Trial Outcomes & Findings for A Study to Evaluate the Safety and Efficacy of MabThera (Rituximab) in Combination With Methotrexate (MTX) in Participants With Active Rheumatoid Arthritis Who Failed on Anti-Tumor Necrosis Factor Alpha Therapy (NCT NCT00468546)

Last Updated: 2016-10-25

Results Overview

American College of Rheumatology (ACR) 20 response is defined as \>= 20% improvement (reduction) in score compared with baseline for both tender joint count (TJC)-68 joints and swollen joint count (SJC)-66 joints, as well as for 3 of the additional 5 ACR core set variables: Patient's Assessment of Pain over the previous 24 hours using a Visual Analog Scale (VAS) ranging from score 0 (no pain) to 100 (unbearable pain); Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS ranging score 0 (no disease activity) to 100 (maximum disease activity); Health Assessment Questionnaire (HAQ):8 domains (dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities) rated on a 4-point scale (0=without any difficulty to 3=unable to do) for a total possible score of 0 (best) to 3 (worst); and acute-phase reactant, either C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

520 participants

Primary outcome timeframe

Week 24

Results posted on

2016-10-25

Participant Flow

A total of 520 participants were enrolled in the study conducted from 02 May 2003 and 12 July 2012 in 11 countries.

Of the total randomized 520 participants who met the eligibility criteria, four did not receive the study treatment and were not included in any analysis population.

Participant milestones

Participant milestones
Measure	Placebo Plus Methotrexate Eligible participants were administered the placebo by intravenous infusion on Days 1 and 15 along with methotrexate (MTX) 10-25 milligrams (mg) per os (p.o.) or parenterally once a week up to Week 24 and were followed up to Week 104.	Rituximab Plus Methotrexate Eligible Participants were administered rituximab 1000 mg as intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to Week 24 and were followed up to Week 104.
Week 24 Analysis STARTED	208	308
Week 24 Analysis COMPLETED	111	253
Week 24 Analysis NOT COMPLETED	97	55
Week 24 to Week 104 Analysis STARTED	208	308
Week 24 to Week 104 Analysis COMPLETED	103	83
Week 24 to Week 104 Analysis NOT COMPLETED	105	225

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Plus Methotrexate Eligible participants were administered the placebo by intravenous infusion on Days 1 and 15 along with methotrexate (MTX) 10-25 milligrams (mg) per os (p.o.) or parenterally once a week up to Week 24 and were followed up to Week 104.	Rituximab Plus Methotrexate Eligible Participants were administered rituximab 1000 mg as intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to Week 24 and were followed up to Week 104.
Week 24 Analysis Lack of Efficacy	83	37
Week 24 Analysis Refused treatment	5	5
Week 24 Analysis Adverse Event	1	8
Week 24 Analysis Failure to return	3	4
Week 24 Analysis Rescue therapy	2	0
Week 24 Analysis Incorrect diagnosis and treatment	0	1
Week 24 Analysis Due to clinical hold	1	0
Week 24 Analysis Went onto rescue therapy	1	0
Week 24 Analysis Participant unblinded (clinical hold)	1	0
Week 24 to Week 104 Analysis Adverse Event	2	5
Week 24 to Week 104 Analysis Death	1	0
Week 24 to Week 104 Analysis Lack of Efficacy	3	12
Week 24 to Week 104 Analysis Protocol Violation	0	2
Week 24 to Week 104 Analysis Refused treatment	4	7
Week 24 to Week 104 Analysis Failure to return	1	2
Week 24 to Week 104 Analysis Movement into re-treatment study	77	183
Week 24 to Week 104 Analysis Other	17	14

Baseline Characteristics

A Study to Evaluate the Safety and Efficacy of MabThera (Rituximab) in Combination With Methotrexate (MTX) in Participants With Active Rheumatoid Arthritis Who Failed on Anti-Tumor Necrosis Factor Alpha Therapy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo Plus Methotrexate n=208 Participants Eligible participants were administered placebo by intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to 24 weeks and were followed up to Week 104.	Rituximab Plus Methotrexate n=308 Participants Eligible Participants were administered rituximab 1000 mg as intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to Week 24 and were followed up to Week 104.	Total n=516 Participants Total of all reporting groups
Age, Continuous	55.0 years n=5 Participants	53.0 years n=7 Participants	53.0 years n=5 Participants
Sex: Female, Male Female	168 Participants n=5 Participants	251 Participants n=7 Participants	419 Participants n=5 Participants
Sex: Female, Male Male	40 Participants n=5 Participants	57 Participants n=7 Participants	97 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 24

