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Effectiveness in Daily Practice of Different Treatment Strategies for Early Rheumatoid Arthritis.

Sponsor
P. Verschueren (Other)
Overall Status
Completed
CT.gov ID
NCT01172639
Collaborator
Agentschap voor Innovatie door Wetenschap en Technologie (Other)
400
Enrollment
17
Locations
5
Arms
75.9
Duration (Months)
23.5
Patients Per Site
0.3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The Combinatietherapie Bij Reumatoide Artritis (CoBRA) trial was a milestone in the development of the present treatment paradigm for Rheumatoid Arthritis (RA). This study introduced the principle of fast remission induction by means of a combination of standard Disease Modifying AntiRheumatic Drugs (DMARDs) and a step down bridge therapy with high dose glucocorticoids in early Rheumatoid Arthritis.

The purpose of the present study is to compare different combinations of traditional DMARDs and glucocorticoids, based on the original CoBRA protocol, for treatment of early Rheumatoid Arthritis.

Besides the efficacy and effectiveness of these strategies, patient centered outcomes and potential implementation problems of such treatment strategies are evaluated.

Condition or Disease Intervention/Treatment Phase
Phase 4

Study Design

Study Type:
Interventional
Actual Enrollment :
400 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
Before randomisation patients were stratified to a high-risk or low-risk group according to the presence of risk factors at screening (having erosions, rheumatoid factor and/or anticitrullinated protein antibody and a high disease activity score calculated with C-reactive protein (DAS28-CRP)). Randomisation to treatment arms was performed via a digitally generated sequence. Patients in the high-risk group were randomised into CoBRA Classic, Clim or Avant-Garde arm. Patients in the low-risk group were randomised into CoBRA Slim or Tight Step Up arm.Before randomisation patients were stratified to a high-risk or low-risk group according to the presence of risk factors at screening (having erosions, rheumatoid factor and/or anticitrullinated protein antibody and a high disease activity score calculated with C-reactive protein (DAS28-CRP)). Randomisation to treatment arms was performed via a digitally generated sequence. Patients in the high-risk group were randomised into CoBRA Classic, Clim or Avant-Garde arm. Patients in the low-risk group were randomised into CoBRA Slim or Tight Step Up arm.
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A 2 Year Prospective Multicentre Randomised Controlled Trial Comparing Effectiveness in Daily Practice of Different Treatment Strategies for Early Rheumatoid Arthritis.
Study Start Date :
Feb 1, 2009
Actual Primary Completion Date :
Jun 1, 2015
Actual Study Completion Date :
Jun 1, 2015

Arms and Interventions

Arm Intervention/Treatment
Other: CoBRA classic high risk group

Methotrexate 15mg tablet by mouth, weekly for entire trial Sulfasalazine 2g tablet by mouth, daily for 40 weeks Prednisone tablet by mouth, weekly step down scheme 60 - 40 - 25 - 20 - 15 - 10 mg daily for 6 weeks, followed by 7.5mg daily till week 28, then further tapered down to stop at week 32

Drug: Methotrexate
Methotrexate tablet
Other Names:
  • Ledertrexate

    • Drug: Sulfasalazine
    Sulfasalazine tablet
    Other Names:
  • Salazopyrine

    • Drug: Prednisone
    Prednisone tablet
    Other: CoBRA slim high risk group

    Methotrexate 15mg tablet by mouth, weekly for entire trial Prednisone tablet by mouth, weekly step down scheme 30 - 20 - 12.5 - 10 - 7.5 mg daily for 5 weeks, followed by 5mg daily till week 28, then further tapered down to stop at week 32

    Drug: Methotrexate
    Methotrexate tablet
    Other Names:
  • Ledertrexate

    • Drug: Prednisone
    Prednisone tablet
    Other: CoBRA avant-garde high risk group

    Methotrexate 15mg tablet by mouth, weekly for 40 weeks (continued for entire trial if randomized to Methotrexate monotherapy at week 40) Leflunomide 10mg tablet by mouth, daily for 40 weeks (continued for entire trial if randomized to Leflunomide monotherapy at week 40) Prednisone tablet by mouth, weekly step down scheme 30 - 20 - 12.5 - 10 - 7.5 mg daily for 5 weeks, followed by 5mg daily till week 28, then further tapered down to stop at week 32

    Drug: Methotrexate
    Methotrexate tablet
    Other Names:
  • Ledertrexate

    • Drug: Leflunomide
    Leflunomide tablet
    Other Names:
  • Arava

    • Drug: Prednisone
    Prednisone tablet
    Other: CoBRA slim low risk group

    Methotrexate 15mg tablet by mouth, weekly for entire trial Prednisone tablet by mouth, weekly step down scheme 30 - 20 - 12.5 - 10 - 7.5 mg daily for 5 weeks, followed by 5mg daily till week 28, then further tapered down to stop at week 32

    Drug: Methotrexate
    Methotrexate tablet
    Other Names:
  • Ledertrexate

    • Drug: Prednisone
    Prednisone tablet
    Other: Tight Step Up low risk group

    Methotrexate 15mg tablet by mouth, weekly for entire trial No oral steroids allowed during the first year of the trial

    Drug: Methotrexate
    Methotrexate tablet
    Other Names:
  • Ledertrexate

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Remission According to DAS28-CRP at Week 16 [week 16]

      Number of patients in remission according to DAS28-CRP (Disease Activity Score based on 28 joint count and C-reactive Protein) at week 16. DAS28-CRP is calculated with the following formula : 0.56*SQRT TJC28+0.28*SQRT SJC28+0.36*ln (CRP+1)+0.014*GH+0.96 in which TJC is the tender joint count, SJC the Swollen Joint Count and GH the general health estimated by the patient on a Visual Analogue Scale (VAS). A value below 2.6 is indicating remission, below or equal to 3.2 low disease activity, between 3.2 and 5.1 moderate disease activity and above 5.1 high disease activity.

