Rheumatoid Arthritis
Conditions
Brief summary
This randomized, multicenter, double-blind, parallel group study will evaluate the impact of MTX discontinuation on the efficacy of SC TCZ in participants with moderate to severe active rheumatoid arthritis who have an inadequate response to current MTX therapy. Participants will initiate treatment with TCZ weekly or every 2 weeks along with MTX at a stable dose orally in an open-label manner for 24 weeks. Participants with a disease activity score based on 28 joints (DAS28) less than or equal to (\</=) 3.2 at Week 24, will be randomized to either continue receiving a stable dose of MTX or to switch to matching placebo up to Week 52. Participants without a DAS28 score \</=3.2 at Week 24, will continue the same treatment in a non-randomized open-label manner up to Week 52.
Interventions
TCZ will be administered at a dose of 162 milligrams (mg) via SC injection weekly (if body weight is greater than or equal to \[\>/=\] 100 kilograms \[kg\]) or every 2 weeks (if body weight was less than \[\<\] 100 kg).
DRUGMethotrexate (MTX)
MTX will be administered at a stable dose (15 mg to 25 mg per week) orally.
DRUGPlacebo (PBO)
PBO matching to MTX will be administered orally.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Body weight \</=150 kg * Active moderate to severe rheumatoid arthritis (DAS28 \>/=4.4) according to the revised 1987 ACR criteria at screening and baseline (prior to treatment on Day 1) * Currently receiving oral MTX for at least 24 weeks and on a stable oral dose of at least 15 mg/week for at least 6 weeks prior to treatment (Day 1), with the following exception: a stable dose of at least 10 mg/week is allowed for participants with a body weight \<50 kg or calculated glomerular filtration rate (or creatinine clearance) \<60 milliliters per minute (mL/min) * History of parenteral (SC or intramuscular \[IM\]) MTX is allowed, but not within 6 weeks prior to treatment (Day 1). Participants must not have a documented, clinically significant intolerance to oral MTX and must be receiving oral MTX at a dose of 15 mg/week for at least 6 weeks prior to treatment (Day 1) * Participants who have received one prior anti-tumor necrosis factor (TNF) must have discontinued etanercept, infliximab, certolizumab, adalimumab, or golimumab for at least 6 months prior to screening * Oral corticosteroids must have been \</=10 mg/day prednisone (or equivalent) and stable for at least 25 out of 28 days prior to treatment (Day 1) * Participants receiving treatment on an outpatient basis
Exclusion criteria
* Documented medical history of significant intolerance to oral MTX \>/=15 mg/week * Participants receiving other (non-MTX) disease modifying anti-rheumatic drugs (DMARDs) within 8 weeks of screening * Previous treatment with abatacept, rituximab, tofacitinib, or anakinra * Treatment with parenteral corticosteroids within 4 weeks prior to treatment * Previous treatment with cell-depleting therapies or alkylating agents * Previous treatment with TCZ * Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery during the study * Rheumatic autoimmune disease other than rheumatoid arthritis * Non-rheumatic active autoimmune diseases (for example, inflammatory bowel diseases, psoriasis, multiple sclerosis) * Prior history of or current inflammatory joint disease other than rheumatoid arthritis * Functional Class IV according to the revised (1987) ACR criteria for rheumatoid arthritis * History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies * Evidence of significant uncontrolled concomitant diseases; uncontrolled disease states where flares are commonly treated with oral or parenteral corticosteroids * Active current or history of recurrent infection, or any major episode of infection requiring hospitalization or treatment with intravenous antibiotics within 4 weeks prior to screening or oral antibiotics within 2 weeks prior to screening * Active tuberculosis requiring treatment within the previous 3 years * History of or currently active primary or secondary immunodeficiency * Pregnant or breast-feeding women * Positive for hepatitis B or hepatitis C infection * For potential MRI substudy participants: the presence of any metal-containing device or object in the body
