Trial Outcomes & Findings for A Study of the Safety of Rituximab in Combination With Other Anti-Rheumatic Drugs in Subjects With Active Rheumatoid Arthritis (NCT NCT00443651)

Last Updated: 2017-04-17

Results Overview

An adverse event (AE) is any unfavorable and unintended sign, symptom, significantly abnormal laboratory finding, or disease temporally associated with the use of an investigational medical product or other protocol-imposed intervention. An AE was classified as an SAE if it: Resulted in death, persistent or significant disability/incapacity, or congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product; required or prolonged inpatient hospitalization; was life-threatening or considered a significant medical event by the investigator.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

578 participants

Primary outcome timeframe

From first treatment with rituximab (Day 1) through Week 24

Results posted on

2017-04-17

Participant Flow

The study was conducted in 2 stages. Stage I: Patients with an inadequate response to non-biological disease-modifying antirheumatic drugs (DMARDS) were treated with rituximab 1000 mg. Stage II: Patients with an inadequate response to a biological DMARD were treated with rituximab 500 mg. Both groups continued to receive DMARDs.

One Stage 1 patient was enrolled but did not receive treatment with rituximab, is not included in the Participant Flow data, and was not included in any of the analyses.

Participant milestones

Participant milestones
Measure	Rituximab 1000 mg (Stage I Patients) Stage I patients received 2 doses of rituximab 1000 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 1000 mg given 14 days apart. Concomitant non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.	Rituximab 500 mg (Stage II Patients) Stage II patients received 2 doses of rituximab 500 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 500 mg given 14 days apart. Concomitant biological and non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.
Overall Study STARTED	401	176
Overall Study Week 24	376	160
Overall Study Week 48	338	134
Overall Study COMPLETED	306	118
Overall Study NOT COMPLETED	95	58

Reasons for withdrawal

Reasons for withdrawal
Measure	Rituximab 1000 mg (Stage I Patients) Stage I patients received 2 doses of rituximab 1000 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 1000 mg given 14 days apart. Concomitant non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.	Rituximab 500 mg (Stage II Patients) Stage II patients received 2 doses of rituximab 500 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 500 mg given 14 days apart. Concomitant biological and non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.
Overall Study Death	1	5
Overall Study Adverse Event	5	6
Overall Study Lost to Follow-up	18	12
Overall Study Patient's/Guardian's Decision	58	30
Overall Study Physician Decision	13	4
Overall Study Pregnancy	0	1

Baseline Characteristics

A Study of the Safety of Rituximab in Combination With Other Anti-Rheumatic Drugs in Subjects With Active Rheumatoid Arthritis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rituximab 1000 mg (Stage I Patients) n=401 Participants Stage I patients received 2 doses of rituximab 1000 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 1000 mg given 14 days apart. Concomitant non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.	Rituximab 500 mg (Stage II Patients) n=176 Participants Stage II patients received 2 doses of rituximab 500 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 500 mg given 14 days apart. Concomitant biological and non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.	Total n=577 Participants Total of all reporting groups
Age, Customized 18 - 25 years	8 Participants n=5 Participants	5 Participants n=7 Participants	13 Participants n=5 Participants
Age, Customized 26 - 35 years	22 Participants n=5 Participants	8 Participants n=7 Participants	30 Participants n=5 Participants
Age, Customized 36 - 45 years	59 Participants n=5 Participants	26 Participants n=7 Participants	85 Participants n=5 Participants
Age, Customized 46 - 55 years	132 Participants n=5 Participants	48 Participants n=7 Participants	180 Participants n=5 Participants
Age, Customized 56 - 65 years	133 Participants n=5 Participants	67 Participants n=7 Participants	200 Participants n=5 Participants
Age, Customized 66 - 75 years	38 Participants n=5 Participants	19 Participants n=7 Participants	57 Participants n=5 Participants
Age, Customized 76 - 85 years	9 Participants n=5 Participants	3 Participants n=7 Participants	12 Participants n=5 Participants
Age, Customized > 85	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Female	302 Participants n=5 Participants	154 Participants n=7 Participants	456 Participants n=5 Participants
Sex: Female, Male Male	99 Participants n=5 Participants	22 Participants n=7 Participants	121 Participants n=5 Participants

PRIMARY outcome

Timeframe: From first treatment with rituximab (Day 1) through Week 24

Population: Safety population: All patients who were enrolled in the study and received any study drug (rituximab).