    2. Remission According to DAS28-CRP at Week 52 [week 52]

      Number of patients in remission according to DAS28-CRP (Disease Activity Score based on 28 joint count and C-reactive Protein) at week 52. (co-primary end point) DAS28-CRP is calculated with the following formula : 0.56*SQRT TJC28+0.28*SQRT SJC28+0.36*ln (CRP+1)+0.014*GH+0.96 in which TJC is the tender joint count, SJC the Swollen Joint Count and GH the general health estimated by the patient on a Visual Analogue Scale (VAS). A value below 2.6 is indicating remission, below or equal to 3.2 low disease activity, between 3.2 and 5.1 moderate disease activity and above 5.1 high disease activity.

    3. Remission According to DAS28-CRP at Week 104 [week 104]

      Number of patients in remission according to DAS28-CRP (Disease Activity Score based on 28 joint count and C-reactive Protein) at week 104. (co-primary endpoints) DAS28-CRP is calculated with the following formula : 0.56*SQRT TJC28+0.28*SQRT SJC28+0.36*ln (CRP+1)+0.014*GH+0.96 in which TJC is the tender joint count, SJC the Swollen Joint Count and GH the general health estimated by the patient on a Visual Analogue Scale (VAS). A value below 2.6 is indicating remission, below or equal to 3.2 low disease activity, between 3.2 and 5.1 moderate disease activity and above 5.1 high disease activity.

    Secondary Outcome Measures

    1. Remission According to SDAI (Simple Disease Activity Index) at Week 16 [week 16]

      Number of patients in remission according to SDAI (Simplified Disease Activity Index) at week 16. SDAI is calculated with the following formula : TJC28+SJC28+GH+GA ph in which TJC is the number of tender joints, SJC the number of Swollen Joint and GH the general health assessed by the patient on a Visual Analogue Scale (VAS) and GA ph the general assessment of the physician on a VAS. A value below 3.3 is indicating remission, between 3.4 and 11.0 low disease activity, between 11.1 and 26.0 moderate disease activity and above 26.0 high disease activity.

    2. Remission According to SDAI at Week 52 [week 52]

      Number of patients in remission according to SDAI (Simplified Disease Activity Index) at week 52. SDAI is calculated with the following formula : TJC28+SJC28+GH+GA ph in which TJC is the number of tender joints, SJC the number of Swollen Joint and GH the general health assessed by the patient on a Visual Analogue Scale (VAS) and GA ph the general assessment of the physician on a VAS. A value below 3.3 is indicating remission, between 3.4 and 11.0 low disease activity, between 11.1 and 26.0 moderate disease activity and above 26.0 high disease activity.

    3. Remission According to SDAI at Week 104 [week 104]

      Number of patients in remission according to SDAI (Simplified Disease Activity Index) at week 104. SDAI is calculated with the following formula : TJC28+SJC28+GH+GA ph in which TJC is the number of tender joints, SJC the number of Swollen Joint and GH the general health assessed by the patient on a Visual Analogue Scale (VAS) and GA ph the general assessment of the physician on a VAS. A value below 3.3 is indicating remission, between 3.4 and 11.0 low disease activity, between 11.1 and 26.0 moderate disease activity and above 26.0 high disease activity.

    4. Clinically Significant Change in HAQ Score [Baseline-week104]

      Number of patients with a change of > 0.22 in the Health Assessment Questionnaire (HAQ) score over the period between baseline and week 104. A change of > 0.22 in this score is considered as clinical relevant for rheumatoid arthritis patients.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Diagnosis of RA as defined by the 1987 or 2010 revised American College of Rheumatology (ACR) criteria

    • Early RA (less than 1 year)

    • Use a reliable method of contraception for women of childbearing potential

    • Able and willing to give written informed consent and participate in the study

    Exclusion Criteria:

    • Previous treatment with DMARDs

    • Previous treatment with oral corticosteroids at a dosage of more than 10 milligrams (mg) prednisone within 4 weeks before baseline

    • Previous treatment with oral corticosteroids at a dosage equal to or less than 10 mg prednisone within 2 weeks before baseline

    • Previous treatment with oral corticosteroids for more than 4 weeks

    • Previous treatment with Intra Articular corticosteroids within 4 weeks before baseline

    • Previous treatment with an investigational drug for the treatment or prevention of RA

    • Contraindications for corticosteroids

    • Contraindications for DMARDs

    • Psoriatic Arthritis

    • Underlying cardiac, pulmonary, metabolic, renal or gastrointestinal conditions, chronic or latent infectious diseases or immune deficiency which in the opinion of the investigator places the patient at an unacceptable risk for participation in the study