Population: Intent to treat (ITT) population included all randomized participants who received any part of an infusion of study drug. Participants whom treatment allocation was unblinded and who received treatment prior to randomization were excluded.

Outcome measures

Outcome measures
Measure	Placebo Plus Methotrexate n=201 Participants Eligible participants were administered placebo by intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to 24 weeks and were followed up to Week 104.	Rituximab Plus Methotrexate n=298 Participants Eligible Participants were administered rituximab 1000 mg as intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to Week 24 and were followed up to Week 104.
Number of Participants With American College of Rheumatology 20 Response at Week 24	36 participants	153 participants

SECONDARY outcome

Timeframe: Week 24

Population: The ITT population included all randomized participants who received any part of an infusion of study drug. Participants whom treatment allocation was unblinded and who received treatment prior to randomization were excluded.

ACR 50 response is defined as a \>= 50% improvement (reduction) in score compared with baseline for both TJC -68 joints and SJC -66 joints, as well as for 3 of the additional 5 ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a VAS ranging from score '0'=no pain to score '100'=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS ranging from score '0'=no disease activity to score '100'=maximum disease activity; HAQ : Health Assessment Questionnaire (HAQ):which included 8 domains (dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities) rated on a 4-point scale (0=without any difficulty to 3=unable to do), where the sum of scores was divided by the number of domains with a score for a total possible score of 0 (best) to 3 (worst); and acute-phase reactant, either CRP or ESR.

Outcome measures

Outcome measures
Measure	Placebo Plus Methotrexate n=201 Participants Eligible participants were administered placebo by intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to 24 weeks and were followed up to Week 104.	Rituximab Plus Methotrexate n=298 Participants Eligible Participants were administered rituximab 1000 mg as intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to Week 24 and were followed up to Week 104.
Number of Participants With an ACR 50 Response at Week 24	11 participants	80 participants

SECONDARY outcome

Timeframe: Week 24

ACR 70 response is defined as a \>= 70% improvement (reduction) in score compared with baseline for both TJC -68 joints and SJC -66 joints, as well as for 3 of the additional 5 ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a VAS ranging from score '0'=no pain to score '100'=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS ranging from score '0'=no disease activity to score '100'=maximum disease activity; HAQ : Health Assessment Questionnaire (HAQ):which included 8 domains (dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities) rated on a 4-point scale (0=without any difficulty to 3=unable to do), where the sum of scores was divided by the number of domains with a score for a total possible score of 0 (best) to 3 (worst); and acute-phase reactant, either CRP or ESR.

Outcome measures

Outcome measures
Measure	Placebo Plus Methotrexate n=201 Participants Eligible participants were administered placebo by intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to 24 weeks and were followed up to Week 104.	Rituximab Plus Methotrexate n=298 Participants Eligible Participants were administered rituximab 1000 mg as intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to Week 24 and were followed up to Week 104.
Number of Participants With ACR 70 Response at Week 24	3 participants	37 participants

SECONDARY outcome

Timeframe: From Baseline (Day 1) to Week 24

The disease activity score (DAS28) is an evaluation index of rheumatoid arthritis. The DAS28 applies a mathematical formula based on the following parameters: 1. TJC-28 joints, 2. SJC -28 joints, 3. ESR or CRP measurement, 4. Participant's judgement on his own overall health (global health \[GH\]) status expressed by a VAS (0 \[no disease activity\] to 100 \[maximum disease activity\]). The mathematical formula is 0.56 × √28TJC + 0.28 × √28SJC + 0.7 x loge ESR + 0.014 × GH. The DAS28 scale ranges from score of 0 to 10, where lower scores indicate best disease control and higher scores indicate worsening of disease. Change from Baseline = difference between the score at Week 24 and the score at Baseline.

