Trial Outcomes & Findings for A Study of Tocilizumab and Methotrexate Treatment Strategies (Adding Tocilizumab to Methotrexate Versus Switching to Tocilizumab) in Patients With Active Rheumatoid Arthritis With Inadequate Response to Prior Methotrexate Treatment (NCT NCT00810199)

Last Updated: 2014-07-18

Results Overview

The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) \[28 joints\], swollen joint count (SJC) \[28 joints\], patient's global assessment of disease activity \[visual analog scale: 0=no disease activity to 100=maximum disease activity\] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. DAS28 Remission is defined as a DAS28 score \< 2.6.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

556 participants

Primary outcome timeframe

Week 24

Results posted on

2014-07-18

Participant Flow

Participant milestones

Participant milestones
Measure	Tocilizumab + Methotrexate Tocilizumab 8 mg/kg (up to 800 mg) intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks. Patients taking oral corticosteroids remained on their pre-study dose (up to 10 mg/day). Week 24 to Week 52 the dose of tocilizumab and methotrexate remained the same. Based on DAS28 assessments, corticosteroid dose was adjusted and disease-modifying antirheumatic drug (DMARDS) added. Week 52 to Week 104, based on the DAS28 assessment, treatment was adjusted to one of four protocol specified treatment regimens: Treatment tapering, Continued treatment, Treatment intensification or Maintenance treatment. After Week 100, patients who discontinued tocilizumab because of remission were retreated with the last effective dose of tocilizumab or blinded methotrexate if a flare occurred.	Tocilizumab + Placebo Tocilizumab 8 mg/kg (up to 800 mg) IV once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study dose for 24 weeks. Patients taking oral corticosteroids remained on their pre-study dose (up to 10 mg/day). Week 24 to Week 52 the dose of tocilizumab and placebo to methotrexate remained the same. Based on DAS28 assessments, corticosteroid dose was adjusted and disease-modifying antirheumatic drug (DMARDS) added. Week 52 to Week 104, based on the DAS28 assessment, treatment was adjusted to one of four protocol specified treatment regimens: Treatment tapering, Continued treatment, Treatment intensification or Maintenance treatment. After Week 100, patients who discontinued tocilizumab because of remission were retreated with the last effective dose of tocilizumab or blinded placebo to methotrexate if a flare occurred.
Overall Study STARTED	279	277
Overall Study Received Study Drug	277	276
Overall Study Completed Week 24	259	250
Overall Study Completed Week 52	243	229
Overall Study Completed Week 104	222	201
Overall Study COMPLETED	220	195
Overall Study NOT COMPLETED	59	82

Reasons for withdrawal

Reasons for withdrawal
Measure	Tocilizumab + Methotrexate Tocilizumab 8 mg/kg (up to 800 mg) intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks. Patients taking oral corticosteroids remained on their pre-study dose (up to 10 mg/day). Week 24 to Week 52 the dose of tocilizumab and methotrexate remained the same. Based on DAS28 assessments, corticosteroid dose was adjusted and disease-modifying antirheumatic drug (DMARDS) added. Week 52 to Week 104, based on the DAS28 assessment, treatment was adjusted to one of four protocol specified treatment regimens: Treatment tapering, Continued treatment, Treatment intensification or Maintenance treatment. After Week 100, patients who discontinued tocilizumab because of remission were retreated with the last effective dose of tocilizumab or blinded methotrexate if a flare occurred.	Tocilizumab + Placebo Tocilizumab 8 mg/kg (up to 800 mg) IV once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study dose for 24 weeks. Patients taking oral corticosteroids remained on their pre-study dose (up to 10 mg/day). Week 24 to Week 52 the dose of tocilizumab and placebo to methotrexate remained the same. Based on DAS28 assessments, corticosteroid dose was adjusted and disease-modifying antirheumatic drug (DMARDS) added. Week 52 to Week 104, based on the DAS28 assessment, treatment was adjusted to one of four protocol specified treatment regimens: Treatment tapering, Continued treatment, Treatment intensification or Maintenance treatment. After Week 100, patients who discontinued tocilizumab because of remission were retreated with the last effective dose of tocilizumab or blinded placebo to methotrexate if a flare occurred.
Overall Study Adverse Event	24	26
Overall Study Death	4	6
Overall Study Withdrew consent	9	12
Overall Study Insufficient therapeutic response	5	14
Overall Study Refused treatment/Did not cooperate	7	7
Overall Study Administrative/Other	5	6
Overall Study Protocol Violation	2	6
Overall Study Failure to return	1	4
Overall Study Did not receive study drug	2	1

Baseline Characteristics

A Study of Tocilizumab and Methotrexate Treatment Strategies (Adding Tocilizumab to Methotrexate Versus Switching to Tocilizumab) in Patients With Active Rheumatoid Arthritis With Inadequate Response to Prior Methotrexate Treatment

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg (up to 800 mg) intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks. Patients taking oral corticosteroids remained on their pre-study dose (up to 10 mg/day). Week 24 to Week 52 the dose of tocilizumab and methotrexate remained the same. Based on DAS28 assessments, corticosteroid dose was adjusted and disease-modifying antirheumatic drug (DMARDS) added. Week 52 to Week 104, based on the DAS28 assessment, treatment was adjusted to one of four protocol specified treatment regimens: Treatment tapering, Continued treatment, Treatment intensification or Maintenance treatment. After Week 100, patients who discontinued tocilizumab because of remission were retreated with the last effective dose of tocilizumab or blinded methotrexate if a flare occurred.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg (up to 800 mg) IV once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study dose for 24 weeks. Patients taking oral corticosteroids remained on their pre-study dose (up to 10 mg/day). Week 24 to Week 52 the dose of tocilizumab and placebo to methotrexate remained the same. Based on DAS28 assessments, corticosteroid dose was adjusted and disease-modifying antirheumatic drug (DMARDS) added. Week 52 to Week 104, based on the DAS28 assessment, treatment was adjusted to one of four protocol specified treatment regimens: Treatment tapering, Continued treatment, Treatment intensification or Maintenance treatment. After Week 100, patients who discontinued tocilizumab because of remission were retreated with the last effective dose of tocilizumab or blinded placebo to methotrexate if a flare occurred.	Total n=553 Participants Total of all reporting groups
Age, Continuous	53.0 years STANDARD_DEVIATION 13.40 • n=5 Participants	53.6 years STANDARD_DEVIATION 11.91 • n=7 Participants	53.3 years STANDARD_DEVIATION 12.67 • n=5 Participants
Sex: Female, Male Female	227 Participants n=5 Participants	217 Participants n=7 Participants	444 Participants n=5 Participants
Sex: Female, Male Male	50 Participants n=5 Participants	59 Participants n=7 Participants	109 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 24

