Rheumatoid Arthritis
Conditions
Keywords
Rituxan, MTX, RA, IMAGE, WA17047
Brief summary
This is a phase III, randomized, controlled, double-blind, parallel group, international study in approximately 750 patients with active Rheumatoid Arthritis (RA) who are naive to Methotrexate (MTX) therapy. Rheumatoid Factor (RF)-positive and RF-negative patients will be enrolled and will be allocated equally between 3 treatment arms.
Interventions
DRUGfolate
Intravenous repeating dose
DRUGmethotrexate
Oral or parenteral repeating dose
DRUGmethylprednisolone
Intravenous repeating dose
DRUGplacebo
Intravenous repeating dose
DRUGrituximab
Intravenous repeating dose
Sponsors
Hoffmann-La Roche
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Adult patients 18-80 years of age * RA for ≥ 2 months; * Receiving outpatient treatment * Patients naive to, and considered to be candidates for, methotrexate treatment
Exclusion criteria
* Rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA * Inflammatory joint disease other than RA, or other systemic autoimmune disorder * Diagnosis of juvenile rheumatoid arthritis, or RA before the age of 16 * Surgery within 12 weeks of study * Previous treatment with any approved or investigational biologic agent for RA, an anti-alpha4-integrin antibody or co-stimulation modulator, or cell-depleting therapy * Concurrent treatment with any biologic agent or DMARD other than methotrexate
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Modified Total Sharp Score (mTSS) From Screening at Week 52 | Baseline and week 52 | Rate of progression in structural joint damage (PJD) by change in Total Modified Sharp Score (TMSS) from screening to Week 52 in the modified intent-to-treat (MITT) population. TMSS is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change and higher scores represent a worsening of joint erosions and joint space narrowing. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Without Radiographic Progression at Week 52 | Baseline, Week 52 | Percentage of patients without radiographic progression at Week 52, defined as change in total modified Sharp score (TMSS) \<= 0. TMSS is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change. |
| Percentage of Patients Without Radiographic Progression in Total Erosion Score at Week 52 | Baseline, Week 52 | No radiographic progression is defined as a change in the total erosion score at Week 52 of less than or equal to zero. |
| Change From Baseline in Modified Joint Space Narrowing (JSN) Score at Week 52 | Baseline and week 52 | Rate of progression in structural joint damage (PJD) by change in modified joint space narrowing (JSN) from screening to Week 52. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change and higher scores represent a worsening of joint space narrowing. |
| Change From Baseline in the Modified Total Sharp Score at Week 24 | Baseline, Week 24 | The modified total sharp score is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change and higher scores represent a worsening of joint erosions and joint space narrowing. |
| Change From Baseline in the Total Erosion Score at Week 24 | Baseline, Week 24 | Total Erosion Score is determined by evaluation of fourteen sites in each wrist and hand and six joints in each foot using an eight-point scale from 0 (normal: no erosions) to 3.5 (Very severe; erosions of 100% of the articular surfaces. The Total Erosion Score at Week 24 - Total Erosion Score at baseline is calculated. |
| Change From Baseline in Modified Joint Space Narrowing (JSN) Score at Week 24 | Baseline, Week 24 | Joint Space Narrowing is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change and higher scores represent a worsening of joint space narrowing. |
| Percentage of Participants Without Radiographic Progression at Week 24 | Baseline, Week 24 | Percentage of patients without radiographic progression at Week 24 defined as change in total modified Sharp score (TMSS) ≤ 0. TMSS is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change. |
| Percentage of Participants With American College of Rheumatology (ACR) ACR50 Response at Week 52 | Week 52 | To achieve an ACR50 response requires at least a 50% improvement compared with baseline in both Total Joint Count and Swollen Joint Count, as well as a 50% improvement in three of five additional measurements from: * the physician's global assessment of disease activity * patient's global assessment of disease activity * patient's assessment of pain * HAQ-DI (Health Assessment Questionnaire disability index) * an acute phase reactant C-Reactive Protein (CRP). (If CRP was missing then Erythrocyte Sedimentation Rate (ESR) was used if available.) |
| Change From Baseline in the Disease Activity Score 28 Joint Count- Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 52 | Baseline, Week 52 | DAS28-ESR is calculated from the following formula: (0.56 \* TJC) + (0.28 \* SJC) + (0.70 \* ln ESR) + (0.014 \* GH) TJC = tender joint count, based on 28 joints SJC = swollen joint count, based on 28 joints ESR = erythrocyte sedimentation rate in mm/h GH = patient's global assessment of disease activity A DAS28-ESR score of 5.1 or above is considered to indicate high disease activity. Patients can also be defined as having low disease activity (DAS28-ESR ≤ 3.2) or remission (DAS28-ESR \< 2.6). |
| Percentage of Participants With American College of Rheumatology (ACR) ACR70 Response at Week 52 | Baseline, Week 52 | To achieve an ACR70 response requires at least a 70% improvement compared with baseline in both Total Joint Count and Swollen Joint Count, as well as a 70% improvement in three of five additional measurements from: * the physician's global assessment of disease activity * patient's global assessment of disease activity * patient's assessment of pain * HAQ-DI (Health Assessment Questionnaire disability index) * an acute phase reactant C-Reactive Protein (CRP). (If CRP was missing then Erythrocyte Sedimentation Rate (ESR) was used if available.) |
| Percentage of Participants With DAS28-ESR Remission at Week 52 | Week 52 | The DAS28-4(ESR) score is a measure of the subject's disease activity. It is based on the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity (mm), and ESR. DAS28-4(ESR) scores range from 0 - 10. Remission is defined as achieving a DAS28-ESR score of less than 2.6 |
| Percentage of Participants With European League Against Rheumatism (EULAR) Good Response at Week 52 | Baseline, Week 52 | European League Against Rheumatism (EULAR) criteria reflects an improvement in disease activity and an attainment of a lower degree of disease activity. A good response is defined as an improvement in the DAS28-ESR of \> 1.2 compared with baseline, and attainment of a DAS28-ESR of \< 3.2. |
| The Percentage of Participants With Major Clinical Response at Week 52 | Week 52 | Major clinical response is defined as a continuous six-month period of success by the ACR70. ACR70= 70% improvement compared with baseline in both Total Joint Count and Swollen Joint Count, as well as a 70% improvement in 3 of five additional measurements from: * the physician's global assessment of disease activity * patient's global assessment of disease activity * patient's assessment of pain * HAQ-DI (Health Assessment Questionnaire disability index) * an acute phase reactant C-Reactive Protein (CRP). (If CRP was missing then Erythrocyte Sedimentation Rate (ESR) was used if available.) |
| Percentage of Participants With DAS28-ESR Low Disease Activity at Week 52 | Week 52 | The DAS28-4(ESR) score is a measure of the subject's disease activity. It is based on the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity (mm), and ESR. DAS28-4(ESR) scores range from 0 - 10. Low disease activity is defined as achieving a DAS28-ESR score of less than or equal to 3.2 |
