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Trial record 66 of 117 for:    "Connective Tissue Disease" | "Methylprednisolone"

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

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ClinicalTrials.gov Identifier: NCT00299130
Recruitment Status : Completed
First Posted : March 6, 2006
Results First Posted : June 28, 2013
Last Update Posted : April 17, 2017
Sponsor:
Collaborator:
Hoffmann-La Roche
Information provided by (Responsible Party):
Genentech, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Rheumatoid Arthritis
Interventions Drug: Folate
Drug: Methotrexate
Drug: Methylprednisolone
Drug: Placebo
Drug: Rituximab
Enrollment 511
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 Details 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
Hide 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 [1] 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
Reason Not Completed
Adverse Event             13             8             13
Death             1             3             1
Insufficient Therapeutic Response             19             6             6
Protocol Violation             0             1             0
Refused Treatment             12             12             19
Failure to Return             4             6             6
Reason not Specified             4             6             4
Withdrawal by Subject             0             1             1
[1]
155 participants in placebo arm switched to active therapy (rituximab 2 x 0.5g) between Weeks 16-48.
Period Title: Safety Follow-up (SFU) (48 Weeks)
Started 167 165 168
Completed 122 120 123
Not Completed 45 45 45
Reason Not Completed
Administrative/Other             4             9             4
Death             4             5             3
Did not Co-operate             1             1             2
Failure to Return             14             7             15
No SFU Week 48 Date Recorded             0             1             0
Withdrawal by Subject             22             22             21
Period Title: Extended SFU (ESFU) (up to 5.1 Years)
Started 0 82 44
Completed 0 74 38
Not Completed 0 8 6
Reason Not Completed
Death             0             3             0
Failure to Return             0             2             2
Did not Cooperate/Withdrew Consent             0             3             4
Arm/Group Title Placebo + MTX Rituximab 2 x 0.5 g + MTX Rituximab 2 x 1.0 g + MTX Total
Hide 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 Number of Baseline Participants 172 167 170 509
Hide Baseline Analysis Population Description
Safety population included all randomized participants who received any part of an infusion.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 172 participants 167 participants 170 participants 509 participants
52.16  (12.39) 51.91  (12.93) 51.30  (12.64) 51.80  (12.64)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 172 participants 167 participants 170 participants 509 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%
1.Primary Outcome
Title Percentage of Participants With American College of Rheumatology (ACR) 20 Response at Week 24
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Measure Type: Number
Unit of Measure: percentage of participants
23.3 54.5 50.6
2.Secondary Outcome
Title Percentage of Participants With an ACR50 Response at Week 24
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Measure Type: Number
Unit of Measure: percentage of participants
9.3 26.3 25.9
3.Secondary Outcome
Title Percentage of Participants With an ACR70 Response at Week 24
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Measure Type: Number
Unit of Measure: percentage of participants
5.2 9.0 10.0
4.Secondary Outcome
Title Change From Baseline in Disease Activity Score (DAS28-ESR) at Week 24
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 171 166 168
Mean (Standard Deviation)
Unit of Measure: 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Measure Type: Number
Unit of Measure: percentage of participants
No Response 66.3 33.5 37.1
Moderate Response 29.1 49.1 51.2
Good Response 4.7 17.4 11.8
6.Secondary Outcome
Title Percent Change From Baseline in Swollen Joint Count
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Mean (Standard Deviation)
Unit of Measure: percent change
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Mean (Standard Deviation)
Unit of Measure: percent change
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Mean (Standard Deviation)
Unit of Measure: percent change
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Mean (Standard Deviation)
Unit of Measure: percent change
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Mean (Standard Deviation)
Unit of Measure: percent change
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Mean (Standard Deviation)
