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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

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ClinicalTrials.gov Identifier: NCT00810199
Recruitment Status : Completed
First Posted : December 17, 2008
Results First Posted : July 18, 2014
Last Update Posted : July 18, 2014
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Rheumatoid Arthritis
Interventions Drug: tocilizumab [RoActemra/Actemra]
Drug: methotrexate
Drug: placebo
Enrollment 556
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description 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 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.
Period Title: Overall Study
Started 279 277
Received Study Drug 277 276
Completed Week 24 259 250
Completed Week 52 243 229
Completed Week 104 222 201
Completed 220 195 [1]
Not Completed 59 82
Reason Not Completed
Adverse Event             24             26
Death             4             6
Withdrew consent             9             12
Insufficient therapeutic response             5             14
Refused treatment/Did not cooperate             7             7
Administrative/Other             5             6
Protocol Violation             2             6
Failure to return             1             4
Did not receive study drug             2             1
[1]
Completed=Completed Treatment
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo Total
Hide Arm/Group Description 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 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 of all reporting groups
Overall Number of Baseline Participants 277 276 553
Hide Baseline Analysis Population Description
Baseline measures are based on the Safety Population and include all randomized participants who received at least one dose of study drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 277 participants 276 participants 553 participants
53.0  (13.40) 53.6  (11.91) 53.3  (12.67)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 277 participants 276 participants 553 participants
Female
227
  81.9%
217
  78.6%
444
  80.3%
Male
50
  18.1%
59
  21.4%
109
  19.7%
1.Primary Outcome
Title Percentage of Participants With Disease Activity Score 28 Joints (DAS28) Remission at Week 24
Hide Description 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.
Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population included all randomized participants who received study drug.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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.
Overall Number of Participants Analyzed 277 276
Measure Type: Number
Unit of Measure: Percentage of participants
40.4 34.8
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2055
Comments Cochran-Mantel-Haenszel test stratified by region and baseline DAS28 (≤5.5 and >5.5).
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.260
Confidence Interval (2-Sided) 95%
0.882 to 1.799
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1894
Comments Logistic regression including treatment , region and baseline DAS28.
Method Regression, Logistic
Comments Odds ratio is for Tocilizumab + Methotrexate relative to Tocilizumab + Placebo.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.270
Confidence Interval (2-Sided) 95%
0.889 to 1.814
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percentage of Participants With American College of Rheumatology (ACR20) Response
Hide Description 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].
Time Frame Baseline, Weeks 24, 52, 104
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population included all randomized participants who received study drug.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Measure Type: Number
Unit of Measure: Percentage of participants
Week 24 71.5 70.3
Week 52 70.8 69.2
Week 104 65.7 59.4
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 24
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8742
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Region and baseline DAS28 (≤5.5 and >5.5) included as stratification variables.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 52
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6212
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Region and baseline DAS28 (≤5.5 and >5.5) included as stratification variables.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 104
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0963
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Region and baseline DAS28 (≤5.5 and >5.5) included as stratification variables.
3.Secondary Outcome
Title Percentage of Participants With ACR50 Response
Hide Description 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].
Time Frame Baseline, Weeks 24, 52, 104
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population included all randomized participants who received study drug.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Measure Type: Number
Unit of Measure: Percentage of participants
Week 24 45.5 40.2
Week 52 50.2 55.4
Week 104 52.7 46.4
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 24
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2969
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Region and baseline DAS28 (≤5.5 and >5.5) included as stratification variables.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 52
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2215
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Region and baseline DAS28 (≤5.5 and >5.5) included as stratification variables.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 104
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1243
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Region and baseline DAS28 (≤5.5 and >5.5) included as stratification variables.
4.Secondary Outcome
Title Percentage of Participants With ACR70 Response
Hide Description 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].
Time Frame Baseline, Weeks 24, 52, 104
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population included all randomized participants who received study drug.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Measure Type: Number
Unit of Measure: Percentage of participants
Week 24 24.5 25.4
Week 52 31.4 31.2
Week 104 34.3 29.3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 24
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6775
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Region and baseline DAS28 (≤5.5 and >5.5) included as stratification variables.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 52
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9976
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Region and baseline DAS28 (≤5.5 and >5.5) included as stratification variables.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 104
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2168
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Region and baseline DAS28 (≤5.5 and >5.5) included as stratification variables.
5.Secondary Outcome
Title Percentage of Participants With ACR90 Response
Hide Description 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].