Population: Intent-to-treat population included all randomized participants who received study drug.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Percentage of Participants With Disease Activity Score 28 Joints (DAS28) Remission at Week 24	40.4 Percentage of participants	34.8 Percentage of participants

SECONDARY outcome

Timeframe: Baseline, Weeks 24, 52, 104

Population: Intent-to-treat population included all randomized participants who received study drug.

ACR20 response is defined as a ≥ 20% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 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 where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant \[either C-reactive protein or Erythrocyte Sedimentation Rate\].

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Percentage of Participants With American College of Rheumatology (ACR20) Response Week 24	71.5 Percentage of participants	70.3 Percentage of participants
Percentage of Participants With American College of Rheumatology (ACR20) Response Week 52	70.8 Percentage of participants	69.2 Percentage of participants
Percentage of Participants With American College of Rheumatology (ACR20) Response Week 104	65.7 Percentage of participants	59.4 Percentage of participants

SECONDARY outcome

Timeframe: Baseline, Weeks 24, 52, 104

Population: Intent-to-treat population included all randomized participants who received study drug.

ACR50 response is defined as a ≥ 50% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 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 where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant \[either C-reactive protein or Erythrocyte Sedimentation Rate\].

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Percentage of Participants With ACR50 Response Week 52	50.2 Percentage of participants	55.4 Percentage of participants
Percentage of Participants With ACR50 Response Week 104	52.7 Percentage of participants	46.4 Percentage of participants
Percentage of Participants With ACR50 Response Week 24	45.5 Percentage of participants	40.2 Percentage of participants

SECONDARY outcome

Timeframe: Baseline, Weeks 24, 52, 104

Population: Intent-to-treat population included all randomized participants who received study drug.

ACR70 response is defined as a ≥ 70% improvement (reduction) compared with Baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 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 where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant \[either C-reactive protein or Erythrocyte Sedimentation Rate\].

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Percentage of Participants With ACR70 Response Week 24	24.5 Percentage of participants	25.4 Percentage of participants
Percentage of Participants With ACR70 Response Week 52	31.4 Percentage of participants	31.2 Percentage of participants
Percentage of Participants With ACR70 Response Week 104	34.3 Percentage of participants	29.3 Percentage of participants

SECONDARY outcome

Timeframe: Baseline, Weeks 24, 52, 104

Population: Intent-to-treat population included all randomized participants who received study drug.

ACR90 response is defined as a ≥ 90% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 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 where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant \[either C-reactive protein or Erythrocyte Sedimentation Rate\].

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Percentage of Participants With ACR90 Response Week 24	5.8 Percentage of participants	5.1 Percentage of participants
Percentage of Participants With ACR90 Response Week 52	12.6 Percentage of participants	11.2 Percentage of participants
Percentage of Participants With ACR90 Response Week 104	11.9 Percentage of participants	9.1 Percentage of participants

SECONDARY outcome

Timeframe: 104 Weeks

Population: Intent-to treat population included all randomized participants who received study drug. Censoring occurred at the last assessment for those completing the study or withdrawing early, if a response was not observed. In calculating ACR response, a last observation carried forward approach is used for missing joint count data.

Time in days from first administration of study drug until ACR20 response. ACR20 response is defined as a ≥ 20% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 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 where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant \[either C-reactive protein or Erythrocyte Sedimentation Rate\].

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Time to First ACR20 Response	57.0 Days The minimum and maximum confidence interval was not estimated; insufficient number of participants with events.	61.0 Days Interval 57.0 to 84.0

SECONDARY outcome

Timeframe: 104 Weeks

Time in days from first administration of study drug until ACR50 response. ACR50 response is defined as a ≥ 50% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 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 where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant \[either C-reactive protein or Erythrocyte Sedimentation Rate).

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Time to First ACR50 Response	140.0 Days Interval 113.0 to 142.0	143.0 Days Interval 137.0 to 169.0

SECONDARY outcome

Timeframe: 104 Weeks

Time in days from first administration of study drug until ACR70 response. ACR70 response is defined as a ≥ 70% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 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 where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant \[either C-reactive protein or Erythrocyte Sedimentation Rate\].

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Time to First ACR70 Response	284.0 Days Interval 225.0 to 327.0	307.0 Days Interval 253.0 to 338.0

SECONDARY outcome

Timeframe: 104 Weeks

Time in days from first administration of study drug until ACR90 response. ACR90 response is defined as a ≥ 90% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 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 where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant \[either C-reactive protein or Erythrocyte Sedimentation Rate\].

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Time to First ACR90 Response	NA Days Interval 844.0 to The median was not reached; the rate was \< 50%.	NA Days Interval 986.0 to The median was not reached; the rate was \< 50%.

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Participants from the Intent-to-treat population, all randomized participants who received study drug, with data available at Baseline and Week 24.

