SERENE: A Study to Evaluate the Safety and Efficacy of Rituximab in Combination With Methotrexate Compared to Methotrexate Alone in Patients With Active Rheumatoid Arthritis

Sponsor

Genentech, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT00299130

Collaborator

Hoffmann-La Roche (Industry)

511

Enrollment

Arms

Duration (Months)

Study Details

Study Description

Brief Summary

This study evaluated the efficacy and safety of rituximab in patients with active rheumatoid arthritis (RA).

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: Folate Drug: Methotrexate Drug: Methylprednisolone Drug: Placebo Drug: Rituximab	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

511 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

A Randomized, Placebo Controlled, Double-blind, Parallel Group, International Study to Evaluate the Safety and Efficacy of Rituximab in Combination With Methotrexate, Compared to Methotrexate Monotherapy, in Patients With Active Rheumatoid Arthritis

Study Start Date :

Oct 1, 2005

Actual Primary Completion Date :

Jun 1, 2008

Actual Study Completion Date :

Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Placebo + methotrexate (MTX) Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 milligrams (mg) intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Drug: Folate A stable dose, ≥ 5 mg/week given as either a single dose or as a divided weekly dose, orally. Drug: Methotrexate A stable dose of between 10-25 mg/week, oral or parenteral, as prescribed by the treating physician. Drug: Methylprednisolone Intravenous infusion Drug: Placebo Placebo to rituximab intravenous infusion Drug: Rituximab Intravenous infusion Other Names: MabThera® Rituxan®
Experimental: Rituximab 2 x 0.5 g + MTX Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Drug: Folate A stable dose, ≥ 5 mg/week given as either a single dose or as a divided weekly dose, orally. Drug: Methotrexate A stable dose of between 10-25 mg/week, oral or parenteral, as prescribed by the treating physician. Drug: Methylprednisolone Intravenous infusion Drug: Rituximab Intravenous infusion Other Names: MabThera® Rituxan®
Experimental: Rituximab 2 x 1.0 g + MTX Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Drug: Folate A stable dose, ≥ 5 mg/week given as either a single dose or as a divided weekly dose, orally. Drug: Methotrexate A stable dose of between 10-25 mg/week, oral or parenteral, as prescribed by the treating physician. Drug: Methylprednisolone Intravenous infusion Drug: Rituximab Intravenous infusion Other Names: MabThera® Rituxan®

Arm

Intervention/Treatment

Active Comparator: Placebo + methotrexate (MTX)

Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 milligrams (mg) intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

Drug: Folate

A stable dose, ≥ 5 mg/week given as either a single dose or as a divided weekly dose, orally.

Drug: Methotrexate

A stable dose of between 10-25 mg/week, oral or parenteral, as prescribed by the treating physician.

Drug: Methylprednisolone

Intravenous infusion

Drug: Placebo

Placebo to rituximab intravenous infusion

Drug: Rituximab

Intravenous infusion

Other Names:

MabThera®

Rituxan®

Experimental: Rituximab 2 x 0.5 g + MTX

Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

Drug: Folate

A stable dose, ≥ 5 mg/week given as either a single dose or as a divided weekly dose, orally.

Drug: Methotrexate

A stable dose of between 10-25 mg/week, oral or parenteral, as prescribed by the treating physician.

Drug: Methylprednisolone

Intravenous infusion

Drug: Rituximab

Intravenous infusion

Other Names:

MabThera®

Rituxan®

Experimental: Rituximab 2 x 1.0 g + MTX

Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

Drug: Folate

A stable dose, ≥ 5 mg/week given as either a single dose or as a divided weekly dose, orally.

Drug: Methotrexate

A stable dose of between 10-25 mg/week, oral or parenteral, as prescribed by the treating physician.

Drug: Methylprednisolone

Intravenous infusion

Drug: Rituximab

Intravenous infusion

Other Names:

MabThera®

Rituxan®

Outcome Measures

Primary Outcome Measures

Percentage of Participants With American College of Rheumatology (ACR) 20 Response at Week 24 [Baseline and Week 24]
To achieve an ACR20 required at least a 20% improvement compared with Baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 20% improvement in three of the following five additional measurements: Physician's global assessment of disease activity (assessed using a 100 mm Visual Analog Scale [VAS]); Patient's global assessment of disease activity (assessed using a 100 mm VAS); Patient's assessment of pain (assessed using a 100 mm VAS); Health Assessment Questionnaire (HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3); Acute phase reactant: C-reactive protein (CRP) or, if CRP was missing, erythrocyte sedimentation rate (ESR). Participants who withdrew prematurely from the study prior to Week 24, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders.

