen Joint Count (SJC: Range 0-28) - Erythrocyte Sedimentation Rate (ESR: Range 0-99) - Patient-completed Visual Analogue Scale of Global Assessment of Arthritis With these four items, the DAS28 score is calculated in the following manner: DAS28=(0.56×√TJC)+(0.28×√SJC)+(0.7×log[e] ESR)+(0.014×VAS(mm)) Where log[e] is the natural logarithm function.
    End point type
    Primary
    End point timeframe
    Baseline to 24 weeks post randomisation
    End point values
    Alternative mechanism TNFi Abatacept Rituximab
    Number of subjects analysed
    41 [1]
    41 [2]
    40 [3]
    Units: units
        arithmetic mean (standard deviation)
    1.4 ± 1.28
    1.2 ± 1.72
    1.3 ± 1.94
    Notes
    [1] - Prior to multiple imputation of missing values, 36/41 patients had complete data at weeks 0 and 24.
    [2] - Prior to multiple imputation of missing values, 34/41 patients had complete data at weeks 0 and 24.
    [3] - Prior to multiple imputation of missing values, 32/40 patients had complete data at weeks 0 and 24.
    Statistical analysis title
    Primary endpoint analysis (ITT - TNFi vs RTX)
    Statistical analysis description
    Mixed-effects linear regression model. Outcome: Reduction in DAS28 between Weeks 0 and 24. Adjusted for covariates used to balance the randomisation system: disease duration category, RF/ACPA seropositivity category and Primary/Secondary Non-response category (all as fixed effects) and randomising centre (random effect). Same model fit to all fully-imputed datasets, resulting parameter estimates combined by Rubin's rules. Non-Inferiority concluded if 95% CI lies wholly above NI margin of -0.6.
    Comparison groups
    Alternative mechanism TNFi v Rituximab
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [4]
    P-value
    = 0.0094 [5]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.45
         upper limit
    1.05
    Notes
    [4] - Non-inferiority margin: -0.6 units of DAS28 score. Position of 2-sided 95% confidence interval judged in relation to margin. If 2-sided interval lies wholly above -0.6, NI conclusion reached in ITT population (must be matched by similar conclusion in Per-protocol population). If 2-sided interval lies wholly above 0, superiority conclusion reached in ITT population.
    [5] - One-sided P-Value, corresponding to a one-sided 97.5% test, using non-inferiority margin of -0.6. Must be less than 0.025 to conclude non-inferiority to rituximab. Per-Protocol population P-value=0.489; non-inferiority to rituximab not demonstrated
    Statistical analysis title
    Primary endpoint analysis (ITT - ABT vs RTX)
    Statistical analysis description
    Mixed-effects linear regression model. Outcome: Reduction in DAS28 between Weeks 0 and 24. Adjusted for covariates used to balance the randomisation system: disease duration category, RF/ACPA seropositivity category and Primary/Secondary Non-response category (all as fixed effects) and randomising centre (random effect). Same model fit to all fully-imputed datasets, resulting parameter estimates combined by Rubin's rules. Non-Inferiority concluded if 95% CI lies wholly above NI margin of -0.6.
    Comparison groups
    Abatacept v Rituximab
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [6]
    P-value
    = 0.0493 [7]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.72
         upper limit
    0.79
    Notes
    [6] - Non-inferiority margin: -0.6 units of DAS28 score. Position of 2-sided 95% confidence interval for (abatacept - rituximab) judged in relation to margin. If 2-sided interval lies wholly above -0.6, Non-inferiority conclusion reached in ITT population (must be matched by similar conclusion in Per-protocol population). If 2-sided interval lies wholly above 0, superiority conclusion reached in ITT population.
    [7] - One-sided P-Value, corresponding to a one-sided 97.5% test, using non-inferiority margin of -0.6. Must be less than 0.025 to conclude non-inferiority to rituximab. Per-Protocol Population P-value=0.216; non-inferiority to rituximab not demonstrated.