The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) \[28 joints\], swollen joint count (SJC) \[28 joints\], patient's global assessment of disease activity \[visual analog scale: 0=no disease activity to 100=maximum disease activity\] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. AUC DAS28 was averaged over study days. Analysis of Covariance was adjusted for Baseline DAS28 as a covariate and treatment group and region as fixed factors. Higher calculated AUC values are worse (indicate higher disease activity).

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=255 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=246 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Area Under Curve (AUC) DAS28	3.97 Score on a scale*week Standard Error 0.098	4.23 Score on a scale*week Standard Error 0.092

SECONDARY outcome

Timeframe: Week 52

Population: Intent-to-treat population included all randomized participants who received study drug.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Percentage of Participants With Disease Activity Score 28 (DAS28) Remission	45.5 Percentage of participants	36.6 Percentage of participants

SECONDARY outcome

Timeframe: Weeks 24, 52

Population: Intent-to-treat population included all randomized participants who received study drug.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Percentage of Participants With DAS28 Low Disease Activity (LDAS) Week 24	61.7 Percentage of participants	51.4 Percentage of participants
Percentage of Participants With DAS28 Low Disease Activity (LDAS) Week 52	62.5 Percentage of participants	57.2 Percentage of participants

SECONDARY outcome

Timeframe: Baseline, Weeks 24, 52

Population: Intent-to-treat population included all randomized participants who received study drug.

The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) \[28 joints\], swollen joint count (SJC) \[28 joints\], patient's global assessment of disease activity \[visual analog scale: 0=no disease activity to 100=maximum disease activity\] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A higher value indicated higher disease activity. A negative change from Baseline indicated improvement.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Change From Baseline in DAS28 Score Week 24	-3.43 Score on a scale Standard Deviation 1.326	-3.21 Score on a scale Standard Deviation 1.305
Change From Baseline in DAS28 Score Week 52	-3.74 Score on a scale Standard Deviation 1.406	-3.67 Score on a scale Standard Deviation 1.291

SECONDARY outcome

Timeframe: Baseline, 24, 52

Population: Intent-to-treat population included all randomized participants who received study drug.

The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) \[28 joints\], swollen joint count (SJC) \[28 joints\], patient's global assessment of disease activity \[visual analog scale: 0=no disease activity to 100=maximum disease activity\] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A negative change from Baseline indicated improvement. European League Against Rheumatism (EULAR) Good response: DAS28 ≤ 3.2 or a change from Baseline \< -1.2. EULAR Moderate response: DAS28 \> 3.2 to ≤ 5.1 or a change from Baseline \< -0.6 to ≥ -1.2.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Percentage of Participants With Good or Moderate European League (EULAR) DAS28 Responses Week 24	89.5 Percentage of participants	86.2 Percentage of participants
Percentage of Participants With Good or Moderate European League (EULAR) DAS28 Responses Week 52	84.5 Percentage of participants	78.2 Percentage of participants

SECONDARY outcome

Timeframe: Baseline, Weeks 24, 52

Population: Intent-to-treat population included all randomized participants who received study drug.

66 joints were assessed for swelling and joints are classified as swollen/not swollen giving a total possible swollen joint count score of 0 to 66. A negative change from Baseline indicated improvement.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Change From Baseline in Swollen Joint Count Week 24 (n=255,246)	-11.33 Joint count Standard Deviation 8.042	-11.74 Joint count Standard Deviation 9.446
Change From Baseline in Swollen Joint Count Week 52 (n=237,220)	-12.29 Joint count Standard Deviation 8.796	-12.25 Joint count Standard Deviation 8.949

SECONDARY outcome

Timeframe: Baseline, Weeks 24, 52

Population: Intent-to-treat population included all randomized participants who received study drug.

68 joints are assessed for tenderness and joints are classified as tender/not tender giving a total possible tender joint count score of 0 to 68. A negative change from Baseline indicated improvement.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Change From Baseline in Tender Joint Count Week 24 (n=255,246)	-17.27 Joint count Standard Deviation 13.358	-17.00 Joint count Standard Deviation 13.632
Change From Baseline in Tender Joint Count Week 52 (n=237,220)	-19.45 Joint count Standard Deviation 13.471	-18.97 Joint count Standard Deviation 12.768

SECONDARY outcome

Timeframe: Baseline, Weeks 24, 52

Population: Intent-to-treat population included all randomized participants who received study drug.

The patients global assessment of disease activity was assessed on a 0 to 100 millimeter (mm) horizontal visual analogue scale (VAS) by the patient. The left-hand extreme of the line equals 0 mm, and was described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm, as "maximum disease activity" (maximum arthritis disease activity). A negative change from Baseline indicated improvement.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Change From Baseline in Patient Global Assessment of Disease Activity Visual Analog Scale (VAS) Week 24 (n=255,246)	-34.31 mm Standard Deviation 25.677	-32.42 mm Standard Deviation 24.344
Change From Baseline in Patient Global Assessment of Disease Activity Visual Analog Scale (VAS) Week 52 (n=239,220)	-38.92 mm Standard Deviation 25.590	-40.94 mm Standard Deviation 26.211

SECONDARY outcome

Timeframe: Baseline, Weeks 24, 52

Population: Intent-to-treat population included all randomized participants who received study drug.

The physician global assessment of disease activity was assessed using a 0 to 100 mm horizontal visual analogue scale (VAS) by the physician. The left-hand extreme of the line equals 0 mm, and is described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm, as "maximum disease activity" (maximum arthritis disease activity). A negative change from Baseline indicated improvement.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Change From Baseline in Physician Global Assessment of Disease Activity Visual Analog Scale (VAS) Week 24 (n=249,244)	-40.67 mm Standard Deviation 19.500	-38.46 mm Standard Deviation 21.654
Change From Baseline in Physician Global Assessment of Disease Activity Visual Analog Scale (VAS) Week 52 (n=232,218)	-44.18 mm Standard Deviation 21.092	-44.68 mm Standard Deviation 21.400

SECONDARY outcome

Timeframe: Baseline, Weeks 24, 52

Population: Intent-to-treat population included all randomized participants who received study drug.