Unit of Measure: percent change
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Mean (Standard Deviation)
Unit of Measure: percent change
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Mean (Standard Deviation)
Unit of Measure: percent change
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)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Mean (Standard Deviation)
Unit of Measure: percent change
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Mean (Standard Deviation)
Unit of Measure: scores on a scale
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Mean (Standard Deviation)
Unit of Measure: scores on a scale
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Mean (Standard Deviation)
Unit of Measure: scores on a scale
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Mean (Standard Deviation)
Unit of Measure: scores on a scale
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Mean (Standard Deviation)
Unit of Measure: scores on a scale
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Mean (Standard Deviation)
Unit of Measure: scores on a scale
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Mean (Standard Deviation)
Unit of Measure: scores on a scale
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Mean (Standard Deviation)
Unit of Measure: scores on a scale
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Mean (Standard Deviation)
Unit of Measure: scores on a scale
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 166 170
Measure Type: Number
Unit of Measure: percentage of participants
Low Disease Activity 4.7 17.5 12.4
Clinical Remission 2.3 9.6 9.4
25.Secondary Outcome
Title Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 24
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 165 170
Measure Type: Number
Unit of Measure: percentage of participants
Improved 47.7 66.1 58.2
No change 32.6 23.6 32.4
Worsened 19.8 10.3 9.4
26.Secondary Outcome
Title Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 48
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 165 170
Measure Type: Number
Unit of Measure: percentage of participants
Improved 54.7 73.3 68.8
No change 29.1 17.0 25.3
Worsened 16.3 9.7 5.9
27.Secondary Outcome
Title Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 48
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Measure Type: Number
Unit of Measure: percentage of participants
No Response 41.3 26.9 31.8
Moderate Response 41.9 53.3 47.6
Good Response 16.9 19.8 20.6
28.Secondary Outcome
Title Percentage of Participants With DAS28-ESR Low Disease Activity Score and Clinical Remission at Week 48
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 171 165 169
Measure Type: Number
Unit of Measure: percentage of participants
Low Disease Activity 18.1 20.0 24.3
Clinical Remission 7.0 9.1 11.2
29.Secondary Outcome
Title Percentage of Participants With an ACR50 Response at Week 48
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Measure Type: Number
Unit of Measure: percentage of participants
18.6 32.9 34.1
30.Secondary Outcome
Title Percentage of Participants With an ACR70 Response at Week 48
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 172 167 170
Measure Type: Number
Unit of Measure: percentage of participants
9.3 12.6 13.5
31.Post-Hoc Outcome
Title Time to Repletion of Peripheral CD19+ B-cells
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 80 43
Median (95% Confidence Interval)
Unit of Measure: Weeks
110.3
(89.6 to 148.3)
109.6
(94.1 to 134.9)
32.Post-Hoc Outcome
Title Percentage of Participants With Low Immunoglobulin Concentrations Pre- and Post-Rituximab Treatment
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 491
Measure Type: Number
Unit of Measure: Percentage of participants
Pre-Rituximab (N=490) 0.2
Post-Rituximab (N=491) 5.1
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
Hide 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
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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   16/172 (9.30%)   52/167 (31.14%)   46/170 (27.06%)   12/155 (7.74%)   45/155 (29.03%)   8/82 (9.76%)   2/44 (4.55%) 
Blood and lymphatic system disorders               
Neutropenia * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Pancytopenia * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Cardiac disorders               
Coronary artery disease * 1  2/172 (1.16%)  3/167 (1.80%)  1/170 (0.59%)  2/155 (1.29%)  3/155 (1.94%)  0/82 (0.00%)  0/44 (0.00%) 
Myocardial infarction * 1  0/172 (0.00%)  4/167 (2.40%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Supraventricular tachycardia * 1  0/172 (0.00%)  1/167 (0.60%)  1/170 (0.59%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Angina pectoris * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  1/44 (2.27%) 