| Change From Baseline in Modified Sharp Erosion Score at Week 52 | Baseline and week 52 | Rate of progression in structural joint damage (PJD) by change in modified Sharp erosion score from screening to Week 52. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. A score of 0 would indicate no change and higher scores represent a worsening of joint erosions. |
| Percentage of Participants With American College of Rheumatology (ACR) ACR90 Response at Week 52 | Baseline, Week 52 | To achieve an ACR90 response requires at least a 90% improvement compared with baseline in both Total Joint Count and Swollen Joint Count, as well as a 90% improvement in three of five additional measurements from: * the physician's global assessment of disease activity * patient's global assessment of disease activity * patient's assessment of pain * HAQ-DI (Health Assessment Questionnaire disability index) * an acute phase reactant C-Reactive Protein (CRP). (If CRP was missing then Erythrocyte Sedimentation Rate (ESR) was used if available.) |
| Change in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Score From Baseline at Week 52 | Baseline, Week 52 | FACIT-F is a 13-item questionnaire. Patients scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the patient's response to the questions (with the exception of 2 negatively stated), the greater the patient's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the patient's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score). A higher score reflects an improvement in the patient's health status. |
| Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52 | Baseline, Week 52 | The Stanford Health Assessment Questionnaire disability index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip,and common daily activities. Each domain has at least two component questions. There are four possible responses for each component ranging from 0(without any difficulty) to 4 (unable to do).HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. A negative change from baseline indicates improvement. |
| Change From Baseline in the SF-36 Physical Health Component Summary Score at Week 52 and Week 104 | Baseline, Week 52, Week 104 | The SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement. Means are adjusted for baseline value, Rheumatoid Factor status and region. |
| Change From Baseline in the SF-36 Mental Health Component Summary Score at Week 52 and Week 104 | Baseline, Weeks 52, Week 104 | The SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement. Means are adjusted for baseline value, Rheumatoid Factor status and region. |
| Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52 | Baseline, Week 52 | The Stanford Health Assessment Questionnaire disability index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and common daily activities. Each domain has at least two component questions. There are four possible responses for each component on a scale of 0 (without difficulty) to 3 (unable to do). Higher scores=greater dysfunction. Improved:HAQ-DI score change \<=-0.22 Unchanged:HAQ-DI score change -0.22 to 0.22 Worsened:HAQ score =\> 0.22 |
| Percentage of Patients With Minimally Clinically Important Difference (MCID) in the SF-36 Physical Health Component Score at Week 52 | Baseline, Week 52 | MCID is defined as a change from baseline in SF-36 Physical Health Component Score of \>5.42. SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement. |
| Percentage of Patients With Minimally Clinically Important Difference (MCID) in the SF-36 Mental Health Component Score at Week 52 | Baseline, Week 52 | MCID is defined as a change from baseline in SF-36 Mental Health Component Score of \>6.33. SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement. |
| Change From Baseline in the Modified Total Sharp Score at Week 104 | Baseline, Week 104 | The modified total sharp score is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change and higher scores represent a worsening of joint erosions and joint space narrowing. |
| Change From Baseline in the Total Erosion Score at Week 104 | Baseline, Week 104 | Total Erosion Score is determined by evaluation of fourteen sites in each wrist and hand and six joints in each foot using an eight-point scale from 0 (normal: no erosions) to 3.5 (Very severe; erosions of 100% of the articular surfaces. The change from the score at baseline to week 104 is calculated. |
| Percentage of Participants Without Radiographic Progression at Week 104 | Baseline, Week 104 | Percentage of patients without radiographic progression at Week 104, defined as change in total modified Sharp score (TMSS) ≤ 0. TMSS is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change. |
| Percentage of Participants Without Radiographic Progression in the Total Erosion Score at Week 104 | Week 104 | Total Erosion Score is determined by evaluation of fourteen sites in each wrist and hand and six joints in each foot using an eight-point scale from 0 (normal: no erosions) to 3.5 (Very severe; erosions of 100% of the articular surfaces. The score at baseline is compared to the score at week 104. No progression is defined as a change from score at screening to week 104 ≤0. |
| Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 104 | Baseline, Week 104 | The Stanford Health Assessment Questionnaire disability index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. Each domain has at least two component questions. There are four possible responses for each component ranging from 0(without any difficulty) to 4 (unable to do). HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. A negative change from baseline indicates improvement. |
| Percentage of Participants With American College of Rheumatology (ACR) ACR20 Response at Week 52 | Baseline, Week 52 | To achieve an ACR20 response requires at least a 20% improvement compared with baseline in both Total Joint Count and Swollen Joint Count, as well as a 20% improvement in three of five additional measurements from: * the physician's global assessment of disease activity * patient's global assessment of disease activity * patient's assessment of pain * HAQ-DI (Health Assessment Questionnaire disability index) * an acute phase reactant C-Reactive Protein (CRP). (If CRP was missing then Erythrocyte Sedimentation Rate (ESR) was used if available.) |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo + Methotrexate Placebo intravenously on Days 1 and 15 + a background of methotrexate orally at a dose of 7.5 mg escalating by 2.5 mg a week every 1-2 weeks to achieve: 15 mg per week by Week 4 and 20 mg per week by Week 8.
From Week 104 participants were eligible to receive Rituximab 2 X 0.5 g or Rituximab 2 X 1.0 g every 24 weeks. | 249 |
| Rituximab (0.5 g x 2) + Methotrexate Rituximab intravenously at a dose of 0.5 g on Days 1 and 15 + a background of methotrexate orally at a dose of 7.5 mg escalating by 2.5 mg a week every 1-2 weeks to achieve: 15 mg per week by Week 4 and 20 mg per week by Week 8.
Subsequent Rituximab treatment courses were given at 24 week intervals for 5 years provided the Disease Activity Score 28 Joint Count- Erythrocyte Sedimentation Rate (DAS-ESR) result was ≥2.6 | 249 |
| Rituximab (1.0 g x 2) + Methotrexate Rituximab intravenously at a dose of 1.0 g on Days 1 and 15 + a background of methotrexate orally at a dose of 7.5 mg escalating by 2.5 mg a week every 1-2 weeks to achieve: 15 mg per week by Week 4 and 20 mg per week by Week 8.