    Secondary: ACR20 Response at 24 weeks

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    End point title
    ACR20 Response at 24 weeks
    End point description
    The ACR20 (American College of Rheumatology) response criterion is a composite endpoint. To achieve response, a patient must achieve between baseline and 24 weeks: 20% reduction in Tender Joint Counts and 20% reduction in Swollen Joint Counts and 20% reduction in 3 of the following 5 criteria: Patient-completed Pain VAS (Range 0-100mm) Patient-completed general health VAS (Range 0-100mm) Patient-completed assessment of disability (HAQ-DI, Range 0-3) Physician-completed assessment of disease activity (Range 0-100mm) Either C-reactive Protein or Erythrocyte Sedimentation Rate measure.
    End point type
    Secondary
    End point timeframe
    From baseline to 24 weeks.
    End point values
    Alternative mechanism TNFi Abatacept Rituximab
    Number of subjects analysed
    41 [8]
    41 [9]
    40 [10]
    Units: Number of patients responding
        Achieved ACR20 Response
    16
    11
    10
        Non-Response
    20
    24
    27
    Notes
    [8] - Prior to multiple imputation of missing values, 36/41 patients had complete data for ACR Response.
    [9] - Prior to multiple imputation of missing data, 35/41 patients had complete data for ACR20 Response.
    [10] - Prior to multiple imputation of missing data, 37/40 patients had complete data for ACR20 Response.
    Statistical analysis title
    ACR20 Response at 24 weeks (ITT - TNFi v RTX)
    Statistical analysis description
    Fixed-effects logistic regression model. Outcome: ACR20 Response at week 24. Adjusted for covariates used to balance the randomisation system: disease duration category, RF/ACPA seropositivity category and Primary/Secondary Non-response category (all as fixed effects). Randomising centre not fitted due to non-convergence. Same model fit to all fully-imputed datasets, resulting parameter estimates combined by Rubin's rules. ITT analysis population.
    Comparison groups
    Alternative mechanism TNFi v Rituximab
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.15 [11]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.77
         upper limit
    5.53
    Notes
    [11] - 2-sided P-Value for null hypothesis that ACR20 response rates at 24 weeks are equal.
    Statistical analysis title
    ACR20 Response at 24 weeks (ITT - ABT v RTX)
    Statistical analysis description
    Fixed-effects logistic regression model. Outcome: ACR20 Response at week 24. Adjusted for covariates used to balance the randomisation system: disease duration category, RF/ACPA seropositivity category and Primary/Secondary Non-response category (all as fixed effects). Randomising centre not fitted due to non-convergence. Same model fit to all fully-imputed datasets, resulting parameter estimates combined by Rubin's rules. ITT analysis population.
    Comparison groups
    Abatacept v Rituximab
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.736
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    3.21