    • Pregnancy, breastfeeding or no use of a reliable method of contraception

    • Alcohol or drug abuse

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 ASZ Aalst Belgium 9300
    2 OLV Ziekenhuis Aalst Belgium 9300
    3 Imelda Ziekenhuis Bonheiden Belgium 2820
    4 AZ St Lucas Brugge Belgium 8310
    5 Reuma praktijk Genk Belgium 3600
    6 Reumacentrum Genk Belgium 3600
    7 UZ Gent, dept. of Rheumatology Gent Belgium 9000
    8 Reuma instituut Hasselt Hasselt Belgium 3500
    9 Reumapraktijk Hasselt Belgium 3500
    10 Jan Yperman Ziekenhuis Ieper Belgium 8900
    11 AZ groeninge Kortrijk Belgium 8500
    12 HHart Ziekenhuis Leuven Belgium 3000
    13 MCH Leuven Belgium 3000
    14 Universitaire Ziekenhuizen Leuven Leuven Belgium 3000
    15 AZ St maarten Mechelen Belgium 2800
    16 ZNA Jan Palfijn Merksem Belgium 2170
    17 Henri Serruys ziekenhuis Oostende Belgium 8400

    Sponsors and Collaborators

    • P. Verschueren
    • Agentschap voor Innovatie door Wetenschap en Technologie

    Investigators

    • Principal Investigator: Patrick Verschueren, MD, PhD, Universitaire Ziekenhuizen Leuven

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    P. Verschueren, Prof. Dr., Universitaire Ziekenhuizen Leuven
    ClinicalTrials.gov Identifier:
    NCT01172639
    Other Study ID Numbers:
    • CareRA
    • 2008-007225-39
    First Posted:
    Jul 30, 2010
    Last Update Posted:
    Jan 22, 2019
    Last Verified:
    Jan 1, 2019
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Keywords provided by P. Verschueren, Prof. Dr., Universitaire Ziekenhuizen Leuven
    CoBRA
    Additional relevant MeSH terms:
    Arthritis
    Arthritis, Rheumatoid
    Sulfasalazine
    Prednisone
    Methotrexate
    Leflunomide

    Study Results

    Participant Flow

    Recruitment Details We recruited 400 participants between January 2009 and May 2013. There were 13 participating Flemish rheumatology centers (2 academic centers, 7 general hospitals and 4 private practices).
    Pre-assignment Detail There were 379 patients randomised to a treatment arm, 21 patients not randomised: 1 screen failure, 10 withdrawals by subject, 10 randomisation errors
    Arm/Group Title CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-garde High Risk Group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Arm/Group Description Methotrexate 15mg tablet by mouth, weekly for entire trial Sulfasalazine 2g tablet by mouth, daily for 40 weeks Prednisone tablet by mouth, weekly step down scheme 60 - 40 - 25 - 20 - 15 - 10 mg daily for 6 weeks, followed by 7.5mg daily till week 28, then further tapered down to stop at week 32 Methotrexate 15mg tablet by mouth, weekly for entire trial Prednisone tablet by mouth, weekly step down scheme 30 - 20 - 12.5 - 10 - 7.5 mg daily for 5 weeks, followed by 5mg daily till week 28, then further tapered down to stop at week 32 Methotrexate 15mg tablet by mouth, weekly for 40 weeks (continued for entire trial if randomized to Methotrexate monotherapy at week 40) Leflunomide 10mg tablet by mouth, daily for 40 weeks (continued for entire trial if randomized to Leflunomide monotherapy at week 40) Prednisone tablet by mouth, weekly step down scheme 30 - 20 - 12.5 - 10 - 7.5 mg daily for 5 weeks, followed by 5mg daily till week 28, then further tapered down to stop at week 32 Methotrexate 15mg tablet by mouth, weekly for entire trial Prednisone tablet by mouth, weekly step down scheme 30 - 20 - 12.5 - 10 - 7.5 mg daily for 5 weeks, followed by 5mg daily till week 28, then further tapered down to stop at week 32 Methotrexate 15mg tablet by mouth, weekly for entire trial No oral steroids allowed during the first year of the trial
    Period Title: Overall Study
    STARTED 98 98 93 43 47
    Week 16 94 96 91 39 47
    Week 52 89 89 88 38 45
    COMPLETED 85 87 77 32 41
    NOT COMPLETED 13 11 16 11 6

    Baseline Characteristics

    Arm/Group Title CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-garde High Risk Group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group Total
    Arm/Group Description Methotrexate (MTX) Sulphasalazine Step down steroid full dose randomisation: Stratification according to risk factors into two groups. Random assignment to different treatment strategies within strata. MTX Step down steroid half dose randomisation: Stratification according to risk factors into two groups. Random assignment to different treatment strategies within strata. MTX Leflunomide Step down steroid half dose randomisation: Stratification according to risk factors into two groups. Random assignment to different treatment strategies within strata. MTX Step down steroid half dose randomisation: Stratification according to risk factors into two groups. Random assignment to different treatment strategies within strata. MTX No additional oral steroids allowed randomisation: Stratification according to risk factors into two groups. Random assignment to different treatment strategies within strata. Total of all reporting groups
    Overall Participants 98 98 93 43 47 379
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    53.2
    (11.9)
    51.8
    (13.1)
    51.1
    (12.8)
    51.4
    (14.4)
    51.0
    (14.0)
    51.9
    (12.9)
    Sex: Female, Male (Count of Participants)
    Female
    64
    65.3%
    63
    64.3%
    64
    68.8%
    33
    76.7%
    38
    80.9%
    262
    69.1%
    Male
    34
    34.7%
    35
    35.7%
    29
    31.2%
    10
    23.3%
    9
    19.1%
    117
    30.9%
    Race/Ethnicity, Customized (Count of Participants)
    Caucasian
    95
    96.9%
    96
    98%
    90
    96.8%
    43
    100%
    47
    100%
    371
    97.9%
    Hispanic
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    2
    2%
    1
    1%
    0
    0%
    0
    0%
    0
    0%
    3
    0.8%
    Black
    1
    1%
    1
    1%
    1
    1.1%
    0
    0%
    0
    0%
    3
    0.8%
    North African
    0
    0%
    0
    0%
    2
    2.2%
    0
    0%
    0
    0%
    2
    0.5%
    Smoking status (Count of Participants)
    current
    30
    30.6%
    30
    30.6%
    23
    24.7%
    10
    23.3%
    4
    8.5%
    97
    25.6%
    past
    26
    26.5%
    28
    28.6%
    33
    35.5%
    11
    25.6%
    14
    29.8%
    112
    29.6%
    never
    42
    42.9%
    40
    40.8%
    37
    39.8%
    22
    51.2%
    29
    61.7%
    170
    44.9%
    Symptom duration (weeks) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [weeks]
    33.8
    (35.5)
    33.2
    (38.2)
    44.3
    (65.9)
    34.4
    (68.2)
    33.1
    (62.2)
    36.2
    (52.6)