Secondary Outcome Measures

Percentage of Participants With an ACR50 Response at Week 24 [Baseline and Week 24]
To achieve an ACR50 required at least a 50% improvement compared with Baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 50% improvement in three of the following five additional measurements: Physician's global assessment of disease activity (assessed using a 100 mm Visual Analog Scale [VAS]); Patient's global assessment of disease activity (assessed using a 100 mm VAS); Patient's assessment of pain (assessed using a 100 mm VAS); Health Assessment Questionnaire (HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3); Acute phase reactant: C-reactive protein (CRP) or, if CRP was missing, erythrocyte sedimentation rate (ESR). Participants who withdrew prematurely from the study prior to Week 24, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders.
Percentage of Participants With an ACR70 Response at Week 24 [Baseline and Week 24]
To achieve an ACR70 required at least a 70% improvement compared with Baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 70% improvement in three of the following five additional measurements: Physician's global assessment of disease activity (assessed using a 100 mm Visual Analog Scale [VAS]); Patient's global assessment of disease activity (assessed using a 100 mm VAS); Patient's assessment of pain (assessed using a 100 mm VAS); Health Assessment Questionnaire (HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3); Acute phase reactant: C-reactive protein (CRP) or, if CRP was missing, erythrocyte sedimentation rate (ESR). Participants who withdrew prematurely from the study prior to Week 24, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders.
Change From Baseline in Disease Activity Score (DAS28-ESR) at Week 24 [Baseline and Week 24]
The DAS28 is a composite score to measure disease activity in patients with rheumatoid arthritis, derived from the following variables: The number of swollen and tender joints assessed using the 28-joint count; Erythrocyte sedimentation rate (ESR); Patient's global assessment of disease activity measured on a 100 mm visual analog scale. The DAS28 score ranges from zero to ten. A DAS28 score above 5.1 means high disease activity whereas a DAS28 less than or equal to 3.2 indicates low disease activity. Remission is achieved by a DAS28 lower than 2.6.
Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 24 [Baseline and Week 24]
A EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS28 score. The DAS28 score ranges from 0-10, with higher scores indicating more disease activity. A Good Response is defined as an improvement (decrease) in the DAS28 of more than 1.2 compared with Baseline and attainment of a DAS28 score of less than or equal to 3.2. A Moderate Response is defined as either: an improvement (decrease) in the DAS28 of greater than 0.6 and less than or equal to 1.2 from Baseline and attainment of a DAS28 score of less than or equal to 5.1 or, an improvement (decrease) in the DAS28 of more than 1.2 from Baseline and attainment of a DAS28 score of greater than 3.2. No Response is defined as either an improvement (decrease) in the DAS28 of less than or equal to 0.6, or an improvement (decrease) in the DAS28 of greater than 0.6 and less than or equal to 1.2 and attainment of a DAS28 of more than 5.1.
Percent Change From Baseline in Swollen Joint Count [Baseline, Week 24 and Week 48]
Sixty-six joints were assessed and classified as swollen/not swollen by pressure and joint manipulation on physical examination. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement.
Percent Change From Baseline in Tender Joint Count [Baseline, Week 24 and Week 48]
Sixty-eight joints were assessed and classified as tender/not tender by pressure and joint manipulation on physical examination. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement.
Percent Change From Baseline in Patient's Global Assessment of Disease Activity [Baseline, Week 24 and Week 48]
The participant's overall assessment of their current disease activity measured on a 100 mm horizontal visual analog scale (VAS). The left-hand extreme of the line (0 mm) was described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme (100 mm) as "maximum disease activity" (maximum arthritis disease activity). The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement.
Percent Change From Baseline in Patient's Pain Assessment [Baseline, Week 24 and Week 48]
The participant's assessment of their current level of pain on a 100 mm horizontal visual analog scale (VAS), where the left-hand extreme of the line (0 mm) was described as "no pain" and the right-hand extreme (100 mm) as "unbearable pain". The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement.
Percent Change From Baseline in Physician's Global Assessment of Disease Activity [Baseline, Week 24 and Week 48]
The physician's assessment of the participant's current disease activity on a 100 mm horizontal VAS, where the left-hand extreme of the line (0 mm) was described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme (100 mm) as "maximum disease activity". The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement.
Percent Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score [Baseline, Week 24 and Week 48]
The Stanford Health Assessment Questionnaire disability index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants choose from four response categories, ranging from 'without any difficulty' (Score=0) to 'unable to do' (Score=3). The overall score is the average of each of the 8 category scores and ranges from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement.
Percent Change From Baseline in C-Reactive Protein [Baseline, Week 24 and Week 48]
C-Reactive Protein (CRP) was measured from blood samples by a central laboratory as a marker for inflammation. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement.
Percent Change From Baseline in Erythrocyte Sedimentation Rate [Baseline, Week 24 and Week 48]
Erythrocyte sedimentation rate (ESR) indirectly measures how much inflammation is in the body. A higher ESR is indicative of increased inflammation. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement.
Percent Change From Baseline in Short Form 36 Health Survey (SF-36) Summary Scores (Physical and Mental Components) [Baseline, Week 24 and Week 48]
The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions split into two major components: physical health and mental health. Under physical health are the following four domains: physical health, bodily pain, physical functioning and physical role limitations. Under the mental health domain there are four domains; mental health, vitality, social functioning, and emotional role limitation. The individual domain scores are aggregated to derive a physical-component summary score and a mental-component summary score which range from 0 to 100, with higher scores indicating a better level of functioning. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A positive percentage change from baseline score indicates an improvement.
Change From Baseline in Short Form 36 Health Survey (SF-36) General Health Domain Score [Baseline, Week 24 and Week 48]
The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement.
Change From Baseline in Short Form 36 Health Survey (SF-36) Bodily Pain Domain Score [Baseline, Week 24 and Week 48]
The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement.
Change From Baseline in Short Form 36 Health Survey (SF-36) Physical Functioning Domain Score [Baseline, Week 24 and Week 48]
The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement.
Change From Baseline in Short Form 36 Health Survey (SF-36) Physical Role Limitations Domain Score [Baseline, Week 24 and Week 48]
The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement.
Change From Baseline in Short Form 36 Health Survey (SF-36) Mental Health Domain Score [Baseline, Week 24 and Week 48]
The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement.
Change From Baseline in Short Form 36 Health Survey (SF-36) Vitality Domain Score [Baseline, Week 24 and Week 48]
The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement.
Change From Baseline in Short Form 36 Health Survey (SF-36) Social Functioning Domain Score [Baseline, Week 24 and Week 48]
The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement.
Change From Baseline in Short Form 36 Health Survey (SF-36) Emotional Role Limitations Domain Score [Baseline, Week 24 and Week 48]
The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement.
Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Scores [Baseline, Week 24 and Week 48]
The FACIT-Fatigue questionnaire is a self-administered patient questionnaire that consists of 13 questions designed to measure the degree of fatigue experienced by participants in the previous 7 days. Participants respond to the questions using a value in the range of 0 (not at all) to 4 (very much). The scale score is computed by summing the item scores, after reversing those items that are worded in the negative direction. The FACIT-Fatigue subscale score ranges from 0 to 52, where higher scores represent less fatigue. A positive change from baseline score indicates an improvement.
Percentage of Participants With DAS28-ESR Low Disease Activity Score and Clinical Remission at Week 24 [Week 24]
The DAS28 is a composite score to measure disease activity in patients with rheumatoid arthritis, derived from the following variables: The number of swollen and tender joints assessed using the 28-joint count; Erythrocyte sedimentation rate (ESR); Patient's global assessment of disease activity measured on a 100 mm visual analog scale. The DAS28 score ranges from zero to ten. DAS28 above 5.1 indicates high disease activity. Low disease activity is defined by a DAS28 score less than or equal to 3.2. Remission is defined by a DAS28 score less than 2.6.
Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 24 [Baseline and Week 24]
The Stanford Health Assessment Questionnaire disability index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants choose from four response categories, ranging from 'without any difficulty' (Score=0) to 'unable to do' (Score=3). The overall score is the average of each of the 8 category scores and ranges from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. A negative change from baseline score indicates an improvement. Improved HAQ-DI is defined as a change from Baseline score less than or equal to -0.22. An Unchanged HAQ-DI is defined as a change from Baseline score greater than -0.22 and less than 0.22. A worsened HAQ-DI score is defined as a change from Baseline score of greater than or equal to 0.22.
Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 48 [Baseline and Week 48]
The Stanford Health Assessment Questionnaire disability index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants choose from four response categories, ranging from 'without any difficulty' (Score=0) to 'unable to do' (Score=3). The overall score is the average of each of the 8 category scores and ranges from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. A negative change from baseline score indicates an improvement. Improved HAQ-DI is defined as a change from Baseline score less than or equal to -0.22. An Unchanged HAQ-DI is defined as a change from Baseline score greater than -0.22 and less than 0.22. A worsened HAQ-DI score is defined as a change from Baseline score of greater than or equal to 0.22.
Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 48 [Baseline and Week 48]
A EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS-28 score. A Good Response is defined as an improvement (decrease) in the DAS28 of more than 1.2 compared with Baseline and attainment of a DAS28 score less than or equal to 3.2. A Moderate Response is defined as either: an improvement (decrease) in the DAS28 of greater than 0.6 and less than or equal to 1.2 and attainment of a DAS28 score of less than or equal to 5.1 or, an improvement (decrease) in the DAS28 of more than 1.2 and attainment of a DAS28 score of greater than 3.2. No Response is defined as either an improvement (decrease) in the DAS28 of less than or equal to 0.6, or an improvement (decrease) in the DAS28 of greater than 0.6 and less than or equal to 1.2 and attainment of a DAS28 score of 5.1 or higher.
Percentage of Participants With DAS28-ESR Low Disease Activity Score and Clinical Remission at Week 48 [Week 48]
The DAS28 is a composite score to measure disease activity in patients with rheumatoid arthritis, derived from the following variables: The number of swollen and tender joints assessed using the 28-joint count; Erythrocyte sedimentation rate (ESR); Patient's global assessment of disease activity measured on a 100 mm visual analog scale. The DAS28 score ranges from zero to ten. DAS28 above 5.1 indicates high disease activity. Low disease activity is defined by a DAS28 score less than or equal to 3.2. Remission is defined by a DAS28 score less than 2.6.
Percentage of Participants With an ACR50 Response at Week 48 [Baseline and Week 48]
To achieve an ACR50 required at least a 50% improvement compared with Baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 50% improvement in three of the following five additional measurements: Physician's global assessment of disease activity (assessed using a 100 mm Visual Analog Scale [VAS]); Patient's global assessment of disease activity (assessed using a 100 mm VAS); Patient's assessment of pain (assessed using a 100 mm VAS); Health Assessment Questionnaire (HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3); Acute phase reactant: C-reactive protein (CRP) or, if CRP was missing, erythrocyte sedimentation rate (ESR). Participants who withdrew prematurely from the study prior to week 48, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders.
Percentage of Participants With an ACR70 Response at Week 48 [Baseline and Week 48]
To achieve an ACR70 required at least a 70% improvement compared with baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 70% improvement in three of the following five additional measurements: Physician's global assessment of disease activity (assessed using a 100 mm Visual Analog Scale [VAS]); Patient's global assessment of disease activity (assessed using a 100 mm VAS); Patient's assessment of pain (assessed using a 100 mm VAS); Health Assessment Questionnaire (HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3); Acute phase reactant: C-reactive protein (CRP) or, if CRP was missing, erythrocyte sedimentation rate (ESR). Participants who withdrew prematurely from the study prior to Week 48, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria:

Adult patients 18-80 years of age.
Rheumatoid arthritis (RA) for ≥ 6 months, diagnosed according to the revised 1987 American College of Rheumatology (ACR) criteria for the classification of rheumatoid arthritis.
Receiving outpatient treatment for RA.
Swollen joint count (SJC) ≥ 8 (66 joint count), and tender joint count (TJC) ≥ 8 (68 joint count) at screening and baseline.
At screening, either
C-reactive protein (CRP) ≥ 0.6 mg/dL (6 mg/L), or
Erythrocyte sedimentation rate (ESR) ≥ 28 mm/hour.
Inadequate response to methotrexate, having received and tolerated at a dose of 10-25 mg/week it for ≥ 12 weeks.