    Secondary: DAS28 Score

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    End point title
    DAS28 Score
    End point description
    For a description of the derivation of the DAS28 score, please refer to description given under Primary Endpoint. NB: Values of mean and Std dev given here are at Week 48.
    End point type
    Secondary
    End point timeframe
    Baseline to 48 weeks. Measured at baseline, weeks 12, 24, 36 and 48.
    End point values
    Alternative mechanism TNFi Abatacept Rituximab
    Number of subjects analysed
    41 [12]
    41 [13]
    40 [14]
    Units: Units of DAS28
        arithmetic mean (standard deviation)
    4.1 ± 1.58
    4.8 ± 1.24
    4.8 ± 1.42
    Notes
    [12] - Prior to multiple imputation of missing data, 26/41 patients had complete data at all timepoints.
    [13] - Prior to multiple imputation of missing data, 24/41 patients had complete data at all timepoints.
    [14] - Prior to multiple imputation of missing data, 21/40 patients had complete data at all timepoints.
    Statistical analysis title
    DAS28 Score (ITT TNFi vs RTX)
    Statistical analysis description
    Mixed-effects linear regression model. Outcome: DAS28 over 48 weeks. Adjusted for covariates used to balance the randomisation system (except for centre) and additionally baseline DAS28. Treatment, Time and Time-by-treatment effects fitted as fixed effects. Within-patient correlation in outcomes modelled using unstructured covariance pattern-model. Values reported are differences at 48 weeks. P-Values for interaction between trt-time are P=0.338 (24weeks), P=0.071 (36 weeks), P=0.552 (48 weeks).
    Comparison groups
    Alternative mechanism TNFi v Rituximab
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.249
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.04
         upper limit
    0.27
    Statistical analysis title
    DAS28 Score (ITT - ABT vs RTX)
    Statistical analysis description
    Mixed-effects linear regression model. Outcome: DAS28 over 48 weeks. Adjusted for covariates used to balance the randomisation system (except for centre) and additionally baseline DAS28. Treatment, Time and Time-by-treatment effects fitted as fixed effects. Within-patient correlation in outcomes modelled using unstructured covariance pattern-model. Values reported are differences at 48 weeks. P-Values for interaction between trt-time are P=0.976 (24weeks), P=0.871 (36 weeks), P=0.755 (48 weeks).
    Comparison groups
    Abatacept v Rituximab
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.859
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.59
         upper limit
    0.71

    Secondary: DAS28 Response

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    End point title
    DAS28 Response
    End point description
    Response defined as the achievement of a reduction in DAS28 of 1.2 or more (ie a change of -1.2 or less) since baseline. NB: The reported number of patients responding given here are for Week 48.
    End point type
    Secondary
    End point timeframe
    Baseline to 48 weeks. DAS28 measured at baseline, 12, 24, 36 and 48 weeks.
    End point values
    Alternative mechanism TNFi Abatacept Rituximab
    Number of subjects analysed
    41 [15]
    41 [16]
    40 [17]
    Units: Number of patients responding
        Response (DAS28 reduced by 1.2 or more)
    19
    18
    13
        Non-Response
    11
    12
    10
    Notes
    [15] - Prior to multiple imputation of missing data, 26/41 patients had complete data at all timepoints.
    [16] - Prior to multiple imputation of missing data, 24/41 patients had complete data at all timepoints.
    [17] - Prior to multiple imputation of missing data, 21/40 patients had complete data at all timepoints.
    Statistical analysis title
    DAS28 Response over 48 weeks (ITT - TNFi vs RTX)
    Statistical analysis description
    Mixed-effects logistic regression model. Outcome: Response over 48 weeks. Adjusted for covariates used to balance the randomisation system (except for centre) and additionally baseline DAS28. Treatment, Time and Time-by-treatment effects fitted as fixed effects. Within-patient correlation in outcomes modelled using unstructured covariance pattern-model. Values reported are ORs at 48 weeks. P-Values for interaction between trt-time are P=0.116 (24weeks), P=0.327 (36weeks), P=0.699 (48weeks).
    Comparison groups
    Alternative mechanism TNFi v Rituximab
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.543
    Method
    Mixed models analysis
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.47
         upper limit
    4.19
    Statistical analysis title
    DAS28 Response over 48 weeks (ITT - ABT vs RTX)
    Statistical analysis description
    Mixed-effects logistic regression model. Outcome: Response over 48 weeks. Adjusted for covariates used to balance the randomisation system (except for centre) and additionally baseline DAS28. Treatment, Time and Time-by-treatment effects fitted as fixed effects. Within-patient correlation in outcomes modelled using unstructured covariance pattern-model. Values reported are ORs at 48 weeks. P-Values for interaction between trt-time are P=0.930 (24weeks), P=0.888 (36weeks), P=0.675 (48weeks).
    Comparison groups
    Abatacept v Rituximab
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.869
    Method
    Mixed models analysis
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.3
         upper limit
    2.73