    Outcome Measures

    1. Primary Outcome
    Title Remission According to DAS28-CRP at Week 16
    Description Number of patients in remission according to DAS28-CRP (Disease Activity Score based on 28 joint count and C-reactive Protein) at week 16. DAS28-CRP is calculated with the following formula : 0.56*SQRT TJC28+0.28*SQRT SJC28+0.36*ln (CRP+1)+0.014*GH+0.96 in which TJC is the tender joint count, SJC the Swollen Joint Count and GH the general health estimated by the patient on a Visual Analogue Scale (VAS). A value below 2.6 is indicating remission, below or equal to 3.2 low disease activity, between 3.2 and 5.1 moderate disease activity and above 5.1 high disease activity.
    Time Frame week 16

    Outcome Measure Data

    Analysis Population Description
    ITT = intention to treat analysis (all randomized subjects included), missing data imputed with Expectation Maximization on complete w104 database.
    Arm/Group Title CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-garde High Risk Group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Arm/Group Description Methotrexate (MTX) Sulphasalazine Step down steroid full dose MTX Step down steroid half dose MTX Leflunomide Step down steroid half dose MTX Step down steroid half dose MTX No additional oral steroids allowed
    Measure Participants 98 98 93 43 47
    Count of Participants [Participants]
    69
    70.4%
    72
    73.5%
    61
    65.6%
    25
    58.1%
    23
    48.9%
    2. Primary Outcome
    Title Remission According to DAS28-CRP at Week 52
    Description Number of patients in remission according to DAS28-CRP (Disease Activity Score based on 28 joint count and C-reactive Protein) at week 52. (co-primary end point) DAS28-CRP is calculated with the following formula : 0.56*SQRT TJC28+0.28*SQRT SJC28+0.36*ln (CRP+1)+0.014*GH+0.96 in which TJC is the tender joint count, SJC the Swollen Joint Count and GH the general health estimated by the patient on a Visual Analogue Scale (VAS). A value below 2.6 is indicating remission, below or equal to 3.2 low disease activity, between 3.2 and 5.1 moderate disease activity and above 5.1 high disease activity.
    Time Frame week 52

    Outcome Measure Data

    Analysis Population Description
    ITT (all randomized subjects included), missing data imputed with Expectation Maximization on complete w104 database.
    Arm/Group Title CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-garde High Risk Group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Arm/Group Description Methotrexate (MTX) Sulphasalazine Step down steroid full dose MTX Step down steroid half dose MTX Leflunomide Step down steroid half dose MTX Step down steroid half dose MTX No additional oral steroids allowed
    Measure Participants 98 98 93 43 47
    Count of Participants [Participants]
    63
    64.3%
    57
    58.2%
    57
    61.3%
    29
    67.4%
    29
    61.7%
    3. Primary Outcome
    Title Remission According to DAS28-CRP at Week 104
    Description Number of patients in remission according to DAS28-CRP (Disease Activity Score based on 28 joint count and C-reactive Protein) at week 104. (co-primary endpoints) DAS28-CRP is calculated with the following formula : 0.56*SQRT TJC28+0.28*SQRT SJC28+0.36*ln (CRP+1)+0.014*GH+0.96 in which TJC is the tender joint count, SJC the Swollen Joint Count and GH the general health estimated by the patient on a Visual Analogue Scale (VAS). A value below 2.6 is indicating remission, below or equal to 3.2 low disease activity, between 3.2 and 5.1 moderate disease activity and above 5.1 high disease activity.
    Time Frame week 104

    Outcome Measure Data

    Analysis Population Description
    ITT (all randomized subjects included), missing data imputed with Expectation Maximization on complete w104 database.
    Arm/Group Title CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-garde High Risk Group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Arm/Group Description Methotrexate (MTX) Sulphasalazine Step down steroid full dose MTX Step down steroid half dose MTX Leflunomide Step down steroid half dose MTX Step down steroid half dose MTX No additional oral steroids allowed
    Measure Participants 98 98 93 43 47
    Count of Participants [Participants]
    64
    65.3%
    71
    72.4%
    69
    74.2%
    29
    67.4%
    34
    72.3%
    4. Secondary Outcome
    Title Remission According to SDAI (Simple Disease Activity Index) at Week 16
    Description Number of patients in remission according to SDAI (Simplified Disease Activity Index) at week 16. SDAI is calculated with the following formula : TJC28+SJC28+GH+GA ph in which TJC is the number of tender joints, SJC the number of Swollen Joint and GH the general health assessed by the patient on a Visual Analogue Scale (VAS) and GA ph the general assessment of the physician on a VAS. A value below 3.3 is indicating remission, between 3.4 and 11.0 low disease activity, between 11.1 and 26.0 moderate disease activity and above 26.0 high disease activity.
    Time Frame week 16

