IMAGE: A Study to Evaluate Rituximab in Combination With Methotrexate in Methotrexate-Naive Patients With Active Rheumatoid Arthritis

Sponsor
Genentech, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT00299104
Collaborator
Hoffmann-La Roche (Industry)
755
3
90

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
755 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Randomized, Phase 3, Controlled, Double-Blind, Parallel-Group, Multicenter Study to Evaluate the Safety and Efficacy of Rituximab in Combination With Methotrexate (MTX) Compared to MTX Alone, in Methotrexate-Naive Patients With Active Rheumatoid Arthritis
Study Start Date :
Jan 1, 2006
Actual Primary Completion Date :
Sep 1, 2008
Actual Study Completion Date :
Jul 1, 2013

Arms and Interventions

Arm Intervention/Treatment
Experimental: 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

Drug: folate
Intravenous repeating dose

Drug: methotrexate
Oral or parenteral repeating dose

Drug: methylprednisolone
Intravenous repeating dose

Drug: rituximab
Intravenous repeating dose

Experimental: 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

Drug: folate
Intravenous repeating dose

Drug: methotrexate
Oral or parenteral repeating dose

Drug: methylprednisolone
Intravenous repeating dose

Drug: rituximab
Intravenous repeating dose

Placebo Comparator: 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.

Drug: folate
Intravenous repeating dose

Drug: methotrexate
Oral or parenteral repeating dose

Drug: methylprednisolone
Intravenous repeating dose

Drug: placebo
Intravenous repeating dose

Outcome Measures

Primary Outcome Measures

  1. 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 Outcome Measures

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.)

  10. 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).

  11. 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.)

  12. 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

  13. 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.

  14. 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.)

  15. 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

  16. 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.)

  17. 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.)

  18. 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.

  19. 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.

  20. 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.

  21. 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.

  22. 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

  23. 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.

  24. 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.

  25. 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.

  26. 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.

  27. 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.

  28. 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.

  29. 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years to 80 Years
Sexes Eligible for Study:
All
Accepts 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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

  • Genentech, Inc.
  • Hoffmann-La Roche

Investigators

  • Study Director: Arndt Schottelius, M.D., Genentech, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Genentech, Inc.
ClinicalTrials.gov Identifier:
NCT00299104
Other Study ID Numbers:
  • U3373g
  • WA17047
First Posted:
Mar 6, 2006
Last Update Posted:
Jul 28, 2017
Last Verified:
Jun 1, 2017
Keywords provided by Genentech, Inc.
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail
Arm/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Period Title: Treatment Period
STARTED 251 252 252
Safety/ITT: Received Study Drug 249 249 250
Completed Week 24 227 240 241
Completed Week 52 213 227 232
Completed Week 104 178 213 216
COMPLETED 62 77 80
NOT COMPLETED 189 175 172
Period Title: Treatment Period
STARTED 184 212 213
COMPLETED 129 171 176
NOT COMPLETED 55 41 37
Period Title: Treatment Period
STARTED 34 40 51
COMPLETED 29 31 39
NOT COMPLETED 5 9 12

Baseline Characteristics

Arm/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate Total
Arm/Group Description 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. 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 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 Total of all reporting groups
Overall Participants 249 249 250 748
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
48.06
(12.692)
47.87
(13.391)
47.89
(13.324)
47.94
(13.136)
Sex: Female, Male (Count of Participants)
Female
192
77.1%
203
81.5%
212
84.8%
607
81.1%
Male
57
22.9%
46
18.5%
38
15.2%
141
18.9%