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 or planned within 24 weeks of randomization.
Previous treatment with any approved or investigational biological agent for RA, an anti-alpha4-integrin antibody or co-stimulation modulator, or cell-depleting therapy.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

Genentech, Inc.
Hoffmann-La Roche

Investigators

Study Director: Clinical Trials, Genentech, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Genentech, Inc.

ClinicalTrials.gov Identifier:

NCT00299130

Other Study ID Numbers:

U2973g
WA17045

First Posted:

Mar 6, 2006

Last Update Posted:

Apr 17, 2017

Last Verified:

Mar 1, 2017

Keywords provided by Genentech, Inc.

Rituxan

SERENE

Additional relevant MeSH terms:

Arthritis

Arthritis, Rheumatoid

Methylprednisolone

Rituximab

Methotrexate

Study Results

Participant Flow

Recruitment Details	A total of 511 participants were recruited and randomized between 27 Oct 2005 and 15 Nov 2006. Of these, 2 participants were randomized but received no infusions (one violated inclusion criteria and the other was randomized to rituximab 2 x 1.0 gram [g] + methotrexate [MTX] but failed to return). A total of 509 participants were treated.
Pre-assignment Detail	Of the 509 participants, one participant was randomized first to rituximab 2 x 1.0 g + MTX and then to rituximab 2 x 0.5 g + MTX. No assessments were recorded or medication given after first randomization and all data used in analyses was following the second randomization; hence, participant is included only in rituximab 2 x 0.5 g + MTX arm.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 milligrams (mg) intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Period Title: Treatment Period (up to 5 Years)
STARTED	172	168	171
Treated	172	167	170
Completed 24 Weeks	159	162	166
Completed 48 Weeks	155	157	158
Completed 144 Weeks	133	138	132
COMPLETED	119	125	121
NOT COMPLETED	53	43	50
Period Title: Treatment Period (up to 5 Years)
STARTED	167	165	168
COMPLETED	122	120	123
NOT COMPLETED	45	45	45
Period Title: Treatment Period (up to 5 Years)
STARTED	0	82	44
COMPLETED	0	74	38
NOT COMPLETED	0	8	6

Baseline Characteristics

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX	Total
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Total of all reporting groups
Overall Participants	172	167	170	509
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.16 (12.39)	51.91 (12.93)	51.30 (12.64)	51.80 (12.64)
Sex: Female, Male (Count of Participants)
Female	147 85.5%	133 79.6%	138 81.2%	418 82.1%
Male	25 14.5%	34 20.4%	32 18.8%	91 17.9%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With American College of Rheumatology (ACR) 20 Response at Week 24
Description	To achieve an ACR20 required at least a 20% improvement compared with Baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 20% improvement in three of the following five additional measurements: Physician's global assessment of disease activity (assessed using a 100 mm Visual Analog Scale [VAS]); Patient's global assessment of disease activity (assessed using a 100 mm VAS); Patient's assessment of pain (assessed using a 100 mm VAS); Health Assessment Questionnaire (HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3); Acute phase reactant: C-reactive protein (CRP) or, if CRP was missing, erythrocyte sedimentation rate (ESR). Participants who withdrew prematurely from the study prior to Week 24, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description
Intent to treat population included all randomized participants who received at least 1 or part of an infusion. ACR was calculated using the last observation carried forward (LOCF) values for each component. Participants who withdrew prior to week 24, received rescue therapy or had insufficient data to calculate ACR were considered non-responders.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Number [percentage of participants]	23.3 13.5%	54.5 32.6%	50.6 29.8%

2. Secondary Outcome

Title	Percentage of Participants With an ACR50 Response at Week 24
Description	To achieve an ACR50 required at least a 50% improvement compared with Baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 50% improvement in three of the following five additional measurements: Physician's global assessment of disease activity (assessed using a 100 mm Visual Analog Scale [VAS]); Patient's global assessment of disease activity (assessed using a 100 mm VAS); Patient's assessment of pain (assessed using a 100 mm VAS); Health Assessment Questionnaire (HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3); Acute phase reactant: C-reactive protein (CRP) or, if CRP was missing, erythrocyte sedimentation rate (ESR). Participants who withdrew prematurely from the study prior to Week 24, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description
Intent to treat population. ACR was calculated using LOCF values for each component. Participants who withdrew prior to Week 24, received rescue therapy or had insufficient data to calculate ACR were considered non-responders.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Number [percentage of participants]	9.3 5.4%	26.3 15.7%	25.9 15.2%

3. Secondary Outcome

Title	Percentage of Participants With an ACR70 Response at Week 24
Description	To achieve an ACR70 required at least a 70% improvement compared with Baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 70% improvement in three of the following five additional measurements: Physician's global assessment of disease activity (assessed using a 100 mm Visual Analog Scale [VAS]); Patient's global assessment of disease activity (assessed using a 100 mm VAS); Patient's assessment of pain (assessed using a 100 mm VAS); Health Assessment Questionnaire (HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3); Acute phase reactant: C-reactive protein (CRP) or, if CRP was missing, erythrocyte sedimentation rate (ESR). Participants who withdrew prematurely from the study prior to Week 24, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description
Intent to treat population. ACR was calculated using LOCF values for each component. Participants who withdrew prior to Week 24, received rescue therapy or had insufficient data to calculate ACR were considered non-responders.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Number [percentage of participants]	5.2 3%	9.0 5.4%	10.0 5.9%

4. Secondary Outcome

Title	Change From Baseline in Disease Activity Score (DAS28-ESR) at Week 24
Description	The DAS28 is a composite score to measure disease activity in patients with rheumatoid arthritis, derived from the following variables: The number of swollen and tender joints assessed using the 28-joint count; Erythrocyte sedimentation rate (ESR); Patient's global assessment of disease activity measured on a 100 mm visual analog scale. The DAS28 score ranges from zero to ten. A DAS28 score above 5.1 means high disease activity whereas a DAS28 less than or equal to 3.2 indicates low disease activity. Remission is achieved by a DAS28 lower than 2.6.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description
Intent to treat population with available data. DAS28 was calculated using last observation carried forward values for each of the component variables. If any of the components were missing then the DAS28 value will be missing.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	171	166	168
Mean (Standard Deviation) [scores on a scale]	-0.76 (1.304)	-1.71 (1.334)	-1.68 (1.342)

5. Secondary Outcome

Title	Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 24
Description	A EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS28 score. The DAS28 score ranges from 0-10, with higher scores indicating more disease activity. A Good Response is defined as an improvement (decrease) in the DAS28 of more than 1.2 compared with Baseline and attainment of a DAS28 score of less than or equal to 3.2. A Moderate Response is defined as either: an improvement (decrease) in the DAS28 of greater than 0.6 and less than or equal to 1.2 from Baseline and attainment of a DAS28 score of less than or equal to 5.1 or, an improvement (decrease) in the DAS28 of more than 1.2 from Baseline and attainment of a DAS28 score of greater than 3.2. No Response is defined as either an improvement (decrease) in the DAS28 of less than or equal to 0.6, or an improvement (decrease) in the DAS28 of greater than 0.6 and less than or equal to 1.2 and attainment of a DAS28 of more than 5.1.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description
Intent-to-treat population. LOCF was used for the individual components of the DAS-28. Non-responder imputation was used. Participants who withdrew prior to Week 24, who received rescue therapy or had insufficient data in order to calculate a EULAR response were considered non-responders.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
No Response	66.3 38.5%	33.5 20.1%	37.1 21.8%
Moderate Response	29.1 16.9%	49.1 29.4%	51.2 30.1%
Good Response	4.7 2.7%	17.4 10.4%	11.8 6.9%