Outcome measures

Outcome measures
Measure	Placebo Plus Methotrexate n=201 Participants Eligible participants were administered placebo by intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to 24 weeks and were followed up to Week 104.	Rituximab Plus Methotrexate n=298 Participants Eligible Participants were administered rituximab 1000 mg as intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to Week 24 and were followed up to Week 104.
Mean Change From Baseline in Disease Activity Score of 28 Joints at Week 24	-0.4 units on a scale Standard Deviation 1.17	-1.9 units on a scale Standard Deviation 1.60

SECONDARY outcome

Timeframe: Week 24

The DAS28 is an evaluation index of RA. The DAS28 applies a mathematical formula based on the following parameters: 1. TJC- 28 joints, 2. SJC- 28 joints, 3. ESR or CRP measurement, 4. Participant's judgement on his own overall health status (GH) expressed by a visual analogue scale VAS (0 \[no disease activity\] to 100 \[maximum disease activity\]). The mathematical formula is 0.56 × √28TJC + 0.28 × √28SJC + 0.7 x loge ESR + 0.014 × GH. The DAS28 scale ranges from score of 0 to 10. A participant was categorized as having low disease activity, if participant's DAS28 score was \<= 3.2, and was categorized as having clinical remission if participant's DAS28 score was \< 2.6.

Outcome measures

Outcome measures
Measure	Placebo Plus Methotrexate n=201 Participants Eligible participants were administered placebo by intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to 24 weeks and were followed up to Week 104.	Rituximab Plus Methotrexate n=298 Participants Eligible Participants were administered rituximab 1000 mg as intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to Week 24 and were followed up to Week 104.
Percentage of Participants With DAS28 Low Disease Activity and DAS28 Remission at Week 24 Low disease activity	2 percentage of participants	15 percentage of participants
Percentage of Participants With DAS28 Low Disease Activity and DAS28 Remission at Week 24 Remission	0 percentage of participants	9 percentage of participants

SECONDARY outcome

Timeframe: Week 24

European League Against Rheumatism (EULAR) response is defined based on the DAS28 score and the EULAR response criteria (Van Gestel et al, 1996 and 1999). The DAS28 scale ranges from score of 0 to 10, where lower scores indicate best disease control and higher scores indicate worsening of disease. At a given visit, participants with a DAS28 score of \< 3.2 are considered good responders if the change from baseline in their DAS28 score is \>1.2. Participants with a DAS28 score \>= 3.2 to 5.1 are considered moderate responders if the change from baseline in their DAS28 score is \<=1.2 to \>=0.6. Participants with DAS28 score \>5.1 are considered non-responders if the change from baseline in their DAS28 score is \<=1.2 to \>=0.6.

Outcome measures

Outcome measures
Measure	Placebo Plus Methotrexate n=201 Participants Eligible participants were administered placebo by intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to 24 weeks and were followed up to Week 104.	Rituximab Plus Methotrexate n=298 Participants Eligible Participants were administered rituximab 1000 mg as intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to Week 24 and were followed up to Week 104.
Number of Participants With Good, Moderate, or no European League Against Rheumatism Responses at Week 24 Moderate response	40 participants	149 participants
Number of Participants With Good, Moderate, or no European League Against Rheumatism Responses at Week 24 No response	157 participants	105 participants
Number of Participants With Good, Moderate, or no European League Against Rheumatism Responses at Week 24 Good response	4 participants	44 participants

SECONDARY outcome

Timeframe: From Baseline (Day 1) to Week 24

Percentage change in the scores of the following parameters of ACR core set relative to respective baseline scores in both study arms was analyzed : SJC (28 and 66 joints) and TJC (28 and 66 joints), patient's global assessment and physician's global assessment based on disease activity (both are expressed by VAS \[0 = no disease activity to 100 = maximum disease activity\]), HAQ (based on HAQ disability index \[HAQDI\]) which included 8 domains (dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities) rated on a 4-point scale (0=without any difficulty to 3=unable to do), where the sum of scores was divided by the number of domains with a score for a total possible score of 0 (best) to 3 (worst), pain assessment using a VAS ranging from score 0 (no pain) to 100 (unbearable pain), CRP concentration, and ESR.