    Secondary: HAQ-DI

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    End point title
    HAQ-DI
    End point description
    HAQ-DI questionnaire (See: Pincus T, Summey JA, Soraci SA, et al. Assessment of patient satisfaction in activities of daily living using a modified stanford health assessment questionnaire. Arthritis & Rheumatism. 1983;26(11):1346-53.). Patients respond to 20 questions across 8 domains relating to physical function, and the need for any help or aids to undertake daily activities. The extent of disability is scored from 0 (no disability) to 3 (severe disability) for each item relating to rising, dressing, walking and other activities. The use of help or aids increases the category score from 0 or 1 to a 2. If the category score is already a 2 or 3, no adjustment is made. The total score is derived by taking the maximum score across all domains and dividing by 8 to provide an average score in the range 0-3. NB: the median and IQR given here corresponds to Week 48
    End point type
    Secondary
    End point timeframe
    HAQ-DI questionnaire completed by the patient at baseline and weeks 12, 24, 36, 48.
    End point values
    Alternative mechanism TNFi Abatacept Rituximab
    Number of subjects analysed
    30
    34
    30
    Units: Units of HAQDI
        median (inter-quartile range (Q1-Q3))
    1.5 (1.1 to 1.9)
    1.6 (1 to 2.1)
    1.7 (1.1 to 2.1)
    No statistical analyses for this end point

    Secondary: RAQOL

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    End point title
    RAQOL
    End point description
    See de Jong Z, van der Heijde D, McKenna SP, Whalley D. The reliability and construct validity of the RAQoL: a rheumatoid arthritis-specific quality of life instrument. Rheumatology. 1997 August 1, 1997;36(8):878-83. Thirty item questionnaire, each item having a Yes (score as 1) / No (score as 0) response to ascertain the extent of rheumatoid arthritis symptoms experienced, maximum score 30. NB: the median and IQR given here corresponds to Week 48
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 12, 24, 36, 48.
    End point values
    Alternative mechanism TNFi Abatacept Rituximab
    Number of subjects analysed
    30
    34
    30
    Units: Units of RAQoL
        median (inter-quartile range (Q1-Q3))
    19 (9 to 23)
    17.5 (11.4 to 24)
    19.5 (12 to 25)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    All AEs/ARs and SAEs were monitored from randomisation until a minimum of 30 days* post last dose of randomised treatment during the interventional phase (week 48 max). Monitoring for SARs and SUSARs continued during the observational phase (week 96 max).
    Adverse event reporting additional description
    At each clinical assessment visit (weeks 12, 24, 36, 48) patients were asked to reported adverse events. Serious Adverse Events, Serious Adverse Reactions and Suspected Unexpected Serious Adverse Reactions were subject to expedited reporting.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Alternative TNFi
    Reporting group description
    All participants randomised to receive alternative TNFi. One participant was withdrawn prior to receiving any IMP due to eligibility randomisation, this patient reported no Adverse Events.

    Reporting group title
    Abatacept
    Reporting group description
    All participants randomised to abatacept. All participants received at least one injection of abatacept.

    Reporting group title
    Rituximab
    Reporting group description
    All patients randomised to receive rituximab. All participants received at least one infusion of rituximab.