Acute myocardial infarction * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Angina unstable * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Aortic valve incompetence * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Atrial fibrillation * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Atrial flutter * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Cardiac failure congestive * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  1/82 (1.22%)  0/44 (0.00%) 
Pleuropericarditis * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Tachycardia * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Cardiac arrest * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  1/82 (1.22%)  0/44 (0.00%) 
Palpitations * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  1/82 (1.22%)  0/44 (0.00%) 
Ear and labyrinth disorders               
Vertigo * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Endocrine disorders               
Goitre * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Eye disorders               
Cataract * 1  0/172 (0.00%)  0/167 (0.00%)  2/170 (1.18%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Gastrointestinal disorders               
Pancreatitis * 1  0/172 (0.00%)  0/167 (0.00%)  2/170 (1.18%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Gastritis * 1  0/172 (0.00%)  0/167 (0.00%)  2/170 (1.18%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Gastrointestinal haemorrhage * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  2/155 (1.29%)  0/82 (0.00%)  0/44 (0.00%) 
Gastrooesophageal reflux disease * 1  0/172 (0.00%)  0/167 (0.00%)  2/170 (1.18%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Inguinal hernia * 1  0/172 (0.00%)  0/167 (0.00%)  2/170 (1.18%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Intestinal perforation * 1  0/172 (0.00%)  2/167 (1.20%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Abdominal pain * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Colitis * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Diarrhoea * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Diverticular perforation * 1  1/172 (0.58%)  0/167 (0.00%)  0/170 (0.00%)  1/155 (0.65%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Diverticulum intestinal * 1  1/172 (0.58%)  0/167 (0.00%)  0/170 (0.00%)  1/155 (0.65%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Duodenal ulcer * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Femoral hernia, obstructive * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Ileal ulcer * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Ileus * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Inguinal hernia, obstructive * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Intestinal obstruction * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Retroperitoneal haemorrhage * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Volvulus * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Abdominal wall haematoma * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  1/82 (1.22%)  0/44 (0.00%) 
Rectal haemorrhage * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  1/82 (1.22%)  0/44 (0.00%) 
General disorders               
Chest pain * 1  0/172 (0.00%)  2/167 (1.20%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Death * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Device failure * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Fibrosis * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Hernia obstructive * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Hepatobiliary disorders               
Cholecystitis * 1  0/172 (0.00%)  2/167 (1.20%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Cholelithiasis * 1  2/172 (1.16%)  0/167 (0.00%)  0/170 (0.00%)  1/155 (0.65%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Cholangitis * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Cholecystitis acute * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Immune system disorders               
Drug hypersensitivity * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Infections and infestations               
Pneumonia * 1  1/172 (0.58%)  3/167 (1.80%)  4/170 (2.35%)  1/155 (0.65%)  3/155 (1.94%)  1/82 (1.22%)  0/44 (0.00%) 
Gastroenteritis * 1  2/172 (1.16%)  1/167 (0.60%)  1/170 (0.59%)  2/155 (1.29%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Urinary tract infection * 1  0/172 (0.00%)  3/167 (1.80%)  1/170 (0.59%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Cellulitis * 1  0/172 (0.00%)  3/167 (1.80%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Appendicitis * 1  0/172 (0.00%)  2/167 (1.20%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Bronchitis * 1  0/172 (0.00%)  2/167 (1.20%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Diverticulitis * 1  0/172 (0.00%)  2/167 (1.20%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  1/82 (1.22%)  0/44 (0.00%) 
