Rheumatoid Arthritis
Conditions
Brief summary
This study will assess the long-term safety and efficacy of repeat treatment courses of rituximab, in combination with methotrexate in a disease-modifying anti-rheumatic drug (DMARD) inadequate responder population of participants who were previously randomized into studies WA16291 (NCT02693210) or WA17043/U2644g (NCT00074438). The study permits multiple re-treatments until the protocol-defined end-of-treatment date (31 December 2011). Participants will then enter a safety follow-up (SFU) period of at least 48 weeks. This will provide at least 7 years follow-up data on all participants initially randomized into WA16291 or WA17043/U2644g. Approximately 600 participants will potentially be eligible to enter this open label extension study from their respective feeder studies.
Interventions
DRUGRituximab
Participants will receive rituximab 1 gram IV on Days 1 and 15 of each course of retreatment.
DRUGMethotrexate
Participants will receive methotrexate 10-25 mg/week orally or parenterally.
DRUGMethylprednisolone
Participants will receive methylprednisolone 100 mg IV 30 minutes prior to each rituximab infusion.
DRUGFolic Acid
Participants will receive folic acid \>= 5 mg/week or equivalent.
Sponsors
Genentech, Inc.
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* participants with active RA * completed 24 weeks of treatment in WA16291 or WA17043 * eligible for re-treatment, based on clinical symptoms (Disease Activity Score in 28 joints \>=2.6) * females of childbearing potential using reliable contraception
Exclusion criteria
* participants who participated in rituximab studies WA16291 or WA17043 but withdrew into the safety follow-up phases of these trials * previous rituximab non-responders * current treatment with any other disease-modifying drug (apart from methotrexate), or any anti-tumor necrosis factor alfa, anti-interleukin-1, or other biologic therapies * participants with known active infection of any kind * evidence of any new or uncontrolled concomitant disease or development of any new contraindications which would preclude repeat treatment with rituximab * history of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies * female participants who are pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With ACR20 Response After Fifth Course | 24 weeks after fifth course of rituximab (median duration of 297.3 weeks) | A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043. |
| Percentage of Participants With ACR20 Response After Sixth Course | 24 weeks after sixth course of rituximab (median duration of 354.4 weeks) | A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043. |
| Percentage of Participants With ACR20 Response After Seventh Course | 24 weeks after seventh course of rituximab (median duration of 406.7 weeks) | A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043. |
| Percentage of Participants With an American College of Rheumatology 20 (ACR20) Response After First Course | 24 weeks after first course of rituximab (up to approximately 26 weeks) | A participant had an ACR20 response if there was at least a 20 percent (%) improvement, ie, reduction from Baseline, in tender joint count (TJC) and swollen joint count (SJC) (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity \[visual analog scale (VAS): 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (either C-reactive protein \[CRP\] or erythrocyte sedimentation rate \[ESR\]). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043. |
| Percentage of Participants With ACR20 Response After Second Course | 24 weeks after second course of rituximab (median duration of 90.9 weeks) | A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043. |
| Percentage of Participants With ACR20 Response After Third Course | 24 weeks after third course of rituximab (median duration of 162.9 weeks) | A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043. |
| Percentage of Participants With ACR20 Response After Fourth Course | 24 weeks after fourth course of rituximab (median duration of 232 weeks) | A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With European League Against Rheumatism (EULAR) Response of 'Good' or 'Moderate' | 24 weeks after first, second, third, fourth, fifth, sixth, and seventh course of rituximab (median duration of 26, 90.9, 162.9, 232, 297.3, 354.4, and 406.7 weeks, respectively) | DAS28-ESR was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and Physician's Global Assessment of Disease Activity (VAS: 0=no disease activity to 100=maximum disease activity). DAS28-ESR = 0.56\*sqrt(TJC28) + 0.28\*sqrt(SJC28) + 0.70\*ln(ESR) + 0.014\*Patient's Global Assessment of Disease Activity. The DAS28-based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders had a change from baseline greater than (\>) 1.2 with a DAS28 score less than or equal to (≤) 3.2; moderate responders had a change from baseline \>1.2 with a DAS28 score \>3.2 to less than or equal to (≤) 5.1 or a change from baseline \>0.6 to ≤1.2 with a DAS28 score ≤5.1. |
| Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at 24 Weeks Following Each Course | 24 weeks after first, second, third, fourth, fifth, sixth, and seventh course of rituximab (median duration of 26, 90.9, 162.9, 232, 297.3, 354.4, and 406.7 weeks, respectively) | The HAQ-DI is a questionnaire specific for rheumatoid arthritis and consists of 20 questions referring to 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Participants completed the questionnaire by answering the 20 questions on a scale of 0 (without difficulty) to 3 (unable to do). The total score ranges from 0 (no disability) to 3 (completely disabled). A negative change score indicates improvement. |
| Change From Baseline in Total Rheumatoid Factors (RF) at 24 Weeks Following Each Course | 24 weeks after first, second, third, fourth, fifth, sixth, and seventh course of rituximab (median duration of 26, 90.9, 162.9, 232, 297.3, 354.4, and 406.7 weeks, respectively) | — |
| Percentage of Participants Who Discontinued Treatment Due to Insufficient Response | First, second, third, fourth, fifth, sixth, and seventh course of rituximab (up to a median of approximately 2, 62, 124, 186, 248, 310, and 372 weeks, respectively) | — |
| Time Since Last Treatment Course | Baseline up to 10 years | Time since last treatment course = The last day of the last dose of rituximab to date of last contact. Date of last contact is the last available date of efficacy, complete medication start date, laboratory, adverse event assessments, early withdrawal visit, date of last contact, or date of death. |
| Percentage of Participants With ACR50 and ACR70 Response | 24 weeks after first, second, third, fourth, fifth, sixth, and seventh course of rituximab (median duration of 26, 90.9, 162.9, 232, 297.3, 354.4, and 406.7 weeks, respectively) | A participant had an ACR50 and ACR70 response if there was at least a 50% or 70% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of disease activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (CRP or ESR). The ACR50 and ACR70 responses were compared to Baseline in the precursor studies WA16291 or WA17043. |
| American College of Rheumatology Index of Improvement (ACRn) Response | 24 weeks after first, second, third, fourth, fifth, sixth, and seventh course of rituximab (median duration of 26, 90.9, 162.9, 232, 297.3, 354.4, and 406.7 weeks, respectively) | The ACRn is calculated for each participant by taking the lowest percentage improvement in (1) SJC or (2) TJC or (3) the median of the remaining 5 components of the ACR response (patient's assessment of disease activity; patient's global assessment of pain; physician's assessment of disease activity; participant's assessment of physical function; an acute phase reactant value \[either CRP or ESR\]). The index of improvement in RA, where 0 indicates no improvement and 100 indicates a 100% improvement across all signs and symptoms of RA. ACRn scores were calculated considering the original baseline in the precursor studies WA16291 or WA17043. |
| Percentage of Participants With Low Disease Activity and Clinical Remission Based on DAS28-ESR | 24 weeks after first, second, third, fourth, fifth, sixth, and seventh course of rituximab (median duration of 26, 90.9, 162.9, 232, 297.3, 354.4, and 406.7 weeks, respectively) | DAS28-ESR was calculated from SJC and TJC using 28 joints count, ESR (millimeters per hour \[mm/hour\]), and Patient's Global Assessment of Disease Activity (VAS: 0=no disease activity to 100=maximum disease activity). DAS28-ESR = 0.56\*square root (sqrt)(TJC28) + 0.28\*sqrt(SJC28) + 0.70\*natural logarithm (ln) (ESR) + 0.014\*Patient's Global Assessment of Disease Activity. Total score range: 0-10, higher score=more disease activity. DAS28-ESR \<= 3.2 implied low disease activity (LDA) and DAS28-ESR \<2.6 = clinical remission. |
Countries
Australia, Belgium, Brazil, Canada, Czechia, Finland, Germany, Israel, Italy, Mexico, New Zealand, Poland, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
This study included participants who had previously participated in studies WA16291 (NCT02693210) or WA17043 (NCT00074438).
