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A Study of Tocilizumab as Monotherapy and in Combination With Methotrexate Versus Methotrexate in Patients With Early Moderate to Severe Rheumatoid Arthritis

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ClinicalTrials.gov Identifier: NCT01007435
Recruitment Status : Completed
First Posted : November 4, 2009
Results First Posted : July 12, 2013
Last Update Posted : July 26, 2017
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Rheumatoid Arthritis
Interventions Drug: Tocilizumab
Drug: Placebo to tocilizumab
Drug: Methotrexate
Drug: Placebo to methotrexate
Enrollment 1162
Recruitment Details  
Pre-assignment Details Five of 1162 randomized patients (2 placebo to tocilizumab + methotrexate, 2 tocilizumab 4 mg/kg + methotrexate, 1 tocilizumab 8 mg/kg + methotrexate) did not receive any study treatment and were excluded from all analysis populations.
Arm/Group Title Placebo to Tocilizumab + Methotrexate Tocilizumab 4 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Placebo to Methotrexate
Hide Arm/Group Description Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks. Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks. Patients received tocilizumab 8 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks. Patients received tocilizumab 8 mg/kg iv every 4 weeks + placebo to methotrexate orally once a week for 104 weeks.
Period Title: Overall Study
Started 289 290 291 292
Completed 226 231 227 236
Not Completed 63 59 64 56
Reason Not Completed
Adverse Event             16             25             47             31
Death             2             4             2             1
Insufficient Therapeutic Response             21             7             2             9
Violation of Selection Criteria at Entry             3             5             2             0
Other Protocol Violation             2             0             1             0
Refused Treatment             13             13             5             8
Failure to Return             5             4             3             6
Reason not Specified             1             1             2             1
Arm/Group Title Placebo to Tocilizumab + Methotrexate Tocilizumab 4 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Placebo to Methotrexate Total
Hide Arm/Group Description Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks. Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks. Patients received tocilizumab 8 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks. Patients received tocilizumab 8 mg/kg iv every 4 weeks + placebo to methotrexate orally once a week for 104 weeks. Total of all reporting groups
Overall Number of Baseline Participants 287 288 290 292 1157
Hide Baseline Analysis Population Description
Baseline Characteristics were based on the intent-to-treat (ITT) population. Five of 1162 randomized patients (2 placebo + methotrexate, 2 tocilizumab 4 mg/kg + methotrexate, 1 tocilizumab 8 mg/kg + methotrexate) did not receive any study treatment and were excluded from all analysis populations. The ITT population therefore included 1157 patients.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 287 participants 288 participants 290 participants 292 participants 1157 participants
49.6  (13.10) 51.2  (13.84) 49.5  (13.70) 49.9  (13.22) 50.1  (13.47)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 287 participants 288 participants 290 participants 292 participants 1157 participants
Female
229
  79.8%
228
  79.2%
228
  78.6%
219
  75.0%
904
  78.1%
Male
58
  20.2%
60
  20.8%
62
  21.4%
73
  25.0%
253
  21.9%
1.Primary Outcome
Title Percentage of Participants With a Disease Activity Score 28 (DAS28) Remission Response at Week 24
Hide Description A participant has a DAS28 remission response if their DAS28 < 2.6. The DAS28 is a combined index for measuring disease activity in rheumatic arthritis (RA) and includes swollen and tender joint counts, erythrocyte sedimentation rate (ESR), and general health (GH) status. The index is calculated with the following formula: DAS28 = (0.56 × √(TJC28)) + (0.28 × √(SJC28)) + (0.7 × log(ESR)) + (0.014 × GH), where TJC28 = tender joint count and SJC28 = swollen joint count, each on 28 joints. GH = a patient’s global assessment of disease activity in the previous 24 hours on a 100 mm visual analog scale (left end = no disease activity [symptom-free and no arthritis symptoms], right end = maximum disease activity [maximum arthritis disease activity]). When ESR equaled 0 mm/hr, it was set to 1 mm/hr. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity.
Time Frame Week 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized participants who received at least 1 tocilizumab/placebo infusion.
Arm/Group Title Placebo to Tocilizumab + Methotrexate Tocilizumab 4 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Placebo to Methotrexate
Hide Arm/Group Description:
Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 8 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 8 mg/kg iv every 4 weeks + placebo to methotrexate orally once a week for 104 weeks.