Subsequent Rituximab treatment courses were given at 24 week intervals for 5 years provided the Disease Activity Score 28 Joint Count- Erythrocyte Sedimentation Rate (DAS-ESR) result was ≥2.6 | 250 |
| Total | 748 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Extended Safety Follow-Up (ESFU) Period | Administrative reasons | 1 | 2 | 2 |
| Extended Safety Follow-Up (ESFU) Period | Death | 0 | 1 | 0 |
| Extended Safety Follow-Up (ESFU) Period | Lost to Follow-up | 2 | 2 | 2 |
| Extended Safety Follow-Up (ESFU) Period | Withdrawal by Subject | 2 | 4 | 8 |
| Safety Follow-Up (SFU) Period | Administrative reasons | 27 | 7 | 5 |
| Safety Follow-Up (SFU) Period | Death | 3 | 2 | 1 |
| Safety Follow-Up (SFU) Period | Lost to Follow-up | 9 | 11 | 20 |
| Safety Follow-Up (SFU) Period | Withdrawal by Subject | 16 | 21 | 11 |
| Treatment Period | Administrative reasons | 106 | 120 | 137 |
| Treatment Period | Adverse Event | 14 | 9 | 7 |
| Treatment Period | Death | 1 | 1 | 1 |
| Treatment Period | Failure to return | 9 | 8 | 8 |
| Treatment Period | Insufficient therapeutic response | 34 | 13 | 8 |
| Treatment Period | Protocol Violation | 1 | 1 | 0 |
| Treatment Period | Refused treatment | 9 | 2 | 2 |
| Treatment Period | Violation of selection criteria | 1 | 2 | 0 |
| Treatment Period | Withdrew consent | 14 | 19 | 9 |
Baseline characteristics
| Characteristic | Placebo + Methotrexate | Rituximab (0.5 g x 2) + Methotrexate | Rituximab (1.0 g x 2) + Methotrexate | Total |
|---|---|---|---|---|
| Age, Continuous | 48.06 years STANDARD_DEVIATION 12.692 | 47.87 years STANDARD_DEVIATION 13.391 | 47.89 years STANDARD_DEVIATION 13.324 | 47.94 years STANDARD_DEVIATION 13.136 |
| Sex: Female, Male Female | 192 Participants | 203 Participants | 212 Participants | 607 Participants |
| Sex: Female, Male Male | 57 Participants | 46 Participants | 38 Participants | 141 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 193 / 249 | 232 / 348 | 208 / 263 |
| serious Total, serious adverse events | 48 / 249 | 54 / 348 | 58 / 263 |
Outcome results
Primary
Change From Baseline in Modified Total Sharp Score (mTSS) From Screening at Week 52
Rate of progression in structural joint damage (PJD) by change in Total Modified Sharp Score (TMSS) from screening to Week 52 in the modified intent-to-treat (MITT) population. TMSS is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change and higher scores represent a worsening of joint erosions and joint space narrowing.
Time frame: Baseline and week 52
Population: Modified intent-to-treat population includes patients with a screening and at least one post-baseline radiographic evaluation, grouped as randomized. Linear interpolation/extrapolation used for missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Methotrexate | Change From Baseline in Modified Total Sharp Score (mTSS) From Screening at Week 52 | 1.079 Score on a scale | Standard Deviation 4.0934 |
| Rituximab (0.5 g x 2) + Methotrexate | Change From Baseline in Modified Total Sharp Score (mTSS) From Screening at Week 52 | 0.646 Score on a scale | Standard Deviation 1.9196 |
| Rituximab (1.0 g x 2) + Methotrexate | Change From Baseline in Modified Total Sharp Score (mTSS) From Screening at Week 52 | 0.359 Score on a scale | Standard Deviation 1.0095 |
Comparison: Comparing all three treatment groupsp-value: 0.0016Kruskal-Wallis
Comparison: Rituximab 2 x 0.5 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline rheumatoid factor (RF) statusp-value: 0.1824Van-Elteren
Comparison: Rituximab 2 x 1.0 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline RF statusp-value: 0.0004Van-Elteren
Secondary
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 104
The Stanford Health Assessment Questionnaire disability index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. Each domain has at least two component questions. There are four possible responses for each component ranging from 0(without any difficulty) to 4 (unable to do). HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. A negative change from baseline indicates improvement.
Time frame: Baseline, Week 104
Population: Participants from the Intent-to treat Population includes all randomized participants who received at least one dose of study drug with data at baseline and Week 104 available for analysis. Last observation carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Methotrexate | Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 104 | -0.806 Score on a scale | Standard Deviation 0.7968 |
| Rituximab (0.5 g x 2) + Methotrexate | Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 104 | -1038 Score on a scale | Standard Deviation 0.8142 |
| Rituximab (1.0 g x 2) + Methotrexate | Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 104 | -1.055 Score on a scale | Standard Deviation 0.7901 |
Comparison: Rituximab (0.5 g x 2) + Methotrexate versus Placebo + Methotrexate, stratified for region and baseline RF status.p-value: <0.0001ANOVA
Comparison: Rituximab (1.0 g x 2) + Methotrexate versus Placebo + Methotrexate, stratified for region and baseline RF status.p-value: <0.0001ANOVA
Secondary
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52
The Stanford Health Assessment Questionnaire disability index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip,and common daily activities. Each domain has at least two component questions. There are four possible responses for each component ranging from 0(without any difficulty) to 4 (unable to do).HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. A negative change from baseline indicates improvement.
Time frame: Baseline, Week 52
Population: Intent-to treat Population includes all randomized participants who received at least one dose of study drug. Last observation carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Methotrexate | Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52 | -0.800 Score on a scale | Standard Deviation 0.7764 |
| Rituximab (0.5 g x 2) + Methotrexate | Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52 | -1.038 Score on a scale | Standard Deviation 0.7625 |
| Rituximab (1.0 g x 2) + Methotrexate | Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52 | -1.023 Score on a scale | Standard Deviation 0.7634 |
Comparison: Rituximab (0.5 g x 2) + Methotrexate versus Placebo + Methotrexate stratified for region and RF status.p-value: <0.0001ANOVA
Comparison: Rituximab (1.0 g x 2) + Methotrexate versus Placebo + Methotrexate, stratified for region and baseline RF status.p-value: <0.0001ANOVA
Secondary
Change From Baseline in Modified Joint Space Narrowing (JSN) Score at Week 24
Joint Space Narrowing is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change and higher scores represent a worsening of joint space narrowing.