6. Secondary Outcome

Title	Percent Change From Baseline in Swollen Joint Count
Description	Sixty-six joints were assessed and classified as swollen/not swollen by pressure and joint manipulation on physical examination. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description
Intent-to-treat population, LOCF was used. "N" indicates the number of participants with non-missing data at each time point.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Week 24 [N=172, 166, 170]	-21.6 (65.82)	-47.4 (43.49)	-49.1 (38.59)
Week 48 [N=172, 166, 170]	-38.9 (66.83)	-54.0 (38.66)	-59.3 (37.04)

7. Secondary Outcome

Title	Percent Change From Baseline in Tender Joint Count
Description	Sixty-eight joints were assessed and classified as tender/not tender by pressure and joint manipulation on physical examination. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description
Intent-to-treat population, LOCF was used. "N" indicates the number of participants with non-missing data at each time point.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Week 24 [N=172, 166, 170]	-14.2 (69.20)	-42.5 (64.41)	-31.5 (66.52)
Week 48 [N=172, 166, 170]	-37.1 (55.08)	-50.2 (62.74)	-45.1 (62.64)

8. Secondary Outcome

Title	Percent Change From Baseline in Patient's Global Assessment of Disease Activity
Description	The participant's overall assessment of their current disease activity measured on a 100 mm horizontal visual analog scale (VAS). The left-hand extreme of the line (0 mm) was described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme (100 mm) as "maximum disease activity" (maximum arthritis disease activity). The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description
Intent-to-treat population, LOCF was used. "N" indicates the number of participants with non-missing data at each time point.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Week 24 [N=171, 166, 169]	-14.0 (48.94)	-31.5 (46.40)	-29.1 (54.43)
Week 48 [N=171, 166, 169]	-28.0 (50.78)	-39.7 (40.53)	-36.6 (47.60)

9. Secondary Outcome

Title	Percent Change From Baseline in Patient's Pain Assessment
Description	The participant's assessment of their current level of pain on a 100 mm horizontal visual analog scale (VAS), where the left-hand extreme of the line (0 mm) was described as "no pain" and the right-hand extreme (100 mm) as "unbearable pain". The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description
Intent-to-treat population, LOCF was used. "N" indicates the number of participants with non-missing data at each time point.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Week 24 [N=171, 166, 169]	-9.7 (52.58)	-25.7 (58.52)	-29.1 (53.11)
Week 48 [N=171, 166, 169]	-24.4 (60.22)	-35.5 (50.45)	-36.3 (47.87)

10. Secondary Outcome

Title	Percent Change From Baseline in Physician's Global Assessment of Disease Activity
Description	The physician's assessment of the participant's current disease activity on a 100 mm horizontal VAS, where the left-hand extreme of the line (0 mm) was described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme (100 mm) as "maximum disease activity". The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description
Intent-to-treat population, LOCF was used. "N" indicates the number of participants with non-missing data at each time point.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Week 24 [N=172, 166, 170]	-25.3 (38.52)	-36.9 (61.26)	-35.4 (46.99)
Week 48 [N=172, 166, 170]	-39.4 (39.95)	-40.5 (74.54)	-49.0 (40.01)

11. Secondary Outcome

Title	Percent Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score
Description	The Stanford Health Assessment Questionnaire disability index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants choose from four response categories, ranging from 'without any difficulty' (Score=0) to 'unable to do' (Score=3). The overall score is the average of each of the 8 category scores and ranges from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description
Intent-to-treat population, LOCF was used. "N" indicates the number of participants with non-missing data at each time point.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Week 24 [N=172, 165, 170]	-14.7 (38.41)	-26.9 (40.89)	-23.4 (49.52)
Week 48 [N=172, 165, 170]	-22.6 (39.63)	-30.2 (41.64)	-30.6 (39.95)

12. Secondary Outcome

Title	Percent Change From Baseline in C-Reactive Protein
Description	C-Reactive Protein (CRP) was measured from blood samples by a central laboratory as a marker for inflammation. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description
Intent-to-treat population, LOCF was used. "N" indicates the number of participants with non-missing data at each time point.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Week 24 [N=172, 166, 170]	58.1 (385.23)	-27.5 (84.36)	-23.1 (119.75)
Week 48 [N=172, 166, 170]	40.1 (402.67)	-37.3 (94.65)	-34.9 (82.40)

13. Secondary Outcome

Title	Percent Change From Baseline in Erythrocyte Sedimentation Rate
Description	Erythrocyte sedimentation rate (ESR) indirectly measures how much inflammation is in the body. A higher ESR is indicative of increased inflammation. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description
Intent-to-treat population, LOCF was used. "N" indicates the number of participants with non-missing data at each time point.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Week 24 [N=172, 166, 169]	8.0 (130.71)	-28.0 (42.20)	-29.2 (52.32)
Week 48 [N=172, 166, 169]	-14.5 (68.55)	-31.3 (49.72)	-36.7 (51.49)

14. Secondary Outcome

Title	Percent Change From Baseline in Short Form 36 Health Survey (SF-36) Summary Scores (Physical and Mental Components)
Description	The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions split into two major components: physical health and mental health. Under physical health are the following four domains: physical health, bodily pain, physical functioning and physical role limitations. Under the mental health domain there are four domains; mental health, vitality, social functioning, and emotional role limitation. The individual domain scores are aggregated to derive a physical-component summary score and a mental-component summary score which range from 0 to 100, with higher scores indicating a better level of functioning. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A positive percentage change from baseline score indicates an improvement.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description
Intent-to-treat population, LOCF was used. "N" indicates the number of participants with non-missing data at each time point.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Physical Component: Week 24 [N=147, 152, 155]	11.1 (27.63)	23.7 (31.63)	22.8 (33.09)
Physical Component: Week 48 [N=154, 154, 162]	21.3 (30.99)	26.4 (35.81)	27.4 (31.93)
Mental Component: Week 24 [N=147, 152, 155]	8.4 (29.43)	12.6 (29.13)	19.6 (56.64)
Mental Component: Week 48 [N=154, 154, 162]	12.7 (30.52)	18.4 (38.87)	18.7 (57.34)

15. Secondary Outcome

Title	Change From Baseline in Short Form 36 Health Survey (SF-36) General Health Domain Score
Description	The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description
Intent-to-treat population. "N" indicates the number of participants with non-missing data at each time point.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Week 24 [N=138, 154, 155]	2.078 (7.3032)	3.532 (8.2747)	3.866 (9.2154)
Week 48 [N=137, 148, 147]	4.214 (8.2352)	4.165 (9.5894)	4.362 (8.1242)

16. Secondary Outcome

Title	Change From Baseline in Short Form 36 Health Survey (SF-36) Bodily Pain Domain Score
Description	The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description
Intent-to-treat population. "N" indicates the number of participants with non-missing data at each time point.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Week 24 [N=138, 152, 156]	3.304 (8.5631)	6.931 (8.2254)	7.604 (8.5238)
Week 48 [N=137, 147, 147]	8.449 (9.3543)	8.079 (9.5435)	8.964 (8.9890)

17. Secondary Outcome

Title	Change From Baseline in Short Form 36 Health Survey (SF-36) Physical Functioning Domain Score
Description	The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description
Intent-to-treat population. "N" indicates the number of participants with non-missing data at each time point.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Week 24 [N=138, 154, 154]	3.553 (8.4181)	5.460 (8.3099)	5.653 (9.6817)
Week 48 [N=137, 148, 146]	6.212 (9.6882)	6.778 (8.7117)	6.854 (9.3833)