Overall Number of Participants Analyzed 287 288 290 292
Measure Type: Number
Unit of Measure: Percentage of participants
15.0 31.9 44.8 38.7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo to Tocilizumab + Methotrexate, Tocilizumab 8 mg/kg + Methotrexate
Comments The null hypothesis is that there is no difference in the DAS28 remission response at Week 24 between the placebo to tocilizumab + methotrexate and the tocilizumab 8 mg/kg + methotrexate treatment groups.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments A hierarchy of statistical testing was implemented in order to control the type I error rate for multiple comparisons.
Method Regression, Logistic
Comments The stratification factors, region and serologic status, were included in the model.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 4.77
Confidence Interval (2-Sided) 95%
3.19 to 7.14
Estimation Comments Last observation carried forward was used for TJC and SJC. No imputation was used for ESR and GH. Patients who withdrew prematurely or where a DAS28 could not be calculated were set to “non-responder”.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo to Tocilizumab + Methotrexate, Tocilizumab 8 mg/kg + Placebo to Methotrexate
Comments The null hypothesis is that there is no difference in the DAS28 remission response at Week 24 between the placebo to tocilizumab + methotrexate and the tocilizumab 8 mg/kg + placebo to methotrexate treatment groups.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments A hierarchy of statistical testing was implemented in order to control the type I error rate for multiple comparisons.
Method Regression, Logistic
Comments The stratification factors, region and serologic status, were included in the model.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 3.70
Confidence Interval (2-Sided) 95%
2.47 to 5.55
Estimation Comments Last observation carried forward was used for TJC and SJC. No imputation was used for ESR and GH. Patients who withdrew prematurely or where a DAS28 could not be calculated were set to “non-responder”.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo to Tocilizumab + Methotrexate, Tocilizumab 4 mg/kg + Methotrexate
Comments The null hypothesis is that there is no difference in the DAS28 remission response at Week 24 between the placebo to tocilizumab + methotrexate and the tocilizumab 4 mg/kg + methotrexate treatment groups.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments A hierarchy of statistical testing was implemented in order to control the type I error rate for multiple comparisons. This comparison came after the break in statistical hierarchy.
Method Regression, Logistic
Comments The stratification factors, region and serologic status, were included in the model.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.72
Confidence Interval (2-Sided) 95%
1.80 to 4.11
Estimation Comments Last observation carried forward was used for TJC and SJC. No imputation was used for ESR and GH. Patients who withdrew prematurely or where a DAS28 could not be calculated were set to “non-responder”.
2.Secondary Outcome
Title Percentage of Participants With a Disease Activity Score 28 (DAS28) Remission Response at Week 52
Hide Description [Not Specified]
Time Frame Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized participants who received at least 1 tocilizumab/placebo infusion.
Arm/Group Title Placebo to Tocilizumab + Methotrexate Tocilizumab 4 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Placebo to Methotrexate
Hide Arm/Group Description:
Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 8 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 8 mg/kg iv every 4 weeks + placebo to methotrexate orally once a week for 104 weeks.
Overall Number of Participants Analyzed 287 288 290 292
Measure Type: Number
Unit of Measure: Percentage of participants
19.5 34.0 49.0 39.4
3.Secondary Outcome
Title Percentage of Patients With an Improvement ≥ 20%, 50%, or 70% in American College of Rheumatology (ACR) Score (ACR20/50/70) From Baseline to Weeks 24 and 52
Hide Description Improvement must be seen in tender (68) and swollen (66) joint counts. Joints were assessed and classified as swollen/not swollen and tender/not tender by pressure and joint manipulation. Improvement must also be seen in at least 3 of the following 5 parameters: Separate patient and physician assessments of patient disease activity in the previous 24 hours on a visual analog scale (VAS, the extreme left end of the line “no disease activity” [symptom-free and no arthritis symptoms] and the extreme right end “maximum disease activity”; patient assessment of pain in previous the 24 hours on a VAS (extreme left end of the line “no pain” and the extreme right end “unbearable pain”); Health Assessment Questionnaire-Disability Index (20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do); and C-reactive protein (CRP), or erythrocyte sedimentation rate if CRP was missing.
Time Frame Baseline to Weeks 24 and 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized participants who received at least 1 tocilizumab/placebo infusion.