Outcome Measures

1. Primary Outcome
Title Change From Baseline in Modified Total Sharp Score (mTSS) From Screening at Week 52
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 232 239 244
Mean (Standard Deviation) [Score on a scale]
1.079
(4.0934)
0.646
(1.9196)
0.359
(1.0095)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo + Methotrexate, Rituximab (0.5 g x 2) + Methotrexate, Rituximab (1.0 g x 2) + Methotrexate
Comments Comparing all three treatment groups
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0016
Comments The Closure Principle was used to adjust for multiple comparisons.
Method Kruskal-Wallis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo + Methotrexate, Rituximab (0.5 g x 2) + Methotrexate
Comments Rituximab 2 x 0.5 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline rheumatoid factor (RF) status
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.1824
Comments The Closure Principle was used to adjust for multiple comparisons.
Method Van-Elteren
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo + Methotrexate, Rituximab (1.0 g x 2) + Methotrexate
Comments Rituximab 2 x 1.0 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline RF status
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0004
Comments The Closure Principle was used to adjust for multiple comparisons.
Method Van-Elteren
Comments
2. Secondary Outcome
Title Change From Baseline in Modified Sharp Erosion Score at Week 52
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 232 239 244
Mean (Standard Deviation) [Score on a scale]
0.738
(2.0480)
0.453
(1.2065)
0.233
(0.6252)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo + Methotrexate, Rituximab (0.5 g x 2) + Methotrexate, Rituximab (1.0 g x 2) + Methotrexate
Comments Comparing all three treatment groups
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0004
Comments The Closure Principle was used to adjust for multiple comparisons. This was a secondary endpoint in a hierarchical testing structure.
Method Kruskal-Wallis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo + Methotrexate, Rituximab (0.5 g x 2) + Methotrexate
Comments Rituximab 2 x 0.5 g + Methotrexate versus Placebo + Methotrexate, stratified for region and baseline RF status
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.1194
Comments The Closure Principle was used to adjust for multiple comparisons. This was a secondary endpoint in a hierarchical testing structure.
Method Van-Elteren
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo + Methotrexate, Rituximab (1.0 g x 2) + Methotrexate
Comments Rituximab 2 x 1.0 g + Methotrexate versus Placebo + Methotrexate, stratified for region and baseline RF status
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0001
Comments The Closure Principle was used to adjust for multiple comparisons. This was a secondary endpoint in a hierarchical testing structure.
Method Van-Elteren
Comments
3. Secondary Outcome
Title Percentage of Patients Without Radiographic Progression at Week 52
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 232 239 244
Number [Percentage]
53.4
57.7
63.5
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo + Methotrexate, Rituximab (0.5 g x 2) + Methotrexate
Comments Rituximab 2 x 0.5 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline RF status
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.3803
Comments This was a secondary endpoint in a hierarchical testing structure.
Method Cochran-Mantel-Haenszel
Comments
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.04
Confidence Interval () 95%
-0.05 to 0.13
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo + Methotrexate, Rituximab (1.0 g x 2) + Methotrexate
Comments Rituximab 2 x 1.0 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline RF status
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0309
Comments This was a secondary endpoint in a hierarchical testing structure.
Method Cochran-Mantel-Haenszel
Comments
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.10
Confidence Interval () 95%
0.01 to 0.18
Parameter Dispersion Type:
Value:
Estimation Comments
4. Secondary Outcome
Title Percentage of Patients Without Radiographic Progression in Total Erosion Score at Week 52
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 232 239 244
Number [Percentage of Participants]
54.7
22%
59.0
23.7%
66.8
26.7%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo + Methotrexate, Rituximab (0.5 g x 2) + Methotrexate
Comments Rituximab (0.5 g x 2) + Methotrexate versus Placebo + Methotrexate, stratified for region and baseline RF status.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.3752
Comments This was a secondary endpoint in a hierarchical testing structure.
Method Cochran-Mantel-Haenszel
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo + Methotrexate, Rituximab (1.0 g x 2) + Methotrexate
Comments Rituximab (1.0 g x 2) + Methotrexate verus Placebo + Methotrexate, stratified for region and Baseline RF status.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0081
Comments This was a secondary endpoint in a hierarchical testing structure.
Method Cochran-Mantel-Haenszel
Comments
5. Secondary Outcome
Title Change From Baseline in Modified Joint Space Narrowing (JSN) Score at Week 52
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 232 239 244
Mean (Standard Deviation) [Score on a scale]
0.341
(2.2408)
0.193
(0.9422)
0.126
(0.6363)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo + Methotrexate, Rituximab (0.5 g x 2) + Methotrexate, Rituximab (1.0 g x 2) + Methotrexate
Comments Comparing all three treatment groups.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.5939
Comments The Closure Principle was used to adjust for multiple comparisons. This was a secondary endpoint in a hierarchical testing structure.
Method Kruskal-Wallis
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo + Methotrexate, Rituximab (0.5 g x 2) + Methotrexate
Comments Rituximab 2 x 0.5 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline RF status
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.5478
Comments The Closure Principle was used to adjust for multiple comparisons. This was a secondary endpoint in a hierarchical testing structure.
Method Van-Elteren
Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo + Methotrexate, Rituximab (1.0 g x 2) + Methotrexate
Comments Rituximab 2 x 1.0 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline RF status
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.3096
Comments The Closure Principle was used to adjust for multiple comparisons. This was a secondary endpoint in a hierarchical testing structure.
Method Van-Elteren
Comments
6. Secondary Outcome
Title Change From Baseline in the Modified Total Sharp Score at Week 24
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 226 238 242
Mean (Standard Deviation) [Score on a scale]
0.701
(2.9116)
0.508
(1.7349)
0.328
(0.9443)
7. Secondary Outcome
Title Change From Baseline in the Total Erosion Score at Week 24
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 226 238 242
Mean (Standard Deviation) [Score on a scale]
0.491
(1.3789)
0.404
(1.0390)
0.220
(0.5802)
8. Secondary Outcome
Title Change From Baseline in Modified Joint Space Narrowing (JSN) Score at Week 24
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 226 238 242
Mean (Standard Deviation) [Score on a scale]
0.210
(1.7403)
0.176
(0.8949)
0.108
(0.6118)
9. Secondary Outcome
Title Percentage of Participants Without Radiographic Progression at Week 24
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 233 239 244
Number [Percentage of Participants]
59.7
24%
65.3
26.2%
71.7
28.7%
10. Secondary Outcome
Title Percentage of Participants With American College of Rheumatology (ACR) ACR50 Response at Week 52
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 249 249 250
Number [Percentage of Participants]
41.8
16.8%
59.4
23.9%
64.8
25.9%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo + Methotrexate, Rituximab (0.5 g x 2) + Methotrexate
Comments Rituximab 2 x 0.5 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline RF status
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments This was a secondary endpoint in a hierarchical testing structure.
Method Cochran-Mantel-Haenszel
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo + Methotrexate, Rituximab (1.0 g x 2) + Methotrexate
Comments Rituximab 2 x 1.0 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline RF status
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments This was a secondary endpoint in a hierarchical testing structure.
Method Cochran-Mantel-Haenszel
Comments
11. Secondary Outcome
Title Change From Baseline in the Disease Activity Score 28 Joint Count- Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 52
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 244 247 248
Mean (Standard Deviation) [Score on a scale]
-2.33
(1.691)
-3.35
(1.663)
-3.46
(1.640)
12. Secondary Outcome
Title Percentage of Participants With American College of Rheumatology (ACR) ACR70 Response at Week 52
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 249 249 250
Number [Percentage of Participants]
24.9
10%
42.2
16.9%
46.8
18.7%
13. Secondary Outcome
Title Percentage of Participants With DAS28-ESR Remission at Week 52
Description 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