The patient assessed their pain using a 0 to 100 millimeter (mm) horizontal visual analogue scale (VAS). The left-hand extreme of the line equals 0 mm, and is described as "no pain" and the right-hand extreme equals 100 mm as "unbearable pain". A negative change from Baseline indicated improvement.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Change From Baseline in Patient Global Assessment of Pain (VAS) Week 24 (n=255,246)	-29.34 mm Standard Deviation 26.639	-29.75 mm Standard Deviation 24.918
Change From Baseline in Patient Global Assessment of Pain (VAS) Week 52 (239,220)	-33.09 mm Standard Deviation 26.933	-38.38 mm Standard Deviation 25.537

SECONDARY outcome

Timeframe: Baseline, Weeks 24, 52

Population: Intent-to-treat population included all randomized participants who received study drug.

Blood was collected for Erythrocyte Sedimentation Rate (ESR) (a test that assesses tissue inflammation) and was analyzed at a local laboratory. ESR was measured in millimeters/hour (mm/hr). A reduction in the level is considered an improvement.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Change From Baseline in Erythrocyte Sedimentation Rate (ESR) Week 24 (n=255,246)	-30.61 mm/hr Standard Deviation 24.187	-29.10 mm/hr Standard Deviation 24.518
Change From Baseline in Erythrocyte Sedimentation Rate (ESR) Week 52 (n=238,220)	-31.81 mm/hr Standard Deviation 23.025	-31.18 mm/hr Standard Deviation 24.527

SECONDARY outcome

Timeframe: Baseline, Weeks 24, 52

Population: Participants from the Intent-to-treat population, all randomized participants who received at least one dose of study drug, with data available for analysis at the given time-point.

Blood was collected for C-Reactive Protein (CRP) (a test for analysis of inflammatory and infectious disorders) and was analyzed at a central laboratory. The serum concentration of CRP was measured in milligrams/deciliter (mg/dL). A reduction in the level is considered an improvement.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Change From Baseline in C-Reactive Protein (CRP) Week 24 (n=252,241)	-1.37 mg/dL Standard Deviation 2.043	-1.39 mg/dL Standard Deviation 2.206
Change From Baseline in C-Reactive Protein (CRP) Week 52 (n=236,221)	-1.39 mg/dL Standard Deviation 1.943	-1.40 mg/dL Standard Deviation 2.216

SECONDARY outcome

Timeframe: Baseline, Weeks 24, 52

Population: Participants from the Intent-to-treat population, all randomized participants who received study drug, with data available for analysis at the given time-point.

The Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis, consisting of 20 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. There are 4 possible responses for each question: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty and 3=unable to do. The score for each of the domains is the highest (worst) score in each domain. A patient must have a domain score for at least 6 of 8 domains to calculate a valid HAQ-DI score which is the sum of domain scores, divided by the number of domains that have a score for a total possible score minimum/maximum 0 (best) to 3 (worst). A negative change from Baseline indicated improvement.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Change From Baseline in the Health Assessment Questionnaire Disability Index Week 24 (n=251,241)	-0.56 Score on a scale Standard Deviation 0.666	-0.55 Score on a scale Standard Deviation 0.531
Change From Baseline in the Health Assessment Questionnaire Disability Index Week 52 (n=235,213)	-0.59 Score on a scale Standard Deviation 0.713	-0.67 Score on a scale Standard Deviation 0.630

SECONDARY outcome

Timeframe: Baseline, Weeks 24, 52, 104

Population: Participants from the Intent-to-treat population, all randomized participants who received study drug, with data available for analysis at Baseline and the given time point.

Radiographs were taken of each hand and foot at Baseline, Weeks 24, 52 and104 and were evaluated using the Genant modified method according to Sharp. Erosion Score: A total of 14 locations in each hand and wrist and 6 joints in the foot were evaluated for erosion using an 8-point scale where 0=Normal to 3.5=very severe erosion. Joint Narrowing Score: A total of 13 locations in each hand and wrist and 6 joints in the foot were evaluated for joint narrowing score using a 9-point scale where 0=Normal to 4.0=definite ankylosis (stiffness or fixation of a joint). The maximum total erosion score in the hands is 98 and in the feet 42. The maximum scores for joint space narrowing (JSN) in the hands was104 and in the feet 48. The total score was the sum of scores for erosions and JSN. The maximum total modified GSS was 292. A lower number change from Baseline was better. Analysis of covariance model, with Baseline DAS28 as a covariate and treatment and site as fixed factors.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Change From Baseline in Total Genant Modified Sharp Scores (GSS) Week 24 (n= 266,258)	0.18 Score on a scale Standard Error 0.161	0.35 Score on a scale Standard Error 0.152
Change From Baseline in Total Genant Modified Sharp Scores (GSS) Week 52 (n= 269,264)	0.35 Score on a scale Standard Error 0.370	0.63 Score on a scale Standard Error 0.350
Change From Baseline in Total Genant Modified Sharp Scores (GSS) Week 104 (n= 215,202)	0.35 Score on a scale Standard Error 0.347	0.95 Score on a scale Standard Error 0.320

SECONDARY outcome

Timeframe: Baseline, Weeks 24, 52, 104

Population: Participants from the Intent-to-treat population, all randomized participants who received study drug, with data available for analysis at Baseline and the given time point.