Arm/Group Title Placebo to Tocilizumab + Methotrexate Tocilizumab 4 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Placebo to Methotrexate
Hide Arm/Group Description:
Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 8 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 8 mg/kg iv every 4 weeks + placebo to methotrexate orally once a week for 104 weeks.
Overall Number of Participants Analyzed 287 288 290 292
Measure Type: Number
Unit of Measure: Percentage of participants
Week 24: ACR 20 65.2 73.6 74.5 70.2
Week 24: ACR 50 43.2 47.9 56.9 47.6
Week 24: ACR 70 25.4 34.7 38.6 30.1
Week 52: ACR 20 57.1 62.8 67.2 63.0
Week 52: ACR 50 40.8 52.4 55.9 49.3
Week 52: ACR 70 28.9 37.2 43.1 36.0
4.Secondary Outcome
Title Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52
Hide Description The mTSS is a measure of joint damage and includes measures of joint erosion (JE) and joint space narrowing (JSN). The JE score, using the van der Heijde modification, measures erosion severity in 32 hand joints and 12 foot joints. Each hand joint is scored from 0 to 5 and each foot joint is scored from 0 to 10; the total score ranges from 0 to 280. Each joint is scored according to the surface area involved. A score of 10 indicates extensive loss of bone from more than one-half of the articulating bone; a score of 0 indicates no erosion. The JSN score measures the severity of JSN in 30 hand joints (15 per hand) and 12 foot joints (6 per foot). Each joint, including subluxation, is scored from 0 to 4; the total score ranges from 0 to 168. A higher score indicates more joint space narrowing. The mTSS ranges from 0 to 448 (280+168). A higher mTSS score indicates greater damage. A negative change score indicates improvement.
Time Frame Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized participants who received at least 1 tocilizumab/placebo infusion.
Arm/Group Title Placebo to Tocilizumab + Methotrexate Tocilizumab 4 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Placebo to Methotrexate
Hide Arm/Group Description:
Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 8 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 8 mg/kg iv every 4 weeks + placebo to methotrexate orally once a week for 104 weeks.
Overall Number of Participants Analyzed 267 267 273 275
Mean (Standard Deviation)
Unit of Measure: Units on a scale
1.14  (4.297) 0.42  (2.929) 0.08  (2.090) 0.26  (1.876)
5.Secondary Outcome
Title Change From Baseline in Modified Sharp Erosion Score at Week 52
Hide Description [Not Specified]
Time Frame Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized participants who received at least 1 tocilizumab/placebo infusion.
Arm/Group Title Placebo to Tocilizumab + Methotrexate Tocilizumab 4 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Placebo to Methotrexate
Hide Arm/Group Description:
Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 8 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 8 mg/kg iv every 4 weeks + placebo to methotrexate orally once a week for 104 weeks.
Overall Number of Participants Analyzed 267 267 273 275
Mean (Standard Deviation)
Unit of Measure: Units on a scale
0.63  (2.556) 0.25  (1.686) 0.05  (1.736) 0.15  (1.544)
6.Secondary Outcome
Title Change From Baseline in Sharp Joint Space Narrowing Score at Week 52
Hide Description [Not Specified]
Time Frame Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized participants who received at least 1 tocilizumab/placebo infusion.
Arm/Group Title Placebo to Tocilizumab + Methotrexate Tocilizumab 4 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Placebo to Methotrexate
Hide Arm/Group Description:
Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 8 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 8 mg/kg iv every 4 weeks + placebo to methotrexate orally once a week for 104 weeks.
Overall Number of Participants Analyzed 267 268 273 275
Mean (Standard Deviation)
Unit of Measure: Units on a scale
0.51  (2.362) 0.17  (1.645) 0.03  (0.751) 0.11  (1.046)
7.Secondary Outcome
Title Percentage of Participants With a Major Clinical Response at Week 52
Hide Description A major clinical response is defined as an ACR70 response that is maintained for 6 consecutive months (24 weeks) for any 24-week period between Week 2 and Week 52.
Time Frame Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized participants who received at least 1 tocilizumab/placebo infusion.
Arm/Group Title Placebo to Tocilizumab + Methotrexate Tocilizumab 4 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Placebo to Methotrexate
Hide Arm/Group Description:
Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 8 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 8 mg/kg iv every 4 weeks + placebo to methotrexate orally once a week for 104 weeks.