    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: Leeds Institute of Clinical Trials Research is an academic trials unit where full MedDRA coding is not the standard. It has therefore not been possible for adverse event data to be accurately entered into the full data view within EudraCT as all mandatory categories cannot be completed.
    Serious adverse events
    Alternative TNFi Abatacept Rituximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 40 (2.50%)
    4 / 41 (9.76%)
    4 / 40 (10.00%)
         number of deaths (all causes)
    0
    1
    1
         number of deaths resulting from adverse events
    0
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant Melanoma
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Left Basal Pneumonia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Epigastric chest pain
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 41 (0.00%)
    0 / 40 (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
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flare of Rheumatoid Arthritis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Collapse, broken coccyx
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         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
    Pneumonia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Chest Infection
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Alternative TNFi Abatacept Rituximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Mar 2012
    Inclusion of the option for subcutaneous IMPs to be sourced and delivered to participants homes by a third party home healthcare providers as per local hospital practice.
    01 Mar 2012
    Amendment from intravenous formulation of abatacept to subcutaneous formulation following agreement from manufacturers of abatacept to provide trial supplies. This also required changes to other documentation to i) include a further vendor responsible for packaging and labelling of the abatacept trial supplies and ii) amend wording on the labels for sub-cutaneous abatacept.
    06 Mar 2012
    Wording added to the label for subcutaneous abatacept as requested by Bristol Myers Squibb (the manufacturers of abatacept).
    29 May 2012
    Addition of Almac Limited as the responsible party for the packaging, labelling and batch release of abatacept. Also, addition of trial identifier (the word 'SWITCH') to the already approved label for abatacept.
    15 May 2013
    Clarification included in the proptocol that where local practice indicates the use of a home healthcare provider for the delivery of subcutaneous IMPs, the trial procedures will map onto the established, standard care practices in place at each individual site in terms of services and record keeping and retention requirements.
    09 Oct 2013
    Approval was obtained for a letter to provide to participants that explained a discrepancy between the expiry date given on the internal and external packaging of abatacept. Amendment was submitted to ethics committee only as competent authority
    09 Oct 2013
    Addition of a Patient Advert designed to advertise the trial directly to patients, with the intention that sites display the patient advert in patient waiting rooms etc. In addition, information contained within the advert was intended to be used via various means e.g. patient websites, e-bulletins, social media for the purpose of advertising the trial to the wider rheumatoid arthritis community. Submitted to Main Research Ethics Committee only as related only to information to be provided to the participant.
    10 Dec 2013
    Addition of golimumab to alternative mechanism TNFi arm following feedback from sites that use of golimumab was becoming more commonplace and therefore the ability to use this may expand the field of potential patients/increase pragmatism of study/would reflect standard practice more closely.
    10 Dec 2013
    Modification of the primary endpoint from a dichotomous endpoint (whether or not the patient achieved a reduction of greater than 1.2 units in DAS28 with no toxicity) to a continuous endpoint (change in DAS28 score).
    02 May 2014
    R&D form amended to enable the use of Participant Identification Centres in order to identify further participants. Submitted to Main Research Ethics Committee only.
    16 May 2014
    Corrections of errors noted in the Research Ethics Committee form and the Patient Information Sheet relating to the amount of radiation patients would be exposed to as part of the imaging aspects of the study. Submitted to Main Research Ethics Committee only as related to information provided on the Patient Information Sheet.
    08 Aug 2014
    A Participant Information Summary Sheet was created to summarise and complement the main Participant Information Sheet & Informed Consent Document before the patient reads the main Participant Information Sheet and Informed Consent Form following feedback from patient and public involvement representatives that the current Participant Information Sheet and Informed Consent Form was lengthy and a supplementary summary sheet would be beneficial. Submitted to Main Research Ethics Committee only as related to information provided on the Patient Information Sheet.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    02 Dec 2014
    A temporary halt to recruitment was necessary following the withdrawal of funding by the NIHR Health Technologies Assessment programme. The halt was considered temporary at the time as the Chief Investigator sought alternative sources of funding. This was submitted as a Substantial Amendment to the Medicines and Healthcare Products Regulatory Authority and the Main Research Ethics Committee on 16th December 2014 and approvals received on 9th January 2015 and 30th December 2014 respectively. Unfortunately, discussions to secure an alternative funding source were not successful and the need for a permanent halt was conveyed to participating sites on 9th February 2015. This was followed by submission of a substantial amendment on 9th April 2015 to update the protocol accordingly .
    -

    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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