Bronchopneumonia * 1  1/172 (0.58%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Lower respiratory tract infection * 1  0/172 (0.00%)  2/167 (1.20%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Postoperative wound infection * 1  1/172 (0.58%)  1/167 (0.60%)  0/170 (0.00%)  1/155 (0.65%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Abdominal abscess * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Abdominal sepsis * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Abscess soft tissue * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Arthritis infective * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Enterocolitis infectious * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Neutropenic sepsis * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Osteomyelitis * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Pulmonary sepsis * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Pulmonary tuberculosis * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Respiratory tract infection * 1  1/172 (0.58%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Sepsis * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Septic shock * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Sinusitis * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Skin infection * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Soft tissue infection * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Tubo-ovarian abscess * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Urosepsis * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Injury, poisoning and procedural complications               
Fall * 1  1/172 (0.58%)  4/167 (2.40%)  3/170 (1.76%)  0/155 (0.00%)  3/155 (1.94%)  0/82 (0.00%)  0/44 (0.00%) 
Incisional hernia * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Road traffic accident * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Ankle fracture * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Foot fracture * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Humerus fracture * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Infusion related reaction * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Limb injury * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Lower limb fracture * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Post procedural haemorrhage * 1  1/172 (0.58%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Stress fracture * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Subdural haematoma * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Synovial rupture * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Tendon rupture * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Thoracic vertebral fracture * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Traumatic coma * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Investigations               
Hepatitis B DNA increased * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Metabolism and nutrition disorders               
Diabetes mellitus * 1  0/172 (0.00%)  0/167 (0.00%)  2/170 (1.18%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Dehydration * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Failure to thrive * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Hypoglycaemia * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  1/44 (2.27%) 
Musculoskeletal and connective tissue disorders               
Osteoarthritis * 1  1/172 (0.58%)  4/167 (2.40%)  5/170 (2.94%)  1/155 (0.65%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Rheumatoid arthritis * 1  1/172 (0.58%)  2/167 (1.20%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Cervical spinal stenosis * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Osteonecrosis * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  2/155 (1.29%)  0/82 (0.00%)  0/44 (0.00%) 
Arthritis * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Back pain * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  1/82 (1.22%)  0/44 (0.00%) 
Intervertebral disc protrusion * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Lumbar spinal stenosis * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Muscular weaknes * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Spinal column stenosis * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Spinal osteoarthritis * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Spondyloarthropathy * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)               