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Week 24 in Disease Activity Score Based on 28 Joints (DAS28) Score at Week 40 | Week 24, Week 40 | The DAS28 was derived from assessments of erythrocyte sedimentation rate (ESR) measured in millimeters per hour (mm/h), tender joint count on 28 joints (TJC28), swollen joint count on 28 joints (SJC28), and Patient's Global Assessment of disease activity according to 100--millimeter (mm) Visual Analog Scale (VAS). DAS28 score was calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. DAS28 score could range from 0 to 10, where higher score represented higher disease activity. The change from Week 24 to Week 40 was averaged among all participants, where negative changes indicated an improvement in disease activity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving 50% Improvement in American College of Rheumatology (ACR50) Response | Weeks 24, 40, and 52 | The ACR50 response at any time was defined as \>/=50% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 50% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via HAQ-DI, and 5) Acute phase reactant (ESR in mm/h or CRP in mg/dL). |
| Percentage of Participants Achieving 70% Improvement in American College of Rheumatology (ACR70) Response | Weeks 24, 40, and 52 | The ACR70 response at any time was defined as \>/=70% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 70% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via HAQ-DI, and 5) Acute phase reactant (ESR in mm/h or CRP in mg/dL). |
| Percentage of Participants With >/=1.2 Points Increase (Worsening) From Week 24 in DAS28 Score at Week 40 and 52 | Week 24, 40, and 52 | The DAS28 was derived from assessments of ESR measured in mm/h, TJC28, SJC28, and Patient's global assessment of disease activity according to 100-mm VAS. DAS28 score was calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. DAS28- score could range from 0 to 10, where higher score represented higher disease activity. |
| Percentage of Participants With DAS28 Score <2.6 (DAS28 Remission) | Week 40, Week 52 | The DAS28 was derived from assessments of ESR measured in mm/h, TJC28, SJC28, and Patient's global assessment of disease activity according to 100-mm VAS. DAS28 score was calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. DAS28 score could range from 0 to 10, where higher score represented higher disease activity. |
| Percentage of Participants Achieving 20% Improvement in American College of Rheumatology (ACR20) Response | Weeks 24, 40, and 52 | The ACR20 response at any time was defined as \>/=20% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 20% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via a Health Assessment Questionnaire-Disability Index (HAQ-DI), and 5) Acute phase reactant (ESR in mm/h or C-Reactive Protein \[CRP\] in milligrams per deciliter \[mg/dL\]). |
| Change From Week 24 in Bone Erosion Score at Week 40 for Participants in the Magnetic Resonance Imaging (MRI) Substudy | Weeks 24, Week 40 | Bones from the wrist regions (carpal bones, distal radius, distal ulna, and metacarpal bases) and the metacarpophalangeal (MCP) joints (metacarpal heads and phalangeal bases) were assessed for erosion via MRI and scored separately based on the proportion of eroded bone compared to the 'assessed bone volume' judged from all available images. Scoring ranged from 0 (no erosion) to 10 (91-100%). Results were summed, resulting in scores from 0 to 80 for the wrist region, 0 to 150 for the MCP joints, and 0 to 230 on aggregate. A negative value for change from Week 24 in bone erosion score indicated an improvement. |
| Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to TCZ | Baseline, Post-baseline (assessed at Weeks 12, 24, 36, 52 and at follow up [Week 60]) | Percentage of participants with positive results for ATA against TCZ at Baseline and at any of the post-baseline assessment time-points was reported. Participants positive at any post-baseline time points were participants who had no positivity at baseline for the same assay. |
| Mean TCZ Serum Concentration | Baseline, Weeks 12, 24, 36, 52 and follow up (Week 60) | — |
| Mean Soluble Interleukin-6 (IL-6) Receptor Concentration | Baseline, Weeks 12, 24, 36, 52 and follow up (Week 60) | — |
| Percentage of Participants With DAS28 Score </=3.2 (Low DAS28) | Week 40, Week 52 | The DAS28 was derived from assessments of ESR measured in mm/h, TJC28, SJC28, and Patient's global assessment of disease activity according to 100-mm VAS. DAS28 score was calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. DAS28-ESR score could range from 0 to 10, where higher score represented higher disease activity. |
Countries
United States
Participant flow
Pre-assignment details
Randomized participants constituted the primary analysis population for the efficacy assessments, while all other analyses including safety assessments were performed on overall study population. An MRI sub-study was planned to evaluate joint inflammation in conjunction with other clinical signs and symptoms.