    Outcome Measure Data

    Analysis Population Description
    ITT (all randomized subjects included), missing data imputed with Expectation Maximization on complete w104 database.
    Arm/Group Title CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-garde High Risk Group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Arm/Group Description Methotrexate (MTX) Sulphasalazine Step down steroid full dose MTX Step down steroid half dose MTX Leflunomide Step down steroid half dose MTX Step down steroid half dose MTX No additional oral steroids allowed
    Measure Participants 98 98 93 43 47
    Count of Participants [Participants]
    42
    42.9%
    33
    33.7%
    44
    47.3%
    12
    27.9%
    12
    25.5%
    5. Secondary Outcome
    Title Remission According to SDAI at Week 52
    Description Number of patients in remission according to SDAI (Simplified Disease Activity Index) at week 52. SDAI is calculated with the following formula : TJC28+SJC28+GH+GA ph in which TJC is the number of tender joints, SJC the number of Swollen Joint and GH the general health assessed by the patient on a Visual Analogue Scale (VAS) and GA ph the general assessment of the physician on a VAS. A value below 3.3 is indicating remission, between 3.4 and 11.0 low disease activity, between 11.1 and 26.0 moderate disease activity and above 26.0 high disease activity.
    Time Frame week 52

    Outcome Measure Data

    Analysis Population Description
    ITT (all randomized subjects included), missing data imputed with Expectation Maximization on complete w104 database.
    Arm/Group Title CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-garde High Risk Group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Arm/Group Description Methotrexate (MTX) Sulphasalazine Step down steroid full dose MTX Step down steroid half dose MTX Leflunomide Step down steroid half dose MTX Step down steroid half dose MTX No additional oral steroids allowed
    Measure Participants 98 98 93 43 47
    Count of Participants [Participants]
    36
    36.7%
    27
    27.6%
    39
    41.9%
    20
    46.5%
    15
    31.9%
    6. Secondary Outcome
    Title Remission According to SDAI at Week 104
    Description Number of patients in remission according to SDAI (Simplified Disease Activity Index) at week 104. SDAI is calculated with the following formula : TJC28+SJC28+GH+GA ph in which TJC is the number of tender joints, SJC the number of Swollen Joint and GH the general health assessed by the patient on a Visual Analogue Scale (VAS) and GA ph the general assessment of the physician on a VAS. A value below 3.3 is indicating remission, between 3.4 and 11.0 low disease activity, between 11.1 and 26.0 moderate disease activity and above 26.0 high disease activity.
    Time Frame week 104

    Outcome Measure Data

    Analysis Population Description
    ITT = intention to treat analysis (all randomized subjects included), missing data imputed with Expectation Maximization on complete w104 database.
    Arm/Group Title CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-garde High Risk Group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Arm/Group Description Methotrexate (MTX) Sulphasalazine Step down steroid full dose MTX Step down steroid half dose MTX Leflunomide Step down steroid half dose MTX Step down steroid half dose MTX No additional oral steroids allowed
    Measure Participants 98 98 93 43 47
    Count of Participants [Participants]
    31
    31.6%
    28
    28.6%
    41
    44.1%
    20
    46.5%
    13
    27.7%
    7. Secondary Outcome
    Title Clinically Significant Change in HAQ Score
    Description Number of patients with a change of > 0.22 in the Health Assessment Questionnaire (HAQ) score over the period between baseline and week 104. A change of > 0.22 in this score is considered as clinical relevant for rheumatoid arthritis patients.
    Time Frame Baseline-week104

    Outcome Measure Data

    Analysis Population Description
    ITT = intention to treat analysis (all randomized subjects included), missing data imputed with Expectation Maximization on complete w104 database.
    Arm/Group Title CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-garde High Risk Group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Arm/Group Description Methotrexate (MTX) Sulphasalazine Step down steroid full dose MTX Step down steroid half dose MTX Leflunomide Step down steroid half dose MTX Step down steroid half dose MTX No additional oral steroids allowed
    Measure Participants 98 98 93 43 47
    Count of Participants [Participants]
    71
    72.4%
    62
    63.3%
    64
    68.8%
    25
    58.1%
    26
    55.3%