Lung squamous cell carcinoma stage unspecified * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Uterine leiomyoma * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Basal cell carcinoma * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Bladder cancer * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Lung adenocarcinoma * 1  1/172 (0.58%)  0/167 (0.00%)  0/170 (0.00%)  1/155 (0.65%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Meningioma * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Non-small cell lung cancer * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Non-small cell lung cancer metastatic * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Oesophageal adenocarcinoma * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Oesophageal carcinoma * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Pancreatic carcinoma * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Squamous cell carcinoma of the cervix * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
T-cell prolymphocytic leukaemia * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Colon cancer * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  1/82 (1.22%)  0/44 (0.00%) 
Nervous system disorders               
Cerebrovascular accident * 1  1/172 (0.58%)  0/167 (0.00%)  0/170 (0.00%)  1/155 (0.65%)  3/155 (1.94%)  1/82 (1.22%)  0/44 (0.00%) 
Demyelination * 1  1/172 (0.58%)  0/167 (0.00%)  0/170 (0.00%)  1/155 (0.65%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Benign intracranial hypertension * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Diabetic hyperosmolar coma * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Dizziness * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Radiculopathy * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Syncope * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  1/82 (1.22%)  0/44 (0.00%) 
Pregnancy, puerperium and perinatal conditions               
Abortion spontaneous * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Abortion threatened * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Psychiatric disorders               
Major depression * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Renal and urinary disorders               
Nephrolithiasis * 1  1/172 (0.58%)  1/167 (0.60%)  0/170 (0.00%)  1/155 (0.65%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Reproductive system and breast disorders               
Vaginal prolapse * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Cystocele * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Menorrhagia * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Ovarian cyst * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Postmenopausal haemorrhage * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Testicular necrosis * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Uterine haemorrhage * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Respiratory, thoracic and mediastinal disorders               
Pulmonary embolism * 1  0/172 (0.00%)  2/167 (1.20%)  0/170 (0.00%)  0/155 (0.00%)  2/155 (1.29%)  1/82 (1.22%)  0/44 (0.00%) 
Interstitial lung disease * 1  0/172 (0.00%)  1/167 (0.60%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Acute respiratory failure * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Asthma * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Dyspnoea * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Epistaxis * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Lung disorder * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Skin and subcutaneous tissue disorders               
Lichen planus * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
Vascular disorders               
Aortic stenosis * 1  0/172 (0.00%)  0/167 (0.00%)  1/170 (0.59%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Intra-abdominal haematoma * 1  0/172 (0.00%)  1/167 (0.60%)  0/170 (0.00%)  0/155 (0.00%)  0/155 (0.00%)  0/82 (0.00%)  0/44 (0.00%) 
Thrombosis * 1  0/172 (0.00%)  0/167 (0.00%)  0/170 (0.00%)  0/155 (0.00%)  1/155 (0.65%)  0/82 (0.00%)  0/44 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 16.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   112/172 (65.12%)   149/167 (89.22%)   151/170 (88.82%)   99/155 (63.87%)   131/155 (84.52%)   5/82 (6.10%)   2/44 (4.55%) 
Blood and lymphatic system disorders               
Anaemia * 1  5/172 (2.91%)  9/167 (5.39%)  12/170 (7.06%)  4/155 (2.58%)  7/155 (4.52%)  0/0  0/0 
Ear and labyrinth disorders               
Vertigo * 1  2/172 (1.16%)  8/167 (4.79%)  6/170 (3.53%)  2/155 (1.29%)  9/155 (5.81%)  0/0  0/0 
Gastrointestinal disorders               
Diarrhoea * 1  7/172 (4.07%)  27/167 (16.17%)  20/170 (11.76%)  7/155 (4.52%)  20/155 (12.90%)  0/0  0/0 
Nausea * 1  4/172 (2.33%)  21/167 (12.57%)  17/170 (10.00%)  4/155 (2.58%)  12/155 (7.74%)  0/0  0/0 
Gastrooesophageal reflux disease * 1  2/172 (1.16%)  7/167 (4.19%)  10/170 (5.88%)  2/155 (1.29%)  4/155 (2.58%)  0/0  0/0 
Dyspepsia * 1  3/172 (1.74%)  4/167 (2.40%)  4/170 (2.35%)  3/155 (1.94%)  11/155 (7.10%)  0/0  0/0 
General disorders               