A total of 13 locations in each hand and wrist and 6 joints in the foot were evaluated for joint narrowing score using a 9-point scale where 0=Normal to 4.0=definite ankylosis (stiffness or fixation of a joint). The maximum scores for joint space narrowing (JSN) in the hands was 104 and in the feet 48 for a total possible score of 0 to 152. A lower change from Baseline indicated a better score. Analysis of covariance model included baseline x-ray and DAS28 as covariates and treatment group and region as fixed effects.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Change From Baseline in Joint Space Narrowing Score Week 24 (n= 266, 258)	0.16 Score on a scale Standard Error 0.121	0.19 Score on a scale Standard Error 0.115
Change From Baseline in Joint Space Narrowing Score Week 52 (n= 269, 264)	0.45 Score on a scale Standard Error 0.314	0.39 Score on a scale Standard Error 0.297
Change From Baseline in Joint Space Narrowing Score Week 104 (n= 215, 202)	0.38 Score on a scale Standard Error 0.218	0.70 Score on a scale Standard Error 0.201

SECONDARY outcome

Timeframe: Baseline, Weeks 24, 52, 104

Population: Participants from the Intent-to-treat population, all randomized participants who received study drug, with data available for analysis at Baseline and the given time point.

A total of 14 locations in each hand and wrist and 6 joints in the foot were evaluated for erosion using an 8-point scale where 0=Normal to 3.5=very severe erosion. The maximum erosion score in the hands was 98 and in the feet 42 for a total possible score of 0 to 140. A lower number change from Baseline indicated a better score.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Change From Baseline in Erosion Score Week 24 (n=266,258)	0.03 Score on a scale Standard Error 0.077	0.15 Score on a scale Standard Error 0.072
Change From Baseline in Erosion Score Week 52 (n= 269,264)	-0.09 Score on a scale Standard Error 0.125	0.25 Score on a scale Standard Error 0.118
Change From Baseline in Erosion Score Week 104 (n= 215,202)	-0.03 Score on a scale Standard Error 0.169	0.26 Score on a scale Standard Error 0.156

SECONDARY outcome

Timeframe: Weeks 52, 104

Population: Participants from the Intent-to-treat population (all randomized participants who received study drug) with non-missing DAS28 assessment.

The percentage of participants who stopped treatment with tocilizumab due to remission.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Percentage of Participants Discontinuing Tocilizumab Due to Remission Week 52 (n=243,231)	28.4 Percentage of participants	21.6 Percentage of participants
Percentage of Participants Discontinuing Tocilizumab Due to Remission Week 104 (n=243,229)	53.1 Percentage of participants	47.6 Percentage of participants

SECONDARY outcome

Timeframe: Up to 3 years

Population: Intent-to-treat population included all randomized participants who received study drug.

Lack of Sufficient Therapeutic Response was defined as the patient not responding to the drug as expected.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Percentage of Participants Who Withdrew Due to Lack of Sufficient Therapeutic Response	1.8 Percentage of participants	4.7 Percentage of participants

SECONDARY outcome

Timeframe: Up to 3 years

Population: Intent-to-treat population included all randomized participants who received study drug.

Safety reasons were defined as adverse events, intercurrent illness or death. An adverse event was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as adverse events.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Percentage of Participants Who Withdrew Due to Safety Reasons	9.7 Percentage of participants	11.2 Percentage of participants

SECONDARY outcome

Timeframe: Baseline, Weeks 24, 52, 104

Population: Participants from the intent-to-treat Population, all participants who received study drug, with data available for analysis at the given time-point. The RAQoL score was administered in a subset of sites for which the questionnaire was available in the local language.

The RAQoL is a disease specific patient-reported outcome measure that determines the effect rheumatoid arthritis has on a patient's quality of life consisting of 30 questions that are answered either yes=1 or no=0 for a total possible score ranging from 0 (best) to 30 (worst). A negative change from Baseline indicated improvement.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Change From Baseline in Rheumatoid Arthritis Quality of Life Questionnaire (RAQoL) Week 24 (n=146,135)	-6.07 Score on a scale Standard Deviation 8.005	-5.19 Score on a scale Standard Deviation 7.064
Change From Baseline in Rheumatoid Arthritis Quality of Life Questionnaire (RAQoL) Week 52 (n=132,111)	-7.28 Score on a scale Standard Deviation 8.141	-6.33 Score on a scale Standard Deviation 7.691
Change From Baseline in Rheumatoid Arthritis Quality of Life Questionnaire (RAQoL) Week 104 (n=87,74)	-6.89 Score on a scale Standard Deviation 8.691	-5.24 Score on a scale Standard Deviation 8.899

SECONDARY outcome

Timeframe: Baseline, Weeks 104

Population: Participants from the Intent-to-treat population, all randomized participants who received study drug, with data available for analysis.

The Academic Medical Center (AMC) Linear Disability Score (ALDS) evaluates the participant's ability to perform activities of daily life consisting of 77 questions answered yes or no . The question difficulty and the patient's ability are arranged on a single hierarchical linear scale. ALDS scores range from 10 to 90 with a higher score representing higher functional status. A positive change from Baseline indicated improvement.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=277 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=276 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Change From Baseline in Academic Medical Center (AMC) Linear Disability Scale (ALDS)	2.42 Score on a scale Standard Deviation 7.773	0.91 Score on a scale Standard Deviation 2.099

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Participants from the intent-to-treat population, all participants who received study drug, with ACR response available for analysis at the time-point. Participants with early withdrawals are not included.