Participants by arm
| Arm | Count |
|---|---|
| Overall Study Population All enrolled participants received TCZ at a dose of 162 mg via SC injection qw (if body weight was \>/=100 kg) or q2w (if body weight was \<100 kg) along with MTX at a stable dose (15 mg to 25 mg per week) in an open-label manner orally for 24 weeks. Participants, who achieved a DAS28 score \</=3.2 at Week 24, were randomized and received double-blind treatment according to the arm in which they were randomized (TCZ + MTX or TCZ + PBO) up to Week 52. Participants who did not achieve a DAS28 score \</=3.2 at Week 24 continued the same treatment in a non-randomized open-label manner up to Week 52. | 711 |
| Total | 711 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| 1) Baseline up to Week 24 | Adverse Event | 37 | 0 | 0 | 0 |
| 1) Baseline up to Week 24 | Death | 2 | 0 | 0 | 0 |
| 1) Baseline up to Week 24 | Lack of Efficacy | 16 | 0 | 0 | 0 |
| 1) Baseline up to Week 24 | Lost to Follow-up | 11 | 0 | 0 | 0 |
| 1) Baseline up to Week 24 | Other | 4 | 0 | 0 | 0 |
| 1) Baseline up to Week 24 | Participant Non-compliance | 3 | 0 | 0 | 0 |
| 1) Baseline up to Week 24 | Physician Decision | 4 | 0 | 0 | 0 |
| 1) Baseline up to Week 24 | Pregnancy | 1 | 0 | 0 | 0 |
| 1) Baseline up to Week 24 | Protocol Violation | 4 | 0 | 0 | 0 |
| 1) Baseline up to Week 24 | Sponsor Decision | 3 | 0 | 0 | 0 |
| 1) Baseline up to Week 24 | Withdrawal by Subject | 31 | 0 | 0 | 0 |
| 2) Week 24 up to End of Study | Adverse Event | 0 | 4 | 5 | 21 |
| 2) Week 24 up to End of Study | Lack of Efficacy | 0 | 2 | 5 | 16 |
| 2) Week 24 up to End of Study | Lost to Follow-up | 0 | 1 | 1 | 4 |
| 2) Week 24 up to End of Study | Other | 0 | 0 | 0 | 1 |
| 2) Week 24 up to End of Study | Participant Non-compliance | 0 | 1 | 0 | 1 |
| 2) Week 24 up to End of Study | Physician Decision | 0 | 0 | 2 | 4 |
| 2) Week 24 up to End of Study | Protocol Violation | 0 | 0 | 0 | 1 |
| 2) Week 24 up to End of Study | Serious Hypersensitivity Reaction | 0 | 0 | 0 | 1 |
| 2) Week 24 up to End of Study | Sponsor Decision | 0 | 0 | 0 | 1 |
| 2) Week 24 up to End of Study | Withdrawal by Subject | 0 | 7 | 5 | 8 |
Baseline characteristics
| Characteristic | Overall Study Population |
|---|---|
| Age, Continuous | 55.8 years STANDARD_DEVIATION 12.31 |
| Sex: Female, Male Female | 556 Participants |
| Sex: Female, Male Male | 155 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 348 / 713 |
| serious Total, serious adverse events | 72 / 713 |
Outcome results
Primary
Change From Week 24 in Disease Activity Score Based on 28 Joints (DAS28) Score at Week 40
The DAS28 was derived from assessments of erythrocyte sedimentation rate (ESR) measured in millimeters per hour (mm/h), tender joint count on 28 joints (TJC28), swollen joint count on 28 joints (SJC28), and Patient's Global Assessment of disease activity according to 100--millimeter (mm) Visual Analog Scale (VAS). DAS28 score was calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. DAS28 score could range from 0 to 10, where higher score represented higher disease activity. The change from Week 24 to Week 40 was averaged among all participants, where negative changes indicated an improvement in disease activity.