Outcome Measure Data

Analysis Population Description
Participants from the Intent to treat (ITT) population includes all randomized participants who received at least one infusion with data available for analyses.
Arm/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 247 248 249
Number [Percentage of Participants]
12.6
5.1%
25.4
10.2%
30.5
12.2%
14. Secondary Outcome
Title Percentage of Participants With European League Against Rheumatism (EULAR) Good Response at Week 52
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 249 249 250
Number [Percentage of Participants]
18.1
7.3%
39.0
15.7%
41.6
16.6%
15. Secondary Outcome
Title The Percentage of Participants With Major Clinical Response at Week 52
Description 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

Outcome Measure Data

Analysis Population Description
Intent to treat (ITT) population includes all randomized participants who received at least one infusion.
Arm/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 249 249 250
Number [Percentage of Participants]
8.4
3.4%
18.1
7.3%
21.2
8.5%
16. Secondary Outcome
Title Percentage of Participants With DAS28-ESR Low Disease Activity at Week 52
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 247 248 249
Number [Percentage of Participants]
19.8
8%
40.3
16.2%
43.0
17.2%
17. Secondary Outcome
Title Percentage of Participants With American College of Rheumatology (ACR) ACR20 Response at Week 52
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 249 249 250
Number [Percentage of Participants]
64.3
25.8%
76.7
30.8%
80.0
32%
18. Secondary Outcome
Title Percentage of Participants With American College of Rheumatology (ACR) ACR90 Response at Week 52
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 249 249 250
Number [Percentage of Participants]
9.2
3.7%
17.3
6.9%
16.4
6.6%
19. Secondary Outcome
Title Change in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Score From Baseline at Week 52
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 198 206 218
Mean (Standard Deviation) [Score on a scale]
10.154
(11.1344)
11.833
(11.5807)
12.426
(12.2535)
20. Secondary Outcome
Title Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52
Description 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