Time frame: Baseline, Week 24
Population: Participants from the modified intent-to-treat population (includes patients with a screening and at least one post-baseline radiographic evaluation, grouped as randomized) with data available at Week 24 for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Methotrexate | Change From Baseline in Modified Joint Space Narrowing (JSN) Score at Week 24 | 0.210 Score on a scale | Standard Deviation 1.7403 |
| Rituximab (0.5 g x 2) + Methotrexate | Change From Baseline in Modified Joint Space Narrowing (JSN) Score at Week 24 | 0.176 Score on a scale | Standard Deviation 0.8949 |
| Rituximab (1.0 g x 2) + Methotrexate | Change From Baseline in Modified Joint Space Narrowing (JSN) Score at Week 24 | 0.108 Score on a scale | Standard Deviation 0.6118 |
Secondary
Change From Baseline in Modified Joint Space Narrowing (JSN) Score at Week 52
Rate of progression in structural joint damage (PJD) by change in modified joint space narrowing (JSN) from screening to Week 52. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change and higher scores represent a worsening of joint space narrowing.
Time frame: Baseline and week 52
Population: Modified intent-to-treat population includes patients with a screening and at least one post-baseline radiographic evaluation, grouped as randomized. Linear interpolation/extrapolation used for missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Methotrexate | Change From Baseline in Modified Joint Space Narrowing (JSN) Score at Week 52 | 0.341 Score on a scale | Standard Deviation 2.2408 |
| Rituximab (0.5 g x 2) + Methotrexate | Change From Baseline in Modified Joint Space Narrowing (JSN) Score at Week 52 | 0.193 Score on a scale | Standard Deviation 0.9422 |
| Rituximab (1.0 g x 2) + Methotrexate | Change From Baseline in Modified Joint Space Narrowing (JSN) Score at Week 52 | 0.126 Score on a scale | Standard Deviation 0.6363 |
Comparison: Comparing all three treatment groups.p-value: 0.5939Kruskal-Wallis
Comparison: Rituximab 2 x 0.5 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline RF statusp-value: 0.5478Van-Elteren
Comparison: Rituximab 2 x 1.0 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline RF statusp-value: 0.3096Van-Elteren
Secondary
Change From Baseline in Modified Sharp Erosion Score at Week 52
Rate of progression in structural joint damage (PJD) by change in modified Sharp erosion score from screening to Week 52. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. A score of 0 would indicate no change and higher scores represent a worsening of joint erosions.
Time frame: Baseline and week 52
Population: Modified intent-to-treat population includes patients with a screening and at least one post-baseline radiographic evaluation, grouped as randomized. Linear interpolation/extrapolation used for missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Methotrexate | Change From Baseline in Modified Sharp Erosion Score at Week 52 | 0.738 Score on a scale | Standard Deviation 2.048 |
| Rituximab (0.5 g x 2) + Methotrexate | Change From Baseline in Modified Sharp Erosion Score at Week 52 | 0.453 Score on a scale | Standard Deviation 1.2065 |
| Rituximab (1.0 g x 2) + Methotrexate | Change From Baseline in Modified Sharp Erosion Score at Week 52 | 0.233 Score on a scale | Standard Deviation 0.6252 |
Comparison: Comparing all three treatment groupsp-value: 0.0004Kruskal-Wallis
Comparison: Rituximab 2 x 0.5 g + Methotrexate versus Placebo + Methotrexate, stratified for region and baseline RF statusp-value: 0.1194Van-Elteren
Comparison: Rituximab 2 x 1.0 g + Methotrexate versus Placebo + Methotrexate, stratified for region and baseline RF statusp-value: 0.0001Van-Elteren
Secondary
Change From Baseline in the Disease Activity Score 28 Joint Count- Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 52
DAS28-ESR is calculated from the following formula: (0.56 \* TJC) + (0.28 \* SJC) + (0.70 \* ln ESR) + (0.014 \* GH) TJC = tender joint count, based on 28 joints SJC = swollen joint count, based on 28 joints ESR = erythrocyte sedimentation rate in mm/h GH = patient's global assessment of disease activity A DAS28-ESR score of 5.1 or above is considered to indicate high disease activity. Patients can also be defined as having low disease activity (DAS28-ESR ≤ 3.2) or remission (DAS28-ESR \< 2.6).
Time frame: Baseline, Week 52
Population: Participants from the Intent to treat (ITT) population includes all randomized participants who received at least one infusion who had data available for analyses. Last observation carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Methotrexate | Change From Baseline in the Disease Activity Score 28 Joint Count- Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 52 | -2.33 Score on a scale | Standard Deviation 1.691 |
| Rituximab (0.5 g x 2) + Methotrexate | Change From Baseline in the Disease Activity Score 28 Joint Count- Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 52 | -3.35 Score on a scale | Standard Deviation 1.663 |
| Rituximab (1.0 g x 2) + Methotrexate | Change From Baseline in the Disease Activity Score 28 Joint Count- Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 52 | -3.46 Score on a scale | Standard Deviation 1.64 |
Secondary
Change From Baseline in the Modified Total Sharp Score at Week 104
The modified total sharp score is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change and higher scores represent a worsening of joint erosions and joint space narrowing.
Time frame: Baseline, Week 104
Population: Participants from the Modified Intent to Treat (MITT) population includes all randomized participants who received at least one infusion and had both screening and post-baseline radiographic assessments at the given time-point for analysis. Linear extrapolation was used for missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Methotrexate | Change From Baseline in the Modified Total Sharp Score at Week 104 | 1.948 Score on a scale | Standard Deviation 5.5782 |
| Rituximab (0.5 g x 2) + Methotrexate | Change From Baseline in the Modified Total Sharp Score at Week 104 | 0.761 Score on a scale | Standard Deviation 2.6181 |
| Rituximab (1.0 g x 2) + Methotrexate | Change From Baseline in the Modified Total Sharp Score at Week 104 | 0.406 Score on a scale | Standard Deviation 1.4312 |
Comparison: Week 104: Rituximab 2 x 0.5 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline rheumatoid factor (RF) status.p-value: <0.0001Van-Elteren
Secondary
Change From Baseline in the Modified Total Sharp Score at Week 24
The modified total sharp score is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change and higher scores represent a worsening of joint erosions and joint space narrowing.
