Arthritis, Rheumatoid
Conditions
Keywords
COBRA-Slim, Accelerated access to anti-TNF, treat to target, remission induction
Brief summary
In the Care in Rheumatoid Arthritis (CareRA) trial (NCT01172639) about 70% of early RA patients are in remission at the 2 year evaluation point independent of the combination scheme used. Interesting to see is that the 30% of insufficient responders can be identified in an early stage of the treatment course. The purpose of the present study is to investigate if, for patients with an insufficient response to a COBRA-Slim regimen, accelerated access to a short course of anti-TNF therapy already early after treatment initiation (from w8 until w32) could improve outcomes compared to a more traditional treat to target sequence.
Interventions
DRUGEtanercept 50 MG/ML
Etanercept 50mg subcutaneous (SC) weekly added for 24 weeks to COBRA-Slim scheme
DRUGLeflunomide 10 milligram (MG)
Leflunomide 10mg PO daily added to the COBRA-Slim scheme
Sponsors
Belgium Health Care Knowledge Centre
P. Verschueren
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Insufficient responders to a COBRA-Slim strategy, defined as not reaching low disease activity based on DAS28 CRP from week 8 until week 32 or not reaching remission based on DAS28 CRP at week 32, will be randomly assigned to one of the two arms. Randomization will be balanced according to time-point of randomization, baseline (BL) disease activity and Anti-Citrullinated Protein Antibody (ACPA) and Rheumatoid Factor (RF) status to ensure comparability of the treatment groups with respect to these prognostic variables.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 18 years and older * Diagnosis of RA as defined by the American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) 2010 criteria for early RA * Early RA defined by a diagnosis made ≤ 1 year ago. * Use a reliable method of contraception for women of childbearing potential to be evaluated as in daily clinical practice * Able and willing to give written informed consent and to participate in the study * Understanding and able to write Dutch or French
Exclusion criteria
* Previous treatment with: * Methotrexate (MTX) or leflunomide * cyclophosphamide, azathioprine or cyclosporine * sulphasalazine (SSZ) for more than 3 weeks * hydroxychloroquine for more than 6 weeks * oral Glucocorticoids (GC) for more than 4 weeks within 4 months before screening * oral GC at a daily dosage of more than 10 mg prednisone equivalent within 4 weeks before baseline * oral GC at a daily dosage equal to or less than 10 mg prednisone equivalent within 2 weeks before baseline * intra-articular GC within 4 weeks before BL * an investigational drug for the treatment/prevention of RA * History of chronic heart failure * History of severe infections or chronic infection * History of malignant neoplasm within 5 years * Contra indications for GC * Contra indications for TNF blocking agents * Contra indications for MTX or leflunomide * 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 for woman of childbearing potential (as in daily clinical practice) * Alcohol or drug abuse * Active tuberculosis (TB) * Latent TB unless adequate prophylactic treatment is given according to local guidelines * No access to the Belgian Health Insurance system-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under Curve (AUC) of Disease Activity Score Based on a 28 Jointcount and C-reactive Protein (DAS28CRP) | baseline, w4, w8, w16, w24, w32, w40, w52, w64, w78, w92 and w104 | Analysis was based on an intention to treat population, which focused on all patients randomized into the study, irrespective if they actually received the randomized treatment. Fifty-five patients were allocated to Standard COBRA-Slim and 55 to COBRA-Slim Bio-induction. This measure is an indication of the total disease-activity over time or long-term effectiveness, a higher area under the curve indicates a higher disease activity over time and so a lower effectiveness over the time frame of the trial. The scale range for the duration of the trial (104 weeks) is 0.0 to 977.6 * remission: value below 270.4 * low disease activity: from 270.4 till 332.8 (included) * moderate disease activity: above 332.8 till 530.4 * high disease activity: above 530.4 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Insufficient Responders Achieving Remission (DAS28CRP<2.6) 28 Weeks After Randomization (Short Term Efficacy) to Either COBRA-Slim Bio-Induction or Standard COBRA-Slim Induction | From randomization till 28 weeks after randomization. | Short-time efficacy of disease activity based on a swollen and tender joint count of 28 joints and C-reactive proteine (scale range 0.0 to 9.4; remission: value below 2.6; low disease activity: from 2.6 till 3.2 (included); moderate disease activity: above 3.2 till 5.1; high disease activity: above 5.1). |