Participants by arm
| Arm | Count |
|---|---|
| Rituximab Participants received rituximab 1 gram IV on Days 1 and 15 of each course of retreatment. In addition, participants received methotrexate 10-25 mg/week orally or parenterally, methylprednisolone 100 mg IV 30 minutes prior to both rituximab infusions, and a stable dose of folic acid \>=5 mg/week or equivalent. Participants received retreatment (next course of rituximab repeat treatment) within 2 weeks of meeting the retreatment criteria as defined in the protocol (minimum of 24 weeks after the first \[Day 1\] infusion of the last course of rituximab). Repeat treatment was based on the investigator's decision of prior clinical response to rituximab, clinical need and evidence of active disease (Disease Activity Score in 28 joints \>=2.6). Retreatment with rituximab was continued until withdrawal of consent or study treatment completion on 31 December 2011, whichever occurred earlier. | 465 |
| Total | 465 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 26 |
| Overall Study | Death | 10 |
| Overall Study | Other | 157 |
Baseline characteristics
| Characteristic | Rituximab |
|---|---|
| Age, Continuous | 51 years STANDARD_DEVIATION 12.01 |
| Sex: Female, Male Female | 364 Participants |
| Sex: Female, Male Male | 101 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 422 / 465 | 93 / 127 |
| serious Total, serious adverse events | 230 / 465 | 12 / 127 |
Outcome results
Primary
Percentage of Participants With ACR20 Response After Fifth Course
A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043.
Time frame: 24 weeks after fifth course of rituximab (median duration of 297.3 weeks)
Population: ITT Population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab | Percentage of Participants With ACR20 Response After Fifth Course | 69.7 percentage of participants |
Primary
Percentage of Participants With ACR20 Response After Fourth Course
A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043.
Time frame: 24 weeks after fourth course of rituximab (median duration of 232 weeks)
Population: ITT Population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab | Percentage of Participants With ACR20 Response After Fourth Course | 75.1 percentage of participants |
Primary
Percentage of Participants With ACR20 Response After Second Course
A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043.
Time frame: 24 weeks after second course of rituximab (median duration of 90.9 weeks)
Population: ITT Population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab | Percentage of Participants With ACR20 Response After Second Course | 70.8 percentage of participants |
Primary
Percentage of Participants With ACR20 Response After Seventh Course
A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043.
Time frame: 24 weeks after seventh course of rituximab (median duration of 406.7 weeks)
Population: ITT Population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab | Percentage of Participants With ACR20 Response After Seventh Course | 59.5 percentage of participants |
Primary
Percentage of Participants With ACR20 Response After Sixth Course
A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043.
Time frame: 24 weeks after sixth course of rituximab (median duration of 354.4 weeks)
Population: ITT Population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab | Percentage of Participants With ACR20 Response After Sixth Course | 68.2 percentage of participants |
Primary
Percentage of Participants With ACR20 Response After Third Course
A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043.
Time frame: 24 weeks after third course of rituximab (median duration of 162.9 weeks)
Population: ITT Population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab | Percentage of Participants With ACR20 Response After Third Course | 73.2 percentage of participants |
Primary
Percentage of Participants With an American College of Rheumatology 20 (ACR20) Response After First Course
A participant had an ACR20 response if there was at least a 20 percent (%) improvement, ie, reduction from Baseline, in tender joint count (TJC) and swollen joint count (SJC) (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity \[visual analog scale (VAS): 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (either C-reactive protein \[CRP\] or erythrocyte sedimentation rate \[ESR\]). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043.
Time frame: 24 weeks after first course of rituximab (up to approximately 26 weeks)
Population: Intent to treat (ITT) Population included all participants who received any part of an infusion of study medication under Study WA16855. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab | Percentage of Participants With an American College of Rheumatology 20 (ACR20) Response After First Course | 67.1 percentage of participants |
Secondary
American College of Rheumatology Index of Improvement (ACRn) Response
The ACRn is calculated for each participant by taking the lowest percentage improvement in (1) SJC or (2) TJC or (3) the median of the remaining 5 components of the ACR response (patient's assessment of disease activity; patient's global assessment of pain; physician's assessment of disease activity; participant's assessment of physical function; an acute phase reactant value \[either CRP or ESR\]). The index of improvement in RA, where 0 indicates no improvement and 100 indicates a 100% improvement across all signs and symptoms of RA. ACRn scores were calculated considering the original baseline in the precursor studies WA16291 or WA17043.
