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    Clinical Trial Results:
    CareRA2020: Effectiveness of a combination of Methotrexate and a step down glucocorticoid regimen (COBRA-Slim) for remission induction in patients with early Rheumatoid Arthritis (RA), with or without fast access to 24 weeks of Tumor Necrosis Factor (TNF) blockade in insufficient responders, a randomised, multicenter, pragmatic trial.

    Summary
    EudraCT number
    		 2017-004054-41
    Trial protocol
    		 BE  
    Global end of trial date
    01 Jul 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    29 May 2024
    First version publication date
    19 Aug 2023
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    some clarification to be added to the database

    Trial information

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    Trial identification
    Sponsor protocol code
    KCE-16002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03649061
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospitals Leuven
    Sponsor organisation address
    herestraat 49, Leuven, Belgium, 3000
    Public contact
    Patrick Verschueren, University Hospitals Leuven, +32 1634 25 41, patrick.verschueren@uzleuven.be
    Scientific contact
    Patrick Verschueren, University Hospitals Leuven, +32 1634 25 41, patrick.verschueren@uzleuven.be
    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
    06 Jun 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Jul 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jul 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to compare in an early RA population with insufficient response (not achieving DAS28CRP≤3.2 within 32 weeks or DAS28CRP<2.6 at week 32) to COBRA-Slim remission induction, the long term effectiveness of accelerated access to a six-month course of anti-TNF therapy (etanercept) within a time window from week 8 up to week 32, versus further treatment adaptation according to the standard COBRA-Slim strategy.
    Protection of trial subjects
    This is a pragmatic trial rooted in daily practice. Patients were started on therapy based on the remission induction principle and were followed by the treat to target principle which means treatment adapatations were done whenever patients fail to comply with low disease activity as defined in the protocol. Patients in need for an adaptation, despite methotrexate (MTX) dose increase, during the remission induction phase of the treatment were eligible for randomisation according to the protocol. Patients rights were protected according to GCP-ICH, Belgian legislation and GDPR.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Mar 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 276
    Worldwide total number of subjects
    276
    EEA total number of subjects
    276
    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)
    215
    From 65 to 84 years
    60
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 284 participants were recruited between June 2018 and June 2020. Patients were recruited in 19 rheumatology centers in Belgium. Patients were recruited in different type of centers: university hospitals, general hospitals and private practices.

    Pre-assignment
    Screening details
    		 Of the 284 patients screened 276 were eligible for the trial. 122 met the criteria of early insufficient reponders to the initial proposed remission-induction regimen (Cobra-Slim). Of this last group 112 were randomised, however 2 were considered randomisation errors. 10 patients were eligible for randomisation, but were not randomised.

    Period 1
    Period 1 title
    Remission-induction phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Remission-induction
    Arm description
    		 All 276 patients started with a COBRA-Slim remission-induction regimen. Patients who fail to reach low disease activity between week 8 and 32, or remission at week 32, were early insufficient responders and considered eligible for randomisation. Of the 276 patients who entered the trial, 264 reached the end of the remission-induction phase (week 32). Of these patients, 112 were considered early insufficient responders and randomised, however 2 of them were considered randomisation-error and excluded from analysis. Subsequently 110 patients started the proposed randomised treatment regimen and were considered for analysis.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Remission-induction
    Started
    276
    Completed
    264
    Not completed
    12
         Consent withdrawn by subject
    3
         Physician decision
    5
         logistic reasons
    1
         revised diagnosis
    2
         Lost to follow-up
    1
    Period 2
    Period 2 title
    Insufficient responders
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard COBRA-Slim
    Arm description
    		 Addition of leflunomide 10mg per os (PO) daily to the standard COBRA-Slim remission induction regimen.
    Arm type
    		 Active comparator

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

    Arm title
    		 COBRA-Slim Bio-induction
    Arm description
    		 Addition of etanercept 50mg Sub-cutaneous (SC) weekly for 6 months to the standard COBRA-Slim remission induction regimen.
    Arm type
    		 Experimental

    Investigational medicinal product name
    etanercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    50mg SC weekly for a period of 6 months

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: During the remission-induction phase, the insufficient responders were identified. Only the insufficient responders were randomised in the next part of the trial.
    Number of subjects in period 2 [2] [3]
    		Standard COBRA-Slim COBRA-Slim Bio-induction
    Started
    55
    55
    Completed
    46
    46
    Not completed
    9
    9
         Adverse event, serious fatal
    1
    1
         Consent withdrawn by subject
    2
    1
         Physician decision
    2
    4
         logistic reasons
    2
    3
         Lost to follow-up
    2
    -
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: During the remission-induction phase, the insufficient responders were identified. Only the insufficient responders were randomised in the next part of the trial.
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: During the remission-induction phase, the insufficient responders were identified. Only the insufficient responders were randomised in the next part of the trial.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard COBRA-Slim
    Reporting group description
    		 Addition of leflunomide 10mg per os (PO) daily to the standard COBRA-Slim remission induction regimen.