18. Secondary Outcome

Title	Change From Baseline in Short Form 36 Health Survey (SF-36) Physical Role Limitations Domain Score
Description	The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description
Intent-to-treat population. "N" indicates the number of participants with non-missing data at each time point.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Week 24 [N=136, 153, 156]	2.713 (8.7263)	5.618 (9.0459)	5.175 (8.8018)
Week 48 [N=137, 148, 147]	6.423 (9.6752)	6.812 (9.8633)	6.497 (8.4820)

19. Secondary Outcome

Title	Change From Baseline in Short Form 36 Health Survey (SF-36) Mental Health Domain Score
Description	The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description
Intent-to-treat population. "N" indicates the number of participants with non-missing data at each time point.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Week 24 [N=137, 153, 156]	3.278 (8.6850)	2.770 (9.9943)	4.486 (9.4930)
Week 48 [N=135, 147, 147]	3.890 (8.7493)	4.583 (10.5625)	4.224 (9.9831)

20. Secondary Outcome

Title	Change From Baseline in Short Form 36 Health Survey (SF-36) Vitality Domain Score
Description	The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description
Intent-to-treat population. "N" indicates the number of participants with non-missing data at each time point.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Week 24 [N=137, 154, 156]	3.631 (8.7662)	4.230 (9.3631)	5.910 (9.5802)
Week 48 [N=135, 147, 147]	6.853 (9.8221)	5.925 (10.1495)	5.869 (9.6168)

21. Secondary Outcome

Title	Change From Baseline in Short Form 36 Health Survey (SF-36) Social Functioning Domain Score
Description	The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description
Intent-to-treat population. "N" indicates the number of participants with non-missing data at each time point.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Week 24 [N=138, 154, 156]	2.529 (9.6435)	5.985 (10.2986)	6.468 (10.8868)
Week 48 [N=137, 148, 147]	6.569 (10.6674)	7.112 (11.5329)	6.159 (11.0244)

22. Secondary Outcome

Title	Change From Baseline in Short Form 36 Health Survey (SF-36) Emotional Role Limitations Domain Score
Description	The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description
Intent-to-treat population. "N" indicates the number of participants with non-missing data at each time point.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Week 24 [N=136, 151, 155]	1.829 (11.5405)	4.634 (11.6419)	4.464 (13.6883)
Week 48 [N=137, 146, 146]	4.724 (12.2649)	6.257 (12.9640)	4.446 (13.4036)

23. Secondary Outcome

Title	Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Scores
Description	The FACIT-Fatigue questionnaire is a self-administered patient questionnaire that consists of 13 questions designed to measure the degree of fatigue experienced by participants in the previous 7 days. Participants respond to the questions using a value in the range of 0 (not at all) to 4 (very much). The scale score is computed by summing the item scores, after reversing those items that are worded in the negative direction. The FACIT-Fatigue subscale score ranges from 0 to 52, where higher scores represent less fatigue. A positive change from baseline score indicates an improvement.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description
Intent-to-treat population, LOCF was used. "N" indicates the number of participants with non-missing data at each time point.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Week 24 [N=170, 165, 168]	2.661 (9.5093)	5.564 (9.7438)	6.398 (10.2143)
Week 48 [N=170, 165, 169]	5.506 (10.9651)	6.269 (9.7495)	6.203 (9.7833)

24. Secondary Outcome

Title	Percentage of Participants With DAS28-ESR Low Disease Activity Score and Clinical Remission at Week 24
Description	The DAS28 is a composite score to measure disease activity in patients with rheumatoid arthritis, derived from the following variables: The number of swollen and tender joints assessed using the 28-joint count; Erythrocyte sedimentation rate (ESR); Patient's global assessment of disease activity measured on a 100 mm visual analog scale. The DAS28 score ranges from zero to ten. DAS28 above 5.1 indicates high disease activity. Low disease activity is defined by a DAS28 score less than or equal to 3.2. Remission is defined by a DAS28 score less than 2.6.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description
Intent to treat population with available data. DAS28 was calculated using last observation carried forward values for each of the component variables. If any of the components were missing then the DAS28 value will be missing. Number of participants analyzed = participants who were evaluable for this outcome.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	166	170
Low Disease Activity	4.7 2.7%	17.5 10.5%	12.4 7.3%
Clinical Remission	2.3 1.3%	9.6 5.7%	9.4 5.5%

25. Secondary Outcome

Title	Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 24
Description	The Stanford Health Assessment Questionnaire disability index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants choose from four response categories, ranging from 'without any difficulty' (Score=0) to 'unable to do' (Score=3). The overall score is the average of each of the 8 category scores and ranges from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. A negative change from baseline score indicates an improvement. Improved HAQ-DI is defined as a change from Baseline score less than or equal to -0.22. An Unchanged HAQ-DI is defined as a change from Baseline score greater than -0.22 and less than 0.22. A worsened HAQ-DI score is defined as a change from Baseline score of greater than or equal to 0.22.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description
Intent-to-treat population including participants with available data. LOCF was used.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	165	170
Improved	47.7 27.7%	66.1 39.6%	58.2 34.2%
No change	32.6 19%	23.6 14.1%	32.4 19.1%
Worsened	19.8 11.5%	10.3 6.2%	9.4 5.5%

26. Secondary Outcome

Title	Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 48
Description	The Stanford Health Assessment Questionnaire disability index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants choose from four response categories, ranging from 'without any difficulty' (Score=0) to 'unable to do' (Score=3). The overall score is the average of each of the 8 category scores and ranges from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. A negative change from baseline score indicates an improvement. Improved HAQ-DI is defined as a change from Baseline score less than or equal to -0.22. An Unchanged HAQ-DI is defined as a change from Baseline score greater than -0.22 and less than 0.22. A worsened HAQ-DI score is defined as a change from Baseline score of greater than or equal to 0.22.
Time Frame	Baseline and Week 48

Outcome Measure Data

Analysis Population Description
Intent-to-treat population including participants with available data. LOCF was used.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	165	170
Improved	54.7 31.8%	73.3 43.9%	68.8 40.5%
No change	29.1 16.9%	17.0 10.2%	25.3 14.9%
Worsened	16.3 9.5%	9.7 5.8%	5.9 3.5%

27. Secondary Outcome

Title	Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 48
Description	A EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS-28 score. A Good Response is defined as an improvement (decrease) in the DAS28 of more than 1.2 compared with Baseline and attainment of a DAS28 score less than or equal to 3.2. A Moderate Response is defined as either: an improvement (decrease) in the DAS28 of greater than 0.6 and less than or equal to 1.2 and attainment of a DAS28 score of less than or equal to 5.1 or, an improvement (decrease) in the DAS28 of more than 1.2 and attainment of a DAS28 score of greater than 3.2. No Response is defined as either an improvement (decrease) in the DAS28 of less than or equal to 0.6, or an improvement (decrease) in the DAS28 of greater than 0.6 and less than or equal to 1.2 and attainment of a DAS28 score of 5.1 or higher.
Time Frame	Baseline and Week 48

Outcome Measure Data

Analysis Population Description
Intent-to-treat population. LOCF was used for the individual components of the DAS-28. Non-responder imputation was used. Patients who withdrew prior to week 48, who received rescue therapy or had insufficient data in order to calculate a EULAR response were considered non-responders.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
No Response	41.3 24%	26.9 16.1%	31.8 18.7%
Moderate Response	41.9 24.4%	53.3 31.9%	47.6 28%
Good Response	16.9 9.8%	19.8 11.9%	20.6 12.1%

28. Secondary Outcome

Title	Percentage of Participants With DAS28-ESR Low Disease Activity Score and Clinical Remission at Week 48
Description	The DAS28 is a composite score to measure disease activity in patients with rheumatoid arthritis, derived from the following variables: The number of swollen and tender joints assessed using the 28-joint count; Erythrocyte sedimentation rate (ESR); Patient's global assessment of disease activity measured on a 100 mm visual analog scale. The DAS28 score ranges from zero to ten. DAS28 above 5.1 indicates high disease activity. Low disease activity is defined by a DAS28 score less than or equal to 3.2. Remission is defined by a DAS28 score less than 2.6.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description
Intent to treat population including participants with available data. DAS28 was calculated using last observation carried forward values for each of the component variables. If any of the components were missing then the DAS28 value will be missing.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	171	165	169
Low Disease Activity	18.1 10.5%	20.0 12%	24.3 14.3%
Clinical Remission	7.0 4.1%	9.1 5.4%	11.2 6.6%