Time frame: 24 weeks after first, second, third, fourth, fifth, sixth, and seventh course of rituximab (median duration of 26, 90.9, 162.9, 232, 297.3, 354.4, and 406.7 weeks, respectively)
Population: ITT Population. Here, number of participants analyzed = participants who were evaluable for this outcome. Number analyzed = participants who were evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rituximab | American College of Rheumatology Index of Improvement (ACRn) Response | 24 weeks after fourth course | 39.59 units on a scale | Standard Deviation 39.393 |
| Rituximab | American College of Rheumatology Index of Improvement (ACRn) Response | 24 weeks after first course | 31.07 units on a scale | Standard Deviation 50.188 |
| Rituximab | American College of Rheumatology Index of Improvement (ACRn) Response | 24 weeks after second course | 34.15 units on a scale | Standard Deviation 58.769 |
| Rituximab | American College of Rheumatology Index of Improvement (ACRn) Response | 24 weeks after third course | 36.93 units on a scale | Standard Deviation 44.912 |
| Rituximab | American College of Rheumatology Index of Improvement (ACRn) Response | 24 weeks after fifth course | 33.76 units on a scale | Standard Deviation 48.309 |
| Rituximab | American College of Rheumatology Index of Improvement (ACRn) Response | 24 weeks after sixth course | 29.74 units on a scale | Standard Deviation 57.197 |
| Rituximab | American College of Rheumatology Index of Improvement (ACRn) Response | 24 weeks after seventh course | 24.87 units on a scale | Standard Deviation 51.336 |
Secondary
Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at 24 Weeks Following Each Course
The HAQ-DI is a questionnaire specific for rheumatoid arthritis and consists of 20 questions referring to 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Participants completed the questionnaire by answering the 20 questions on a scale of 0 (without difficulty) to 3 (unable to do). The total score ranges from 0 (no disability) to 3 (completely disabled). A negative change score indicates improvement.
Time frame: 24 weeks after first, second, third, fourth, fifth, sixth, and seventh course of rituximab (median duration of 26, 90.9, 162.9, 232, 297.3, 354.4, and 406.7 weeks, respectively)
Population: ITT Population. Here, number of participants analyzed = participants who were evaluable for this outcome. Number analyzed = participants who were evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rituximab | Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at 24 Weeks Following Each Course | 24 weeks after first course | -0.51 units on a scale | Standard Deviation 0.555 |
| Rituximab | Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at 24 Weeks Following Each Course | 24 weeks after second course | -0.48 units on a scale | Standard Deviation 0.556 |
| Rituximab | Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at 24 Weeks Following Each Course | 24 weeks after third course | -0.43 units on a scale | Standard Deviation 0.532 |
| Rituximab | Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at 24 Weeks Following Each Course | 24 weeks after fourth course | -0.47 units on a scale | Standard Deviation 0.529 |
| Rituximab | Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at 24 Weeks Following Each Course | 24 weeks after fifth course | -0.44 units on a scale | Standard Deviation 0.541 |
| Rituximab | Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at 24 Weeks Following Each Course | 24 weeks after sixth course | -0.38 units on a scale | Standard Deviation 0.6 |
| Rituximab | Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at 24 Weeks Following Each Course | 24 weeks after seventh course | -0.37 units on a scale | Standard Deviation 0.576 |
Secondary
Change From Baseline in Total Rheumatoid Factors (RF) at 24 Weeks Following Each Course
Time frame: 24 weeks after first, second, third, fourth, fifth, sixth, and seventh course of rituximab (median duration of 26, 90.9, 162.9, 232, 297.3, 354.4, and 406.7 weeks, respectively)
Population: The data for this outcome measure was not analyzed as this outcome was removed per changes in the planned analysis. Per changes in the planned analysis, only key efficacy parameters were analyzed as the long-term efficacy of rituximab is well established.