Time Frame Baseline, Weeks 24, 52, 104
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population included all randomized participants who received study drug.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Measure Type: Number
Unit of Measure: Percentage of participants
Week 24 5.8 5.1
Week 52 12.6 11.2
Week 104 11.9 9.1
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 24
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8369
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Region and baseline DAS28 (≤5.5 and >5.5) included as stratification variables.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 52
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6528
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Region and baseline DAS28 (≤5.5 and >5.5) included as stratification variables.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 104
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2546
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Region and baseline DAS28 (≤5.5 and >5.5) included as stratification variables.
6.Secondary Outcome
Title Time to First ACR20 Response
Hide Description 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].
Time Frame 104 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Median (95% Confidence Interval)
Unit of Measure: Days
57.0 [1] 
(NA to NA)
61.0
(57.0 to 84.0)
[1]
The minimum and maximum confidence interval was not estimated; insufficient number of participants with events.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1018
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
7.Secondary Outcome
Title Time to First ACR50 Response
Hide Description 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).
Time Frame 104 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Median (95% Confidence Interval)
Unit of Measure: Days
140.0
(113.0 to 142.0)
143.0
(137.0 to 169.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7176
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
8.Secondary Outcome
Title Time to First ACR70 Response
Hide Description 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].
Time Frame 104 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Median (95% Confidence Interval)
Unit of Measure: Days
284.0
(225.0 to 327.0)
307.0
(253.0 to 338.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8526
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
9.Secondary Outcome
Title Time to First ACR90 Response
Hide Description 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].
Time Frame 104 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Median (95% Confidence Interval)
Unit of Measure: Days
NA [1] 
(844.0 to NA)
NA [1] 
(986.0 to NA)
[1]
The median was not reached; the rate was < 50%.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2217
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
10.Secondary Outcome
Title Area Under Curve (AUC) DAS28
Hide Description 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).
Time Frame Baseline to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the Intent-to-treat population, all randomized participants who received study drug, with data available at Baseline and Week 24.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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.
Overall Number of Participants Analyzed 255 246
Least Squares Mean (Standard Error)
Unit of Measure: Score on a scale*week
3.97  (0.098) 4.23  (0.092)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0008
Comments [Not Specified]
Method ANCOVA
Comments Baseline DAS28 as a covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.26
Confidence Interval (2-Sided) 95%
-0.41 to -0.11
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Percentage of Participants With Disease Activity Score 28 (DAS28) Remission
Hide Description 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.
Time Frame Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population included all randomized participants who received study drug.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 277 276
Measure Type: Number
Unit of Measure: Percentage of participants
45.5 36.6
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0245
Comments [Not Specified]
Method Regression, Logistic
Comments Logistic regression including treatment, region and baseline DAS28.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.490
Confidence Interval (2-Sided) 95%
1.053 to 2.109
Estimation Comments Odds ratio is for Tocilizumab + Methotrexate relative to Tocilizumab + Placebo.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0258
Comments Stratified by region and baseline DAS28 (≤ 5.5 and > 5.5).
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.482
Confidence Interval 95%
1.048 to 2.095
Estimation Comments [Not Specified]
12.Secondary Outcome
Title Percentage of Participants With DAS28 Low Disease Activity (LDAS)
Hide Description 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. LDAS is defined as DAS28 ≤ 3.2.
Time Frame Weeks 24, 52
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population included all randomized participants who received study drug.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Measure Type: Number
Unit of Measure: Percentage of participants
Week 24 61.7 51.4
Week 52 62.5 57.2
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 24
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0287
Comments [Not Specified]
Method Wald Chi-square
Comments Asymptotic test; parameter estimate is zero.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 52
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2240
Comments [Not Specified]
Method Wald Chi-square
Comments Asymptotic test; parameter estimate is zero.
13.Secondary Outcome
Title Change From Baseline in DAS28 Score
Hide Description 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.
Time Frame Baseline, Weeks 24, 52
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population included all randomized participants who received study drug.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Mean (Standard Deviation)
Unit of Measure: Score on a scale
Week 24 -3.43  (1.326) -3.21  (1.305)
Week 52 -3.74  (1.406) -3.67  (1.291)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 24
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0497
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 52
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3918
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
14.Secondary Outcome
Title Percentage of Participants With Good or Moderate European League (EULAR) DAS28 Responses
Hide Description

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.