29. Secondary Outcome

Title	Percentage of Participants With an ACR50 Response at Week 48
Description	To achieve an ACR50 required at least a 50% improvement compared with Baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 50% improvement in three of the following five additional measurements: Physician's global assessment of disease activity (assessed using a 100 mm Visual Analog Scale [VAS]); Patient's global assessment of disease activity (assessed using a 100 mm VAS); Patient's assessment of pain (assessed using a 100 mm VAS); Health Assessment Questionnaire (HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3); Acute phase reactant: C-reactive protein (CRP) or, if CRP was missing, erythrocyte sedimentation rate (ESR). Participants who withdrew prematurely from the study prior to week 48, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders.
Time Frame	Baseline and Week 48

Outcome Measure Data

Analysis Population Description
Intent to treat population. ACR was calculated using LOCF values for each component. Participants who withdrew prior to Week 48, received rescue therapy or had insufficient data to calculate ACR were considered non-responders.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Number [percentage of participants]	18.6 10.8%	32.9 19.7%	34.1 20.1%

30. Secondary Outcome

Title	Percentage of Participants With an ACR70 Response at Week 48
Description	To achieve an ACR70 required at least a 70% improvement compared with baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 70% improvement in three of the following five additional measurements: Physician's global assessment of disease activity (assessed using a 100 mm Visual Analog Scale [VAS]); Patient's global assessment of disease activity (assessed using a 100 mm VAS); Patient's assessment of pain (assessed using a 100 mm VAS); Health Assessment Questionnaire (HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3); Acute phase reactant: C-reactive protein (CRP) or, if CRP was missing, erythrocyte sedimentation rate (ESR). Participants who withdrew prematurely from the study prior to Week 48, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders.
Time Frame	Baseline and Week 48

Outcome Measure Data

Analysis Population Description
Intent to treat population. ACR was calculated using LOCF values for each component. Participants who withdrew prior to Week 48, received rescue therapy or had insufficient data to calculate ACR were considered non-responders.

Arm/Group Title	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	172	167	170
Number [percentage of participants]	9.3 5.4%	12.6 7.5%	13.5 7.9%

31. Post-Hoc Outcome

Title	Time to Repletion of Peripheral CD19+ B-cells
Description	Peripheral CD19+ B-cell repletion was defined as a CD19+ B-cell count that returned to the Baseline value or returned to ≥ the lower limit of normal, whichever was lower.
Time Frame	Beginning of the first infusion (Day 1) in the last treatment cycle until repletion or the end of the study (approximately 6.5 years)

Outcome Measure Data

Analysis Population Description
Extended safety follow-up population: All participants who were randomized, received any part of a rituximab infusion, and entered the extended safety follow-up period.

Arm/Group Title	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Arm/Group Description	Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.	Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	80	43
Median (95% Confidence Interval) [Weeks]	110.3	109.6

32. Post-Hoc Outcome

Title	Percentage of Participants With Low Immunoglobulin Concentrations Pre- and Post-Rituximab Treatment
Description	A low immunoglobulin concentration was defined as a concentration below the lower level of normal.
Time Frame	Baseline (pre-rituximab), Beginning of the safety follow-up period to the end of the study (approximately 6 years) (post-rituximab)

Outcome Measure Data

Analysis Population Description
Safety follow-up population: All participants who were randomized and received any part of a rituximab infusion. Number of participants analyzed = participants with available data. "N" indicates the number of participants with non-missing data at each time point.

Arm/Group Title	Rituximab + MTX
Arm/Group Description	Participants received 0.5 g or 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.
Measure Participants	491
Pre-Rituximab (N=490)	0.2 0.1%
Post-Rituximab (N=491)	5.1 3%

Adverse Events

	Placebo + MTX		Rituximab 2 x 0.5 g + MTX		Rituximab 1.0 g + MTX		Switch Population: Placebo + MTX		Switch Population: Rituximab		Rituximab 2 x 0.5 g + MTX - Extended Safety Follow-up Period		Rituximab 2 x 1.0 g + MTX - Extended Safety Follow-up Period
Time Frame	Up to 5.1 years after last dose in treatment period (treatment period = up to 5 years)
Adverse Event Reporting Description	During the 5-year treatment period, all adverse events (AEs) regardless of seriousness were reported. During the standard 48-week safety follow-up (SFU) and extended safety follow-up (ESFU), all serious adverse events (SAEs) and all non-serious infections were reported.