Secondary
Percentage of Participants Who Discontinued Treatment Due to Insufficient Response
Time frame: First, second, third, fourth, fifth, sixth, and seventh course of rituximab (up to a median of approximately 2, 62, 124, 186, 248, 310, and 372 weeks, respectively)
Population: Safety Population. Number analyzed = participants who were evaluable for specified category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab | Percentage of Participants Who Discontinued Treatment Due to Insufficient Response | First course | 1.1 percentage of participants |
| Rituximab | Percentage of Participants Who Discontinued Treatment Due to Insufficient Response | Second course | 2.3 percentage of participants |
| Rituximab | Percentage of Participants Who Discontinued Treatment Due to Insufficient Response | Third course | 2.0 percentage of participants |
| Rituximab | Percentage of Participants Who Discontinued Treatment Due to Insufficient Response | Fourth course | 2.0 percentage of participants |
| Rituximab | Percentage of Participants Who Discontinued Treatment Due to Insufficient Response | Fifth course | 0.8 percentage of participants |
| Rituximab | Percentage of Participants Who Discontinued Treatment Due to Insufficient Response | Sixth course | 0.0 percentage of participants |
| Rituximab | Percentage of Participants Who Discontinued Treatment Due to Insufficient Response | Seventh course | 0.6 percentage of participants |
Secondary
Percentage of Participants With ACR50 and ACR70 Response
A participant had an ACR50 and ACR70 response if there was at least a 50% or 70% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of disease activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[VAS: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[VAS: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) an acute-phase reactant (CRP or ESR). The ACR50 and ACR70 responses were compared to Baseline in the precursor studies WA16291 or WA17043.
Time frame: 24 weeks after first, second, third, fourth, fifth, sixth, and seventh course of rituximab (median duration of 26, 90.9, 162.9, 232, 297.3, 354.4, and 406.7 weeks, respectively)
Population: ITT Population. Here, number of participants analyzed = participants who were evaluable for this outcome. Number analyzed = participants who were evaluable for specified category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab | Percentage of Participants With ACR50 and ACR70 Response | ACR50: 24 weeks after first course | 39.4 percentage of participants |
| Rituximab | Percentage of Participants With ACR50 and ACR70 Response | ACR50: 24 weeks after second course | 41.9 percentage of participants |
| Rituximab | Percentage of Participants With ACR50 and ACR70 Response | ACR50: 24 weeks after third course | 44.8 percentage of participants |
| Rituximab | Percentage of Participants With ACR50 and ACR70 Response | ACR50: 24 weeks after fourth course | 46.9 percentage of participants |
| Rituximab | Percentage of Participants With ACR50 and ACR70 Response | ACR50: 24 weeks after fifth course | 40.0 percentage of participants |
| Rituximab | Percentage of Participants With ACR50 and ACR70 Response | ACR50: 24 weeks after sixth course | 40.0 percentage of participants |
| Rituximab | Percentage of Participants With ACR50 and ACR70 Response | ACR50: 24 weeks after seventh course | 36.5 percentage of participants |
| Rituximab | Percentage of Participants With ACR50 and ACR70 Response | ACR70: 24 weeks after first course | 16.3 percentage of participants |
| Rituximab | Percentage of Participants With ACR50 and ACR70 Response | ACR70: 24 weeks after second course | 21.6 percentage of participants |
| Rituximab | Percentage of Participants With ACR50 and ACR70 Response | ACR70: 24 weeks after third course | 20.0 percentage of participants |
| Rituximab | Percentage of Participants With ACR50 and ACR70 Response | ACR70: 24 weeks after fourth course | 20.0 percentage of participants |
| Rituximab | Percentage of Participants With ACR50 and ACR70 Response | ACR70: 24 weeks after fifth course | 18.9 percentage of participants |
| Rituximab | Percentage of Participants With ACR50 and ACR70 Response | ACR70: 24 weeks after sixth course | 20.9 percentage of participants |
| Rituximab | Percentage of Participants With ACR50 and ACR70 Response | ACR70: 24 weeks after seventh course | 18.9 percentage of participants |
Secondary
Percentage of Participants With European League Against Rheumatism (EULAR) Response of 'Good' or 'Moderate'
DAS28-ESR was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and Physician's Global Assessment of Disease Activity (VAS: 0=no disease activity to 100=maximum disease activity). DAS28-ESR = 0.56\*sqrt(TJC28) + 0.28\*sqrt(SJC28) + 0.70\*ln(ESR) + 0.014\*Patient's Global Assessment of Disease Activity. The DAS28-based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders had a change from baseline greater than (\>) 1.2 with a DAS28 score less than or equal to (≤) 3.2; moderate responders had a change from baseline \>1.2 with a DAS28 score \>3.2 to less than or equal to (≤) 5.1 or a change from baseline \>0.6 to ≤1.2 with a DAS28 score ≤5.1.