Time Frame Baseline, 24, 52
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population included all randomized participants who received study drug.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Measure Type: Number
Unit of Measure: Percentage of participants
Week 24 89.5 86.2
Week 52 84.5 78.2
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 24
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0019
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Region and baseline DAS28 (≤5.5 and >5.5) included as stratification variables.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 52
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1181
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Region and baseline DAS28 (≤5.5 and >5.5) included as stratification variables.
15.Secondary Outcome
Title Change From Baseline in Swollen Joint Count
Hide Description 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.
Time Frame Baseline, Weeks 24, 52
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population included all randomized participants who received study drug.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Mean (Standard Deviation)
Unit of Measure: Joint count
Week 24 (n=255,246) -11.33  (8.042) -11.74  (9.446)
Week 52 (n=237,220) -12.29  (8.796) -12.25  (8.949)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 24
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7776
Comments P-value is from a 2-sided, Wilcoxon rank-sum test of no difference between the 2 treatment groups in change from baseline.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 52
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8843
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
16.Secondary Outcome
Title Change From Baseline in Tender Joint Count
Hide Description 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.
Time Frame Baseline, Weeks 24, 52
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population included all randomized participants who received study drug.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Mean (Standard Deviation)
Unit of Measure: Joint count
Week 24 (n=255,246) -17.27  (13.358) -17.00  (13.632)
Week 52 (n=237,220) -19.45  (13.471) -18.97  (12.768)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 24
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9095
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 52
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7179
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
17.Secondary Outcome
Title Change From Baseline in Patient Global Assessment of Disease Activity Visual Analog Scale (VAS)
Hide Description 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.
Time Frame Baseline, Weeks 24, 52
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population included all randomized participants who received study drug.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Mean (Standard Deviation)
Unit of Measure: mm
Week 24 (n=255,246) -34.31  (25.677) -32.42  (24.344)
Week 52 (n=239,220) -38.92  (25.590) -40.94  (26.211)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 24
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3113
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 52
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2931
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
18.Secondary Outcome
Title Change From Baseline in Physician Global Assessment of Disease Activity Visual Analog Scale (VAS)
Hide Description 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.
Time Frame Baseline, Weeks 24, 52
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population included all randomized participants who received study drug.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Mean (Standard Deviation)
Unit of Measure: mm
Week 24 (n=249,244) -40.67  (19.500) -38.46  (21.654)
Week 52 (n=232,218) -44.18  (21.092) -44.68  (21.400)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 24
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2451
Comments P-value is from a 2-sided, Wilcoxon rank-sum test of no difference between the 2 treatment groups in change from baseline.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 52
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8841
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
19.Secondary Outcome
Title Change From Baseline in Patient Global Assessment of Pain (VAS)
Hide Description 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.
Time Frame Baseline, Weeks 24, 52
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population included all randomized participants who received study drug.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Mean (Standard Deviation)
Unit of Measure: mm
Week 24 (n=255,246) -29.34  (26.639) -29.75  (24.918)
Week 52 (239,220) -33.09  (26.933) -38.38  (25.537)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 24
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9655
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 52
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0308
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
20.Secondary Outcome
Title Change From Baseline in Erythrocyte Sedimentation Rate (ESR)
Hide Description 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.
Time Frame Baseline, Weeks 24, 52
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population included all randomized participants who received study drug.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Mean (Standard Deviation)
Unit of Measure: mm/hr
Week 24 (n=255,246) -30.61  (24.187) -29.10  (24.518)
Week 52 (n=238,220) -31.81  (23.025) -31.18  (24.527)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 24
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5186
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 52
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7706
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
21.Secondary Outcome
Title Change From Baseline in C-Reactive Protein (CRP)
Hide Description 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.
Time Frame Baseline, Weeks 24, 52
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Mean (Standard Deviation)
Unit of Measure: mg/dL
Week 24 (n=252,241) -1.37  (2.043) -1.39  (2.206)
Week 52 (n=236,221) -1.39  (1.943) -1.40  (2.216)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 24
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6067
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 52
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6810
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
22.Secondary Outcome
Title Change From Baseline in the Health Assessment Questionnaire Disability Index
Hide Description 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.
Time Frame Baseline, Weeks 24, 52
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the Intent-to-treat population, all randomized participants who received study drug, with data available for analysis at the given time-point.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Mean (Standard Deviation)
Unit of Measure: Score on a scale
Week 24 (n=251,241) -0.56  (0.666) -0.55  (0.531)
Week 52 (n=235,213) -0.59  (0.713) -0.67  (0.630)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 24
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9323
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 52
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1448
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
23.Secondary Outcome
Title Change From Baseline in Total Genant Modified Sharp Scores (GSS)
Hide Description 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.