ACR response was defined as an improvement (reduction) compared with baseline for both total joint count-68 joints and swollen joint count-66 joints, and for three of five variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) where 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 where: 0=no disease activity to 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant \[either C-reactive protein or Erythrocyte Sedimentation Rate\]. Area under the curve for ACR response to Week 24 was averaged over study days. Analysis of covariance model includes treatment group, region and baseline DAS28 (≤ 5.5 and \> 5.5) as fixed factors.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=253 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=246 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Area Under the Curve (AUC) From Baseline to Week 24 for ACR Response	18.95 Score on a scale*day Standard Error 4.220	13.74 Score on a scale*day Standard Error 3.979

SECONDARY outcome

Timeframe: Baseline to Week 52

ACR response was defined as an improvement (reduction) compared with baseline for both total joint count-68 joints and swollen joint count-66 joints, and for three of five variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) where 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 where: 0=no disease activity to 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant \[either C-reactive protein or Erythrocyte Sedimentation Rate\].Area under the curve for ACR response to Week 52 averaged over study days. Analysis of covariance model includes treatment group, region and baseline DAS28 (\<=5.5 and \>5.5) as fixed factors.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=236 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=220 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Area Under the Curve (AUC) From Baseline to Week 52 for ACR Response	30.48 Score on a scale*day Standard Error 4.901	32.59 Score on a scale*day Standard Error 4.611

SECONDARY outcome

Timeframe: 104 Weeks

Population: Participants from the Intent-to-treat population (all randomized participants who received study drug) with data available for this outcome measure. Participants were censored at the last observed value.

The time in days from initial study drug treatment to tocilizumab remission that occurred when the patient discontinued treatment with tocilizumab.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=243 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=229 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Time to Tocilizumab Remission	645.0 Days Interval 360.0 to 855.0	786.0 Days Interval 351.0 to 829.0

SECONDARY outcome

Timeframe: 104 Weeks

The time in days from initial study drug treatment to drug free remission that occurred when the participant was able to discontinue tocilizumab, methotrexate/placebo and open label disease-modifying antirheumatic drugs (DMARDS).

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=243 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=229 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Time to Drug-Free Remission	NA Days Interval 366.0 to 1121.0 Median was not estimated due to the low number of participants with drug-free remission.	NA Days Interval 365.0 to 1151.0 Median was not estimated due to the low number of participants with drug-free remission.

SECONDARY outcome

Timeframe: 104 Weeks

The time in days to a flare (recurrence of disease symptoms) after the patient discontinued treatment with tocilizumab.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=129 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=109 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Time to Flare After Tocilizumab Remission	113.0 Days Interval 25.0 to 400.0	84.0 Days Interval 1.0 to 415.0

SECONDARY outcome

Timeframe: 104 Weeks

Population: Participants from the intent-to-treat population, all participants who received study drug, with data available for analysis. Censoring occurred at the last assessment for those completing the study or withdrawing early, if a response had not been observed.

The time in days from treatment discontinuation or remission to the restart of treatment.

Outcome measures

Outcome measures
Measure	Tocilizumab + Methotrexate n=129 Participants Tocilizumab 8 mg/kg intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks.	Tocilizumab + Placebo n=109 Participants Tocilizumab 8 mg/kg intravenous once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study methotrexate dose for 24 weeks.
Time to Restart of Treatment After Discontinuation/Remission	113.0 Days Interval 87.0 to 150.0	81.0 Days Interval 58.0 to 91.0