Time frame: Week 24, Week 40
Population: Analysis was performed on randomized group which included participants in ITT population who were randomized and received blinded treatment at Week 24. Missing Week 40 values were imputed using last available assessment obtained after Week 24. Here, 'Number Analyzed' signifies number of participants with assessment at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Period 2: Randomized Participants (TCZ + MTX) | Change From Week 24 in Disease Activity Score Based on 28 Joints (DAS28) Score at Week 40 | Week 24 | 2.13 units on a scale | Standard Deviation 0.816 |
| Period 2: Randomized Participants (TCZ + MTX) | Change From Week 24 in Disease Activity Score Based on 28 Joints (DAS28) Score at Week 40 | Change at Week 40 | 0.15 units on a scale | Standard Deviation 1.127 |
| Period 2: Randomized Participants (TCZ + PBO) | Change From Week 24 in Disease Activity Score Based on 28 Joints (DAS28) Score at Week 40 | Week 24 | 2.11 units on a scale | Standard Deviation 0.822 |
| Period 2: Randomized Participants (TCZ + PBO) | Change From Week 24 in Disease Activity Score Based on 28 Joints (DAS28) Score at Week 40 | Change at Week 40 | 0.48 units on a scale | Standard Deviation 1.275 |
Comparison: Analysis of covariance (ANCOVA) model included Week 24 DAS28 as a covariate, treatment group, and the randomization stratification factors: DAS28 remission status at Week 24 (\<2.6, \>/=2.6 to \</=3.2), baseline weight-by-dosing group (\<80 kg q2w, \<80 kg qw, 80-\<100 kg q2w, 80-\<100 kg qw, \>/=100 kg qw), participant anti-tumor necrosis factor (anti-TNF) exposure (Yes/No).95% CI: [0.045, 0.592]
Secondary
Change From Week 24 in Bone Erosion Score at Week 40 for Participants in the Magnetic Resonance Imaging (MRI) Substudy
Bones from the wrist regions (carpal bones, distal radius, distal ulna, and metacarpal bases) and the metacarpophalangeal (MCP) joints (metacarpal heads and phalangeal bases) were assessed for erosion via MRI and scored separately based on the proportion of eroded bone compared to the 'assessed bone volume' judged from all available images. Scoring ranged from 0 (no erosion) to 10 (91-100%). Results were summed, resulting in scores from 0 to 80 for the wrist region, 0 to 150 for the MCP joints, and 0 to 230 on aggregate. A negative value for change from Week 24 in bone erosion score indicated an improvement.
Time frame: Weeks 24, Week 40
Population: Analysis was performed on MRI subset which included all participants in the randomized group who passed MRI eligibility requirements and who had an MRI performed on or after the Week 24 visit. Here, 'Number Analyzed' signifies participants with assessment at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Period 2: Randomized Participants (TCZ + MTX) | Change From Week 24 in Bone Erosion Score at Week 40 for Participants in the Magnetic Resonance Imaging (MRI) Substudy | Week 24 | 10.66 units on a scale | Standard Deviation 11.217 |
| Period 2: Randomized Participants (TCZ + MTX) | Change From Week 24 in Bone Erosion Score at Week 40 for Participants in the Magnetic Resonance Imaging (MRI) Substudy | Change at Week 40 | -0.10 units on a scale | Standard Deviation 0.844 |
| Period 2: Randomized Participants (TCZ + PBO) | Change From Week 24 in Bone Erosion Score at Week 40 for Participants in the Magnetic Resonance Imaging (MRI) Substudy | Week 24 | 9.05 units on a scale | Standard Deviation 7.926 |
| Period 2: Randomized Participants (TCZ + PBO) | Change From Week 24 in Bone Erosion Score at Week 40 for Participants in the Magnetic Resonance Imaging (MRI) Substudy | Change at Week 40 | 0.17 units on a scale | Standard Deviation 1.067 |
Comparison: ANCOVA model included Week 24 bone erosion as a covariate, treatment group, and the randomization stratification factors: DAS28 remission status at Week 24 (\<2.6, \>/=2.6 to \</=3.2), participant anti-TNF exposure (Yes/No), baseline weight-by-dosing group (\<80 kg q2w, 80-\<100 kg q2w, 80-\<100 kg qw, \>=100 kg qw).95% CI: [-0.21, 0.68]
Secondary
Mean Soluble Interleukin-6 (IL-6) Receptor Concentration
Time frame: Baseline, Weeks 12, 24, 36, 52 and follow up (Week 60)
Population: Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups. 'Number Analyzed' = number of participants with assessment at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Period 2: Randomized Participants (TCZ + MTX) | Mean Soluble Interleukin-6 (IL-6) Receptor Concentration | Baseline | 40.4 nanograms per milliliter | Standard Deviation 18.14 |
| Period 2: Randomized Participants (TCZ + MTX) | Mean Soluble Interleukin-6 (IL-6) Receptor Concentration | Week 12 | 366.4 nanograms per milliliter | Standard Deviation 179.21 |
| Period 2: Randomized Participants (TCZ + MTX) | Mean Soluble Interleukin-6 (IL-6) Receptor Concentration | Week 24 | 441.3 nanograms per milliliter | Standard Deviation 190.78 |