Time Frame Baseline, Weeks 24, 52, 104
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Least Squares Mean (Standard Error)
Unit of Measure: Score on a scale
Week 24 (n= 266,258) 0.18  (0.161) 0.35  (0.152)
Week 52 (n= 269,264) 0.35  (0.370) 0.63  (0.350)
Week 104 (n= 215,202) 0.35  (0.347) 0.95  (0.320)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 24
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2034
Comments Baseline x-ray and DAS28 as covariates and treatment group and region as fixed effects.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.17
Confidence Interval (2-Sided) 95%
-0.43 to 0.09
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 52
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3611
Comments Baseline x-ray and DAS28 as covariates and treatment group and region as fixed effects.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.28
Confidence Interval (2-Sided) 95%
-0.88 to 0.32
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 104
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0342
Comments Baseline x-ray and DAS28 as covariates and treatment group and region as fixed effects.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.60
Confidence Interval (2-Sided) 95%
-1.16 to -0.05
Estimation Comments [Not Specified]
24.Secondary Outcome
Title Change From Baseline in Joint Space Narrowing Score
Hide Description 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.
Time Frame Baseline, Weeks 24, 52, 104
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Least Squares Mean (Standard Error)
Unit of Measure: Score on a scale
Week 24 (n= 266, 258) 0.16  (0.121) 0.19  (0.115)
Week 52 (n= 269, 264) 0.45  (0.314) 0.39  (0.297)
Week 104 (n= 215, 202) 0.38  (0.218) 0.70  (0.201)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 24
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7095
Comments Baseline x-ray and DAS28 as covariates and treatment group and region as fixed effects.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.04
Confidence Interval (2-Sided) 95%
-0.23 to 0.16
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 52
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8147
Comments Baseline x-ray and DAS28 as covariates and treatment group and region as fixed effects.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.06
Confidence Interval (2-Sided) 95%
-0.45 to 0.57
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 104
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0778
Comments Baseline x-ray and DAS28 as covariates and treatment group and region as fixed effects.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.32
Confidence Interval (2-Sided) 95%
-0.67 to 0.04
Estimation Comments [Not Specified]
25.Secondary Outcome
Title Change From Baseline in Erosion Score
Hide Description 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.
Time Frame Baseline, Weeks 24, 52, 104
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Least Squares Mean (Standard Error)
Unit of Measure: Score on a scale
Week 24 (n=266,258) 0.03  (0.077) 0.15  (0.072)
Week 52 (n= 269,264) -0.09  (0.125) 0.25  (0.118)
Week 104 (n= 215,202) -0.03  (0.169) 0.26  (0.156)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 24
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0441
Comments Baseline x-ray and DAS28 as covariates and treatment group and region as fixed effects.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.13
Confidence Interval (2-Sided) 95%
-0.25 to -0.00
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 52
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0012
Comments Baseline x-ray and DAS28 as covariates and treatment group and region as fixed effects.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.33
Confidence Interval (2-Sided) 95%
-0.54 to -0.13
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 104
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0372
Comments Baseline x-ray and DAS28 as covariates and treatment group and region as fixed effects.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.29
Confidence Interval (2-Sided) 95%
-0.56 to -0.02
Estimation Comments [Not Specified]
26.Secondary Outcome
Title Percentage of Participants Discontinuing Tocilizumab Due to Remission
Hide Description The percentage of participants who stopped treatment with tocilizumab due to remission.
Time Frame Weeks 52, 104
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the Intent-to-treat population (all randomized participants who received study drug) with non-missing DAS28 assessment.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Measure Type: Number
Unit of Measure: Percentage of participants
Week 52 (n=243,231) 28.4 21.6
Week 104 (n=243,229) 53.1 47.6
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 52
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0694
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Stratified by region and categorical baseline DAS28 (≤ 5.5 and > 5.5).
Method of Estimation Estimation Parameter Difference
Estimated Value 6.75
Confidence Interval (2-Sided) 95%
-1.02 to 14.52
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 104
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1695
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
27.Secondary Outcome
Title Percentage of Participants Who Withdrew Due to Lack of Sufficient Therapeutic Response
Hide Description Lack of Sufficient Therapeutic Response was defined as the patient not responding to the drug as expected.
Time Frame Up to 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population included all randomized participants who received study drug.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Measure Type: Number
Unit of Measure: Percentage of participants
1.8 4.7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0496
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Stratified by region and categorical baseline DAS28 (≤ 5.5 and > 5.5).