| Proportion of Patients in Remission Defined as DAS28CRP<2.6 | at week 104 | Short-time efficacy of disease activity based on a swollen and tender joint count of 28 joints and C-reactive proteine (scale range 0.0 to 9.4; remission: value below 2.6; low disease activity: from 2.6 till 3.2 (included); moderate disease activity: above 3.2 till 5.1; high disease activity: above 5.1). |
| Proportion of Patients Achieving a EULAR Response | at 28 weeks after randomization | proportion of patients achieving a EULAR response, based on actual disease activity on a tender/swollen joint count and C-reactive proteine (DAS28-CRP) 28 weeks after randomization and improvement in DAS28-CRP from baseline. The EULAR response criteria classify patients as good, moderate or non-responders, using the individual amount of change in the DAS28-CRP and the DAS28-CRP value (low, moderate, or high) reached according to the following tabel: DAS28-CRP at endpoint improvement in DAS28-CRP from baseline \<=1,2 \>0,6 and \<= 1,2 \<=0,6 \<= 3,2 good moderate none \>3,2 and \<= 5,1 moderate moderate none \>5,1 moderate none none Additionally all patients with a good response were also included in the number of participants with at least a moderate response. |
| Health Assessment Questionnaire (HAQ) Response | at 28 weeks after randomization | HAQ measures physical function as reported by the patient, total score range from 0-3 of which higher scores represent worse physical function. |
| Radiographic Progression | at week 52 | Radiographic progression at week 52 is scored according to the Sharp-Van der Heijde score (SvdH). The SvdH method scores the presence of erosions in 16 joints of hands and wrists (graded from 0 to 5), and in 6 joints of the feet (graded from 0 to 10), and the presence of joint space narrowing in 15 joints of the hands and wrists (graded from 0 to 4) and in 6 joints of the feet (graded from 0 to 4). The maximal range is 280 units for erosion and 168 units for joint space narrowing, summing up to 448 units for the total score. The progression is calculated by subtracting the total score at week 52 minus the total score at baseline (ranging from 0 to 448) Higher values in each (sub) scale represents a worse outcome. |
Countries
Belgium
Participant flow
Recruitment details
Of the 284 patients screened, 276 were eligible for the trial and 122 met the criteria of early insufficient responders to an initial COBRA-Slim remission induction regimen. Of this last group 112 patients were randomized, however 2 were considered randomization errors, 10 patients were eligible for randomization but were not randomized per investigator decision.
Pre-assignment details
All patients received a COBRA-Slim remission induction regimen, consisting of methotrexate (MTX) with a step-down scheme of glucocorticosteroids (GC). Patient not reaching low disease activity, based on DAS28CRP, before week 32 or DAS28CRP remission at week 32 were considered early insufficient responders and were eligible for randomization.
Participants by arm
| Arm | Count |
|---|---|
| Standard COBRA-Slim Induction Leflunomide 10mg PO daily added to the COBRA-Slim scheme (Methotrexate 15 mg PO weekly, Step down scheme of GC: 30-20-12,5-10-7,5-5 mg prednisone PO daily, each for 7 days except for the lowest dose of 5 mg, this will be maintained until w28 and then tapered to 2.5 mg daily for two weeks before stopping completely.)
Leflunomide 10 milligram (MG): Leflunomide 10mg PO daily added to the COBRA-Slim scheme | 55 |
| COBRA-Slim Bio-induction Etanercept 50mg subcutaneous (SC) weekly added for 24 weeks to COBRA-Slim scheme (Methotrexate 15 mg PO weekly, Step down scheme of GC: 30-20-12,5-10-7,5-5 mg prednisone PO daily, each for 7 days except for the lowest dose of 5 mg, this will be maintained until w28 and then tapered to 2.5 mg daily for two weeks before stopping completely.)