| Period 2: Randomized Participants (TCZ + MTX) | Mean Soluble Interleukin-6 (IL-6) Receptor Concentration | Week 36 | 468.9 nanograms per milliliter | Standard Deviation 211.73 |
| Period 2: Randomized Participants (TCZ + MTX) | Mean Soluble Interleukin-6 (IL-6) Receptor Concentration | Week 52 | 336.3 nanograms per milliliter | Standard Deviation 267.2 |
| Period 2: Randomized Participants (TCZ + MTX) | Mean Soluble Interleukin-6 (IL-6) Receptor Concentration | Week 60 | 166.8 nanograms per milliliter | Standard Deviation 211.39 |
Secondary
Mean TCZ Serum Concentration
Time frame: Baseline, Weeks 12, 24, 36, 52 and follow up (Week 60)
Population: Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups. 'Number Analyzed' = number of participants with assessment at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Period 2: Randomized Participants (TCZ + MTX) | Mean TCZ Serum Concentration | Baseline | 0.01 micrograms per milliliter | Standard Deviation 0.223 |
| Period 2: Randomized Participants (TCZ + MTX) | Mean TCZ Serum Concentration | Week 12 | 8.66 micrograms per milliliter | Standard Deviation 10.59 |
| Period 2: Randomized Participants (TCZ + MTX) | Mean TCZ Serum Concentration | Week 24 | 23.38 micrograms per milliliter | Standard Deviation 22.979 |
| Period 2: Randomized Participants (TCZ + MTX) | Mean TCZ Serum Concentration | Week 36 | 25.58 micrograms per milliliter | Standard Deviation 23.133 |
| Period 2: Randomized Participants (TCZ + MTX) | Mean TCZ Serum Concentration | Week 52 | 16.46 micrograms per milliliter | Standard Deviation 20.976 |
| Period 2: Randomized Participants (TCZ + MTX) | Mean TCZ Serum Concentration | Week 60 | 6.16 micrograms per milliliter | Standard Deviation 15.768 |
Secondary
Percentage of Participants Achieving 20% Improvement in American College of Rheumatology (ACR20) Response
The ACR20 response at any time was defined as \>/=20% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 20% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via a Health Assessment Questionnaire-Disability Index (HAQ-DI), and 5) Acute phase reactant (ESR in mm/h or C-Reactive Protein \[CRP\] in milligrams per deciliter \[mg/dL\]).
Time frame: Weeks 24, 40, and 52
Population: Analysis was performed on randomized group. Missing assessments of response were treated as no response.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Period 2: Randomized Participants (TCZ + MTX) | Percentage of Participants Achieving 20% Improvement in American College of Rheumatology (ACR20) Response | Week 24 | 91.2 percentage of participants | 0.816 |
| Period 2: Randomized Participants (TCZ + MTX) | Percentage of Participants Achieving 20% Improvement in American College of Rheumatology (ACR20) Response | Week 40 | 78.9 percentage of participants | 1.127 |
| Period 2: Randomized Participants (TCZ + MTX) | Percentage of Participants Achieving 20% Improvement in American College of Rheumatology (ACR20) Response | Week 52 | 74.1 percentage of participants | — |
| Period 2: Randomized Participants (TCZ + PBO) | Percentage of Participants Achieving 20% Improvement in American College of Rheumatology (ACR20) Response | Week 24 | 83.0 percentage of participants | 0.822 |
| Period 2: Randomized Participants (TCZ + PBO) | Percentage of Participants Achieving 20% Improvement in American College of Rheumatology (ACR20) Response | Week 40 | 68.7 percentage of participants | 1.275 |
| Period 2: Randomized Participants (TCZ + PBO) | Percentage of Participants Achieving 20% Improvement in American College of Rheumatology (ACR20) Response | Week 52 | 65.3 percentage of participants | — |
Comparison: Week 40: Analysis of association between treatment group and response, stratified by the randomization stratification factors: DAS28 remission status at Week 24 (\<2.6, \>=2.6 to \<=3.2), baseline weight-by-dosing group (\<80 kg q2w, \<80 kg qw, 80-\<100 kg q2w, 80-\<100 kg qw, \>=100 kg qw), participant anti-TNF exposure (Yes/No).p-value: 0.074695% CI: [-20.2, -0.2]Cochran-Mantel-Haenszel
Comparison: Week 52: Analysis of association between treatment group and response, stratified by the randomization stratification factors: DAS28 remission status at Week 24 (\<2.6, \>=2.6 to \<=3.2), baseline weight-by-dosing group (\<80 kg q2w, \<80 kg qw, 80-\<100 kg q2w, 80-\<100 kg qw, \>=100 kg qw), participant anti-TNF exposure (Yes/No).p-value: 0.115995% CI: [-19.3, 1.6]Cochran-Mantel-Haenszel
Comparison: Week 2495% CI: [-15.8, -0.6]
Secondary
Percentage of Participants Achieving 50% Improvement in American College of Rheumatology (ACR50) Response
The ACR50 response at any time was defined as \>/=50% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 50% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via HAQ-DI, and 5) Acute phase reactant (ESR in mm/h or CRP in mg/dL).