Adverse Events

Tocilizumab + Methotrexate

Serious events: 49 serious events

Other events: 189 other events

Deaths: 0 deaths

Tocilizumab + Placebo

Serious events: 48 serious events

Other events: 179 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Tocilizumab + Methotrexate n=277 participants at risk Tocilizumab 8 mg/kg (up to 800 mg) intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks. Patients taking oral corticosteroids remained on their pre-study dose (up to 10 mg/day). Week 24 to Week 52 the dose of tocilizumab and methotrexate remained the same. Based on DAS28 assessments, corticosteroid dose was adjusted and disease-modifying antirheumatic drug (DMARDS) added. Week 52 to Week 104, based on the DAS28 assessment, treatment was adjusted to one of four protocol specified treatment regimens: Treatment tapering, Continued treatment, Treatment intensification or Maintenance treatment. After Week 100, patients who discontinued tocilizumab because of remission were retreated with the last effective dose of tocilizumab or blinded methotrexate if a flare occurred.	Tocilizumab + Placebo n=276 participants at risk Tocilizumab 8 mg/kg (up to 800 mg) IV once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study dose for 24 weeks. Patients taking oral corticosteroids remained on their pre-study dose (up to 10 mg/day). Week 24 to Week 52 the dose of tocilizumab and placebo to methotrexate remained the same. Based on DAS28 assessments, corticosteroid dose was adjusted and disease-modifying antirheumatic drug (DMARDS) added. Week 52 to Week 104, based on the DAS28 assessment, treatment was adjusted to one of four protocol specified treatment regimens: Treatment tapering, Continued treatment, Treatment intensification or Maintenance treatment. After Week 100, patients who discontinued tocilizumab because of remission were retreated with the last effective dose of tocilizumab or blinded placebo to methotrexate if a flare occurred.
Infections and infestations Bronchopneumonia	1.1% 3/277	0.00% 0/276
Infections and infestations Pneumonia	0.00% 0/277	1.1% 3/276
Infections and infestations Erysipelas	0.00% 0/277	0.72% 2/276
Infections and infestations Septic shock	0.72% 2/277	0.00% 0/276
Infections and infestations Abdominal abscess	0.00% 0/277	0.36% 1/276
Infections and infestations Abscess limb	0.00% 0/277	0.36% 1/276
Infections and infestations Anal abscess	0.36% 1/277	0.00% 0/276
Infections and infestations Appendicitis	0.00% 0/277	0.36% 1/276
Infections and infestations Arthritis bacterial	0.36% 1/277	0.00% 0/276
Infections and infestations Candida endophthalmitis	0.00% 0/277	0.36% 1/276
Infections and infestations Cellulitis	0.36% 1/277	0.00% 0/276
Infections and infestations Clostridium difficile colitis	0.00% 0/277	0.36% 1/276
Infections and infestations Disseminated tuberculosis	0.36% 1/277	0.00% 0/276
Infections and infestations Diverticulitis	0.00% 0/277	0.36% 1/276
Infections and infestations Gangrene	0.36% 1/277	0.00% 0/276
Infections and infestations Gastroenteritis	0.36% 1/277	0.00% 0/276
Infections and infestations Gastrointestinal candidiasis	0.36% 1/277	0.00% 0/276
Infections and infestations Herpes zoster	0.36% 1/277	0.00% 0/276
Infections and infestations Infected bunion	0.36% 1/277	0.00% 0/276
Infections and infestations Infection	0.00% 0/277	0.36% 1/276
Infections and infestations Influenza	0.00% 0/277	0.36% 1/276
Infections and infestations Meningitis	0.00% 0/277	0.36% 1/276
Infections and infestations Otitis externa	0.36% 1/277	0.00% 0/276
Infections and infestations Pelvic abscess	0.00% 0/277	0.36% 1/276
Infections and infestations Postoperative wound infection	0.00% 0/277	0.36% 1/276
Infections and infestations Pyelonephritis acute	0.00% 0/277	0.36% 1/276
Infections and infestations Renal abscess	0.36% 1/277	0.00% 0/276
Infections and infestations Scrotal abscess	0.36% 1/277	0.00% 0/276
Infections and infestations Sepsis	0.36% 1/277	0.00% 0/276
Infections and infestations Skin infection	0.36% 1/277	0.00% 0/276
Infections and infestations Soft tissue infection	0.00% 0/277	0.36% 1/276
Infections and infestations Staphylococcal infection	0.36% 1/277	0.00% 0/276
Infections and infestations Subcutaneous abscess	0.36% 1/277	0.00% 0/276
Infections and infestations Typhoid fever	0.00% 0/277	0.36% 1/276
Nervous system disorders Transient ischaemic attack	0.36% 1/277	0.72% 2/276
Nervous system disorders Cerebral haemorrhage	0.00% 0/277	0.36% 1/276
Nervous system disorders Dizziness	0.36% 1/277	0.00% 0/276
Nervous system disorders Epilepsy	0.36% 1/277	0.00% 0/276
Nervous system disorders Haemorrhagic stroke	0.36% 1/277	0.00% 0/276
Nervous system disorders Ischaemic cerebral infarction	0.00% 0/277	0.36% 1/276
Nervous system disorders Ischaemic stroke	0.00% 0/277	0.36% 1/276
Nervous system disorders Optic neuritis	0.36% 1/277	0.00% 0/276
Nervous system disorders Sciatica	0.00% 0/277	0.36% 1/276
Injury, poisoning and procedural complications Femoral neck fracture	0.36% 1/277	0.72% 2/276
Injury, poisoning and procedural complications Tendon rupture	0.00% 0/277	0.72% 2/276
Injury, poisoning and procedural complications Fall	0.36% 1/277	0.00% 0/276
Injury, poisoning and procedural complications Hip fracture	0.36% 1/277	0.00% 0/276
Injury, poisoning and procedural complications Radius fracture	0.36% 1/277	0.00% 0/276
Injury, poisoning and procedural complications Synovial rupture	0.00% 0/277	0.36% 1/276
Injury, poisoning and procedural complications Ulna fracture	0.00% 0/277	0.36% 1/276
Cardiac disorders Cardiac failure congestive	0.72% 2/277	0.36% 1/276
Cardiac disorders Acute myocardial infarction	0.00% 0/277	0.72% 2/276
Cardiac disorders Atrial fibrillation	0.36% 1/277	0.36% 1/276
Cardiac disorders Myocardial infarction	0.36% 1/277	0.36% 1/276
Cardiac disorders Cardiomyopathy	0.00% 0/277	0.36% 1/276
Cardiac disorders Ischaemic cardiomyopathy	0.00% 0/277	0.36% 1/276
Cardiac disorders Mitral valve incompetence	0.00% 0/277	0.36% 1/276
Gastrointestinal disorders Gastric ulcer	0.00% 0/277	0.36% 1/276
Gastrointestinal disorders Gastrointestinal angiodysplasia	0.00% 0/277	0.36% 1/276
Gastrointestinal disorders Gastrointestinal disorder	0.00% 0/277	0.36% 1/276
Gastrointestinal disorders Gastrointestinal necrosis	0.00% 0/277	0.36% 1/276
Gastrointestinal disorders Inguinal hernia	0.36% 1/277	0.00% 0/276
Gastrointestinal disorders Intestinal perforation	0.00% 0/277	0.36% 1/276
Gastrointestinal disorders Pancreatitis acute	0.36% 1/277	0.00% 0/276
Gastrointestinal disorders Rectal haemorrhage	0.36% 1/277	0.00% 0/276
Gastrointestinal disorders Vomiting	0.36% 1/277	0.00% 0/276
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.36% 1/277	0.36% 1/276
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Anal cancer	0.00% 0/277	0.36% 1/276
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.00% 0/277	0.36% 1/276
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Benign lung neoplasm	0.36% 1/277	0.00% 0/276
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Gastrointestinal carcinoma	0.36% 1/277	0.00% 0/276
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Glioblastoma	0.00% 0/277	0.36% 1/276
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.00% 0/277	0.36% 1/276
General disorders Chest pain	0.72% 2/277	0.00% 0/276
General disorders Death	0.00% 0/277	0.36% 1/276
General disorders Device breakage	0.00% 0/277	0.36% 1/276
General disorders Hyperthermia malignant	0.00% 0/277	0.36% 1/276
General disorders Sudden death	0.00% 0/277	0.36% 1/276
Respiratory, thoracic and mediastinal disorders Pleurisy	0.36% 1/277	0.36% 1/276
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	0.36% 1/277	0.00% 0/276
Respiratory, thoracic and mediastinal disorders Alveolitis	0.00% 0/277	0.36% 1/276
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.36% 1/277	0.00% 0/276
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.00% 0/277	0.36% 1/276
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.36% 1/277	0.00% 0/276
Musculoskeletal and connective tissue disorders Musculoskeletal discomfort	0.36% 1/277	0.00% 0/276
Musculoskeletal and connective tissue disorders Myofascial pain syndrome	0.36% 1/277	0.00% 0/276
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/277	0.36% 1/276
Musculoskeletal and connective tissue disorders Spinal osteoarthritis	0.36% 1/277	0.00% 0/276
Vascular disorders Aortic stenosis	0.00% 0/277	0.36% 1/276
Vascular disorders Hypertension	0.36% 1/277	0.00% 0/276
Vascular disorders Intermittent claudication	0.00% 0/277	0.36% 1/276
Vascular disorders Peripheral artery stenosis	0.00% 0/277	0.36% 1/276
Vascular disorders Phlebitis	0.00% 0/277	0.36% 1/276
Investigations Transaminases increased	0.72% 2/277	0.72% 2/276
Psychiatric disorders Anxiety	0.72% 2/277	0.36% 1/276
Psychiatric disorders Stress	0.00% 0/277	0.36% 1/276
Blood and lymphatic system disorders Anaemia	0.36% 1/277	0.36% 1/276
Blood and lymphatic system disorders Leukopenia	0.00% 0/277	0.36% 1/276
Blood and lymphatic system disorders Lymphadenitis	0.00% 0/277	0.36% 1/276
Ear and labyrinth disorders Vertigo	0.00% 0/277	0.36% 1/276
Ear and labyrinth disorders Vertigo positional	0.36% 1/277	0.00% 0/276
Hepatobiliary disorders Cholecystitis acute	0.00% 0/277	0.36% 1/276
Hepatobiliary disorders Cholelithiasis	0.36% 1/277	0.00% 0/276
Immune system disorders Anaphylactic shock	0.00% 0/277	0.36% 1/276
Immune system disorders Anaphylactoid reaction	0.36% 1/277	0.00% 0/276
Renal and urinary disorders Renal colic	0.36% 1/277	0.00% 0/276
Renal and urinary disorders Renal failure acute	0.36% 1/277	0.00% 0/276
Skin and subcutaneous tissue disorders Skin necrosis	0.36% 1/277	0.00% 0/276
Skin and subcutaneous tissue disorders Skin ulcer	0.00% 0/277	0.36% 1/276
Eye disorders Keratitis	0.00% 0/277	0.36% 1/276
Pregnancy, puerperium and perinatal conditions Abortion spontaneous	0.36% 1/277	0.00% 0/276
Reproductive system and breast disorders Colpocele	0.00% 0/277	0.36% 1/276