Etanercept 50 MG/ML: Etanercept 50mg subcutaneous (SC) weekly added for 24 weeks to COBRA-Slim scheme | 55 |
| Total | 110 |
Baseline characteristics
| Characteristic | Standard COBRA-Slim Induction | COBRA-Slim Bio-induction | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 12 Participants | 7 Participants | 19 Participants |
| Age, Categorical Between 18 and 65 years | 43 Participants | 48 Participants | 91 Participants |
| Age, Continuous | 53.4 years STANDARD_DEVIATION 13.1 | 52.5 years STANDARD_DEVIATION 12.9 | 52.9 years STANDARD_DEVIATION 13 |
| Disease activity (DAS28CRP) | 5.4 units on a scale STANDARD_DEVIATION 1.1 | 5.2 units on a scale STANDARD_DEVIATION 1.3 | 5.3 units on a scale STANDARD_DEVIATION 1.2 |
| Disease duration | 7.0 days | 7.0 days | 7.0 days |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Belgium | 55 participants | 55 participants | 110 participants |
| Rheumatoid factor (RF)/Anti-citrullinated protein antibodies (ACPA ) status negative | 13 Participants | 14 Participants | 27 Participants |
| Rheumatoid factor (RF)/Anti-citrullinated protein antibodies (ACPA ) status positive | 42 Participants | 41 Participants | 83 Participants |
| Sex: Female, Male Female | 41 Participants | 38 Participants | 79 Participants |
| Sex: Female, Male Male | 14 Participants | 17 Participants | 31 Participants |
| smoking current | 19 Participants | 23 Participants | 42 Participants |
| smoking never | 22 Participants | 19 Participants | 41 Participants |
| smoking past | 14 Participants | 13 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 55 | 1 / 55 |
| other Total, other adverse events | 43 / 55 | 47 / 55 |
| serious Total, serious adverse events | 4 / 55 | 5 / 55 |
Outcome results
Primary
Area Under Curve (AUC) of Disease Activity Score Based on a 28 Jointcount and C-reactive Protein (DAS28CRP)
Analysis was based on an intention to treat population, which focused on all patients randomized into the study, irrespective if they actually received the randomized treatment. Fifty-five patients were allocated to Standard COBRA-Slim and 55 to COBRA-Slim Bio-induction. This measure is an indication of the total disease-activity over time or long-term effectiveness, a higher area under the curve indicates a higher disease activity over time and so a lower effectiveness over the time frame of the trial. The scale range for the duration of the trial (104 weeks) is 0.0 to 977.6 * remission: value below 270.4 * low disease activity: from 270.4 till 332.8 (included) * moderate disease activity: above 332.8 till 530.4 * high disease activity: above 530.4
Time frame: baseline, w4, w8, w16, w24, w32, w40, w52, w64, w78, w92 and w104
Population: intention to treat (ITT) population
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Standard COBRA-Slim Induction | Area Under Curve (AUC) of Disease Activity Score Based on a 28 Jointcount and C-reactive Protein (DAS28CRP) | 297.4 units on a scale*week |
| COBRA-Slim Bio-induction | Area Under Curve (AUC) of Disease Activity Score Based on a 28 Jointcount and C-reactive Protein (DAS28CRP) | 300.7 units on a scale*week |
Comparison: To compare the two randomization groups, a linear mixed model with DAS28-CRP as outcome (Bell et al. 2014), including random intercepts per patient, adjusted for baseline DAS28-CRP, randomization timepoint, and RF and/or ACPA seropositivity was used.p-value: <0.05Mixed Models Analysis
Secondary
Health Assessment Questionnaire (HAQ) Response
HAQ measures physical function as reported by the patient, total score range from 0-3 of which higher scores represent worse physical function.