Time frame: Weeks 24, 40, and 52
Population: Analysis was performed on randomized group. Missing assessments of response were treated as no response.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Period 2: Randomized Participants (TCZ + MTX) | Percentage of Participants Achieving 50% Improvement in American College of Rheumatology (ACR50) Response | Week 24 | 74.1 percentage of participants | 0.816 |
| Period 2: Randomized Participants (TCZ + MTX) | Percentage of Participants Achieving 50% Improvement in American College of Rheumatology (ACR50) Response | Week 40 | 63.9 percentage of participants | 1.127 |
| Period 2: Randomized Participants (TCZ + MTX) | Percentage of Participants Achieving 50% Improvement in American College of Rheumatology (ACR50) Response | Week 52 | 62.6 percentage of participants | — |
| Period 2: Randomized Participants (TCZ + PBO) | Percentage of Participants Achieving 50% Improvement in American College of Rheumatology (ACR50) Response | Week 24 | 63.3 percentage of participants | 0.822 |
| Period 2: Randomized Participants (TCZ + PBO) | Percentage of Participants Achieving 50% Improvement in American College of Rheumatology (ACR50) Response | Week 40 | 50.3 percentage of participants | 1.275 |
| Period 2: Randomized Participants (TCZ + PBO) | Percentage of Participants Achieving 50% Improvement in American College of Rheumatology (ACR50) Response | Week 52 | 47.6 percentage of participants | — |
Comparison: Week 40: Analysis of association between treatment group and response, stratified by the randomization stratification factors: DAS28 remission status at Week 24 (\<2.6, \>=2.6 to \<=3.2), baseline weight-by-dosing group (\<80 kg q2w, \<80 kg qw, 80-\<100 kg q2w, 80-\<100 kg qw, \>=100 kg qw), participant anti-TNF exposure (Yes/No).p-value: 0.037795% CI: [-24.8, -2.4]Cochran-Mantel-Haenszel
Comparison: Week 52: Analysis of association between treatment group and response, stratified by the randomization stratification factors: DAS28 remission status at Week 24 (\<2.6, \>=2.6 to \<=3.2), baseline weight-by-dosing group (\<80 kg q2w, \<80 kg qw, 80-\<100 kg q2w, 80-\<100 kg qw, \>=100 kg qw), participant anti-TNF exposure (Yes/No).p-value: 0.01395% CI: [-26.2, -3.7]Cochran-Mantel-Haenszel
Comparison: Week 2495% CI: [-21.4, -0.4]
Secondary
Percentage of Participants Achieving 70% Improvement in American College of Rheumatology (ACR70) Response
The ACR70 response at any time was defined as \>/=70% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 70% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via HAQ-DI, and 5) Acute phase reactant (ESR in mm/h or CRP in mg/dL).
Time frame: Weeks 24, 40, and 52
Population: Analysis was performed on randomized group. Missing assessments of response were treated as no response.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Period 2: Randomized Participants (TCZ + MTX) | Percentage of Participants Achieving 70% Improvement in American College of Rheumatology (ACR70) Response | Week 24 | 45.6 percentage of participants | 0.816 |
| Period 2: Randomized Participants (TCZ + MTX) | Percentage of Participants Achieving 70% Improvement in American College of Rheumatology (ACR70) Response | Week 40 | 42.2 percentage of participants | 1.127 |
| Period 2: Randomized Participants (TCZ + MTX) | Percentage of Participants Achieving 70% Improvement in American College of Rheumatology (ACR70) Response | Week 52 | 48.3 percentage of participants | — |
| Period 2: Randomized Participants (TCZ + PBO) | Percentage of Participants Achieving 70% Improvement in American College of Rheumatology (ACR70) Response | Week 24 | 37.4 percentage of participants | 0.822 |
| Period 2: Randomized Participants (TCZ + PBO) | Percentage of Participants Achieving 70% Improvement in American College of Rheumatology (ACR70) Response | Week 40 | 34.0 percentage of participants | 1.275 |
| Period 2: Randomized Participants (TCZ + PBO) | Percentage of Participants Achieving 70% Improvement in American College of Rheumatology (ACR70) Response | Week 52 | 36.7 percentage of participants | — |
Comparison: Week 40: Analysis of association between treatment group and response, stratified by the randomization stratification factors: DAS28 remission status at Week 24 (\<2.6, \>=2.6 to \<=3.2), baseline weight-by-dosing group (\<80 kg q2w, \<80 kg qw, 80-\<100 kg q2w, 80-\<100 kg qw, \>=100 kg qw), participant anti-TNF exposure (Yes/No).p-value: 0.359995% CI: [-19.2, 2.9]Cochran-Mantel-Haenszel