Time frame: Baseline, Week 24
Population: Participants from the Modified Intent to Treat (MITT) population includes all randomized participants who received at least one infusion and had both screening and post-baseline radiographic assessments at the given time point for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Methotrexate | Change From Baseline in the Modified Total Sharp Score at Week 24 | 0.701 Score on a scale | Standard Deviation 2.9116 |
| Rituximab (0.5 g x 2) + Methotrexate | Change From Baseline in the Modified Total Sharp Score at Week 24 | 0.508 Score on a scale | Standard Deviation 1.7349 |
| Rituximab (1.0 g x 2) + Methotrexate | Change From Baseline in the Modified Total Sharp Score at Week 24 | 0.328 Score on a scale | Standard Deviation 0.9443 |
Secondary
Change From Baseline in the SF-36 Mental Health Component Summary Score at Week 52 and Week 104
The SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement. Means are adjusted for baseline value, Rheumatoid Factor status and region.
Time frame: Baseline, Weeks 52, Week 104
Population: Intent to treat (ITT) population includes all randomized participants who received at least one infusion. Last observation carried forward. n in each of the categories is the number of participants with data available for analyses at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo + Methotrexate | Change From Baseline in the SF-36 Mental Health Component Summary Score at Week 52 and Week 104 | Week 52 (n=239,236,241) | 6.689 Score on a scale | Standard Deviation 13.116 |
| Placebo + Methotrexate | Change From Baseline in the SF-36 Mental Health Component Summary Score at Week 52 and Week 104 | Week 104 (n= 240,236,242) | 6.295 Score on a scale | Standard Deviation 13.9813 |
| Rituximab (0.5 g x 2) + Methotrexate | Change From Baseline in the SF-36 Mental Health Component Summary Score at Week 52 and Week 104 | Week 52 (n=239,236,241) | 7.718 Score on a scale | Standard Deviation 11.8903 |
| Rituximab (0.5 g x 2) + Methotrexate | Change From Baseline in the SF-36 Mental Health Component Summary Score at Week 52 and Week 104 | Week 104 (n= 240,236,242) | 7.617 Score on a scale | Standard Deviation 12.0793 |
| Rituximab (1.0 g x 2) + Methotrexate | Change From Baseline in the SF-36 Mental Health Component Summary Score at Week 52 and Week 104 | Week 104 (n= 240,236,242) | 9.066 Score on a scale | Standard Deviation 12.5325 |
| Rituximab (1.0 g x 2) + Methotrexate | Change From Baseline in the SF-36 Mental Health Component Summary Score at Week 52 and Week 104 | Week 52 (n=239,236,241) | 8.167 Score on a scale | Standard Deviation 12.1709 |
Secondary
Change From Baseline in the SF-36 Physical Health Component Summary Score at Week 52 and Week 104
The SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement. Means are adjusted for baseline value, Rheumatoid Factor status and region.
Time frame: Baseline, Week 52, Week 104
Population: Intent to treat (ITT) population includes all participants who received at least one infusion. Last observation carried forward. n in each of the categories is the number of participants with data available for analyses at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo + Methotrexate | Change From Baseline in the SF-36 Physical Health Component Summary Score at Week 52 and Week 104 | Week 52 (n=239,236,241) | 8.953 Score on a scale | Standard Deviation 9.3986 |
| Placebo + Methotrexate | Change From Baseline in the SF-36 Physical Health Component Summary Score at Week 52 and Week 104 | Week 104 (n=240,236,242) | 8.617 Score on a scale | Standard Deviation 9.85 |
| Rituximab (0.5 g x 2) + Methotrexate | Change From Baseline in the SF-36 Physical Health Component Summary Score at Week 52 and Week 104 | Week 52 (n=239,236,241) | 11.022 Score on a scale | Standard Deviation 9.6246 |
| Rituximab (0.5 g x 2) + Methotrexate | Change From Baseline in the SF-36 Physical Health Component Summary Score at Week 52 and Week 104 | Week 104 (n=240,236,242) | 11.032 Score on a scale | Standard Deviation 9.9631 |
| Rituximab (1.0 g x 2) + Methotrexate | Change From Baseline in the SF-36 Physical Health Component Summary Score at Week 52 and Week 104 | Week 104 (n=240,236,242) | 12.649 Score on a scale | Standard Deviation 10.4331 |
| Rituximab (1.0 g x 2) + Methotrexate | Change From Baseline in the SF-36 Physical Health Component Summary Score at Week 52 and Week 104 | Week 52 (n=239,236,241) | 12.205 Score on a scale | Standard Deviation 9.4986 |
Secondary
Change From Baseline in the Total Erosion Score at Week 104
Total Erosion Score is determined by evaluation of fourteen sites in each wrist and hand and six joints in each foot using an eight-point scale from 0 (normal: no erosions) to 3.5 (Very severe; erosions of 100% of the articular surfaces. The change from the score at baseline to week 104 is calculated.
Time frame: Baseline, Week 104
Population: Participants from the Modified Intent to Treat (MITT) population includes all randomized participants who received at least one infusion and who had both screening and post-baseline radiographic assessments at the given time point for analyses. Linear extrapolation used for missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Methotrexate | Change From Baseline in the Total Erosion Score at Week 104 | 1.315 Score on a scale | Standard Deviation 3.2466 |
| Rituximab (0.5 g x 2) + Methotrexate | Change From Baseline in the Total Erosion Score at Week 104 | 0.499 Score on a scale | Standard Deviation 1.7221 |
| Rituximab (1.0 g x 2) + Methotrexate | Change From Baseline in the Total Erosion Score at Week 104 | 0.227 Score on a scale | Standard Deviation 0.7939 |
Secondary
Change From Baseline in the Total Erosion Score at Week 24
Total Erosion Score is determined by evaluation of fourteen sites in each wrist and hand and six joints in each foot using an eight-point scale from 0 (normal: no erosions) to 3.5 (Very severe; erosions of 100% of the articular surfaces. The Total Erosion Score at Week 24 - Total Erosion Score at baseline is calculated.
Time frame: Baseline, Week 24
Population: Participants from the modified intent-to-treat population (includes patients with a screening and at least one post-baseline radiographic evaluation, grouped as randomized) who had data available at Week 24 for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Methotrexate | Change From Baseline in the Total Erosion Score at Week 24 | 0.491 Score on a scale | Standard Deviation 1.3789 |
| Rituximab (0.5 g x 2) + Methotrexate | Change From Baseline in the Total Erosion Score at Week 24 | 0.404 Score on a scale | Standard Deviation 1.039 |
| Rituximab (1.0 g x 2) + Methotrexate | Change From Baseline in the Total Erosion Score at Week 24 | 0.220 Score on a scale | Standard Deviation 0.5802 |
Secondary
Change in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Score From Baseline at Week 52
FACIT-F is a 13-item questionnaire. Patients scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the patient's response to the questions (with the exception of 2 negatively stated), the greater the patient's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the patient's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score). A higher score reflects an improvement in the patient's health status.