Method of Estimation Estimation Parameter Difference
Estimated Value -2.91
Confidence Interval 95%
-5.86 to 0.05
Estimation Comments [Not Specified]
28.Secondary Outcome
Title Percentage of Participants Who Withdrew Due to Safety Reasons
Hide Description 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.
Time Frame Up to 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population included all randomized participants who received study drug.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Measure Type: Number
Unit of Measure: Percentage of participants
9.7 11.2
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5188
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Stratified by region and categorical baseline DAS28 (≤ 5.5 and > 5.5).
Method of Estimation Estimation Parameter Difference
Estimated Value -1.48
Confidence Interval (2-Sided) 95%
-6.59 to 3.62
Estimation Comments [Not Specified]
29.Secondary Outcome
Title Change From Baseline in Rheumatoid Arthritis Quality of Life Questionnaire (RAQoL)
Hide Description 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.
Time Frame Baseline, Weeks 24, 52, 104
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Mean (Standard Deviation)
Unit of Measure: Score on a scale
Week 24 (n=146,135) -6.07  (8.005) -5.19  (7.064)
Week 52 (n=132,111) -7.28  (8.141) -6.33  (7.691)
Week 104 (n=87,74) -6.89  (8.691) -5.24  (8.899)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 24
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2652
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments Week 52
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1970
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1671
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
30.Secondary Outcome
Title Change From Baseline in Academic Medical Center (AMC) Linear Disability Scale (ALDS)
Hide Description 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.
Time Frame Baseline, Weeks 104
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the Intent-to-treat population, all randomized participants who received study drug, with data available for analysis.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 277 276
Mean (Standard Deviation)
Unit of Measure: Score on a scale
2.42  (7.773) 0.91  (2.099)
31.Secondary Outcome
Title Area Under the Curve (AUC) From Baseline to Week 24 for ACR Response
Hide Description 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.
Time Frame Baseline to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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.
Overall Number of Participants Analyzed 253 246
Least Squares Mean (Standard Error)
Unit of Measure: Score on a scale*day
18.95  (4.220) 13.74  (3.979)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1110
Comments [Not Specified]
Method ANCOVA
Comments The analysis of covariance model included treatment group, region and baseline DAS28 (≤ 5.5 and > 5.5) as fixed factors.
Method of Estimation Estimation Parameter Adjusted Mean Difference (Wald CI)
Estimated Value 5.22
Confidence Interval (2-Sided) 95%
-1.20 to 11.64
Estimation Comments [Not Specified]
32.Secondary Outcome
Title Area Under the Curve (AUC) From Baseline to Week 52 for ACR Response
Hide Description 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.
Time Frame Baseline to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
Tocilizumab 8 mg/kg 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.
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. 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
Overall Number of Participants Analyzed 236 220
Least Squares Mean (Standard Error)
Unit of Measure: Score on a scale*day
30.48  (4.901) 32.59  (4.611)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6027
Comments [Not Specified]
Method ANCOVA
Comments The analysis of covariance model included treatment group, region and baseline DAS28 (≤ 5.5 and > 5.5) as fixed factors.
Method of Estimation Estimation Parameter Adjusted Mean Difference (Wald CI)
Estimated Value -2.11
Confidence Interval (2-Sided) 95%
-10.07 to 5.85
Estimation Comments [Not Specified]
33.Secondary Outcome
Title Time to Tocilizumab Remission
Hide Description The time in days from initial study drug treatment to tocilizumab remission that occurred when the patient discontinued treatment with tocilizumab.
Time Frame 104 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 243 229
Median (Full Range)
Unit of Measure: Days
645.0
(360 to 855)
786.0
(351 to 829)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1695
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
34.Secondary Outcome
Title Time to Drug-Free Remission
Hide Description 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).
Time Frame 104 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 243 229
Median (Full Range)
Unit of Measure: Days
NA [1] 
(366 to 1121)
NA [1] 
(365 to 1151)
[1]
Median was not estimated due to the low number of participants with drug-free remission.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0096
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
35.Secondary Outcome
Title Time to Flare After Tocilizumab Remission
Hide Description The time in days to a flare (recurrence of disease symptoms) after the patient discontinued treatment with tocilizumab.