Outcome measures

Outcome measures
Measure	Placebo Plus Methotrexate n=201 Participants Eligible participants were administered placebo by intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to 24 weeks and were followed up to Week 104.	Rituximab Plus Methotrexate n=298 Participants Eligible Participants were administered rituximab 1000 mg as intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to Week 24 and were followed up to Week 104.
Percentage Change From Baseline in the ACR Core Set (SJC, TJC, Patient's and Physician's Global Assessments, Health Assessment Questionnaire, Pain, C-Reactive Protein, and Erythrocyte Sedimentation Rate) Score SJC (66)	-5.6 percent change Standard Deviation 59.19	-43.0 percent change Standard Deviation 52.65
Percentage Change From Baseline in the ACR Core Set (SJC, TJC, Patient's and Physician's Global Assessments, Health Assessment Questionnaire, Pain, C-Reactive Protein, and Erythrocyte Sedimentation Rate) Score SJC (28)	-7.1 percent change Standard Deviation 55.35	-41.3 percent change Standard Deviation 52.77
Percentage Change From Baseline in the ACR Core Set (SJC, TJC, Patient's and Physician's Global Assessments, Health Assessment Questionnaire, Pain, C-Reactive Protein, and Erythrocyte Sedimentation Rate) Score TJC (68)	7.2 percent change Standard Deviation 144.58	-41.8 percent change Standard Deviation 52.39
Percentage Change From Baseline in the ACR Core Set (SJC, TJC, Patient's and Physician's Global Assessments, Health Assessment Questionnaire, Pain, C-Reactive Protein, and Erythrocyte Sedimentation Rate) Score TJC (28)	15.7 percent change Standard Deviation 195.94	-42.0 percent change Standard Deviation 63.47
Percentage Change From Baseline in the ACR Core Set (SJC, TJC, Patient's and Physician's Global Assessments, Health Assessment Questionnaire, Pain, C-Reactive Protein, and Erythrocyte Sedimentation Rate) Score Physician's global assessment	-4.2 percent change Standard Deviation 47.23	-40.8 percent change Standard Deviation 39.31
Percentage Change From Baseline in the ACR Core Set (SJC, TJC, Patient's and Physician's Global Assessments, Health Assessment Questionnaire, Pain, C-Reactive Protein, and Erythrocyte Sedimentation Rate) Score Patient's global assessment	-3.1 percent change Standard Deviation 44.01	-25.4 percent change Standard Deviation 117.90
Percentage Change From Baseline in the ACR Core Set (SJC, TJC, Patient's and Physician's Global Assessments, Health Assessment Questionnaire, Pain, C-Reactive Protein, and Erythrocyte Sedimentation Rate) Score Patient's pain assessment	2.8 percent change Standard Deviation 55.61	-23.8 percent change Standard Deviation 131.59
Percentage Change From Baseline in the ACR Core Set (SJC, TJC, Patient's and Physician's Global Assessments, Health Assessment Questionnaire, Pain, C-Reactive Protein, and Erythrocyte Sedimentation Rate) Score HAQ	-2.0 percent change Standard Deviation 30.46	-24.3 percent change Standard Deviation 34.92
Percentage Change From Baseline in the ACR Core Set (SJC, TJC, Patient's and Physician's Global Assessments, Health Assessment Questionnaire, Pain, C-Reactive Protein, and Erythrocyte Sedimentation Rate) Score CRP	80.0 percent change Standard Deviation 452.94	-36.3 percent change Standard Deviation 80.3
Percentage Change From Baseline in the ACR Core Set (SJC, TJC, Patient's and Physician's Global Assessments, Health Assessment Questionnaire, Pain, C-Reactive Protein, and Erythrocyte Sedimentation Rate) Score ESR	11.4 percent change Standard Deviation 95.95	-29.3 percent change Standard Deviation 59.92

SECONDARY outcome

Timeframe: From Baseline (Day 1) to Week 24

Population: The ITT population included all randomized participants who received any part of an infusion of study drug. Participants with available data at the time of evaluation were analyzed.