Time frame: 24 weeks after first, second, third, fourth, fifth, sixth, and seventh course of rituximab (median duration of 26, 90.9, 162.9, 232, 297.3, 354.4, and 406.7 weeks, respectively)
Population: ITT Population. Here, number of participants analyzed = participants who were evaluable for this outcome. Number analyzed = participants who were evaluable for specified category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab | Percentage of Participants With European League Against Rheumatism (EULAR) Response of 'Good' or 'Moderate' | Moderate: 24 weeks after first course | 57.8 percentage of participants |
| Rituximab | Percentage of Participants With European League Against Rheumatism (EULAR) Response of 'Good' or 'Moderate' | Moderate: 24 weeks after second course | 58.5 percentage of participants |
| Rituximab | Percentage of Participants With European League Against Rheumatism (EULAR) Response of 'Good' or 'Moderate' | Moderate: 24 weeks after third course | 59.5 percentage of participants |
| Rituximab | Percentage of Participants With European League Against Rheumatism (EULAR) Response of 'Good' or 'Moderate' | Moderate: 24 weeks after fourth course | 60.9 percentage of participants |
| Rituximab | Percentage of Participants With European League Against Rheumatism (EULAR) Response of 'Good' or 'Moderate' | Moderate: 24 weeks after fifth course | 62.1 percentage of participants |
| Rituximab | Percentage of Participants With European League Against Rheumatism (EULAR) Response of 'Good' or 'Moderate' | Moderate: 24 weeks after sixth course | 57.0 percentage of participants |
| Rituximab | Percentage of Participants With European League Against Rheumatism (EULAR) Response of 'Good' or 'Moderate' | Moderate: 24 weeks after seventh course | 60.0 percentage of participants |
| Rituximab | Percentage of Participants With European League Against Rheumatism (EULAR) Response of 'Good' or 'Moderate' | Good: 24 weeks after first course | 24.3 percentage of participants |
| Rituximab | Percentage of Participants With European League Against Rheumatism (EULAR) Response of 'Good' or 'Moderate' | Good: 24 weeks after second course | 30.4 percentage of participants |
| Rituximab | Percentage of Participants With European League Against Rheumatism (EULAR) Response of 'Good' or 'Moderate' | Good: 24 weeks after third course | 29.1 percentage of participants |
| Rituximab | Percentage of Participants With European League Against Rheumatism (EULAR) Response of 'Good' or 'Moderate' | Good: 24 weeks after fourth course | 27.9 percentage of participants |
| Rituximab | Percentage of Participants With European League Against Rheumatism (EULAR) Response of 'Good' or 'Moderate' | Good: 24 weeks after fifth course | 24.3 percentage of participants |
| Rituximab | Percentage of Participants With European League Against Rheumatism (EULAR) Response of 'Good' or 'Moderate' | Good: 24 weeks after sixth course | 27.1 percentage of participants |
| Rituximab | Percentage of Participants With European League Against Rheumatism (EULAR) Response of 'Good' or 'Moderate' | Good: 24 weeks after seventh course | 25.7 percentage of participants |
Secondary
Percentage of Participants With Low Disease Activity and Clinical Remission Based on DAS28-ESR
DAS28-ESR was calculated from SJC and TJC using 28 joints count, ESR (millimeters per hour \[mm/hour\]), and Patient's Global Assessment of Disease Activity (VAS: 0=no disease activity to 100=maximum disease activity). DAS28-ESR = 0.56\*square root (sqrt)(TJC28) + 0.28\*sqrt(SJC28) + 0.70\*natural logarithm (ln) (ESR) + 0.014\*Patient's Global Assessment of Disease Activity. Total score range: 0-10, higher score=more disease activity. DAS28-ESR \<= 3.2 implied low disease activity (LDA) and DAS28-ESR \<2.6 = clinical remission.