Comparison: Week 52: Analysis of association between treatment group and response, stratified by the randomization stratification factors: DAS28 remission status at Week 24 (\<2.6, \>=2.6 to \<=3.2), baseline weight-by-dosing group (\<80 kg q2w, \<80 kg qw, 80-\<100 kg q2w, 80-\<100 kg qw, \>=100 kg qw), participant anti-TNF exposure (Yes/No).p-value: 0.066395% CI: [-22.8, -0.3]Cochran-Mantel-Haenszel
Comparison: Week 2495% CI: [-19.4, 3.1]
Secondary
Percentage of Participants With >/=1.2 Points Increase (Worsening) From Week 24 in DAS28 Score at Week 40 and 52
The DAS28 was derived from assessments of ESR measured in mm/h, TJC28, SJC28, and Patient's global assessment of disease activity according to 100-mm VAS. DAS28 score was calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. DAS28- score could range from 0 to 10, where higher score represented higher disease activity.
Time frame: Week 24, 40, and 52
Population: Analysis was performed on randomized group. Missing assessments of DAS28 were treated as worsening.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Period 2: Randomized Participants (TCZ + MTX) | Percentage of Participants With >/=1.2 Points Increase (Worsening) From Week 24 in DAS28 Score at Week 40 and 52 | Week 40 | 21.1 percentage of participants | 0.816 |
| Period 2: Randomized Participants (TCZ + MTX) | Percentage of Participants With >/=1.2 Points Increase (Worsening) From Week 24 in DAS28 Score at Week 40 and 52 | Week 52 | 26.5 percentage of participants | 1.127 |
| Period 2: Randomized Participants (TCZ + PBO) | Percentage of Participants With >/=1.2 Points Increase (Worsening) From Week 24 in DAS28 Score at Week 40 and 52 | Week 40 | 28.6 percentage of participants | 0.822 |
| Period 2: Randomized Participants (TCZ + PBO) | Percentage of Participants With >/=1.2 Points Increase (Worsening) From Week 24 in DAS28 Score at Week 40 and 52 | Week 52 | 29.9 percentage of participants | 1.275 |
Comparison: Week 40: Analysis of association between treatment group and worsening in DAS28, stratified by the randomization stratification factors: DAS28 remission status at Week 24 (\<2.6, \>=2.6 to \<=3.2), baseline weight-by-dosing group (\<80 kg q2w, \<80 kg qw, 80-\<100 kg q2w, 80-\<100 kg qw, \>=100 kg qw), participant anti-TNF exposure (Yes/No).p-value: 0.237195% CI: [-2.4, 17.3]Cochran-Mantel-Haenszel
Comparison: Week 52: Analysis of association between treatment group and worsening in DAS28, stratified by the randomization stratification factors: DAS28 remission status at Week 24 (\<2.6, \>=2.6 to \<=3.2), baseline weight-by-dosing group (\<80 kg q2w, \<80 kg qw, 80-\<100 kg q2w, 80-\<100 kg qw, \>=100 kg qw), participant anti-TNF exposure (Yes/No).p-value: 0.481195% CI: [-6.9, 13.7]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to TCZ
Percentage of participants with positive results for ATA against TCZ at Baseline and at any of the post-baseline assessment time-points was reported. Participants positive at any post-baseline time points were participants who had no positivity at baseline for the same assay.
Time frame: Baseline, Post-baseline (assessed at Weeks 12, 24, 36, 52 and at follow up [Week 60])
Population: Analysis was performed on safety population which included all participants who received at least 1 dose of study drug and had at least 1 post-dose safety assessment. The analysis included overall study population and was not intended to compare the 2 randomized groups. 'Number Analyzed' = participants with ATA assessment at specified time points.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Period 2: Randomized Participants (TCZ + MTX) | Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to TCZ | Baseline | 1.8 percentage of participants |
| Period 2: Randomized Participants (TCZ + MTX) | Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to TCZ | Post-baseline | 1.5 percentage of participants |
Secondary
Percentage of Participants With DAS28 Score <2.6 (DAS28 Remission)
The DAS28 was derived from assessments of ESR measured in mm/h, TJC28, SJC28, and Patient's global assessment of disease activity according to 100-mm VAS. DAS28 score was calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. DAS28 score could range from 0 to 10, where higher score represented higher disease activity.