The Short Form (SF)-36 determined participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual daily activities because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems since last month; 7) limitations in usual work (house hold and outside) due to emotional problems 8) current and 1 year past status of health 9) general mental health. Transforming and standardizing these domains leads to the calculation of the physical component summary and mental component summary measures. Scores on each item were summed and averaged (range 0 \[worst\] to 100 \[best\]); increase in score from baseline indicated improvement. Change from Baseline = difference between the score at Week 24 and the score at Baseline.

Outcome measures

Outcome measures
Measure	Placebo Plus Methotrexate n=197 Participants Eligible participants were administered placebo by intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to 24 weeks and were followed up to Week 104.	Rituximab Plus Methotrexate n=294 Participants Eligible Participants were administered rituximab 1000 mg as intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to Week 24 and were followed up to Week 104.
Mean Change From Baseline of Short Form 36 Total Scores at Week 24 Physical score	0.9 units on a scale Standard Deviation 5.65	5.8 units on a scale Standard Deviation 8.47
Mean Change From Baseline of Short Form 36 Total Scores at Week 24 Mental health score	1.3 units on a scale Standard Deviation 9.43	4.7 units on a scale Standard Deviation 11.75

SECONDARY outcome

Timeframe: From Baseline (Day 1) to Week 24

Population: The ITT population included all randomized participants who received any part of an infusion of study drug. Participants with available data at the time of evaluation were analyzed.

The SF-36 determined participants' overall quality of life by assessing :1) limitations in physical functioning due to health problems; 2) limitations in usual daily activities because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems since last month; 7) limitations in usual work (house hold and outside) due to emotional problems 8) current and 1 year past status of health 9) general mental health. Scores on physical component were summed and averaged (range 0 \[worst\] to 100 \[best\]); If participants' had shown change from baseline in physical health component score \>5.42, it was considered as improved; score between -5.42 to 5.42 was considered as unchanged, and score \< -5.42 was considered as worsened. Change from Baseline = difference between the score of physical component at Week 24 and the score at Baseline.

Outcome measures

Outcome measures
Measure	Placebo Plus Methotrexate n=197 Participants Eligible participants were administered placebo by intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to 24 weeks and were followed up to Week 104.	Rituximab Plus Methotrexate n=294 Participants Eligible Participants were administered rituximab 1000 mg as intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to Week 24 and were followed up to Week 104.
Number of Participants With Categorical Change From Baseline in the Physical Component Scores of SF-36 Improved	25 participants	141 participants
Number of Participants With Categorical Change From Baseline in the Physical Component Scores of SF-36 Unchanged	158 participants	136 participants
Number of Participants With Categorical Change From Baseline in the Physical Component Scores of SF-36 Worsened	14 participants	17 participants

SECONDARY outcome

Timeframe: From Baseline (Day 1) to Week 24

Population: The ITT population included all randomized participants who received any part of an infusion of study drug. Participants with available data at the time of evaluation were analyzed.

The SF-36 determined participants' overall quality of life by assessing :1) limitations in physical functioning due to health problems; 2) limitations in usual daily activities because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems since last month; 7) limitations in usual work (house hold and outside) due to emotional problems 8) current and 1 year past status of health 9) general mental health. Scores on mental component were summed and averaged (range = 0 \[worst\]-100 \[best\]); increase from baseline indicated improvement. If participants' had shown change from baseline in mental health score \>6.33, it was considered as improved; scores between -6.33 to 6.33 was considered unchanged, and score \<-6.33 was considered as worsened. Change from Baseline = difference between the mental component score at Week 24 and the score at Baseline.