Time Frame 104 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 129 109
Median (Full Range)
Unit of Measure: Days
113.0
(25 to 400)
84.0
(1 to 415)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab + Methotrexate, Tocilizumab + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0734
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
36.Secondary Outcome
Title Time to Restart of Treatment After Discontinuation/Remission
Hide Description The time in days from treatment discontinuation or remission to the restart of treatment.
Time Frame 104 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description:
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 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 Number of Participants Analyzed 129 109
Median (95% Confidence Interval)
Unit of Measure: Days
113.0
(87.0 to 150.0)
81.0
(58.0 to 91.0)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Tocilizumab + Methotrexate Tocilizumab + Placebo
Hide Arm/Group Description 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 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.
All-Cause Mortality
Tocilizumab + Methotrexate Tocilizumab + Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Tocilizumab + Methotrexate Tocilizumab + Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   49/277 (17.69%)   48/276 (17.39%) 
Blood and lymphatic system disorders     
Anaemia  1  1/277 (0.36%)  1/276 (0.36%) 
Leukopenia  1  0/277 (0.00%)  1/276 (0.36%) 
Lymphadenitis  1  0/277 (0.00%)  1/276 (0.36%) 
Cardiac disorders     
Cardiac failure congestive  1  2/277 (0.72%)  1/276 (0.36%) 
Acute myocardial infarction  1  0/277 (0.00%)  2/276 (0.72%) 
Atrial fibrillation  1  1/277 (0.36%)  1/276 (0.36%) 
Myocardial infarction  1  1/277 (0.36%)  1/276 (0.36%) 
Cardiomyopathy  1  0/277 (0.00%)  1/276 (0.36%) 
Ischaemic cardiomyopathy  1  0/277 (0.00%)  1/276 (0.36%) 
Mitral valve incompetence  1  0/277 (0.00%)  1/276 (0.36%) 
Ear and labyrinth disorders     
Vertigo  1  0/277 (0.00%)  1/276 (0.36%) 
Vertigo positional  1  1/277 (0.36%)  0/276 (0.00%) 
Eye disorders     
Keratitis  1  0/277 (0.00%)  1/276 (0.36%) 
Gastrointestinal disorders     
Gastric ulcer  1  0/277 (0.00%)  1/276 (0.36%) 
Gastrointestinal angiodysplasia  1  0/277 (0.00%)  1/276 (0.36%) 
Gastrointestinal disorder  1  0/277 (0.00%)  1/276 (0.36%) 
Gastrointestinal necrosis  1  0/277 (0.00%)  1/276 (0.36%) 
Inguinal hernia  1  1/277 (0.36%)  0/276 (0.00%) 
Intestinal perforation  1  0/277 (0.00%)  1/276 (0.36%) 
Pancreatitis acute  1  1/277 (0.36%)  0/276 (0.00%) 
Rectal haemorrhage  1  1/277 (0.36%)  0/276 (0.00%) 
Vomiting  1  1/277 (0.36%)  0/276 (0.00%) 
General disorders     
Chest pain  1  2/277 (0.72%)  0/276 (0.00%) 
Death  1  0/277 (0.00%)  1/276 (0.36%) 
Device breakage  1  0/277 (0.00%)  1/276 (0.36%) 
Hyperthermia malignant  1  0/277 (0.00%)  1/276 (0.36%) 
Sudden death  1  0/277 (0.00%)  1/276 (0.36%) 
Hepatobiliary disorders     
Cholecystitis acute  1  0/277 (0.00%)  1/276 (0.36%) 
Cholelithiasis  1  1/277 (0.36%)  0/276 (0.00%) 
Immune system disorders     
Anaphylactic shock  1  0/277 (0.00%)  1/276 (0.36%) 
Anaphylactoid reaction  1  1/277 (0.36%)  0/276 (0.00%) 
Infections and infestations     
Bronchopneumonia  1  3/277 (1.08%)  0/276 (0.00%) 
Pneumonia  1  0/277 (0.00%)  3/276 (1.09%) 