Outcome Measure Data

Analysis Population Description
Intent-to treat Population includes all randomized participants who received at least one dose of study drug. Last observation carried forward.
Arm/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 248 247 249
Mean (Standard Deviation) [Score on a scale]
-0.800
(0.7764)
-1.038
(0.7625)
-1.023
(0.7634)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo + Methotrexate, Rituximab (0.5 g x 2) + Methotrexate
Comments Rituximab (0.5 g x 2) + Methotrexate versus Placebo + Methotrexate stratified for region and RF status.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments Secondary endpoint in hierarchical testing structure.
Method ANOVA
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo + Methotrexate, Rituximab (1.0 g x 2) + Methotrexate
Comments Rituximab (1.0 g x 2) + Methotrexate versus Placebo + Methotrexate, stratified for region and baseline RF status.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments Secondary endpoint in hierarchical testing structure.
Method ANOVA
Comments
21. Secondary Outcome
Title Change From Baseline in the SF-36 Physical Health Component Summary Score at Week 52 and Week 104
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 249 249 250
Week 52 (n=239,236,241)
8.953
(9.3986)
11.022
(9.6246)
12.205
(9.4986)
Week 104 (n=240,236,242)
8.617
(9.8500)
11.032
(9.9631)
12.649
(10.4331)
22. Secondary Outcome
Title Change From Baseline in the SF-36 Mental Health Component Summary Score at Week 52 and Week 104
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 249 249 250
Week 52 (n=239,236,241)
6.689
(13.1160)
7.718
(11.8903)
8.167
(12.1709)
Week 104 (n= 240,236,242)
6.295
(13.9813)
7.617
(12.0793)
9.066
(12.5325)
23. Secondary Outcome
Title Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52
Description 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

Outcome Measure Data

Analysis Population Description
Intent to treat (ITT) population includes all randomized participants who received at least one infusion. Last observation carried forward.
Arm/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 249 249 250
Improved
77.1
31%
86.7
34.8%
86.8
34.7%
Unchanged
14.1
5.7%
8.8
3.5%
8.0
3.2%
Worsened
8.4
3.4%
3.6
1.4%
4.4
1.8%
Not Assessable
0.4
0.2%
0.8
0.3%
0.8
0.3%
24. Secondary Outcome
Title Percentage of Patients With Minimally Clinically Important Difference (MCID) in the SF-36 Physical Health Component Score at Week 52
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 239 236 242
Number [Percentage of Participants]
63.2
25.4%
69.9
28.1%
76.4
30.6%
25. Secondary Outcome
Title Percentage of Patients With Minimally Clinically Important Difference (MCID) in the SF-36 Mental Health Component Score at Week 52
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 239 236 242
Number [Percentage of Participants]
49.0
19.7%
50.8
20.4%
57.0
22.8%
26. Secondary Outcome
Title Change From Baseline in the Modified Total Sharp Score at Week 104
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 229 238 243
Mean (Standard Deviation) [Score on a scale]
1.948
(5.5782)
0.761
(2.6181)
0.406
(1.4312)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo + Methotrexate, Rituximab (1.0 g x 2) + Methotrexate
Comments Week 104: Rituximab 2 x 0.5 g + Methotrexate arm versus Placebo + Methotrexate, stratified for region and baseline rheumatoid factor (RF) status.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments This was a secondary endpoint in a hierarchical testing structure.
Method Van-Elteren
Comments
27. Secondary Outcome
Title Change From Baseline in the Total Erosion Score at Week 104
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 229 238 243
Mean (Standard Deviation) [Score on a scale]
1.315
(3.2466)
0.499
(1.7221)
0.227
(0.7939)
28. Secondary Outcome
Title Percentage of Participants Without Radiographic Progression at Week 104
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 233 239 244
Number [Percentage of Participants]
37.3
15%
49.4
19.8%
56.6
22.6%
29. Secondary Outcome
Title Percentage of Participants Without Radiographic Progression in the Total Erosion Score at Week 104
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 233 239 244
Number [Percentage of Participants]
38.2
15.3%
52.7
21.2%
58.6
23.4%
30. Secondary Outcome
Title Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 104
Description 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