Fatigue * 1  1/172 (0.58%)  13/167 (7.78%)  11/170 (6.47%)  0/155 (0.00%)  8/155 (5.16%)  0/0  0/0 
Oedema peripheral * 1  2/172 (1.16%)  9/167 (5.39%)  12/170 (7.06%)  2/155 (1.29%)  5/155 (3.23%)  0/0  0/0 
Hepatobiliary disorders               
Hepatotoxicity * 1  2/172 (1.16%)  8/167 (4.79%)  7/170 (4.12%)  2/155 (1.29%)  8/155 (5.16%)  0/0  0/0 
Infections and infestations               
Upper respiratory tract infection * 1  13/172 (7.56%)  59/167 (35.33%)  50/170 (29.41%)  13/155 (8.39%)  39/155 (25.16%)  0/82 (0.00%)  0/44 (0.00%) 
Nasopharyngitis * 1  17/172 (9.88%)  43/167 (25.75%)  42/170 (24.71%)  16/155 (10.32%)  34/155 (21.94%)  0/82 (0.00%)  0/44 (0.00%) 
Urinary tract infection * 1  12/172 (6.98%)  41/167 (24.55%)  25/170 (14.71%)  9/155 (5.81%)  34/155 (21.94%)  5/82 (6.10%)  2/44 (4.55%) 
Bronchitis * 1  3/172 (1.74%)  27/167 (16.17%)  25/170 (14.71%)  2/155 (1.29%)  24/155 (15.48%)  0/82 (0.00%)  0/44 (0.00%) 
Sinusitis * 1  6/172 (3.49%)  24/167 (14.37%)  21/170 (12.35%)  6/155 (3.87%)  29/155 (18.71%)  0/82 (0.00%)  0/44 (0.00%) 
Gastroenteritis * 1  8/172 (4.65%)  15/167 (8.98%)  14/170 (8.24%)  7/155 (4.52%)  17/155 (10.97%)  0/82 (0.00%)  0/44 (0.00%) 
Influenza * 1  1/172 (0.58%)  17/167 (10.18%)  20/170 (11.76%)  1/155 (0.65%)  13/155 (8.39%)  0/82 (0.00%)  0/44 (0.00%) 
Pharyngitis * 1  10/172 (5.81%)  15/167 (8.98%)  11/170 (6.47%)  10/155 (6.45%)  9/155 (5.81%)  0/82 (0.00%)  0/44 (0.00%) 
Tooth abscess * 1  0/172 (0.00%)  9/167 (5.39%)  8/170 (4.71%)  0/155 (0.00%)  7/155 (4.52%)  0/82 (0.00%)  0/44 (0.00%) 
Herpes zoster * 1  2/172 (1.16%)  10/167 (5.99%)  4/170 (2.35%)  2/155 (1.29%)  5/155 (3.23%)  0/82 (0.00%)  0/44 (0.00%) 
Lower respiratory tract infection * 1  1/172 (0.58%)  2/167 (1.20%)  8/170 (4.71%)  1/155 (0.65%)  9/155 (5.81%)  0/82 (0.00%)  0/44 (0.00%) 
Injury, poisoning and procedural complications               
Infusion related reaction * 1  33/172 (19.19%)  59/167 (35.33%)  59/170 (34.71%)  28/155 (18.06%)  39/155 (25.16%)  0/0  0/0 
Fall * 1  5/172 (2.91%)  14/167 (8.38%)  5/170 (2.94%)  4/155 (2.58%)  18/155 (11.61%)  0/0  0/0 
Laceration * 1  1/172 (0.58%)  2/167 (1.20%)  10/170 (5.88%)  1/155 (0.65%)  6/155 (3.87%)  0/0  0/0 
Metabolism and nutrition disorders               
Diabetes mellitus * 1  4/172 (2.33%)  13/167 (7.78%)  6/170 (3.53%)  3/155 (1.94%)  7/155 (4.52%)  0/0  0/0 
Hypercholesterolaemia * 1  1/172 (0.58%)  7/167 (4.19%)  9/170 (5.29%)  1/155 (0.65%)  5/155 (3.23%)  0/0  0/0 
Musculoskeletal and connective tissue disorders               
Rheumatoid arthritis * 1  30/172 (17.44%)  49/167 (29.34%)  36/170 (21.18%)  26/155 (16.77%)  31/155 (20.00%)  0/0  0/0 
Back pain * 1  3/172 (1.74%)  22/167 (13.17%)  14/170 (8.24%)  3/155 (1.94%)  10/155 (6.45%)  0/0  0/0 
Arthralgia * 1  3/172 (1.74%)  9/167 (5.39%)  15/170 (8.82%)  2/155 (1.29%)  7/155 (4.52%)  0/0  0/0 
Osteoarthritis * 1  1/172 (0.58%)  8/167 (4.79%)  10/170 (5.88%)  1/155 (0.65%)  8/155 (5.16%)  0/0  0/0 
Muscle spasms * 1  4/172 (2.33%)  7/167 (4.19%)  7/170 (4.12%)  4/155 (2.58%)  10/155 (6.45%)  0/0  0/0 
Pain in extremity * 1  1/172 (0.58%)  9/167 (5.39%)  9/170 (5.29%)  1/155 (0.65%)  7/155 (4.52%)  0/0  0/0 
Nervous system disorders               
Headache * 1  6/172 (3.49%)  18/167 (10.78%)  15/170 (8.82%)  5/155 (3.23%)  16/155 (10.32%)  0/0  0/0 
Dizziness * 1  4/172 (2.33%)  11/167 (6.59%)  10/170 (5.88%)  3/155 (1.94%)  0/155 (0.00%)  0/0  0/0 
Psychiatric disorders               
Depression * 1  0/172 (0.00%)  15/167 (8.98%)  7/170 (4.12%)  0/155 (0.00%)  7/155 (4.52%)  0/0  0/0 
Insomnia * 1  7/172 (4.07%)  9/167 (5.39%)  8/170 (4.71%)  6/155 (3.87%)  5/155 (3.23%)  0/0  0/0 
Respiratory, thoracic and mediastinal disorders               
Cough * 1  7/172 (4.07%)  13/167 (7.78%)  22/170 (12.94%)  7/155 (4.52%)  11/155 (7.10%)  0/0  0/0 
Rhinitis allergic * 1  0/172 (0.00%)  6/167 (3.59%)  10/170 (5.88%)  0/155 (0.00%)  6/155 (3.87%)  0/0  0/0 
Skin and subcutaneous tissue disorders               
Rash * 1  1/172 (0.58%)  9/167 (5.39%)  7/170 (4.12%)  1/155 (0.65%)  6/155 (3.87%)  0/0  0/0 
Alopecia * 1  1/172 (0.58%)  9/167 (5.39%)  6/170 (3.53%)  0/155 (0.00%)  3/155 (1.94%)  0/0  0/0 
Vascular disorders               
Hypertension * 1  3/172 (1.74%)  28/167 (16.77%)  18/170 (10.59%)  2/155 (1.29%)  15/155 (9.68%)  0/0  0/0 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 16.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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
Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT00299130     History of Changes
Other Study ID Numbers: U2973g
WA17045 ( Other Identifier: F. Hoffmann-La Roche )
First Submitted: March 3, 2006
First Posted: March 6, 2006
Results First Submitted: February 21, 2013
Results First Posted: June 28, 2013
Last Update Posted: April 17, 2017