Rheumatoid Arthritis
Conditions
Keywords
CoBRA
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.
Interventions
DRUGMethotrexate
Methotrexate tablet
DRUGSulfasalazine
Sulfasalazine tablet
DRUGLeflunomide
Leflunomide tablet
DRUGPrednisone
Prednisone tablet
Sponsors
Agentschap voor Innovatie door Wetenschap en Technologie
P. Verschueren
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Belgium
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 details
There were 379 patients randomised to a treatment arm, 21 patients not randomised: 1 screen failure, 10 withdrawals by subject, 10 randomisation errors
Participants by arm
| Arm | Count |
|---|---|
| CoBRA Classic High Risk Group * 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. | 98 |
| CoBRA Slim High Risk Group * MTX
* Step down steroid half dose
randomisation: Stratification according to risk factors into two groups. Random assignment to different treatment strategies within strata. | 98 |
| CoBRA Avant-garde High Risk Group * MTX
* Leflunomide
* Step down steroid half dose
randomisation: Stratification according to risk factors into two groups. Random assignment to different treatment strategies within strata. | 93 |
| CoBRA Slim Low Risk Group * MTX
* Step down steroid half dose
randomisation: Stratification according to risk factors into two groups. Random assignment to different treatment strategies within strata. | 43 |
| Tight Step Up Low Risk Group * MTX
* No additional oral steroids allowed
randomisation: Stratification according to risk factors into two groups. Random assignment to different treatment strategies within strata. | 47 |
| Total | 379 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 1 | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 9 | 7 | 11 | 6 | 6 |
| Overall Study | Withdrawal by Subject | 3 | 3 | 5 | 5 | 0 |
Baseline characteristics
| Characteristic | CoBRA Slim High Risk Group | CoBRA Avant-garde High Risk Group | CoBRA Slim Low Risk Group | CoBRA Classic High Risk Group | Tight Step Up Low Risk Group | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 51.8 years STANDARD_DEVIATION 13.1 | 51.1 years STANDARD_DEVIATION 12.8 | 51.4 years STANDARD_DEVIATION 14.4 | 53.2 years STANDARD_DEVIATION 11.9 | 51.0 years STANDARD_DEVIATION 14 | 51.9 years STANDARD_DEVIATION 12.9 |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Black | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Caucasian | 96 Participants | 90 Participants | 43 Participants | 95 Participants | 47 Participants | 371 Participants |
| Race/Ethnicity, Customized Hispanic | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized North African | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Female | 63 Participants | 64 Participants | 33 Participants | 64 Participants | 38 Participants | 262 Participants |
| Sex: Female, Male Male | 35 Participants | 29 Participants | 10 Participants | 34 Participants | 9 Participants | 117 Participants |
| Smoking status current | 30 Participants | 23 Participants | 10 Participants | 30 Participants | 4 Participants | 97 Participants |
| Smoking status never | 40 Participants | 37 Participants | 22 Participants | 42 Participants | 29 Participants | 170 Participants |
| Smoking status past | 28 Participants | 33 Participants | 11 Participants | 26 Participants | 14 Participants | 112 Participants |
| Symptom duration | 33.2 weeks STANDARD_DEVIATION 38.2 | 44.3 weeks STANDARD_DEVIATION 65.9 | 34.4 weeks STANDARD_DEVIATION 68.2 | 33.8 weeks STANDARD_DEVIATION 35.5 | 33.1 weeks STANDARD_DEVIATION 62.2 | 36.2 weeks STANDARD_DEVIATION 52.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 98 | 1 / 98 | 0 / 93 | 0 / 43 | 0 / 47 |
| other Total, other adverse events | 85 / 98 | 88 / 98 | 84 / 93 | 34 / 43 | 45 / 47 |
| serious Total, serious adverse events | 21 / 98 | 22 / 98 | 16 / 93 | 9 / 43 | 7 / 47 |
Outcome results
Primary
Remission According to DAS28-CRP at 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.
Time frame: week 104
Population: ITT (all randomized subjects included), missing data imputed with Expectation Maximization on complete w104 database.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CoBRA Classic High Risk Group | Remission According to DAS28-CRP at Week 104 | 64 Participants |
| CoBRA Slim High Risk Group | Remission According to DAS28-CRP at Week 104 | 71 Participants |
| CoBRA Avant-garde High Risk Group | Remission According to DAS28-CRP at Week 104 | 69 Participants |
| CoBRA Slim Low Risk Group | Remission According to DAS28-CRP at Week 104 | 29 Participants |
| Tight Step Up Low Risk Group | Remission According to DAS28-CRP at Week 104 | 34 Participants |
Primary
Remission According to DAS28-CRP at 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.