Time frame: 24 weeks after first, second, third, fourth, fifth, sixth, and seventh course of rituximab (median duration of 26, 90.9, 162.9, 232, 297.3, 354.4, and 406.7 weeks, respectively)
Population: ITT Population. Here, number of participants analyzed = participants who were evaluable for this outcome. Number analyzed = participants who were evaluable for specified category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab | Percentage of Participants With Low Disease Activity and Clinical Remission Based on DAS28-ESR | LDA: 24 weeks after first course | 24.3 percentage of participants |
| Rituximab | Percentage of Participants With Low Disease Activity and Clinical Remission Based on DAS28-ESR | LDA: 24 weeks after second course | 30.1 percentage of participants |
| Rituximab | Percentage of Participants With Low Disease Activity and Clinical Remission Based on DAS28-ESR | LDA: 24 weeks after third course | 29.3 percentage of participants |
| Rituximab | Percentage of Participants With Low Disease Activity and Clinical Remission Based on DAS28-ESR | LDA: 24 weeks after fourth course | 28.0 percentage of participants |
| Rituximab | Percentage of Participants With Low Disease Activity and Clinical Remission Based on DAS28-ESR | LDA: 24 weeks after fifth course | 23.8 percentage of participants |
| Rituximab | Percentage of Participants With Low Disease Activity and Clinical Remission Based on DAS28-ESR | LDA: 24 weeks after sixth course | 27.3 percentage of participants |
| Rituximab | Percentage of Participants With Low Disease Activity and Clinical Remission Based on DAS28-ESR | LDA: 24 weeks after seventh course | 24.7 percentage of participants |
| Rituximab | Percentage of Participants With Low Disease Activity and Clinical Remission Based on DAS28-ESR | Remission: 24 weeks after first course | 11.3 percentage of participants |
| Rituximab | Percentage of Participants With Low Disease Activity and Clinical Remission Based on DAS28-ESR | Remission: 24 weeks after second course | 16.8 percentage of participants |
| Rituximab | Percentage of Participants With Low Disease Activity and Clinical Remission Based on DAS28-ESR | Remission: 24 weeks after third course | 17.1 percentage of participants |
| Rituximab | Percentage of Participants With Low Disease Activity and Clinical Remission Based on DAS28-ESR | Remission: 24 weeks after fourth course | 15.7 percentage of participants |
| Rituximab | Percentage of Participants With Low Disease Activity and Clinical Remission Based on DAS28-ESR | Remission: 24 weeks after fifth course | 15.7 percentage of participants |
| Rituximab | Percentage of Participants With Low Disease Activity and Clinical Remission Based on DAS28-ESR | Remission: 24 weeks after sixth course | 17.3 percentage of participants |
| Rituximab | Percentage of Participants With Low Disease Activity and Clinical Remission Based on DAS28-ESR | Remission: 24 weeks after seventh course | 13.7 percentage of participants |
Secondary
Time Since Last Treatment Course
Time since last treatment course = The last day of the last dose of rituximab to date of last contact. Date of last contact is the last available date of efficacy, complete medication start date, laboratory, adverse event assessments, early withdrawal visit, date of last contact, or date of death.
Time frame: Baseline up to 10 years
Population: ITT Population. Here, number of participants analyzed = participants who entered into safety follow-up.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rituximab | Time Since Last Treatment Course | 4.21 years | Standard Deviation 2.234 |