    Reporting group title
    COBRA-Slim Bio-induction
    Reporting group description
    		 Addition of etanercept 50mg Sub-cutaneous (SC) weekly for 6 months to the standard COBRA-Slim remission induction regimen.

    Reporting group values
    		 Standard COBRA-Slim COBRA-Slim Bio-induction Total
    Number of subjects
    		 55 55 110
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 43 48 91
        From 65-84 years
    		 12 7 19
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.4 ( 13.1 ) 52.5 ( 12.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 41 38 79
        Male
    		 14 17 31
    Smoking
    Units: Subjects
        Never
    		 22 19 41
        Past
    		 14 13 27
        Current
    		 19 23 42
    RF/ACPA status
    Units: Subjects
        positive
    		 42 41 83
        negative
    		 13 14 27
    DAS28-CRP
    Disease activity score based on a 28 joint count and CRP value (mg/L)
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 5.4 ( 1.1 ) 5.2 ( 1.3 ) -
    disease duration
    Units: days
        median (inter-quartile range (Q1-Q3))
    		 7.0 (2.5 to 20.0) 7.0 (2.5 to 19.5) -

    End points

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    End points reporting groups
    Reporting group title
    Remission-induction
    Reporting group description
    		 All 276 patients started with a COBRA-Slim remission-induction regimen. Patients who fail to reach low disease activity between week 8 and 32, or remission at week 32, were early insufficient responders and considered eligible for randomisation. Of the 276 patients who entered the trial, 264 reached the end of the remission-induction phase (week 32). Of these patients, 112 were considered early insufficient responders and randomised, however 2 of them were considered randomisation-error and excluded from analysis. Subsequently 110 patients started the proposed randomised treatment regimen and were considered for analysis.
    Reporting group title
    Standard COBRA-Slim
    Reporting group description
    		 Addition of leflunomide 10mg per os (PO) daily to the standard COBRA-Slim remission induction regimen.

    Reporting group title
    COBRA-Slim Bio-induction
    Reporting group description
    		 Addition of etanercept 50mg Sub-cutaneous (SC) weekly for 6 months to the standard COBRA-Slim remission induction regimen.

    Primary: Area under the curve (AUC) of DAS28CRP over 104 weeks.

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    End point title
    		 Area under the curve (AUC) of DAS28CRP over 104 weeks.
    End point description
    Long-term effectiveness.
    End point type
    Primary
    End point timeframe
    104 weeks (Baseline (BL) until week 104)
    End point values
    		 Standard COBRA-Slim COBRA-Slim Bio-induction
    Number of subjects analysed
    55
    55
    Units: units on a scale
        arithmetic mean (confidence interval 95%)
    297.4 (277.1 to 317.7)
    300.7 (282.3 to 319.1)
    Statistical analysis title
    		 Area under the Curve (AUC) over 104 weeks
    Statistical analysis description
    To compare the two randomisation groups, a linear mixed model with DAS28-CRP as outcome (Bell et al. 2014), including random intercepts per patient, adjusted for baseline DAS28-CRP, randomisation timepoint, and RF and/or ACPA seropositivity was used. Superiority of COBRA-Slim Bio-induction compared to Standard COBRA-Slim in terms of disease control over 2 years could not be demonstrated (ß = -0.204, 95% CI [-0.486 to 0.078], p = 0.157).
    Comparison groups
    Standard COBRA-Slim v COBRA-Slim Bio-induction
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Proportion of insufficient responders achieving DAS28CRP remission 28 weeks after randomisation