Outcome measures

Outcome measures
Measure	Placebo Plus Methotrexate n=197 Participants Eligible participants were administered placebo by intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to 24 weeks and were followed up to Week 104.	Rituximab Plus Methotrexate n=294 Participants Eligible Participants were administered rituximab 1000 mg as intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to Week 24 and were followed up to Week 104.
Number of Participants With Change From Baseline in the Mental Component Scores of SF-36 Improved	40 participants	111 participants
Number of Participants With Change From Baseline in the Mental Component Scores of SF-36 Unchanged	128 participants	144 participants
Number of Participants With Change From Baseline in the Mental Component Scores of SF-36 Worsened	29 participants	39 participants

SECONDARY outcome

Timeframe: From Baseline (Day 1) to Weeks (W) 24, 56, and 104

The Genant-modified Sharp scoring system assesses structural damage due to rheumatoid arthritis in radiographs. A score for erosions of 0-3.5 (8 gradations) is assigned for 14 joints in each hand and wrist, and 6 joints in each foot. Joint space narrowing scores of 0-4 (9 gradations) are assigned to 13 joints in each hand and 6 joints in each foot. The maximum erosion score is 40 x 3.5 = 140. The maximum joint space narrowing score is 38 x 4.0 = 152. Both the erosion and joint space narrowing scores are normalized to 145 and are added together for a maximum total Genant-modified Sharp score of 290. For all the three radiograph assessment, the minimum score is 0. A higher score indicates more damage and a negative change score indicates improvement. The change in score is to be calculated as: Change from Baseline = difference between the score at Weeks 24, 56, or 104 and the score at Baseline.

Outcome measures

Outcome measures
Measure	Placebo Plus Methotrexate n=201 Participants Eligible participants were administered placebo by intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to 24 weeks and were followed up to Week 104.	Rituximab Plus Methotrexate n=298 Participants Eligible Participants were administered rituximab 1000 mg as intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to Week 24 and were followed up to Week 104.
Mean Change From Baseline in the Genant-modified Sharp Joint Space Narrowing Score, Genant-modified Sharp Total Score, and Erosion Score Sharp-Genant total score, W24, n = 201, 298	-4.3 units on a scale Standard Deviation 24.09	-1.2 units on a scale Standard Deviation 20.90
Mean Change From Baseline in the Genant-modified Sharp Joint Space Narrowing Score, Genant-modified Sharp Total Score, and Erosion Score Sharp-Genant total score, W56, n = 184, 273	2.31 units on a scale Standard Deviation 5.283	1.00 units on a scale Standard Deviation 2.751
Mean Change From Baseline in the Genant-modified Sharp Joint Space Narrowing Score, Genant-modified Sharp Total Score, and Erosion Score Sharp-Genant total score, W104, n = 186,279	2.82 units on a scale Standard Deviation 6.398	1.16 units on a scale Standard Deviation 3.429
Mean Change From Baseline in the Genant-modified Sharp Joint Space Narrowing Score, Genant-modified Sharp Total Score, and Erosion Score Erosion score, W24, n = 201, 298	-1.6 units on a scale Standard Deviation 12.15	-0.4 units on a scale Standard Deviation 10.45
Mean Change From Baseline in the Genant-modified Sharp Joint Space Narrowing Score, Genant-modified Sharp Total Score, and Erosion Score Erosion score, W56, n = 184, 273	1.32 units on a scale Standard Deviation 3.155	0.59 units on a scale Standard Deviation 1.843
Mean Change From Baseline in the Genant-modified Sharp Joint Space Narrowing Score, Genant-modified Sharp Total Score, and Erosion Score Erosion score, W104, n = 186,279	1.81 units on a scale Standard Deviation 4.187	0.73 units on a scale Standard Deviation 2.262
Mean Change From Baseline in the Genant-modified Sharp Joint Space Narrowing Score, Genant-modified Sharp Total Score, and Erosion Score Joint space narrowing score, W24, n = 201, 298	-2.5 units on a scale Standard Deviation 12.71	-0.9 units on a scale Standard Deviation 10.90
Mean Change From Baseline in the Genant-modified Sharp Joint Space Narrowing Score, Genant-modified Sharp Total Score, and Erosion Score Joint space narrowing score, W56, n = 184, 273	0.99 units on a scale Standard Deviation 2.571	0.41 units on a scale Standard Deviation 1.323
Mean Change From Baseline in the Genant-modified Sharp Joint Space Narrowing Score, Genant-modified Sharp Total Score, and Erosion Score Joint space narrowing score, W104, n = 186,279	1.01 units on a scale Standard Deviation 2.618	0.43 units on a scale Standard Deviation 1.563

SECONDARY outcome

Timeframe: Up to Week 104

Population: ITT population included all randomized participants who received any part of an infusion of study medication. Participants with available data at the time of evaluation were analyzed.