Arm/Group Title	Placebo + MTX		Rituximab 2 x 0.5 g + MTX		Rituximab 1.0 g + MTX		Switch Population: Placebo + MTX		Switch Population: Rituximab		Rituximab 2 x 0.5 g + MTX - Extended Safety Follow-up Period		Rituximab 2 x 1.0 g + MTX - Extended Safety Follow-up Period
Arm/Group Description	Includes all data for participants who remained on placebo, and data up to the point of switch if the participant switched to treatment with rituximab. Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.		Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.		Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.		Includes all data up to the point of switch for participants in the Placebo + Methotrexate treatment group who switched to treatment with rituximab after Week 24.		Includes all data from the point of switch for participants who switched from Placebo + Methotrexate to treatment with rituximab.		Participants received no treatment during the extended safety follow-up period.		Participants received no treatment during the extended safety follow-up period.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo + MTX		Rituximab 2 x 0.5 g + MTX		Rituximab 1.0 g + MTX		Switch Population: Placebo + MTX		Switch Population: Rituximab		Rituximab 2 x 0.5 g + MTX - Extended Safety Follow-up Period		Rituximab 2 x 1.0 g + MTX - Extended Safety Follow-up Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/172 (9.3%)		52/167 (31.1%)		46/170 (27.1%)		12/155 (7.7%)		45/155 (29%)		8/82 (9.8%)		2/44 (4.5%)
Blood and lymphatic system disorders
Neutropenia	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Pancytopenia	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Cardiac disorders
Coronary artery disease	2/172 (1.2%)		3/167 (1.8%)		1/170 (0.6%)		2/155 (1.3%)		3/155 (1.9%)		0/82 (0%)		0/44 (0%)
Myocardial infarction	0/172 (0%)		4/167 (2.4%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Supraventricular tachycardia	0/172 (0%)		1/167 (0.6%)		1/170 (0.6%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Angina pectoris	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		1/44 (2.3%)
Acute myocardial infarction	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Angina unstable	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Aortic valve incompetence	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Atrial fibrillation	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Atrial flutter	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Cardiac failure congestive	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		1/82 (1.2%)		0/44 (0%)
Pleuropericarditis	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Tachycardia	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Cardiac arrest	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		1/82 (1.2%)		0/44 (0%)
Palpitations	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		1/82 (1.2%)		0/44 (0%)
Ear and labyrinth disorders
Vertigo	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Endocrine disorders
Goitre	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Eye disorders
Cataract	0/172 (0%)		0/167 (0%)		2/170 (1.2%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Gastrointestinal disorders
Pancreatitis	0/172 (0%)		0/167 (0%)		2/170 (1.2%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Gastritis	0/172 (0%)		0/167 (0%)		2/170 (1.2%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Gastrointestinal haemorrhage	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		2/155 (1.3%)		0/82 (0%)		0/44 (0%)
Gastrooesophageal reflux disease	0/172 (0%)		0/167 (0%)		2/170 (1.2%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Inguinal hernia	0/172 (0%)		0/167 (0%)		2/170 (1.2%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Intestinal perforation	0/172 (0%)		2/167 (1.2%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Abdominal pain	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Colitis	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Diarrhoea	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Diverticular perforation	1/172 (0.6%)		0/167 (0%)		0/170 (0%)		1/155 (0.6%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Diverticulum intestinal	1/172 (0.6%)		0/167 (0%)		0/170 (0%)		1/155 (0.6%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Duodenal ulcer	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Femoral hernia, obstructive	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Ileal ulcer	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Ileus	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Inguinal hernia, obstructive	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Intestinal obstruction	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Retroperitoneal haemorrhage	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Volvulus	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Abdominal wall haematoma	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		1/82 (1.2%)		0/44 (0%)
Rectal haemorrhage	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		1/82 (1.2%)		0/44 (0%)
General disorders
Chest pain	0/172 (0%)		2/167 (1.2%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Death	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Device failure	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Fibrosis	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Hernia obstructive	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Hepatobiliary disorders
Cholecystitis	0/172 (0%)		2/167 (1.2%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Cholelithiasis	2/172 (1.2%)		0/167 (0%)		0/170 (0%)		1/155 (0.6%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Cholangitis	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Cholecystitis acute	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Immune system disorders
Drug hypersensitivity	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Infections and infestations
Pneumonia	1/172 (0.6%)		3/167 (1.8%)		4/170 (2.4%)		1/155 (0.6%)		3/155 (1.9%)		1/82 (1.2%)		0/44 (0%)
Gastroenteritis	2/172 (1.2%)		1/167 (0.6%)		1/170 (0.6%)		2/155 (1.3%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Urinary tract infection	0/172 (0%)		3/167 (1.8%)		1/170 (0.6%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Cellulitis	0/172 (0%)		3/167 (1.8%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Appendicitis	0/172 (0%)		2/167 (1.2%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Bronchitis	0/172 (0%)		2/167 (1.2%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Diverticulitis	0/172 (0%)		2/167 (1.2%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		1/82 (1.2%)		0/44 (0%)
Bronchopneumonia	1/172 (0.6%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Lower respiratory tract infection	0/172 (0%)		2/167 (1.2%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Postoperative wound infection	1/172 (0.6%)		1/167 (0.6%)		0/170 (0%)		1/155 (0.6%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Abdominal abscess	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Abdominal sepsis	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Abscess soft tissue	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Arthritis infective	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Enterocolitis infectious	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Neutropenic sepsis	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Osteomyelitis	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Pulmonary sepsis	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Pulmonary tuberculosis	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Respiratory tract infection	1/172 (0.6%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Sepsis	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Septic shock	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Sinusitis	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Skin infection	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Soft tissue infection	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Tubo-ovarian abscess	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Urosepsis	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Injury, poisoning and procedural complications
Fall	1/172 (0.6%)		4/167 (2.4%)		3/170 (1.8%)		0/155 (0%)		3/155 (1.9%)		0/82 (0%)		0/44 (0%)
Incisional hernia	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Road traffic accident	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Ankle fracture	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Foot fracture	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Humerus fracture	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Infusion related reaction	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Limb injury	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Lower limb fracture	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Post procedural haemorrhage	1/172 (0.6%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Stress fracture	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Subdural haematoma	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Synovial rupture	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Tendon rupture	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Thoracic vertebral fracture	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Traumatic coma	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Investigations
Hepatitis B DNA increased	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Metabolism and nutrition disorders
Diabetes mellitus	0/172 (0%)		0/167 (0%)		2/170 (1.2%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Dehydration	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Failure to thrive	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Hypoglycaemia	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		1/44 (2.3%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/172 (0.6%)		4/167 (2.4%)		5/170 (2.9%)		1/155 (0.6%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Rheumatoid arthritis	1/172 (0.6%)		2/167 (1.2%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Cervical spinal stenosis	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Osteonecrosis	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		2/155 (1.3%)		0/82 (0%)		0/44 (0%)