Time frame: at week 104
Population: Intention to treat (ITT) population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard COBRA-Slim Induction | Health Assessment Questionnaire (HAQ) Response | 0.7 score on a scale | Standard Deviation 0.7 |
| COBRA-Slim Bio-induction | Health Assessment Questionnaire (HAQ) Response | 0.9 score on a scale | Standard Deviation 0.7 |
Secondary
Health Assessment Questionnaire (HAQ) Response
HAQ measures physical function as reported by the patient, total score range from 0-3 of which higher scores represent worse physical function.
Time frame: at 28 weeks after randomization
Population: Intention to treat (ITT) population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard COBRA-Slim Induction | Health Assessment Questionnaire (HAQ) Response | 0.7 score on a scale | Standard Deviation 0.7 |
| COBRA-Slim Bio-induction | Health Assessment Questionnaire (HAQ) Response | 0.8 score on a scale | Standard Deviation 0.7 |
Secondary
Proportion of Insufficient Responders Achieving Remission (DAS28CRP<2.6) 28 Weeks After Randomization (Short Term Efficacy) to Either COBRA-Slim Bio-Induction or Standard COBRA-Slim Induction
Short-time efficacy of disease activity based on a swollen and tender joint count of 28 joints and C-reactive proteine (scale range 0.0 to 9.4; remission: value below 2.6; low disease activity: from 2.6 till 3.2 (included); moderate disease activity: above 3.2 till 5.1; high disease activity: above 5.1).
Time frame: From randomization till 28 weeks after randomization.
Population: intention to treat (ITT) population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard COBRA-Slim Induction | Proportion of Insufficient Responders Achieving Remission (DAS28CRP<2.6) 28 Weeks After Randomization (Short Term Efficacy) to Either COBRA-Slim Bio-Induction or Standard COBRA-Slim Induction | 24 participants |
| COBRA-Slim Bio-induction | Proportion of Insufficient Responders Achieving Remission (DAS28CRP<2.6) 28 Weeks After Randomization (Short Term Efficacy) to Either COBRA-Slim Bio-Induction or Standard COBRA-Slim Induction | 32 participants |
Comparison: A binomial generalized linear mixed effect model for repeated measures of remission from randomization up until 28 weeks after was carried out, with adjustment for baseline DAS28-CRP, moment of randomization, and RF and/or ACPA seropositivity.p-value: <0.05Mixed Models Analysis
Secondary
Proportion of Patients Achieving a EULAR Response
proportion of patients achieving a EULAR response, based on actual disease activity on a tender/swollen joint count and C-reactive proteine (DAS28-CRP) at week 104 and improvement in DAS28-CRP from baseline. The EULAR response criteria classify patients as good, moderate or non-responders, using the individual amount of change in the DAS28-CRP and the DAS28-CRP value (low, moderate, or high) reached according to the following tabel: DAS28-CRP at endpoint improvement in DAS28-CRP from baseline \<=1,2 \>0,6 and \<= 1,2 \<=0,6 \<= 3,2 good moderate none \>3,2 and \<= 5,1 moderate moderate none \>5,1 moderate none none Additionally all patients with a good response were also included in the number of participants with at least a moderate response.
Time frame: at week 104
Population: Intention to treat (ITT) population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard COBRA-Slim Induction | Proportion of Patients Achieving a EULAR Response | Good Response | 42 participants |
| Standard COBRA-Slim Induction | Proportion of Patients Achieving a EULAR Response | Moderate Response | 52 participants |
| COBRA-Slim Bio-induction | Proportion of Patients Achieving a EULAR Response | Good Response | 34 participants |
| COBRA-Slim Bio-induction | Proportion of Patients Achieving a EULAR Response | Moderate Response | 49 participants |
Secondary
Proportion of Patients Achieving a EULAR Response
proportion of patients achieving a EULAR response, based on actual disease activity on a tender/swollen joint count and C-reactive proteine (DAS28-CRP) 28 weeks after randomization and improvement in DAS28-CRP from baseline. The EULAR response criteria classify patients as good, moderate or non-responders, using the individual amount of change in the DAS28-CRP and the DAS28-CRP value (low, moderate, or high) reached according to the following tabel: DAS28-CRP at endpoint improvement in DAS28-CRP from baseline \<=1,2 \>0,6 and \<= 1,2 \<=0,6 \<= 3,2 good moderate none \>3,2 and \<= 5,1 moderate moderate none \>5,1 moderate none none Additionally all patients with a good response were also included in the number of participants with at least a moderate response.