    Adverse Events

    Time Frame Adverse event data were collected over a two year period per patient
    Adverse Event Reporting Description All adverse events were registered by healthcare professionals questioning the patients at each visit
    Arm/Group Title CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-garde High Risk Group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Arm/Group Description Methotrexate (MTX) Sulphasalazine Step down steroid full dose randomisation: Stratification according to risk factors into two groups. Random assignment to different treatment strategies within strata. MTX Step down steroid half dose randomisation: Stratification according to risk factors into two groups. Random assignment to different treatment strategies within strata. MTX Leflunomide Step down steroid half dose randomisation: Stratification according to risk factors into two groups. Random assignment to different treatment strategies within strata. MTX Step down steroid half dose randomisation: Stratification according to risk factors into two groups. Random assignment to different treatment strategies within strata. MTX No additional oral steroids allowed randomisation: Stratification according to risk factors into two groups. Random assignment to different treatment strategies within strata.
    All Cause Mortality
    CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-garde High Risk Group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/98 (1%) 1/98 (1%) 0/93 (0%) 0/43 (0%) 0/47 (0%)
    Serious Adverse Events
    CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-garde High Risk Group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 21/98 (21.4%) 22/98 (22.4%) 16/93 (17.2%) 9/43 (20.9%) 7/47 (14.9%)
    Blood and lymphatic system disorders
    Anaemia 0/98 (0%) 0 0/98 (0%) 0 0/93 (0%) 0 1/43 (2.3%) 1 0/47 (0%) 0
    Bone marrow supression 1/98 (1%) 1 0/98 (0%) 0 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Pancytopenia 0/98 (0%) 0 1/98 (1%) 1 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Cardiac disorders
    Angina 0/98 (0%) 0 0/98 (0%) 0 0/93 (0%) 0 1/43 (2.3%) 1 1/47 (2.1%) 1
    Atrial fibrillation 0/98 (0%) 0 3/98 (3.1%) 4 1/93 (1.1%) 1 0/43 (0%) 0 0/47 (0%) 0
    Atrioventricular block third degree 0/98 (0%) 0 0/98 (0%) 0 0/93 (0%) 0 0/43 (0%) 0 1/47 (2.1%) 1
    Myocardial infarction 0/98 (0%) 0 2/98 (2%) 2 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Pericarditis 0/98 (0%) 0 1/98 (1%) 2 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Sinus venosus defect 0/98 (0%) 0 1/98 (1%) 1 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Endocrine disorders
    Uncontrolled diabetes mellitus 0/98 (0%) 0 0/98 (0%) 0 2/93 (2.2%) 2 0/43 (0%) 0 0/47 (0%) 0
    Gastrointestinal disorders
    Abdominal discomfort 1/98 (1%) 1 1/98 (1%) 1 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Gastroenteritis 1/98 (1%) 1 1/98 (1%) 1 1/93 (1.1%) 1 2/43 (4.7%) 3 0/47 (0%) 0
    Reflux oesophagitis 0/98 (0%) 0 1/98 (1%) 1 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Volvulus 1/98 (1%) 1 0/98 (0%) 0 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Hepatobiliary disorders
    Cholecystitis 1/98 (1%) 1 1/98 (1%) 1 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Immune system disorders
    Anaphylaxis after a wasp sting 0/98 (0%) 0 0/98 (0%) 0 0/93 (0%) 0 0/43 (0%) 0 1/47 (2.1%) 2
    Infections and infestations
    Bacterial infection 0/98 (0%) 0 1/98 (1%) 1 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Viral infection 0/98 (0%) 0 0/98 (0%) 0 1/93 (1.1%) 1 0/43 (0%) 0 0/47 (0%) 0
    Septic bursitis olecrani 0/98 (0%) 0 1/98 (1%) 1 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Injury, poisoning and procedural complications
    Post procedural complication 1/98 (1%) 1 0/98 (0%) 0 1/93 (1.1%) 1 0/43 (0%) 0 0/47 (0%) 0
    Trauma 1/98 (1%) 1 2/98 (2%) 2 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Musculoskeletal and connective tissue disorders
    Hernia diaphragmatica 0/98 (0%) 0 0/98 (0%) 0 1/93 (1.1%) 1 0/43 (0%) 0 0/47 (0%) 0