Erysipelas  1  0/277 (0.00%)  2/276 (0.72%) 
Septic shock  1  2/277 (0.72%)  0/276 (0.00%) 
Abdominal abscess  1  0/277 (0.00%)  1/276 (0.36%) 
Abscess limb  1  0/277 (0.00%)  1/276 (0.36%) 
Anal abscess  1  1/277 (0.36%)  0/276 (0.00%) 
Appendicitis  1  0/277 (0.00%)  1/276 (0.36%) 
Arthritis bacterial  1  1/277 (0.36%)  0/276 (0.00%) 
Candida endophthalmitis  1  0/277 (0.00%)  1/276 (0.36%) 
Cellulitis  1  1/277 (0.36%)  0/276 (0.00%) 
Clostridium difficile colitis  1  0/277 (0.00%)  1/276 (0.36%) 
Disseminated tuberculosis  1  1/277 (0.36%)  0/276 (0.00%) 
Diverticulitis  1  0/277 (0.00%)  1/276 (0.36%) 
Gangrene  1  1/277 (0.36%)  0/276 (0.00%) 
Gastroenteritis  1  1/277 (0.36%)  0/276 (0.00%) 
Gastrointestinal candidiasis  1  1/277 (0.36%)  0/276 (0.00%) 
Herpes zoster  1  1/277 (0.36%)  0/276 (0.00%) 
Infected bunion  1  1/277 (0.36%)  0/276 (0.00%) 
Infection  1  0/277 (0.00%)  1/276 (0.36%) 
Influenza  1  0/277 (0.00%)  1/276 (0.36%) 
Meningitis  1  0/277 (0.00%)  1/276 (0.36%) 
Otitis externa  1  1/277 (0.36%)  0/276 (0.00%) 
Pelvic abscess  1  0/277 (0.00%)  1/276 (0.36%) 
Postoperative wound infection  1  0/277 (0.00%)  1/276 (0.36%) 
Pyelonephritis acute  1  0/277 (0.00%)  1/276 (0.36%) 
Renal abscess  1  1/277 (0.36%)  0/276 (0.00%) 
Scrotal abscess  1  1/277 (0.36%)  0/276 (0.00%) 
Sepsis  1  1/277 (0.36%)  0/276 (0.00%) 
Skin infection  1  1/277 (0.36%)  0/276 (0.00%) 
Soft tissue infection  1  0/277 (0.00%)  1/276 (0.36%) 
Staphylococcal infection  1  1/277 (0.36%)  0/276 (0.00%) 
Subcutaneous abscess  1  1/277 (0.36%)  0/276 (0.00%) 
Typhoid fever  1  0/277 (0.00%)  1/276 (0.36%) 
Injury, poisoning and procedural complications     
Femoral neck fracture  1  1/277 (0.36%)  2/276 (0.72%) 
Tendon rupture  1  0/277 (0.00%)  2/276 (0.72%) 
Fall  1  1/277 (0.36%)  0/276 (0.00%) 
Hip fracture  1  1/277 (0.36%)  0/276 (0.00%) 
Radius fracture  1  1/277 (0.36%)  0/276 (0.00%) 
Synovial rupture  1  0/277 (0.00%)  1/276 (0.36%) 
Ulna fracture  1  0/277 (0.00%)  1/276 (0.36%) 
Investigations     
Transaminases increased  1  2/277 (0.72%)  2/276 (0.72%) 
Musculoskeletal and connective tissue disorders     
Musculoskeletal chest pain  1  1/277 (0.36%)  0/276 (0.00%) 
Musculoskeletal discomfort  1  1/277 (0.36%)  0/276 (0.00%) 
Myofascial pain syndrome  1  1/277 (0.36%)  0/276 (0.00%) 
Osteoarthritis  1  0/277 (0.00%)  1/276 (0.36%) 
Spinal osteoarthritis  1  1/277 (0.36%)  0/276 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Breast cancer  1  1/277 (0.36%)  1/276 (0.36%) 
Anal cancer  1  0/277 (0.00%)  1/276 (0.36%) 
Basal cell carcinoma  1  0/277 (0.00%)  1/276 (0.36%) 
Benign lung neoplasm  1  1/277 (0.36%)  0/276 (0.00%) 
Gastrointestinal carcinoma  1  1/277 (0.36%)  0/276 (0.00%) 
Glioblastoma  1  0/277 (0.00%)  1/276 (0.36%) 
Lung neoplasm malignant  1  0/277 (0.00%)  1/276 (0.36%) 
Nervous system disorders     
Transient ischaemic attack  1  1/277 (0.36%)  2/276 (0.72%) 
Cerebral haemorrhage  1  0/277 (0.00%)  1/276 (0.36%) 
Dizziness  1  1/277 (0.36%)  0/276 (0.00%) 
Epilepsy  1  1/277 (0.36%)  0/276 (0.00%) 
Haemorrhagic stroke  1  1/277 (0.36%)  0/276 (0.00%) 
Ischaemic cerebral infarction  1  0/277 (0.00%)  1/276 (0.36%) 
Ischaemic stroke  1  0/277 (0.00%)  1/276 (0.36%) 
Optic neuritis  1  1/277 (0.36%)  0/276 (0.00%) 