Outcome measures

Outcome measures
Measure	Rituximab 1000 mg (Stage I Patients) n=401 Participants Stage I patients received 2 doses of rituximab 1000 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 1000 mg given 14 days apart. Concomitant non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.	Rituximab 500 mg (Stage II Patients) n=176 Participants Stage II patients received 2 doses of rituximab 500 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 500 mg given 14 days apart. Concomitant biological and non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.
Percentage of Patients Developing a Serious Adverse Event (SAE) Within 24 Weeks After Receiving the First Course of Rituximab Treatment	6.0 Percentage of participants	9.1 Percentage of participants

SECONDARY outcome

Timeframe: From start of rituximab treatment through 24 hours

Population: Safety population: All patients who were enrolled in the study and received any study drug (rituximab).

The percentage of patients developing a SAE during or within 24 hours of a rituximab infusion is reported separately for each of the 2 infusions in the first course of treatment (Days 1 and 15) and the second course of treatment (optional retreatment during Weeks 24 to 40). See the Primary Outcome Measure for a definition of a SAE.

Outcome measures

Outcome measures
Measure	Rituximab 1000 mg (Stage I Patients) n=401 Participants Stage I patients received 2 doses of rituximab 1000 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 1000 mg given 14 days apart. Concomitant non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.	Rituximab 500 mg (Stage II Patients) n=176 Participants Stage II patients received 2 doses of rituximab 500 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 500 mg given 14 days apart. Concomitant biological and non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.
Percentage of Patients Who Developed a Serious Adverse Event (SAE) During or Within 24 Hours of Rituximab Infusions 1st infusion, 1st course of treatment	0.2 Percentage of participants	0.0 Percentage of participants
Percentage of Patients Who Developed a Serious Adverse Event (SAE) During or Within 24 Hours of Rituximab Infusions 2nd infusion, 1st course of treatment	0.0 Percentage of participants	0.0 Percentage of participants
Percentage of Patients Who Developed a Serious Adverse Event (SAE) During or Within 24 Hours of Rituximab Infusions 1st infusion, 2nd course of treatment	0.0 Percentage of participants	0.0 Percentage of participants
Percentage of Patients Who Developed a Serious Adverse Event (SAE) During or Within 24 Hours of Rituximab Infusions 2nd infusion, 2nd course of treatment	0.0 Percentage of participants	0.0 Percentage of participants

SECONDARY outcome

Timeframe: From start of the second course of rituximab treatment through Week 48

Population: Safety population: All patients who were enrolled in the study and received any study drug (rituximab).

Outcome measures

Outcome measures
Measure	Rituximab 1000 mg (Stage I Patients) n=321 Participants Stage I patients received 2 doses of rituximab 1000 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 1000 mg given 14 days apart. Concomitant non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.	Rituximab 500 mg (Stage II Patients) n=147 Participants Stage II patients received 2 doses of rituximab 500 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 500 mg given 14 days apart. Concomitant biological and non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.
Percentage of Patients Who Developed a Serious Adverse Event (SAE) Within 24 Weeks After Receiving the Second Course (Optional Retreatment) of Rituximab Treatment	7.2 Percentage of participants	6.1 Percentage of participants

SECONDARY outcome

Timeframe: Baseline to Week 24 and Week 48

Population: Safety population: All patients who were enrolled in the study and received any study drug (rituximab).