    Intervertebral disc disorder 1/98 (1%) 2 0/98 (0%) 0 3/93 (3.2%) 4 1/43 (2.3%) 1 0/47 (0%) 0
    Ischialgy leg 1/98 (1%) 1 0/98 (0%) 0 0/93 (0%) 0 0/43 (0%) 0 1/47 (2.1%) 1
    Lumbago 0/98 (0%) 0 0/98 (0%) 0 1/93 (1.1%) 1 0/43 (0%) 0 0/47 (0%) 0
    Rheumatoid arthritis flare 1/98 (1%) 1 1/98 (1%) 1 2/93 (2.2%) 2 0/43 (0%) 0 0/47 (0%) 0
    Baker's cyst 1/98 (1%) 1 0/98 (0%) 0 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer malignant 3/98 (3.1%) 3 0/98 (0%) 0 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Cervixcarcinoma 0/98 (0%) 0 1/98 (1%) 1 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Cholesteatoma 0/98 (0%) 0 0/98 (0%) 0 1/93 (1.1%) 1 0/43 (0%) 0 0/47 (0%) 0
    Endometrioid adenocarcinoma 0/98 (0%) 0 0/98 (0%) 0 0/93 (0%) 0 1/43 (2.3%) 1 0/47 (0%) 0
    Intestinal polyps 1/98 (1%) 1 0/98 (0%) 0 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Kidney cancer malignant 0/98 (0%) 0 0/98 (0%) 0 0/93 (0%) 0 1/43 (2.3%) 1 0/47 (0%) 0
    Lung cancer malignant 1/98 (1%) 1 0/98 (0%) 0 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Lung noduli 1/98 (1%) 1 0/98 (0%) 0 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Neoplasms parotid gland 0/98 (0%) 0 0/98 (0%) 0 1/93 (1.1%) 1 0/43 (0%) 0 0/47 (0%) 0
    Noduli submandibular salivary glands 0/98 (0%) 0 1/98 (1%) 1 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Nervous system disorders
    Diffuse pain 1/98 (1%) 1 0/98 (0%) 0 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Transient ischemic attack 0/98 (0%) 0 0/98 (0%) 0 0/93 (0%) 0 0/43 (0%) 0 1/47 (2.1%) 1
    Product Issues
    Mucositis 1/98 (1%) 1 0/98 (0%) 0 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Psychiatric disorders
    Severe depression 0/98 (0%) 0 1/98 (1%) 1 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Renal and urinary disorders
    Bladder infection 0/98 (0%) 0 0/98 (0%) 0 0/93 (0%) 0 1/43 (2.3%) 1 0/47 (0%) 0
    Nephrolithiasis 1/98 (1%) 1 0/98 (0%) 0 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease 0/98 (0%) 0 1/98 (1%) 1 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Interstitial Lung Disease 0/98 (0%) 0 0/98 (0%) 0 1/93 (1.1%) 1 0/43 (0%) 0 0/47 (0%) 0
    Peribronchitis 1/98 (1%) 1 0/98 (0%) 0 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Pneumonia 0/98 (0%) 0 0/98 (0%) 0 0/93 (0%) 0 1/43 (2.3%) 1 0/47 (0%) 0
    Surgical and medical procedures
    Orthopaedic surgery 2/98 (2%) 3 1/98 (1%) 1 4/93 (4.3%) 6 0/43 (0%) 0 1/47 (2.1%) 1
    Abdominal surgery 1/98 (1%) 1 2/98 (2%) 2 1/93 (1.1%) 1 0/43 (0%) 0 1/47 (2.1%) 1
    Amygdalectomy 1/98 (1%) 1 0/98 (0%) 0 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Hysterectomy 1/98 (1%) 1 0/98 (0%) 0 1/93 (1.1%) 1 0/43 (0%) 0 0/47 (0%) 0
    Liposuction arms 0/98 (0%) 0 1/98 (1%) 1 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Vascular disorders
    Coronary artery disorder 1/98 (1%) 1 0/98 (0%) 0 0/93 (0%) 0 0/43 (0%) 0 1/47 (2.1%) 1
    Pulmonary embolisms 0/98 (0%) 0 1/98 (1%) 1 0/93 (0%) 0 0/43 (0%) 0 0/47 (0%) 0
    Peripheral vascular ischemia 0/98 (0%) 0 1/98 (1%) 1 0/93 (0%) 0 0/43 (0%) 0 1/47 (2.1%) 2
    Other (Not Including Serious) Adverse Events
    CoBRA Classic High Risk Group CoBRA Slim High Risk Group CoBRA Avant-garde High Risk Group CoBRA Slim Low Risk Group Tight Step Up Low Risk Group
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 85/98 (86.7%) 88/98 (89.8%) 84/93 (90.3%) 34/43 (79.1%) 45/47 (95.7%)
    Blood and lymphatic system disorders
    Anaemia 8/98 (8.2%) 8 1/98 (1%) 1 5/93 (5.4%) 6 2/43 (4.7%) 2 2/47 (4.3%) 3
    Cardiac disorders
    Palpitations 8/98 (8.2%) 9 3/98 (3.1%) 3 6/93 (6.5%) 6 2/43 (4.7%) 2 2/47 (4.3%) 2
    Eye disorders
    Eye infection 6/98 (6.1%) 8 4/98 (4.1%) 4 5/93 (5.4%) 5 1/43 (2.3%) 1 0/47 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 25/98 (25.5%) 27 23/98 (23.5%) 26 37/93 (39.8%) 46 11/43 (25.6%) 14 9/47 (19.1%) 9
    Nausea 15/98 (15.3%) 16 21/98 (21.4%) 25 12/93 (12.9%) 14 10/43 (23.3%) 14 11/47 (23.4%) 12
    Gastroenteritis 8/98 (8.2%) 9 8/98 (8.2%) 9 8/93 (8.6%) 8 8/43 (18.6%) 9 3/47 (6.4%) 3
    Diarrhoea 5/98 (5.1%) 5 11/98 (11.2%) 12 24/93 (25.8%) 28 1/43 (2.3%) 1 4/47 (8.5%) 4