Outcome Measure Data

Analysis Population Description
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/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
Measure Participants 248 247 248
Mean (Standard Deviation) [Score on a scale]
-0.806
(0.7968)
-1038
(0.8142)
-1.055
(0.7901)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo + Methotrexate, Rituximab (0.5 g x 2) + Methotrexate
Comments Rituximab (0.5 g x 2) + Methotrexate versus Placebo + Methotrexate, stratified for region and baseline RF status.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments Secondary endpoint in hierarchical testing structure.
Method ANOVA
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo + Methotrexate, Rituximab (1.0 g x 2) + Methotrexate
Comments Rituximab (1.0 g x 2) + Methotrexate versus Placebo + Methotrexate, stratified for region and baseline RF status.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments Secondary endpoint in hierarchical testing structure.
Method ANOVA
Comments

Adverse Events

Time Frame From Baseline to End of ESFU
Adverse Event Reporting Description Safety Population includes all participants who received at least one dose of study drug, grouped as treated. After Week 104 participants in the placebo group were eligible to receive either Rituximab 2 X 0.5 g + MTX or Rituximab 2 X 1.0g + MTX. Adverse events reported for placebo patients after switching to Rituximab are not included below.
Arm/Group Title Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Arm/Group Description 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. 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 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
All Cause Mortality
Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total / (NaN) / (NaN) / (NaN)
Serious Adverse Events
Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 48/249 (19.3%) 54/348 (15.5%) 58/263 (22.1%)
Blood and lymphatic system disorders
Neutropenia 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Pancytopenia 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Cardiac disorders
Myocardial Infarction 0/249 (0%) 2/348 (0.6%) 1/263 (0.4%)
Angina Pectoris 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Angina Unstable 1/249 (0.4%) 0/348 (0%) 1/263 (0.4%)
Atrioventricular Block Complete 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Atrial Fibrillation 0/249 (0%) 1/348 (0.3%) 2/263 (0.8%)
Acute Myocardial Infarction 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Coronary Artery Occlusion 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Mitral Valve Sclerosis 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Pericardial Effusion 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Supraventricular Tachycardia 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Ear and labyrinth disorders
Vertigo Positional 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Meniere's Disease 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Endocrine disorders
Goitre 1/249 (0.4%) 0/348 (0%) 1/263 (0.4%)
Gastrointestinal disorders
Inguinal Hernia 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Diarrhoea 1/249 (0.4%) 0/348 (0%) 1/263 (0.4%)
Diverticular Perforation 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Gastrointestinal Haemorrhage 1/249 (0.4%) 0/348 (0%) 1/263 (0.4%)
Gastrointestinal Hypomotility 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Inguinal Hernia, Obstructive 0/249 (0%) 1/348 (0.3%) 1/263 (0.4%)
Abdominal Hernia 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Colitis 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Duodenal Ulcer 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Gastritis 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Gastrooesophageal Reflux Disease 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Rectal Polyp 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Umbilical Hernia 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Colitis Ulcerative 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Intestinal Perforation 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Large Intestinal Stenosis 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Gastrointestinal Dysplasia 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Upper Gastrointestinal Haemorrhage 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
General disorders
Non-Cardiac Chest Pain 1/249 (0.4%) 0/348 (0%) 1/263 (0.4%)
Surgical Failure 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Chest Pain 1/249 (0.4%) 2/348 (0.6%) 2/263 (0.8%)
Ulcer Haemorrhage 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Hepatobiliary disorders
Cholecystitis 0/249 (0%) 2/348 (0.6%) 1/263 (0.4%)
Cholelithiasis 1/249 (0.4%) 0/348 (0%) 1/263 (0.4%)
Cholecystitis Acute 1/249 (0.4%) 0/348 (0%) 1/263 (0.4%)
Cholangitis 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Liver Disorder 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Infections and infestations
Pneumonia 6/249 (2.4%) 7/348 (2%) 4/263 (1.5%)
Urinary Tract Infection 4/249 (1.6%) 2/348 (0.6%) 0/263 (0%)