Arthritis	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Back pain	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		1/82 (1.2%)		0/44 (0%)
Intervertebral disc protrusion	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Lumbar spinal stenosis	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Muscular weaknes	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Spinal column stenosis	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Spinal osteoarthritis	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Spondyloarthropathy	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung squamous cell carcinoma stage unspecified	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Uterine leiomyoma	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Basal cell carcinoma	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Bladder cancer	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Lung adenocarcinoma	1/172 (0.6%)		0/167 (0%)		0/170 (0%)		1/155 (0.6%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Meningioma	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Non-small cell lung cancer	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Non-small cell lung cancer metastatic	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Oesophageal adenocarcinoma	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Oesophageal carcinoma	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Pancreatic carcinoma	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Squamous cell carcinoma of the cervix	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
T-cell prolymphocytic leukaemia	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Colon cancer	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		1/82 (1.2%)		0/44 (0%)
Nervous system disorders
Cerebrovascular accident	1/172 (0.6%)		0/167 (0%)		0/170 (0%)		1/155 (0.6%)		3/155 (1.9%)		1/82 (1.2%)		0/44 (0%)
Demyelination	1/172 (0.6%)		0/167 (0%)		0/170 (0%)		1/155 (0.6%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Benign intracranial hypertension	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Diabetic hyperosmolar coma	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Dizziness	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Radiculopathy	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Syncope	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		1/82 (1.2%)		0/44 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Abortion threatened	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Psychiatric disorders
Major depression	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Renal and urinary disorders
Nephrolithiasis	1/172 (0.6%)		1/167 (0.6%)		0/170 (0%)		1/155 (0.6%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Reproductive system and breast disorders
Vaginal prolapse	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Cystocele	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Menorrhagia	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Ovarian cyst	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Postmenopausal haemorrhage	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Testicular necrosis	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Uterine haemorrhage	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/172 (0%)		2/167 (1.2%)		0/170 (0%)		0/155 (0%)		2/155 (1.3%)		1/82 (1.2%)		0/44 (0%)
Interstitial lung disease	0/172 (0%)		1/167 (0.6%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Acute respiratory failure	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Asthma	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Dyspnoea	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Epistaxis	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Lung disorder	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Skin and subcutaneous tissue disorders
Lichen planus	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Vascular disorders
Aortic stenosis	0/172 (0%)		0/167 (0%)		1/170 (0.6%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Intra-abdominal haematoma	0/172 (0%)		1/167 (0.6%)		0/170 (0%)		0/155 (0%)		0/155 (0%)		0/82 (0%)		0/44 (0%)
Thrombosis	0/172 (0%)		0/167 (0%)		0/170 (0%)		0/155 (0%)		1/155 (0.6%)		0/82 (0%)		0/44 (0%)
Other (Not Including Serious) Adverse Events
	Placebo + MTX		Rituximab 2 x 0.5 g + MTX		Rituximab 1.0 g + MTX		Switch Population: Placebo + MTX		Switch Population: Rituximab		Rituximab 2 x 0.5 g + MTX - Extended Safety Follow-up Period		Rituximab 2 x 1.0 g + MTX - Extended Safety Follow-up Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	112/172 (65.1%)		149/167 (89.2%)		151/170 (88.8%)		99/155 (63.9%)		131/155 (84.5%)		5/82 (6.1%)		2/44 (4.5%)
Blood and lymphatic system disorders
Anaemia	5/172 (2.9%)		9/167 (5.4%)		12/170 (7.1%)		4/155 (2.6%)		7/155 (4.5%)		0/0 (NaN)		0/0 (NaN)
Ear and labyrinth disorders
Vertigo	2/172 (1.2%)		8/167 (4.8%)		6/170 (3.5%)		2/155 (1.3%)		9/155 (5.8%)		0/0 (NaN)		0/0 (NaN)
Gastrointestinal disorders
Diarrhoea	7/172 (4.1%)		27/167 (16.2%)		20/170 (11.8%)		7/155 (4.5%)		20/155 (12.9%)		0/0 (NaN)		0/0 (NaN)
Nausea	4/172 (2.3%)		21/167 (12.6%)		17/170 (10%)		4/155 (2.6%)		12/155 (7.7%)		0/0 (NaN)		0/0 (NaN)
Gastrooesophageal reflux disease	2/172 (1.2%)		7/167 (4.2%)		10/170 (5.9%)		2/155 (1.3%)		4/155 (2.6%)		0/0 (NaN)		0/0 (NaN)
Dyspepsia	3/172 (1.7%)		4/167 (2.4%)		4/170 (2.4%)		3/155 (1.9%)		11/155 (7.1%)		0/0 (NaN)		0/0 (NaN)
General disorders
Fatigue	1/172 (0.6%)		13/167 (7.8%)		11/170 (6.5%)		0/155 (0%)		8/155 (5.2%)		0/0 (NaN)		0/0 (NaN)
Oedema peripheral	2/172 (1.2%)		9/167 (5.4%)		12/170 (7.1%)		2/155 (1.3%)		5/155 (3.2%)		0/0 (NaN)		0/0 (NaN)
Hepatobiliary disorders
Hepatotoxicity	2/172 (1.2%)		8/167 (4.8%)		7/170 (4.1%)		2/155 (1.3%)		8/155 (5.2%)		0/0 (NaN)		0/0 (NaN)
Infections and infestations
Upper respiratory tract infection	13/172 (7.6%)		59/167 (35.3%)		50/170 (29.4%)		13/155 (8.4%)		39/155 (25.2%)		0/82 (0%)		0/44 (0%)
Nasopharyngitis	17/172 (9.9%)		43/167 (25.7%)		42/170 (24.7%)		16/155 (10.3%)		34/155 (21.9%)		0/82 (0%)		0/44 (0%)
Urinary tract infection	12/172 (7%)		41/167 (24.6%)		25/170 (14.7%)		9/155 (5.8%)		34/155 (21.9%)		5/82 (6.1%)		2/44 (4.5%)
Bronchitis	3/172 (1.7%)		27/167 (16.2%)		25/170 (14.7%)		2/155 (1.3%)		24/155 (15.5%)		0/82 (0%)		0/44 (0%)
Sinusitis	6/172 (3.5%)		24/167 (14.4%)		21/170 (12.4%)		6/155 (3.9%)		29/155 (18.7%)		0/82 (0%)		0/44 (0%)
Gastroenteritis	8/172 (4.7%)		15/167 (9%)		14/170 (8.2%)		7/155 (4.5%)		17/155 (11%)		0/82 (0%)		0/44 (0%)
Influenza	1/172 (0.6%)		17/167 (10.2%)		20/170 (11.8%)		1/155 (0.6%)		13/155 (8.4%)		0/82 (0%)		0/44 (0%)
Pharyngitis	10/172 (5.8%)		15/167 (9%)		11/170 (6.5%)		10/155 (6.5%)		9/155 (5.8%)		0/82 (0%)		0/44 (0%)
Tooth abscess	0/172 (0%)		9/167 (5.4%)		8/170 (4.7%)		0/155 (0%)		7/155 (4.5%)		0/82 (0%)		0/44 (0%)
Herpes zoster	2/172 (1.2%)		10/167 (6%)		4/170 (2.4%)		2/155 (1.3%)		5/155 (3.2%)		0/82 (0%)		0/44 (0%)
Lower respiratory tract infection	1/172 (0.6%)		2/167 (1.2%)		8/170 (4.7%)		1/155 (0.6%)		9/155 (5.8%)		0/82 (0%)		0/44 (0%)
Injury, poisoning and procedural complications
Infusion related reaction	33/172 (19.2%)		59/167 (35.3%)		59/170 (34.7%)		28/155 (18.1%)		39/155 (25.2%)		0/0 (NaN)		0/0 (NaN)
Fall	5/172 (2.9%)		14/167 (8.4%)		5/170 (2.9%)		4/155 (2.6%)		18/155 (11.6%)		0/0 (NaN)		0/0 (NaN)
Laceration	1/172 (0.6%)		2/167 (1.2%)		10/170 (5.9%)		1/155 (0.6%)		6/155 (3.9%)		0/0 (NaN)		0/0 (NaN)
Metabolism and nutrition disorders
Diabetes mellitus	4/172 (2.3%)		13/167 (7.8%)		6/170 (3.5%)		3/155 (1.9%)		7/155 (4.5%)		0/0 (NaN)		0/0 (NaN)
Hypercholesterolaemia	1/172 (0.6%)		7/167 (4.2%)		9/170 (5.3%)		1/155 (0.6%)		5/155 (3.2%)		0/0 (NaN)		0/0 (NaN)
Musculoskeletal and connective tissue disorders
Rheumatoid arthritis	30/172 (17.4%)		49/167 (29.3%)		36/170 (21.2%)		26/155 (16.8%)		31/155 (20%)		0/0 (NaN)		0/0 (NaN)
Back pain	3/172 (1.7%)		22/167 (13.2%)		14/170 (8.2%)		3/155 (1.9%)		10/155 (6.5%)		0/0 (NaN)		0/0 (NaN)
Arthralgia	3/172 (1.7%)		9/167 (5.4%)		15/170 (8.8%)		2/155 (1.3%)		7/155 (4.5%)		0/0 (NaN)		0/0 (NaN)
Osteoarthritis	1/172 (0.6%)		8/167 (4.8%)		10/170 (5.9%)		1/155 (0.6%)		8/155 (5.2%)		0/0 (NaN)		0/0 (NaN)
Muscle spasms	4/172 (2.3%)		7/167 (4.2%)		7/170 (4.1%)		4/155 (2.6%)		10/155 (6.5%)		0/0 (NaN)		0/0 (NaN)
Pain in extremity	1/172 (0.6%)		9/167 (5.4%)		9/170 (5.3%)		1/155 (0.6%)		7/155 (4.5%)		0/0 (NaN)		0/0 (NaN)
Nervous system disorders
Headache	6/172 (3.5%)		18/167 (10.8%)		15/170 (8.8%)		5/155 (3.2%)		16/155 (10.3%)		0/0 (NaN)		0/0 (NaN)
Dizziness	4/172 (2.3%)		11/167 (6.6%)		10/170 (5.9%)		3/155 (1.9%)		0/155 (0%)		0/0 (NaN)		0/0 (NaN)
Psychiatric disorders
Depression	0/172 (0%)		15/167 (9%)		7/170 (4.1%)		0/155 (0%)		7/155 (4.5%)		0/0 (NaN)		0/0 (NaN)
Insomnia	7/172 (4.1%)		9/167 (5.4%)		8/170 (4.7%)		6/155 (3.9%)		5/155 (3.2%)		0/0 (NaN)		0/0 (NaN)
Respiratory, thoracic and mediastinal disorders
Cough	7/172 (4.1%)		13/167 (7.8%)		22/170 (12.9%)		7/155 (4.5%)		11/155 (7.1%)		0/0 (NaN)		0/0 (NaN)
Rhinitis allergic	0/172 (0%)		6/167 (3.6%)		10/170 (5.9%)		0/155 (0%)		6/155 (3.9%)		0/0 (NaN)		0/0 (NaN)
Skin and subcutaneous tissue disorders
Rash	1/172 (0.6%)		9/167 (5.4%)		7/170 (4.1%)		1/155 (0.6%)		6/155 (3.9%)		0/0 (NaN)		0/0 (NaN)
Alopecia	1/172 (0.6%)		9/167 (5.4%)		6/170 (3.5%)		0/155 (0%)		3/155 (1.9%)		0/0 (NaN)		0/0 (NaN)
Vascular disorders
Hypertension	3/172 (1.7%)		28/167 (16.8%)		18/170 (10.6%)		2/155 (1.3%)		15/155 (9.7%)		0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

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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	Hoffman-La Roche
Phone	800-821-8590
Email	genentech@druginfo.com

Responsible Party:

Genentech, Inc.

ClinicalTrials.gov Identifier:

NCT00299130

Other Study ID Numbers:

U2973g
WA17045

First Posted:

Mar 6, 2006

Last Update Posted:

Apr 17, 2017

Last Verified:

Mar 1, 2017

SERENE: A Study to Evaluate the Safety and Efficacy of Rituximab in Combination With Methotrexate Compared to Methotrexate Alone in Patients With Active Rheumatoid Arthritis

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