Time frame: Baseline, Week 52
Population: Participants from the Intent to treat (ITT) population includes all randomized participants who received at least one infusion who had data available for analyses. Observed data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Methotrexate | Change in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Score From Baseline at Week 52 | 10.154 Score on a scale | Standard Deviation 11.1344 |
| Rituximab (0.5 g x 2) + Methotrexate | Change in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Score From Baseline at Week 52 | 11.833 Score on a scale | Standard Deviation 11.5807 |
| Rituximab (1.0 g x 2) + Methotrexate | Change in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Score From Baseline at Week 52 | 12.426 Score on a scale | Standard Deviation 12.2535 |
Secondary
Percentage of Participants With American College of Rheumatology (ACR) ACR20 Response at Week 52
To achieve an ACR20 response requires at least a 20% improvement compared with baseline in both Total Joint Count and Swollen Joint Count, as well as a 20% improvement in three of five additional measurements from: * the physician's global assessment of disease activity * patient's global assessment of disease activity * patient's assessment of pain * HAQ-DI (Health Assessment Questionnaire disability index) * an acute phase reactant C-Reactive Protein (CRP). (If CRP was missing then Erythrocyte Sedimentation Rate (ESR) was used if available.)
Time frame: Baseline, Week 52
Population: Intent to treat (ITT) population includes all randomized participants who received at least one infusion. Patients are considered non-responders if data are missing or from the point of withdrawal, rescue use or receipt of non-permitted Disease-modifying anti-rheumatic drugs (DMARDs).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Methotrexate | Percentage of Participants With American College of Rheumatology (ACR) ACR20 Response at Week 52 | 64.3 Percentage of Participants |
| Rituximab (0.5 g x 2) + Methotrexate | Percentage of Participants With American College of Rheumatology (ACR) ACR20 Response at Week 52 | 76.7 Percentage of Participants |
| Rituximab (1.0 g x 2) + Methotrexate | Percentage of Participants With American College of Rheumatology (ACR) ACR20 Response at Week 52 | 80.0 Percentage of Participants |
Secondary
Percentage of Participants With American College of Rheumatology (ACR) ACR50 Response at Week 52
To achieve an ACR50 response requires at least a 50% improvement compared with baseline in both Total Joint Count and Swollen Joint Count, as well as a 50% improvement in three of five additional measurements from: * the physician's global assessment of disease activity * patient's global assessment of disease activity * patient's assessment of pain * HAQ-DI (Health Assessment Questionnaire disability index) * an acute phase reactant C-Reactive Protein (CRP). (If CRP was missing then Erythrocyte Sedimentation Rate (ESR) was used if available.)
Time frame: Week 52
Population: Intent to treat (ITT) population includes all randomized participants who received at least one infusion. Patients are considered non-responders if data are missing or from the point of withdrawal, rescue use or receipt of non-permitted Disease-modifying anti-rheumatic drugs (DMARDs).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Methotrexate | Percentage of Participants With American College of Rheumatology (ACR) ACR50 Response at Week 52 | 41.8 Percentage of Participants |
| Rituximab (0.5 g x 2) + Methotrexate | Percentage of Participants With American College of Rheumatology (ACR) ACR50 Response at Week 52 | 59.4 Percentage of Participants |
| Rituximab (1.0 g x 2) + Methotrexate | Percentage of Participants With American College of Rheumatology (ACR) ACR50 Response at Week 52 | 64.8 Percentage of Participants |
Comparison: Rituximab 2 x 0.5 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline RF statusp-value: <0.0001Cochran-Mantel-Haenszel
Comparison: Rituximab 2 x 1.0 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline RF statusp-value: <0.0001Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With American College of Rheumatology (ACR) ACR70 Response at Week 52
To achieve an ACR70 response requires at least a 70% improvement compared with baseline in both Total Joint Count and Swollen Joint Count, as well as a 70% improvement in three of five additional measurements from: * the physician's global assessment of disease activity * patient's global assessment of disease activity * patient's assessment of pain * HAQ-DI (Health Assessment Questionnaire disability index) * an acute phase reactant C-Reactive Protein (CRP). (If CRP was missing then Erythrocyte Sedimentation Rate (ESR) was used if available.)
Time frame: Baseline, Week 52
Population: Intent to treat (ITT) population includes all randomized participants who received at least one infusion. Patients are considered non-responders if data are missing or from the point of withdrawal, rescue use or receipt of non-permitted Disease-modifying anti-rheumatic drugs (DMARDs).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Methotrexate | Percentage of Participants With American College of Rheumatology (ACR) ACR70 Response at Week 52 | 24.9 Percentage of Participants |
| Rituximab (0.5 g x 2) + Methotrexate | Percentage of Participants With American College of Rheumatology (ACR) ACR70 Response at Week 52 | 42.2 Percentage of Participants |
| Rituximab (1.0 g x 2) + Methotrexate | Percentage of Participants With American College of Rheumatology (ACR) ACR70 Response at Week 52 | 46.8 Percentage of Participants |
Secondary
Percentage of Participants With American College of Rheumatology (ACR) ACR90 Response at Week 52
To achieve an ACR90 response requires at least a 90% improvement compared with baseline in both Total Joint Count and Swollen Joint Count, as well as a 90% improvement in three of five additional measurements from: * the physician's global assessment of disease activity * patient's global assessment of disease activity * patient's assessment of pain * HAQ-DI (Health Assessment Questionnaire disability index) * an acute phase reactant C-Reactive Protein (CRP). (If CRP was missing then Erythrocyte Sedimentation Rate (ESR) was used if available.)