Improvement must be seen in tender and swollen joint counts and in at least 3 of the following 5 parameters. Patient and physician assessment of patient disease activity (DA) in previous 24 hours on a visual analog scale (VAS, no DA to maximum DA); patient assessment of pain in previous 24 hours on a VAS (none to unbearable); Health Assessment Questionnaire-Disability Index (20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do); and C reactive protein or, if missing, erythrocyte sedimentation rate.

Outcome measures

Outcome measures
Measure	Rituximab 1000 mg (Stage I Patients) n=401 Participants Stage I patients received 2 doses of rituximab 1000 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 1000 mg given 14 days apart. Concomitant non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.	Rituximab 500 mg (Stage II Patients) n=176 Participants Stage II patients received 2 doses of rituximab 500 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 500 mg given 14 days apart. Concomitant biological and non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.
Percentage of Patients With an Improvement of 20%, 50%, and 70% in American College of Rheumatology (ACR) Scores (ACR20/50/70) From Baseline at Weeks 24 and 48 ACR20 at Week 24	36.9 Percentage of participants	30.7 Percentage of participants
Percentage of Patients With an Improvement of 20%, 50%, and 70% in American College of Rheumatology (ACR) Scores (ACR20/50/70) From Baseline at Weeks 24 and 48 ACR50 at Week 24	15.7 Percentage of participants	10.2 Percentage of participants
Percentage of Patients With an Improvement of 20%, 50%, and 70% in American College of Rheumatology (ACR) Scores (ACR20/50/70) From Baseline at Weeks 24 and 48 ACR70 at Week 24	7.7 Percentage of participants	5.1 Percentage of participants
Percentage of Patients With an Improvement of 20%, 50%, and 70% in American College of Rheumatology (ACR) Scores (ACR20/50/70) From Baseline at Weeks 24 and 48 ACR20 at Week 48	50.6 Percentage of participants	48.9 Percentage of participants
Percentage of Patients With an Improvement of 20%, 50%, and 70% in American College of Rheumatology (ACR) Scores (ACR20/50/70) From Baseline at Weeks 24 and 48 ACR50 at Week 48	25.9 Percentage of participants	22.7 Percentage of participants
Percentage of Patients With an Improvement of 20%, 50%, and 70% in American College of Rheumatology (ACR) Scores (ACR20/50/70) From Baseline at Weeks 24 and 48 ACR70 at Week 48	11.0 Percentage of participants	9.1 Percentage of participants

SECONDARY outcome

Timeframe: Week 24 and Week 48

Population: Safety population: All patients who were enrolled in the study and received any study drug (rituximab). There were 401 patients in the rituximab 1000 mg and 176 patients in the 500 mg safety populations. n = number of patients with non-missing DAS28-ESR last observation carried forward scores at Weeks 24 and 48 in the safety populations.

DAS 28-ESR was calculated using counts of tender and swollen joints (28 joints, 28TJC and 28SJC), a patient assessment (PA) of disease activity (DA) in previous 24 hours on a visual analog scale (no DA to maximum DA), and ESR at the current visit, using the following formula: 0.56 × 28TJC + 0.28 × 28SJC + 0.70 × ln(ESR) + 0.014 × PADA. The DAS 28-ESR score ranges from 0 to 10, with higher scores indicating more rheumatoid arthritis. DAS28-ESR Remission was defined as a DAS 28-ESR score of \< 2.6. DAS28-ESR Low Disease Activity was defined as a DAS28-ESR score of ≤ 3.2.