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    End point title
    		 Proportion of insufficient responders achieving DAS28CRP remission 28 weeks after randomisation
    End point description
    Short-time efficacy.
    End point type
    Secondary
    End point timeframe
    Randomisation until 28 weeks after randomisation.
    End point values
    		 Standard COBRA-Slim COBRA-Slim Bio-induction
    Number of subjects analysed
    55
    55
    Units: procent
    44
    59
    Statistical analysis title
    		 short time efficacy
    Statistical analysis description
    To obtain this outcome, a binomial generalized linear mixed effect model for repeated measures of remission from randomisation up until 28 weeks after was carried out, adjusted for baseline DAS28-CRP, moment of randomisation, and RF and/or ACPA seropositivity. Patients in the COBRA-Slim Bio-induction group had a significantly higher odds of reaching DAS28-CRP remission during 28 weeks after randomisation compared to the Standard COBRA-Slim group (Odds ratio 2.06 (95% CI 1.20-3.56), p=0.009).
    Comparison groups
    Standard COBRA-Slim v COBRA-Slim Bio-induction
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Proportion of patients in remission (DAS28CRP<2.6) at week 104

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    End point title
    		 Proportion of patients in remission (DAS28CRP<2.6) at week 104
    End point description
    Proportion of patients achieving DAS28CRP<2.6 at the end of the trial (week 104).
    End point type
    Secondary
    End point timeframe
    week 104
    End point values
    		 Standard COBRA-Slim COBRA-Slim Bio-induction
    Number of subjects analysed
    55
    55
    Units: procent
        number (confidence interval 95%)
    69 (55 to 81)
    55 (40 to 68)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected over a two year period per patient (BL-week 104).
    Adverse event reporting additional description
    In the CareRA2020 trial, adverse events were collected if they were related to RA, the RA treatment, or in case of an event of special interest. All adverse events were registered by health care professionals questioning the patients at each visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Standard COBRA-Slim
    Reporting group description
    		 addition of leflunomide to the standard COBRA-Slim remission induction regimen

    Reporting group title
    COBRA-Slim Bio-induction
    Reporting group description
    		 addition of etanercept for 6 months to the standard COBRA-Slim remission induction regimen

    Serious adverse events
    		 Standard COBRA-Slim COBRA-Slim Bio-induction
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 55 (7.27%)
    5 / 55 (9.09%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    1
    1
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac disorders
    Myocardial ischaemia
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychiatric decompensation
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Enterococcal sepsis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Standard COBRA-Slim COBRA-Slim Bio-induction
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 55 (78.18%)
    47 / 55 (85.45%)
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 55 (0.00%)
    4 / 55 (7.27%)
         occurrences all number
    0
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 55 (1.82%)
    3 / 55 (5.45%)
         occurrences all number
    1
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    12 / 55 (21.82%)
    13 / 55 (23.64%)
         occurrences all number
    12
    13
    Injection site erythema
         subjects affected / exposed
    1 / 55 (1.82%)
    3 / 55 (5.45%)
         occurrences all number
    1
    3
    Pyrexia
         subjects affected / exposed
    0 / 55 (0.00%)
    4 / 55 (7.27%)
         occurrences all number
    0
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    8 / 55 (14.55%)
    14 / 55 (25.45%)
         occurrences all number
    11
    17
    Abdominal discomfort
         subjects affected / exposed
    5 / 55 (9.09%)
    6 / 55 (10.91%)
         occurrences all number
    5
    6
    Diarrhoea
         subjects affected / exposed
    10 / 55 (18.18%)
    6 / 55 (10.91%)
         occurrences all number
    11
    7
    Abdominal pain upper
         subjects affected / exposed
    4 / 55 (7.27%)
    4 / 55 (7.27%)
         occurrences all number
    4
    5
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 55 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    0
    3
    Dyspepsia
         subjects affected / exposed
    3 / 55 (5.45%)
    2 / 55 (3.64%)
         occurrences all number
    3
    2
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    14 / 55 (25.45%)
    9 / 55 (16.36%)
         occurrences all number
    18
    12
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    6 / 55 (10.91%)
    6 / 55 (10.91%)
         occurrences all number
    6
    6
    Acne
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 55 (1.82%)
         occurrences all number
    4
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 55 (1.82%)
         occurrences all number
    3
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 55 (7.27%)
    3 / 55 (5.45%)
         occurrences all number
    4
    4
    COVID-19
         subjects affected / exposed
    2 / 55 (3.64%)
    6 / 55 (10.91%)
         occurrences all number
    2
    6
    Bronchitis
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 55 (1.82%)
         occurrences all number
    4
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Feb 2019
    addition of 5 extra sites to the protocol
    13 May 2019
    change in investigator at site 014
    09 Jul 2019
    addition of 1 extra site to the protocol
    17 Apr 2020
    to add measurements to cover COVID19 pandemic
    19 Aug 2020
    change in investigator at site005

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

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