    Pyrosis 5/98 (5.1%) 6 7/98 (7.1%) 8 2/93 (2.2%) 2 1/43 (2.3%) 1 3/47 (6.4%) 3
    General disorders
    General malaise 9/98 (9.2%) 9 4/98 (4.1%) 4 5/93 (5.4%) 6 2/43 (4.7%) 2 1/47 (2.1%) 1
    Insomnia 8/98 (8.2%) 8 4/98 (4.1%) 4 2/93 (2.2%) 2 1/43 (2.3%) 1 0/47 (0%) 0
    Fatigue 7/98 (7.1%) 7 4/98 (4.1%) 6 4/93 (4.3%) 5 2/43 (4.7%) 2 5/47 (10.6%) 5
    Hairloss 7/98 (7.1%) 7 12/98 (12.2%) 13 19/93 (20.4%) 20 7/43 (16.3%) 7 6/47 (12.8%) 6
    Increased transpiration 7/98 (7.1%) 7 3/98 (3.1%) 3 6/93 (6.5%) 7 3/43 (7%) 4 1/47 (2.1%) 1
    Agitation 6/98 (6.1%) 7 2/98 (2%) 2 10/93 (10.8%) 10 3/43 (7%) 3 0/47 (0%) 0
    Flushes 6/98 (6.1%) 6 4/98 (4.1%) 4 2/93 (2.2%) 2 2/43 (4.7%) 2 0/47 (0%) 0
    Sjogren's disease 5/98 (5.1%) 5 2/98 (2%) 2 6/93 (6.5%) 6 2/43 (4.7%) 2 1/47 (2.1%) 1
    Hepatobiliary disorders
    Liver function disturbance 17/98 (17.3%) 22 15/98 (15.3%) 19 24/93 (25.8%) 25 6/43 (14%) 6 6/47 (12.8%) 8
    Infections and infestations
    Influenza infection 5/98 (5.1%) 6 10/98 (10.2%) 10 10/93 (10.8%) 10 2/43 (4.7%) 3 4/47 (8.5%) 5
    Aphtosis 2/98 (2%) 2 3/98 (3.1%) 3 8/93 (8.6%) 10 0/43 (0%) 0 5/47 (10.6%) 5
    Injury, poisoning and procedural complications
    Trauma 6/98 (6.1%) 7 1/98 (1%) 1 6/93 (6.5%) 7 0/43 (0%) 0 1/47 (2.1%) 1
    Musculoskeletal and connective tissue disorders
    Arthralgia 15/98 (15.3%) 15 7/98 (7.1%) 8 12/93 (12.9%) 13 5/43 (11.6%) 5 3/47 (6.4%) 4
    Back pain 12/98 (12.2%) 13 19/98 (19.4%) 22 13/93 (14%) 14 3/43 (7%) 4 9/47 (19.1%) 13
    Arthritis 7/98 (7.1%) 8 4/98 (4.1%) 4 4/93 (4.3%) 4 2/43 (4.7%) 2 1/47 (2.1%) 1
    Muscle cramps 6/98 (6.1%) 7 5/98 (5.1%) 6 5/93 (5.4%) 5 2/43 (4.7%) 2 4/47 (8.5%) 4
    Rotator cuff lesion 6/98 (6.1%) 6 0/98 (0%) 0 2/93 (2.2%) 2 1/43 (2.3%) 1 1/47 (2.1%) 1
    Tendinopathy 5/98 (5.1%) 5 9/98 (9.2%) 9 11/93 (11.8%) 12 5/43 (11.6%) 5 2/47 (4.3%) 3
    Arthrosis 2/98 (2%) 2 2/98 (2%) 2 6/93 (6.5%) 6 3/43 (7%) 4 2/47 (4.3%) 2
    Nervous system disorders
    Headache 12/98 (12.2%) 14 6/98 (6.1%) 8 9/93 (9.7%) 12 2/43 (4.7%) 2 3/47 (6.4%) 3
    Vertigo 11/98 (11.2%) 11 7/98 (7.1%) 8 6/93 (6.5%) 7 4/43 (9.3%) 5 3/47 (6.4%) 3
    Paresthesia 7/98 (7.1%) 9 8/98 (8.2%) 8 7/93 (7.5%) 7 3/43 (7%) 3 0/47 (0%) 0
    Renal and urinary disorders
    Urinary tract infection 6/98 (6.1%) 7 3/98 (3.1%) 3 7/93 (7.5%) 9 0/43 (0%) 0 3/47 (6.4%) 3
    Renal insufficiency 1/98 (1%) 1 2/98 (2%) 2 3/93 (3.2%) 4 0/43 (0%) 0 4/47 (8.5%) 6
    Reproductive system and breast disorders
    Genital infection 2/98 (2%) 2 2/98 (2%) 2 8/93 (8.6%) 9 1/43 (2.3%) 2 0/47 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Upper respiratory tract infection 28/98 (28.6%) 50 42/98 (42.9%) 72 29/93 (31.2%) 46 14/43 (32.6%) 29 18/47 (38.3%) 40
    Bronchitis 9/98 (9.2%) 12 10/98 (10.2%) 10 20/93 (21.5%) 23 2/43 (4.7%) 2 3/47 (6.4%) 3
    Cough 9/98 (9.2%) 9 13/98 (13.3%) 14 7/93 (7.5%) 7 1/43 (2.3%) 1 1/47 (2.1%) 1
    Dyspnea 4/98 (4.1%) 4 3/98 (3.1%) 4 5/93 (5.4%) 5 0/43 (0%) 0 4/47 (8.5%) 4
    Skin and subcutaneous tissue disorders
    Eczema 2/98 (2%) 2 9/98 (9.2%) 11 12/93 (12.9%) 12 4/43 (9.3%) 5 5/47 (10.6%) 5
    Pruritus 0/98 (0%) 0 1/98 (1%) 1 3/93 (3.2%) 3 3/43 (7%) 3 2/47 (4.3%) 2
    Surgical and medical procedures
    Tooth extraction 1/98 (1%) 1 4/98 (4.1%) 4 0/93 (0%) 0 3/43 (7%) 3 0/47 (0%) 0
    Vascular disorders
    Hypertension 9/98 (9.2%) 9 8/98 (8.2%) 8 13/93 (14%) 13 4/43 (9.3%) 4 1/47 (2.1%) 1
    Venous insufficiency 4/98 (4.1%) 5 5/98 (5.1%) 5 6/93 (6.5%) 6 2/43 (4.7%) 2 1/47 (2.1%) 1
    Syncope 1/98 (1%) 1 0/98 (0%) 0 0/93 (0%) 0 0/43 (0%) 0 3/47 (6.4%) 3

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Prof. Dr. Patrick Verschueren
    Organization University Hospitals Leuven
    Phone +32 16 34 25 41
    Email patrick.verschueren@uzleuven.be
    Responsible Party:
    P. Verschueren, Prof. Dr., Universitaire Ziekenhuizen Leuven
    ClinicalTrials.gov Identifier:
    NCT01172639
    Other Study ID Numbers:
    • CareRA
    • 2008-007225-39
    First Posted:
    Jul 30, 2010
    Last Update Posted:
    Jan 22, 2019
    Last Verified:
    Jan 1, 2019