Appendicitis 0/249 (0%) 2/348 (0.6%) 0/263 (0%)
Acute Tonsillitis 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Cellulitis 0/249 (0%) 1/348 (0.3%) 1/263 (0.4%)
Febrile Infection 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Gastroenteritis 0/249 (0%) 1/348 (0.3%) 1/263 (0.4%)
Infection 0/249 (0%) 0/348 (0%) 3/263 (1.1%)
Lung Infection 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Pneumocystis Jirovecii Pneumonia 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Pneumonia Pneumococcal 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Septic Shock 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Subcutaneous Abscess 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Tonsillitis 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Appendicitis Perforated 1/249 (0.4%) 1/348 (0.3%) 0/263 (0%)
Peritonitis 1/249 (0.4%) 0/348 (0%) 1/263 (0.4%)
Diverticulitis 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Endophthalmitis 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Gangrene 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Pulmonary Tuberculosis 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Pyelonephritis 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Pyelonephritis Acute 1/249 (0.4%) 2/348 (0.6%) 0/263 (0%)
Dengue Fever 0/249 (0%) 1/348 (0.3%) 1/263 (0.4%)
Abscess Limb 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Arthritis Bacterial 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Atypical Pneumonia 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Colonic Abscess 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
H1N1 Influenza 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Influenza 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Lower Respiratory Tract Infection 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Necrotising Fasciitis 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Sepsis 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Tracheobronchitis 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Respiratory Tract Infection 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Bronchitis 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Injury, poisoning and procedural complications
Infusion Related Reaction 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Fall 3/249 (1.2%) 2/348 (0.6%) 1/263 (0.4%)
Accident 1/249 (0.4%) 0/348 (0%) 1/263 (0.4%)
Femur Fracture 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Contusion 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Intentional Overdose 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Road Traffic Accident 2/249 (0.8%) 1/348 (0.3%) 0/263 (0%)
Ligament Sprain 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Multiple Fractures 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Rib Fracture 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Metabolism and nutrition disorders
Diabetic Ketoacidosis 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Diabetes Mellitus 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Musculoskeletal and connective tissue disorders
Rheumatoid Arthritis 1/249 (0.4%) 3/348 (0.9%) 2/263 (0.8%)
Bursitis 1/249 (0.4%) 1/348 (0.3%) 0/263 (0%)
Osteonecrosis 1/249 (0.4%) 0/348 (0%) 1/263 (0.4%)
Arthritis 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Foot Deformity 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Pathological Fracture 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Spinal Pain 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Intervertebral Disc Protrusion 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Carcinoma In Situ of Skin 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Cervix Carcinoma 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Myelodysplastic Syndrome 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Primary Mediastinal Large B-Cell Lymphoma 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Metastatic Malignant Melanoma 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Lymphoma 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Breast Cancer 0/249 (0%) 1/348 (0.3%) 1/263 (0.4%)
Uterine Leiomyoma 1/249 (0.4%) 0/348 (0%) 1/263 (0.4%)
Lung Neoplasm Malignant 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Prostate Cancer Stage II 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Endometrial Adenocarcinoma 1/249 (0.4%) 1/348 (0.3%) 0/263 (0%)
Adenocarcinoma of Colon 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Anaplastic Large-Cell Lymphoma 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Invasive Ductal Breast Carcinoma 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Lung Adenocarcinoma 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Metastatic Neoplasm 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Monoclonal Gammopathy 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Paget's Disease of Nipple 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Nervous system disorders