Time frame: Baseline, Week 52
Population: Intent to treat (ITT) population includes all randomized participants who received at least one infusion. Patients are considered non-responders if data are missing or from the point of withdrawal, rescue use or receipt of non-permitted Disease-modifying anti-rheumatic drugs (DMARDs).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Methotrexate | Percentage of Participants With American College of Rheumatology (ACR) ACR90 Response at Week 52 | 9.2 Percentage of Participants |
| Rituximab (0.5 g x 2) + Methotrexate | Percentage of Participants With American College of Rheumatology (ACR) ACR90 Response at Week 52 | 17.3 Percentage of Participants |
| Rituximab (1.0 g x 2) + Methotrexate | Percentage of Participants With American College of Rheumatology (ACR) ACR90 Response at Week 52 | 16.4 Percentage of Participants |
Secondary
Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52
The Stanford Health Assessment Questionnaire disability index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and common daily activities. Each domain has at least two component questions. There are four possible responses for each component on a scale of 0 (without difficulty) to 3 (unable to do). Higher scores=greater dysfunction. Improved:HAQ-DI score change \<=-0.22 Unchanged:HAQ-DI score change -0.22 to 0.22 Worsened:HAQ score =\> 0.22
Time frame: Baseline, Week 52
Population: Intent to treat (ITT) population includes all randomized participants who received at least one infusion. Last observation carried forward.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Methotrexate | Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52 | Not Assessable | 0.4 Percentage of participants |
| Placebo + Methotrexate | Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52 | Unchanged | 14.1 Percentage of participants |
| Placebo + Methotrexate | Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52 | Worsened | 8.4 Percentage of participants |
| Placebo + Methotrexate | Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52 | Improved | 77.1 Percentage of participants |
| Rituximab (0.5 g x 2) + Methotrexate | Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52 | Unchanged | 8.8 Percentage of participants |
| Rituximab (0.5 g x 2) + Methotrexate | Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52 | Worsened | 3.6 Percentage of participants |
| Rituximab (0.5 g x 2) + Methotrexate | Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52 | Improved | 86.7 Percentage of participants |
| Rituximab (0.5 g x 2) + Methotrexate | Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52 | Not Assessable | 0.8 Percentage of participants |
| Rituximab (1.0 g x 2) + Methotrexate | Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52 | Worsened | 4.4 Percentage of participants |
| Rituximab (1.0 g x 2) + Methotrexate | Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52 | Unchanged | 8.0 Percentage of participants |
| Rituximab (1.0 g x 2) + Methotrexate | Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52 | Not Assessable | 0.8 Percentage of participants |
| Rituximab (1.0 g x 2) + Methotrexate | Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52 | Improved | 86.8 Percentage of participants |
Secondary
Percentage of Participants With DAS28-ESR Low Disease Activity at Week 52
The DAS28-4(ESR) score is a measure of the subject's disease activity. It is based on the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity (mm), and ESR. DAS28-4(ESR) scores range from 0 - 10. Low disease activity is defined as achieving a DAS28-ESR score of less than or equal to 3.2
Time frame: Week 52
Population: Participants from the Intent to treat (ITT) population includes all randomized participants who received at least one infusion who had data available for analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Methotrexate | Percentage of Participants With DAS28-ESR Low Disease Activity at Week 52 | 19.8 Percentage of Participants |
| Rituximab (0.5 g x 2) + Methotrexate | Percentage of Participants With DAS28-ESR Low Disease Activity at Week 52 | 40.3 Percentage of Participants |
| Rituximab (1.0 g x 2) + Methotrexate | Percentage of Participants With DAS28-ESR Low Disease Activity at Week 52 | 43.0 Percentage of Participants |
Secondary
Percentage of Participants With DAS28-ESR Remission at Week 52
The DAS28-4(ESR) score is a measure of the subject's disease activity. It is based on the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity (mm), and ESR. DAS28-4(ESR) scores range from 0 - 10. Remission is defined as achieving a DAS28-ESR score of less than 2.6
Time frame: Week 52
Population: Participants from the Intent to treat (ITT) population includes all randomized participants who received at least one infusion with data available for analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Methotrexate | Percentage of Participants With DAS28-ESR Remission at Week 52 | 12.6 Percentage of Participants |
| Rituximab (0.5 g x 2) + Methotrexate | Percentage of Participants With DAS28-ESR Remission at Week 52 | 25.4 Percentage of Participants |
| Rituximab (1.0 g x 2) + Methotrexate | Percentage of Participants With DAS28-ESR Remission at Week 52 | 30.5 Percentage of Participants |
Secondary
Percentage of Participants With European League Against Rheumatism (EULAR) Good Response at Week 52
European League Against Rheumatism (EULAR) criteria reflects an improvement in disease activity and an attainment of a lower degree of disease activity. A good response is defined as an improvement in the DAS28-ESR of \> 1.2 compared with baseline, and attainment of a DAS28-ESR of \< 3.2.
Time frame: Baseline, Week 52
Population: Intent to treat (ITT) population includes all randomized participants who received at least one infusion. Patients are considered non-responders if data are missing
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Methotrexate | Percentage of Participants With European League Against Rheumatism (EULAR) Good Response at Week 52 | 18.1 Percentage of Participants |
| Rituximab (0.5 g x 2) + Methotrexate | Percentage of Participants With European League Against Rheumatism (EULAR) Good Response at Week 52 | 39.0 Percentage of Participants |
| Rituximab (1.0 g x 2) + Methotrexate | Percentage of Participants With European League Against Rheumatism (EULAR) Good Response at Week 52 | 41.6 Percentage of Participants |
Secondary
Percentage of Participants Without Radiographic Progression at Week 104
Percentage of patients without radiographic progression at Week 104, defined as change in total modified Sharp score (TMSS) ≤ 0. TMSS is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change.
Time frame: Baseline, Week 104
Population: Modified Intent to Treat (MITT) population includes all randomized participants who received at least one infusion and had both screening and post-baseline radiographic assessments. Patients with missing data are classified as progressing
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Methotrexate | Percentage of Participants Without Radiographic Progression at Week 104 | 37.3 Percentage of Participants |
| Rituximab (0.5 g x 2) + Methotrexate | Percentage of Participants Without Radiographic Progression at Week 104 | 49.4 Percentage of Participants |
| Rituximab (1.0 g x 2) + Methotrexate | Percentage of Participants Without Radiographic Progression at Week 104 | 56.6 Percentage of Participants |
Secondary
Percentage of Participants Without Radiographic Progression at Week 24
Percentage of patients without radiographic progression at Week 24 defined as change in total modified Sharp score (TMSS) ≤ 0. TMSS is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change.
Time frame: Baseline, Week 24
Population: Modified Intent to Treat (MITT) population includes all randomized participants who received at least one infusion and had both screening and post-baseline radiographic assessments. Patients with missing data are classified as progressing
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Methotrexate | Percentage of Participants Without Radiographic Progression at Week 24 | 59.7 Percentage of Participants |
| Rituximab (0.5 g x 2) + Methotrexate | Percentage of Participants Without Radiographic Progression at Week 24 | 65.3 Percentage of Participants |
| Rituximab (1.0 g x 2) + Methotrexate | Percentage of Participants Without Radiographic Progression at Week 24 | 71.7 Percentage of Participants |
Secondary
Percentage of Participants Without Radiographic Progression in the Total Erosion Score at Week 104
Total Erosion Score is determined by evaluation of fourteen sites in each wrist and hand and six joints in each foot using an eight-point scale from 0 (normal: no erosions) to 3.5 (Very severe; erosions of 100% of the articular surfaces. The score at baseline is compared to the score at week 104. No progression is defined as a change from score at screening to week 104 ≤0.