Outcome measures

Outcome measures
Measure	Rituximab 1000 mg (Stage I Patients) n=401 Participants Stage I patients received 2 doses of rituximab 1000 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 1000 mg given 14 days apart. Concomitant non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.	Rituximab 500 mg (Stage II Patients) n=176 Participants Stage II patients received 2 doses of rituximab 500 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 500 mg given 14 days apart. Concomitant biological and non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.
Percentage of Patients Achieving Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS 28-ESR) Remission and DAS 28-ESR Low Disease Activity Scores at Weeks 24 and 48 DAS 28-ESR Remission at Week 24 (n=391, 171)	8.4 Percentage of participants	6.4 Percentage of participants
Percentage of Patients Achieving Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS 28-ESR) Remission and DAS 28-ESR Low Disease Activity Scores at Weeks 24 and 48 DAS 28-ESR Low DA at Week 24 (n=391, 171)	15.6 Percentage of participants	11.7 Percentage of participants
Percentage of Patients Achieving Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS 28-ESR) Remission and DAS 28-ESR Low Disease Activity Scores at Weeks 24 and 48 DAS 28-ESR Remission at Week 48 (n=389, 172)	12.6 Percentage of participants	7.0 Percentage of participants
Percentage of Patients Achieving Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS 28-ESR) Remission and DAS 28-ESR Low Disease Activity Scores at Weeks 24 and 48 DAS 28-ESR Low DA at Week 48 (n=389, 172)	23.4 Percentage of participants	22.1 Percentage of participants

SECONDARY outcome

Timeframe: Baseline to Week 24 and Week 48

Population: Safety population: All patients who were enrolled in the study and received any study drug (rituximab).

Improvement in the post-baseline DAS 28-ESR score from baseline was used to determine the EULAR responses of moderate response and good response. The DAS 28-ESR score ranges from 0 to 10, with higher scores indicating more rheumatoid arthritis. For a post-baseline score ≤ 3.2, an improvement \> 0.6 to ≤ 1.2 was a moderate response and ≥ 1.2 a good response. For a post-baseline score \> 3.2 to ≤ 5.1, an improvement \> 0.6 was a moderate response. For a post-baseline score \> 5.1, an improvement ≥ 1.2 was a moderate response. A good response could not be achieved for post-baseline scores \> 3.2.

Outcome measures

Outcome measures
Measure	Rituximab 1000 mg (Stage I Patients) n=401 Participants Stage I patients received 2 doses of rituximab 1000 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 1000 mg given 14 days apart. Concomitant non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.	Rituximab 500 mg (Stage II Patients) n=176 Participants Stage II patients received 2 doses of rituximab 500 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 500 mg given 14 days apart. Concomitant biological and non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.
Percentage of Patients With European League Against Rheumatism (EULAR) Good and Moderate Responses at Weeks 24 and 48 Good EULAR Response at Week 24	13.7 Percentage of participants	9.1 Percentage of participants
Percentage of Patients With European League Against Rheumatism (EULAR) Good and Moderate Responses at Weeks 24 and 48 Moderate EULAR Response at Week 24	39.2 Percentage of participants	34.1 Percentage of participants
Percentage of Patients With European League Against Rheumatism (EULAR) Good and Moderate Responses at Weeks 24 and 48 Good EULAR Response at Week 48	21.2 Percentage of participants	18.2 Percentage of participants
Percentage of Patients With European League Against Rheumatism (EULAR) Good and Moderate Responses at Weeks 24 and 48 Moderate EULAR Response at Week 48	44.1 Percentage of participants	43.8 Percentage of participants

SECONDARY outcome

Timeframe: Baseline to Week 24 and Week 48

Population: Safety population: All patients who were enrolled in the study and received any study drug (rituximab).

The HAQ-DI assesses how well the patient is able to perform 8 activities: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. The patient answers 20 questions with 1 of 4 responses with the past week as the time frame: 0=without difficulty, 1=with some difficulty, 2=with much difficulty, and 3=unable to do. The highest score for any question in a category determines the category score. The total score ranges from 0 (no disability) to 3 (completely disabled). A negative change score indicates improvement.