Time frame: week 16
Population: ITT = intention to treat analysis (all randomized subjects included), missing data imputed with Expectation Maximization on complete w104 database.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CoBRA Classic High Risk Group | Remission According to DAS28-CRP at Week 16 | 69 Participants |
| CoBRA Slim High Risk Group | Remission According to DAS28-CRP at Week 16 | 72 Participants |
| CoBRA Avant-garde High Risk Group | Remission According to DAS28-CRP at Week 16 | 61 Participants |
| CoBRA Slim Low Risk Group | Remission According to DAS28-CRP at Week 16 | 25 Participants |
| Tight Step Up Low Risk Group | Remission According to DAS28-CRP at Week 16 | 23 Participants |
Primary
Remission According to DAS28-CRP at 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.
Time frame: week 52
Population: ITT (all randomized subjects included), missing data imputed with Expectation Maximization on complete w104 database.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CoBRA Classic High Risk Group | Remission According to DAS28-CRP at Week 52 | 63 Participants |
| CoBRA Slim High Risk Group | Remission According to DAS28-CRP at Week 52 | 57 Participants |
| CoBRA Avant-garde High Risk Group | Remission According to DAS28-CRP at Week 52 | 57 Participants |
| CoBRA Slim Low Risk Group | Remission According to DAS28-CRP at Week 52 | 29 Participants |
| Tight Step Up Low Risk Group | Remission According to DAS28-CRP at Week 52 | 29 Participants |
Secondary
Clinically Significant Change in HAQ Score
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
Population: ITT = intention to treat analysis (all randomized subjects included), missing data imputed with Expectation Maximization on complete w104 database.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CoBRA Classic High Risk Group | Clinically Significant Change in HAQ Score | 71 Participants |
| CoBRA Slim High Risk Group | Clinically Significant Change in HAQ Score | 62 Participants |
| CoBRA Avant-garde High Risk Group | Clinically Significant Change in HAQ Score | 64 Participants |
| CoBRA Slim Low Risk Group | Clinically Significant Change in HAQ Score | 25 Participants |
| Tight Step Up Low Risk Group | Clinically Significant Change in HAQ Score | 26 Participants |
Secondary
Remission According to SDAI at 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.
Time frame: week 104
Population: ITT = intention to treat analysis (all randomized subjects included), missing data imputed with Expectation Maximization on complete w104 database.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CoBRA Classic High Risk Group | Remission According to SDAI at Week 104 | 31 Participants |
| CoBRA Slim High Risk Group | Remission According to SDAI at Week 104 | 28 Participants |
| CoBRA Avant-garde High Risk Group | Remission According to SDAI at Week 104 | 41 Participants |
| CoBRA Slim Low Risk Group | Remission According to SDAI at Week 104 | 20 Participants |
| Tight Step Up Low Risk Group | Remission According to SDAI at Week 104 | 13 Participants |
Secondary
Remission According to SDAI at 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.
Time frame: week 52
Population: ITT (all randomized subjects included), missing data imputed with Expectation Maximization on complete w104 database.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CoBRA Classic High Risk Group | Remission According to SDAI at Week 52 | 36 Participants |
| CoBRA Slim High Risk Group | Remission According to SDAI at Week 52 | 27 Participants |
| CoBRA Avant-garde High Risk Group | Remission According to SDAI at Week 52 | 39 Participants |
| CoBRA Slim Low Risk Group | Remission According to SDAI at Week 52 | 20 Participants |
| Tight Step Up Low Risk Group | Remission According to SDAI at Week 52 | 15 Participants |
Secondary
Remission According to SDAI (Simple Disease Activity Index) at 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.
Time frame: week 16
Population: ITT (all randomized subjects included), missing data imputed with Expectation Maximization on complete w104 database.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CoBRA Classic High Risk Group | Remission According to SDAI (Simple Disease Activity Index) at Week 16 | 42 Participants |
| CoBRA Slim High Risk Group | Remission According to SDAI (Simple Disease Activity Index) at Week 16 | 33 Participants |
| CoBRA Avant-garde High Risk Group | Remission According to SDAI (Simple Disease Activity Index) at Week 16 | 44 Participants |
| CoBRA Slim Low Risk Group | Remission According to SDAI (Simple Disease Activity Index) at Week 16 | 12 Participants |
| Tight Step Up Low Risk Group | Remission According to SDAI (Simple Disease Activity Index) at Week 16 | 12 Participants |