The Genant-modified Sharp scoring system assesses structural damage due to rheumatoid arthritis in radiographs. A score for erosions of 0-3.5 (8 gradations) is assigned for 14 joints in each hand and wrist, and 6 joints in each foot. The maximum erosion score is 40 x 3.5 = 140 which is normalized to 145. The minimum score is 0 and the maximum score is 145. A higher score indicates more damage and negative change score indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo Plus Methotrexate n=187 Participants Eligible participants were administered placebo by intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to 24 weeks and were followed up to Week 104.	Rituximab Plus Methotrexate n=281 Participants Eligible Participants were administered rituximab 1000 mg as intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to Week 24 and were followed up to Week 104.
Percentage of Participants Without Erosive Progression Baseline to Year 1, n = 186, 278	51 percentage of participants	66 percentage of participants
Percentage of Participants Without Erosive Progression Year 1 to Year 2, n = 186, 278	58 percentage of participants	73 percentage of participants
Percentage of Participants Without Erosive Progression Baseline to Year 2, n = 187, 281	44 percentage of participants	60 percentage of participants

Adverse Events

Placebo Plus Methotrexate

Serious events: 26 serious events

Other events: 152 other events

Deaths: 0 deaths

Rituximab Plus Methotrexate

Serious events: 50 serious events

Other events: 225 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Roche Trial Information Hotline

F. Hoffmann-La Roche AG

Phone: +41 616878333

Email: [email protected]

Results disclosure agreements

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

Restriction type: OTHER

Measure	Placebo Plus Methotrexate n=208 participants at risk Eligible participants were administered placebo by intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to 24 weeks and were followed up to Week 104.	Rituximab Plus Methotrexate n=308 participants at risk Eligible Participants were administered rituximab 1000 mg as intravenous infusion on Days 1 and 15 along with MTX 10-25 mg p.o. or parenterally once a week up to Week 24 and were followed up to Week 104.
Musculoskeletal and connective tissue disorders Rheumatoid Arthritis	41.8% 87/208 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.	34.4% 106/308 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.
Musculoskeletal and connective tissue disorders Arthralgia	3.8% 8/208 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.	7.8% 24/308 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.
Musculoskeletal and connective tissue disorders Back Pain	4.8% 10/208 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.	5.2% 16/308 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.
Infections and infestations Upper Respiratory Tract infection	8.2% 17/208 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.	11.7% 36/308 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.
Infections and infestations Nasopharyngitis	7.2% 15/208 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.	9.7% 30/308 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.
Infections and infestations Bronchitis	7.2% 15/208 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.	8.1% 25/308 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.
Infections and infestations Urinary Tract Infection	7.2% 15/208 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.	6.8% 21/308 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.
Infections and infestations Sinusitis	6.7% 14/208 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.	3.9% 12/308 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.
Nervous system disorders Headache	10.1% 21/208 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.	10.1% 31/308 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.
Nervous system disorders Dizziness	3.8% 8/208 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.	5.2% 16/308 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.
Gastrointestinal disorders Diarrhoea	8.7% 18/208 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.	6.8% 21/308 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.
Gastrointestinal disorders Nausea	3.8% 8/208 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.	7.5% 23/308 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.
General disorders Fatigue	5.8% 12/208 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.	6.8% 21/308 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.
General disorders Pyrexia	3.4% 7/208 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.	5.5% 17/308 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.
Vascular disorders Hypertension	5.8% 12/208 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.	8.4% 26/308 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.
Psychiatric disorders Insomnia	4.3% 9/208 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.	5.5% 17/308 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.
Skin and subcutaneous tissue disorders Rash	4.3% 9/208 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.	5.2% 16/308 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.
Respiratory, thoracic and mediastinal disorders Cough	5.3% 11/208 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.	3.9% 12/308 • Up to Week 104 Adverse events were captured in safety analysis population. Safety population included participants who were randomized and received any part of an infusion of the study drug.