Outcome measures

Outcome measures
Measure	Rituximab 1000 mg (Stage I Patients) n=389 Participants Stage I patients received 2 doses of rituximab 1000 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 1000 mg given 14 days apart. Concomitant non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.	Rituximab 500 mg (Stage II Patients) n=172 Participants Stage II patients received 2 doses of rituximab 500 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 500 mg given 14 days apart. Concomitant biological and non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.
Health Assessment Questionnaire-Disability Index (HAQ-DI) Change From Baseline at Weeks 24 and 48 Week 24	-0.28 Units on a scale Standard Deviation 0.474	-0.28 Units on a scale Standard Deviation 0.495
Health Assessment Questionnaire-Disability Index (HAQ-DI) Change From Baseline at Weeks 24 and 48 Week 48	-0.33 Units on a scale Standard Deviation 0.508	-0.32 Units on a scale Standard Deviation 0.512

Adverse Events

Rituximab 1000 mg (Stage I Patients)

Serious events: 48 serious events

Other events: 278 other events

Deaths: 0 deaths

Rituximab 500 mg (Stage II Patients)

Serious events: 27 serious events

Other events: 128 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Genentech, Inc.

Phone: 800-821-8590

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Rituximab 1000 mg (Stage I Patients) n=401 participants at risk Stage I patients received 2 doses of rituximab 1000 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 1000 mg given 14 days apart. Concomitant non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.	Rituximab 500 mg (Stage II Patients) n=176 participants at risk Stage II patients received 2 doses of rituximab 500 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 500 mg given 14 days apart. Concomitant biological and non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations.
Infections and infestations Upper respiratory tract infection	12.7% 51/401 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).	15.3% 27/176 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).
Gastrointestinal disorders Nausea	7.7% 31/401 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).	12.5% 22/176 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).
Gastrointestinal disorders Vomiting	5.2% 21/401 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).	4.5% 8/176 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).
Gastrointestinal disorders Diarrhoea	6.2% 25/401 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).	5.7% 10/176 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).
General disorders Oedema peripheral	3.2% 13/401 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).	5.7% 10/176 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).
Infections and infestations Sinusitis	11.2% 45/401 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).	13.1% 23/176 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).
Infections and infestations Urinary tract infection	11.2% 45/401 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).	8.5% 15/176 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).
Infections and infestations Bronchitis	8.7% 35/401 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).	6.8% 12/176 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).
Infections and infestations Influenza	3.2% 13/401 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).	5.1% 9/176 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).
Injury, poisoning and procedural complications Contusion	1.2% 5/401 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).	5.7% 10/176 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).
Musculoskeletal and connective tissue disorders Back pain	7.7% 31/401 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).	2.3% 4/176 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).
Musculoskeletal and connective tissue disorders Rheumatoid arthritis	12.5% 50/401 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).	15.9% 28/176 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).
Musculoskeletal and connective tissue disorders Arthralgia	11.7% 47/401 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).	6.8% 12/176 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).
Nervous system disorders Headache	9.5% 38/401 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).	14.2% 25/176 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).
Psychiatric disorders Depression	5.0% 20/401 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).	3.4% 6/176 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).
Respiratory, thoracic and mediastinal disorders Cough	9.0% 36/401 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).	5.7% 10/176 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).
Respiratory, thoracic and mediastinal disorders Sinus congestion	2.5% 10/401 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).	6.2% 11/176 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).
Skin and subcutaneous tissue disorders Rash	7.0% 28/401 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).	4.5% 8/176 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).
Skin and subcutaneous tissue disorders Pruritus	4.5% 18/401 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).	6.2% 11/176 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).
Vascular disorders Hypertension	7.0% 28/401 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).	8.0% 14/176 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).
Vascular disorders Flushing	4.5% 18/401 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).	6.8% 12/176 • Adverse events (AE) were recorded from the time when informed consent was obtained until Week 48, Week 4 of the safety follow-up (SFU) period, or early discontinuation. Beyond Week 4 of the SFU period, only serious or infectious AEs were recorded. Safety population: All patients who were enrolled in the study and received any study drug (rituximab).