Time frame: Week 40, Week 52
Population: Analysis was performed on randomized group. Missing assessments of DAS28 were treated as no response.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Period 2: Randomized Participants (TCZ + MTX) | Percentage of Participants With DAS28 Score <2.6 (DAS28 Remission) | Week 40 | 59.2 percentage of participants | 0.816 |
| Period 2: Randomized Participants (TCZ + MTX) | Percentage of Participants With DAS28 Score <2.6 (DAS28 Remission) | Week 52 | 55.1 percentage of participants | 1.127 |
| Period 2: Randomized Participants (TCZ + PBO) | Percentage of Participants With DAS28 Score <2.6 (DAS28 Remission) | Week 40 | 49.7 percentage of participants | 0.822 |
| Period 2: Randomized Participants (TCZ + PBO) | Percentage of Participants With DAS28 Score <2.6 (DAS28 Remission) | Week 52 | 48.3 percentage of participants | 1.275 |
Comparison: Week 40: Analysis of association between treatment group and response, stratified by the randomization stratification factors: DAS28 remission status at Week 24 (\<2.6, \>=2.6 to \<=3.2), baseline weight-by-dosing group (\<80 kg q2w, \<80 kg qw, 80-\<100 kg q2w, 80-\<100 kg qw, \>=100 kg qw), participant anti-TNF exposure (Yes/No).p-value: 0.106295% CI: [-20.9, 1.8]Cochran-Mantel-Haenszel
Comparison: Week 52: Analysis of association between treatment group and response, stratified by the randomization stratification factors: DAS28 remission status at Week 24 (\<2.6, \>=2.6 to \<=3.2), baseline weight-by-dosing group (\<80 kg q2w, \<80 kg qw, 80-\<100 kg q2w, 80-\<100 kg qw, \>=100 kg qw), participant anti-TNF exposure (Yes/No).p-value: 0.361195% CI: [-18.2, 4.6]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With DAS28 Score </=3.2 (Low DAS28)
The DAS28 was derived from assessments of ESR measured in mm/h, TJC28, SJC28, and Patient's global assessment of disease activity according to 100-mm VAS. DAS28 score was calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. DAS28-ESR score could range from 0 to 10, where higher score represented higher disease activity.
Time frame: Week 40, Week 52
Population: Analysis was performed on randomized group. Missing assessments of DAS28 were treated as no response.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Period 2: Randomized Participants (TCZ + MTX) | Percentage of Participants With DAS28 Score </=3.2 (Low DAS28) | Week 40 | 76.9 percentage of participants | 0.816 |
| Period 2: Randomized Participants (TCZ + MTX) | Percentage of Participants With DAS28 Score </=3.2 (Low DAS28) | Week 52 | 68.0 percentage of participants | 1.127 |
| Period 2: Randomized Participants (TCZ + PBO) | Percentage of Participants With DAS28 Score </=3.2 (Low DAS28) | Week 40 | 63.3 percentage of participants | 0.822 |
| Period 2: Randomized Participants (TCZ + PBO) | Percentage of Participants With DAS28 Score </=3.2 (Low DAS28) | Week 52 | 62.6 percentage of participants | 1.275 |
Comparison: Week 40: Analysis of association between treatment group and response, stratified by the randomization stratification factors: DAS28 remission status at Week 24 (\<2.6, \>=2.6 to \<=3.2), baseline weight-by-dosing group (\<80 kg q2w, \<80 kg qw, 80-\<100 kg q2w, 80-\<100 kg qw, \>=100 kg qw), participant anti-TNF exposure (Yes/No).p-value: 0.022895% CI: [-24, -3.3]Cochran-Mantel-Haenszel
Comparison: Week 52: Analysis of association between treatment group and response, stratified by the randomization stratification factors: DAS28 remission status at Week 24 (\<2.6, \>=2.6 to \<=3.2), baseline weight-by-dosing group (\<80 kg q2w, \<80 kg qw, 80-\<100 kg q2w, 80-\<100 kg qw, \>=100 kg qw), participant anti-TNF exposure (Yes/No).p-value: 0.366595% CI: [-16.3, 5.4]Cochran-Mantel-Haenszel