Other adverse events

Other adverse events
Measure	Tocilizumab + Methotrexate n=277 participants at risk Tocilizumab 8 mg/kg (up to 800 mg) intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks. Patients taking oral corticosteroids remained on their pre-study dose (up to 10 mg/day). Week 24 to Week 52 the dose of tocilizumab and methotrexate remained the same. Based on DAS28 assessments, corticosteroid dose was adjusted and disease-modifying antirheumatic drug (DMARDS) added. Week 52 to Week 104, based on the DAS28 assessment, treatment was adjusted to one of four protocol specified treatment regimens: Treatment tapering, Continued treatment, Treatment intensification or Maintenance treatment. After Week 100, patients who discontinued tocilizumab because of remission were retreated with the last effective dose of tocilizumab or blinded methotrexate if a flare occurred.	Tocilizumab + Placebo n=276 participants at risk Tocilizumab 8 mg/kg (up to 800 mg) IV once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study dose for 24 weeks. Patients taking oral corticosteroids remained on their pre-study dose (up to 10 mg/day). Week 24 to Week 52 the dose of tocilizumab and placebo to methotrexate remained the same. Based on DAS28 assessments, corticosteroid dose was adjusted and disease-modifying antirheumatic drug (DMARDS) added. Week 52 to Week 104, based on the DAS28 assessment, treatment was adjusted to one of four protocol specified treatment regimens: Treatment tapering, Continued treatment, Treatment intensification or Maintenance treatment. After Week 100, patients who discontinued tocilizumab because of remission were retreated with the last effective dose of tocilizumab or blinded placebo to methotrexate if a flare occurred.
Infections and infestations Nasopharyngitis	15.5% 43/277	14.5% 40/276
Investigations Transaminases increase	10.8% 30/277	5.4% 15/276
Investigations Alanine aminotransferase increased	11.9% 33/277	5.4% 15/276
Gastrointestinal disorders Nausea	9.7% 27/277	3.3% 9/276
Metabolism and nutrition disorders Hypercholesterolemia	12.3% 34/277	12.0% 33/276
Infections and infestations Upper respiratory tract infection	11.2% 31/277	9.1% 25/276
Infections and infestations Urinary tract infection	8.3% 23/277	6.5% 18/276
Infections and infestations Influenza	6.5% 18/277	4.0% 11/276
Infections and infestations Gastroenteritis	5.8% 16/277	2.5% 7/276
Infections and infestations Bronchitis	6.1% 17/277	1.8% 5/276
Musculoskeletal and connective tissue disorders Back pain	10.5% 29/277	7.6% 21/276
Musculoskeletal and connective tissue disorders Rheumatoid arthritis	5.1% 14/277	5.4% 15/276
Gastrointestinal disorders Diarrhoea	7.2% 20/277	7.6% 21/276
Investigations Blood cholesterol increased	4.3% 12/277	5.4% 15/276
Skin and subcutaneous tissue disorders Rash	5.4% 15/277	2.5% 7/276
Respiratory, thoracic and mediastinal disorders Cough	7.6% 21/277	5.8% 16/276
Nervous system disorders Headache	6.5% 18/277	7.6% 21/276
Blood and lymphatic system disorders Leukopenia	7.2% 20/277	4.7% 13/276
Blood and lymphatic system disorders Neutropenia	5.4% 15/277	5.1% 14/276
Vascular disorders Hypertension	4.7% 13/277	6.9% 19/276

Additional Information

Medical Communications

Hoffman-LaRoche

Phone: 800-821-8590

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