Time frame: at 28 weeks after randomization
Population: Intention to treat (ITT) population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard COBRA-Slim Induction | Proportion of Patients Achieving a EULAR Response | Good Response | 26 participants |
| Standard COBRA-Slim Induction | Proportion of Patients Achieving a EULAR Response | Moderate Response | 41 participants |
| COBRA-Slim Bio-induction | Proportion of Patients Achieving a EULAR Response | Good Response | 25 participants |
| COBRA-Slim Bio-induction | Proportion of Patients Achieving a EULAR Response | Moderate Response | 40 participants |
Secondary
Proportion of Patients in Remission Defined as DAS28CRP<2.6
Short-time efficacy of disease activity based on a swollen and tender joint count of 28 joints and C-reactive proteine (scale range 0.0 to 9.4; remission: value below 2.6; low disease activity: from 2.6 till 3.2 (included); moderate disease activity: above 3.2 till 5.1; high disease activity: above 5.1).
Time frame: at week 104
Population: intention to treat (ITT) population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard COBRA-Slim Induction | Proportion of Patients in Remission Defined as DAS28CRP<2.6 | 38 participants |
| COBRA-Slim Bio-induction | Proportion of Patients in Remission Defined as DAS28CRP<2.6 | 30 participants |
Secondary
Radiographic Progression
Radiographic progression at week 52 is scored according to the Sharp-Van der Heijde score (SvdH). The SvdH method scores the presence of erosions in 16 joints of hands and wrists (graded from 0 to 5), and in 6 joints of the feet (graded from 0 to 10), and the presence of joint space narrowing in 15 joints of the hands and wrists (graded from 0 to 4) and in 6 joints of the feet (graded from 0 to 4). The maximal range is 280 units for erosion and 168 units for joint space narrowing, summing up to 448 units for the total score. The progression is calculated by subtracting the total score at week 52 minus the total score at baseline (ranging from 0 to 448) Higher values in each (sub) scale represents a worse outcome.
Time frame: at week 52
Population: Intention to treat (ITT) population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard COBRA-Slim Induction | Radiographic Progression | 0.5 units on a scale | Standard Deviation 1.2 |
| COBRA-Slim Bio-induction | Radiographic Progression | 0.3 units on a scale | Standard Deviation 0.9 |
Secondary
Radiographic Progression
Radiographic progression at week 104 is scored according to the Sharp-Van der Heijde score (SvdH). The SvdH method scores the presence of erosions in 16 joints of hands and wrists (graded from 0 to 5), and in 6 joints of the feet (graded from 0 to 10), and the presence of joint space narrowing in 15 joints of the hands and wrists (graded from 0 to 4) and in 6 joints of the feet (graded from 0 to 4). The maximal range is 280 units for erosion and 168 units for joint space narrowing, summing up to 448 units for the total score. The progression is calculated by subtracting the total score at week 104 minus the total score at baseline (ranging from 0 to 448) Higher values in each (sub) scale represents a worse outcome.
Time frame: at week 104
Population: Intention to treat (ITT) population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard COBRA-Slim Induction | Radiographic Progression | 0.7 units on a scale | Standard Deviation 2.1 |
| COBRA-Slim Bio-induction | Radiographic Progression | 0.8 units on a scale | Standard Deviation 1.7 |