Sciatica  1  0/277 (0.00%)  1/276 (0.36%) 
Pregnancy, puerperium and perinatal conditions     
Abortion spontaneous  1  1/277 (0.36%)  0/276 (0.00%) 
Psychiatric disorders     
Anxiety  1  2/277 (0.72%)  1/276 (0.36%) 
Stress  1  0/277 (0.00%)  1/276 (0.36%) 
Renal and urinary disorders     
Renal colic  1  1/277 (0.36%)  0/276 (0.00%) 
Renal failure acute  1  1/277 (0.36%)  0/276 (0.00%) 
Reproductive system and breast disorders     
Colpocele  1  0/277 (0.00%)  1/276 (0.36%) 
Respiratory, thoracic and mediastinal disorders     
Pleurisy  1  1/277 (0.36%)  1/276 (0.36%) 
Acute respiratory distress syndrome  1  1/277 (0.36%)  0/276 (0.00%) 
Alveolitis  1  0/277 (0.00%)  1/276 (0.36%) 
Chronic obstructive pulmonary disease  1  1/277 (0.36%)  0/276 (0.00%) 
Pulmonary oedema  1  0/277 (0.00%)  1/276 (0.36%) 
Skin and subcutaneous tissue disorders     
Skin necrosis  1  1/277 (0.36%)  0/276 (0.00%) 
Skin ulcer  1  0/277 (0.00%)  1/276 (0.36%) 
Vascular disorders     
Aortic stenosis  1  0/277 (0.00%)  1/276 (0.36%) 
Hypertension  1  1/277 (0.36%)  0/276 (0.00%) 
Intermittent claudication  1  0/277 (0.00%)  1/276 (0.36%) 
Peripheral artery stenosis  1  0/277 (0.00%)  1/276 (0.36%) 
Phlebitis  1  0/277 (0.00%)  1/276 (0.36%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Tocilizumab + Methotrexate Tocilizumab + Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   189/277 (68.23%)   179/276 (64.86%) 
Blood and lymphatic system disorders     
Leukopenia  1  20/277 (7.22%)  13/276 (4.71%) 
Neutropenia  1  15/277 (5.42%)  14/276 (5.07%) 
Gastrointestinal disorders     
Nausea  1  27/277 (9.75%)  9/276 (3.26%) 
Diarrhoea  1  20/277 (7.22%)  21/276 (7.61%) 
Infections and infestations     
Nasopharyngitis  1  43/277 (15.52%)  40/276 (14.49%) 
Upper respiratory tract infection  1  31/277 (11.19%)  25/276 (9.06%) 
Urinary tract infection  1  23/277 (8.30%)  18/276 (6.52%) 
Influenza  1  18/277 (6.50%)  11/276 (3.99%) 
Gastroenteritis  1  16/277 (5.78%)  7/276 (2.54%) 
Bronchitis  1  17/277 (6.14%)  5/276 (1.81%) 
Investigations     
Transaminases increase  1  30/277 (10.83%)  15/276 (5.43%) 
Alanine aminotransferase increased  1  33/277 (11.91%)  15/276 (5.43%) 
Blood cholesterol increased  1  12/277 (4.33%)  15/276 (5.43%) 
Metabolism and nutrition disorders     
Hypercholesterolemia  1  34/277 (12.27%)  33/276 (11.96%) 
Musculoskeletal and connective tissue disorders     
Back pain  1  29/277 (10.47%)  21/276 (7.61%) 
Rheumatoid arthritis  1  14/277 (5.05%)  15/276 (5.43%) 
Nervous system disorders     
Headache  1  18/277 (6.50%)  21/276 (7.61%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  21/277 (7.58%)  16/276 (5.80%) 
Skin and subcutaneous tissue disorders     
Rash  1  15/277 (5.42%)  7/276 (2.54%) 
Vascular disorders     
Hypertension  1  13/277 (4.69%)  19/276 (6.88%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Results Point of Contact
Name/Title: Medical Communications
Organization: Hoffman-LaRoche
Phone: 800-821-8590
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT00810199     History of Changes
Other Study ID Numbers: MA21488
2008-001847-20
First Submitted: December 16, 2008
First Posted: December 17, 2008
Results First Submitted: May 1, 2014
Results First Posted: July 18, 2014
Last Update Posted: July 18, 2014