Carotid Arteriosclerosis 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Embolic Stroke 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Epilepsy 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Migraine 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Sciatica 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Syncope 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Transient Ischaemic Attack 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Cerebrovascular Accident 0/249 (0%) 1/348 (0.3%) 1/263 (0.4%)
Hypertensive Encephalopathy 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Cereberal Infarction 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Convulsion 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Cerebral Infarction 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Headache 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion Spontaneous 0/249 (0%) 1/348 (0.3%) 1/263 (0.4%)
Psychiatric disorders
Anxiety 0/249 (0%) 0/348 (0%) 2/263 (0.8%)
Depression 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Drug Dependence 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Renal and urinary disorders
Calculus Urinary 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Nephrolithiasis 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Reproductive system and breast disorders
Cystocele 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Cervical Dysplasia 2/249 (0.8%) 0/348 (0%) 0/263 (0%)
Menorrhagia 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Ovarian Cyst Ruptured 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Respiratory, thoracic and mediastinal disorders
Interstitial Lung Disease 1/249 (0.4%) 1/348 (0.3%) 2/263 (0.8%)
Dyspnoea 0/249 (0%) 1/348 (0.3%) 1/263 (0.4%)
Epistaxis 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Pulmonary Embolism 1/249 (0.4%) 1/348 (0.3%) 0/263 (0%)
Status Asthmaticus 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Laryngeal Hypertrophy 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Nasal Polyps 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Pulmonary Fibrosis 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Asthma 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Respiratory Failure 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Skin and subcutaneous tissue disorders
Diabetic Ulcer 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Surgical and medical procedures
Abortion Induced 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Vascular disorders
Angiopathy 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Deep Vein Thrombosis 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Hypertensive Crisis 0/249 (0%) 0/348 (0%) 1/263 (0.4%)
Pelvic Venous Thrombosis 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Venous Insufficiency 0/249 (0%) 1/348 (0.3%) 1/263 (0.4%)
Hypertension 1/249 (0.4%) 0/348 (0%) 0/263 (0%)
Peripheral Ischaemia 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Peripheral Vascular Disorder 0/249 (0%) 1/348 (0.3%) 0/263 (0%)
Other (Not Including Serious) Adverse Events
Placebo + Methotrexate Rituximab (0.5 g x 2) + Methotrexate Rituximab (1.0 g x 2) + Methotrexate
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 193/249 (77.5%) 232/348 (66.7%) 208/263 (79.1%)
Blood and lymphatic system disorders
Anaemia 25/249 (10%) 14/348 (4%) 19/263 (7.2%)
Gastrointestinal disorders
Nausea 42/249 (16.9%) 45/348 (12.9%) 46/263 (17.5%)
Diarrhoea 15/249 (6%) 24/348 (6.9%) 18/263 (6.8%)
Dyspepsia 13/249 (5.2%) 15/348 (4.3%) 14/263 (5.3%)
Gastritis 13/249 (5.2%) 11/348 (3.2%) 10/263 (3.8%)
Hepatobiliary disorders
Drug-Induced Liver Injury 35/249 (14.1%) 37/348 (10.6%) 38/263 (14.4%)
Infections and infestations
Upper Respiratory Tract Infection 44/249 (17.7%) 59/348 (17%) 58/263 (22.1%)
Nasopharyngitis 43/249 (17.3%) 53/348 (15.2%) 52/263 (19.8%)
Urinary Tract Infection 26/249 (10.4%) 36/348 (10.3%) 43/263 (16.3%)
Bronchitis 15/249 (6%) 32/348 (9.2%) 20/263 (7.6%)
Sinusitis 11/249 (4.4%) 23/348 (6.6%) 20/263 (7.6%)
Pharyngitis 16/249 (6.4%) 14/348 (4%) 14/263 (5.3%)
Gastroenteritis 7/249 (2.8%) 9/348 (2.6%) 16/263 (6.1%)
Influenza 11/249 (4.4%) 9/348 (2.6%) 16/263 (6.1%)
Injury, poisoning and procedural complications
Infusion Related Reaction 53/249 (21.3%) 69/348 (19.8%) 67/263 (25.5%)
Musculoskeletal and connective tissue disorders
Rheumatoid Arthritis 42/249 (16.9%) 30/348 (8.6%) 29/263 (11%)
Back pain 14/249 (5.6%) 19/348 (5.5%) 9/263 (3.4%)
Nervous system disorders
Headache 18/249 (7.2%) 17/348 (4.9%) 31/263 (11.8%)
Dizziness 13/249 (5.2%) 12/348 (3.4%) 20/263 (7.6%)
Respiratory, thoracic and mediastinal disorders
Cough 11/249 (4.4%) 19/348 (5.5%) 24/263 (9.1%)
Vascular disorders
Hypertension 18/249 (7.2%) 22/348 (6.3%) 24/263 (9.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

Results Point of Contact

Name/Title Medical Communications
Organization Genentech, Inc.
Phone 800-821-8590
Email genentech@druginfo.com
Responsible Party:
Genentech, Inc.
ClinicalTrials.gov Identifier:
NCT00299104
Other Study ID Numbers:
  • U3373g
  • WA17047
First Posted:
Mar 6, 2006
Last Update Posted:
Jul 28, 2017
Last Verified:
Jun 1, 2017