Time frame: Week 104
Population: Participants from the Modified Intent to Treat (MITT) population includes all randomized participants who received at least one infusion and had both screening and post-baseline radiographic assessments. Patients with missing data are classified as progressing.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Methotrexate | Percentage of Participants Without Radiographic Progression in the Total Erosion Score at Week 104 | 38.2 Percentage of Participants |
| Rituximab (0.5 g x 2) + Methotrexate | Percentage of Participants Without Radiographic Progression in the Total Erosion Score at Week 104 | 52.7 Percentage of Participants |
| Rituximab (1.0 g x 2) + Methotrexate | Percentage of Participants Without Radiographic Progression in the Total Erosion Score at Week 104 | 58.6 Percentage of Participants |
Secondary
Percentage of Patients With Minimally Clinically Important Difference (MCID) in the SF-36 Mental Health Component Score at Week 52
MCID is defined as a change from baseline in SF-36 Mental Health Component Score of \>6.33. SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement.
Time frame: Baseline, Week 52
Population: Participants from the Intent-to-treat population, includes all randomized participants who received at least one dose of study drug, with data available for analysis at Baseline and Week 52. Last observation carried forward.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Methotrexate | Percentage of Patients With Minimally Clinically Important Difference (MCID) in the SF-36 Mental Health Component Score at Week 52 | 49.0 Percentage of Participants |
| Rituximab (0.5 g x 2) + Methotrexate | Percentage of Patients With Minimally Clinically Important Difference (MCID) in the SF-36 Mental Health Component Score at Week 52 | 50.8 Percentage of Participants |
| Rituximab (1.0 g x 2) + Methotrexate | Percentage of Patients With Minimally Clinically Important Difference (MCID) in the SF-36 Mental Health Component Score at Week 52 | 57.0 Percentage of Participants |
Secondary
Percentage of Patients With Minimally Clinically Important Difference (MCID) in the SF-36 Physical Health Component Score at Week 52
MCID is defined as a change from baseline in SF-36 Physical Health Component Score of \>5.42. SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement.
Time frame: Baseline, Week 52
Population: Participants from the Intent-to-treat population, includes all randomized participants who received at least one dose of study drug, with data available for analysis at Baseline and Week 52. Last observation carried forward.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Methotrexate | Percentage of Patients With Minimally Clinically Important Difference (MCID) in the SF-36 Physical Health Component Score at Week 52 | 63.2 Percentage of Participants |
| Rituximab (0.5 g x 2) + Methotrexate | Percentage of Patients With Minimally Clinically Important Difference (MCID) in the SF-36 Physical Health Component Score at Week 52 | 69.9 Percentage of Participants |
| Rituximab (1.0 g x 2) + Methotrexate | Percentage of Patients With Minimally Clinically Important Difference (MCID) in the SF-36 Physical Health Component Score at Week 52 | 76.4 Percentage of Participants |
Secondary
Percentage of Patients Without Radiographic Progression at Week 52
Percentage of patients without radiographic progression at Week 52, defined as change in total modified Sharp score (TMSS) \<= 0. TMSS is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change.
Time frame: Baseline, Week 52
Population: Modified intent-to-treat population includes patients with a screening and at least one post-baseline radiographic evaluation, grouped as randomized. Patients with missing data are classified as progressing.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Methotrexate | Percentage of Patients Without Radiographic Progression at Week 52 | 53.4 Percentage |
| Rituximab (0.5 g x 2) + Methotrexate | Percentage of Patients Without Radiographic Progression at Week 52 | 57.7 Percentage |
| Rituximab (1.0 g x 2) + Methotrexate | Percentage of Patients Without Radiographic Progression at Week 52 | 63.5 Percentage |
Comparison: Rituximab 2 x 0.5 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline RF statusp-value: 0.380395% CI: [-0.05, 0.13]Cochran-Mantel-Haenszel
Comparison: Rituximab 2 x 1.0 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline RF statusp-value: 0.030995% CI: [0.01, 0.18]Cochran-Mantel-Haenszel
Secondary
Percentage of Patients Without Radiographic Progression in Total Erosion Score at Week 52
No radiographic progression is defined as a change in the total erosion score at Week 52 of less than or equal to zero.
Time frame: Baseline, Week 52
Population: Modified intent-to-treat population includes patients with a screening and at least one post-baseline radiographic evaluation, grouped as randomized. Linear interpolation/extrapolation used for missing data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Methotrexate | Percentage of Patients Without Radiographic Progression in Total Erosion Score at Week 52 | 54.7 Percentage of Participants |
| Rituximab (0.5 g x 2) + Methotrexate | Percentage of Patients Without Radiographic Progression in Total Erosion Score at Week 52 | 59.0 Percentage of Participants |
| Rituximab (1.0 g x 2) + Methotrexate | Percentage of Patients Without Radiographic Progression in Total Erosion Score at Week 52 | 66.8 Percentage of Participants |
Comparison: Rituximab (0.5 g x 2) + Methotrexate versus Placebo + Methotrexate, stratified for region and baseline RF status.p-value: 0.3752Cochran-Mantel-Haenszel
Comparison: Rituximab (1.0 g x 2) + Methotrexate verus Placebo + Methotrexate, stratified for region and Baseline RF status.p-value: 0.0081Cochran-Mantel-Haenszel
Secondary
The Percentage of Participants With Major Clinical Response at Week 52
Major clinical response is defined as a continuous six-month period of success by the ACR70. ACR70= 70% improvement compared with baseline in both Total Joint Count and Swollen Joint Count, as well as a 70% improvement in 3 of five additional measurements from: * the physician's global assessment of disease activity * patient's global assessment of disease activity * patient's assessment of pain * HAQ-DI (Health Assessment Questionnaire disability index) * an acute phase reactant C-Reactive Protein (CRP). (If CRP was missing then Erythrocyte Sedimentation Rate (ESR) was used if available.)
Time frame: Week 52
Population: Intent to treat (ITT) population includes all randomized participants who received at least one infusion.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Methotrexate | The Percentage of Participants With Major Clinical Response at Week 52 | 8.4 Percentage of Participants |
| Rituximab (0.5 g x 2) + Methotrexate | The Percentage of Participants With Major Clinical Response at Week 52 | 18.1 Percentage of Participants |
| Rituximab (1.0 g x 2) + Methotrexate | The Percentage of Participants With Major Clinical Response at Week 52 | 21.2 Percentage of Participants |