Overall Number of Participants Analyzed 287 288 290 292
Measure Type: Number
Unit of Measure: Percentage of participants
16 22 31 22
8.Secondary Outcome
Title Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Weeks 24 and 52
Hide Description The Stanford HAQ-DI is a patient completed questionnaire specific for rheumatoid arthritis. The HAQ-DI assesses how well the patient is able to perform 8 activities: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. The patient answers 20 questions with 1 of 4 responses with the past week as the time frame: 0=without difficulty, 1=with some difficulty, 2=with much difficulty, and 3=unable to do. The highest score for any question in a category determines the category score. The total score ranges from 0 (no disability) to 3 (completely disabled). A negative change score indicates improvement.
Time Frame Baseline to Weeks 24 and 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized participants who received at least 1 tocilizumab/placebo infusion.
Arm/Group Title Placebo to Tocilizumab + Methotrexate Tocilizumab 4 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Placebo to Methotrexate
Hide Arm/Group Description:
Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 8 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 8 mg/kg iv every 4 weeks + placebo to methotrexate orally once a week for 104 weeks.
Overall Number of Participants Analyzed 287 288 290 292
Mean (Standard Deviation)
Unit of Measure: Units on a scale
Week 24 (n=246, 255, 250, 265) -0.71  (0.718) -0.92  (0.736) -0.91  (0.695) -0.82  (0.739)
Week 52 (n=214, 227, 228, 230) -0.76  (0.800) -1.00  (0.795) -0.97  (0.700) -0.87  (0.776)
9.Secondary Outcome
Title Change From Baseline in Short Form 36 (SF-36) Physical Component Summary (PCS) Scores at Weeks 24 and 52
Hide Description The SF-36 Health Survey (Version 2) is a standardized questionnaire consisting of 36 questions that measures patient-reported symptoms on 8 dimensions; it is used to assess health-related quality of life (HRQoL). The Physical Component Summary (PCS) score summarizes the subscales Physical Functioning, Role-Physical, Bodily Pain, and General Health. The Mental Component Summary (MCS) score summarizes the subscales Vitality, Social Functioning, Role-Emotional, and Mental Health. Each score was scaled from 0 to 100. A positive change score indicates better HRQoL.
Time Frame Baseline to Weeks 24 and 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized participants who received at least 1 tocilizumab/placebo infusion.
Arm/Group Title Placebo to Tocilizumab + Methotrexate Tocilizumab 4 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Placebo to Methotrexate
Hide Arm/Group Description:
Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 8 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
Patients received tocilizumab 8 mg/kg iv every 4 weeks + placebo to methotrexate orally once a week for 104 weeks.
Overall Number of Participants Analyzed 287 288 290 292
Mean (Standard Deviation)
Unit of Measure: Units on a scale
Week 24 (n=237, 247, 246, 255) 9.35  (9.763) 11.33  (9.282) 12.13  (9.263) 10.75  (10.055)
Week 52 (n=204, 225, 221, 224) 10.72  (10.389) 12.27  (10.509) 13.52  (9.848) 11.73  (10.691)
Time Frame Adverse events were reported from Baseline through Week 52.
Adverse Event Reporting Description Safety population: All patients who received at least 1 tocilizumab/placebo infusion and had at least 1 post-dose safety assessment. 7 patients were excluded from the safety population (no treatment received or no post-baseline safety data). The total safety population included 1153 patients.
 
Arm/Group Title Placebo to Tocilizumab + Methotrexate Tocilizumab 4 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Placebo to Methotrexate
Hide Arm/Group Description Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks. Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks. Patients received tocilizumab 8 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks. Patients received tocilizumab 8 mg/kg iv every 4 weeks + placebo to methotrexate orally once a week for 104 weeks.
All-Cause Mortality
Placebo to Tocilizumab + Methotrexate Tocilizumab 4 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Placebo to Methotrexate
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo to Tocilizumab + Methotrexate Tocilizumab 4 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Placebo to Methotrexate
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   24/282 (8.51%)   29/289 (10.03%)   31/290 (10.69%)   25/292 (8.56%) 
Blood and lymphatic system disorders         
Anaemia  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Cardiac disorders         
Acute myocardial infarction  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  1/292 (0.34%) 
Myocardial infarction  1  0/282 (0.00%)  1/289 (0.35%)  1/290 (0.34%)  0/292 (0.00%) 
Angina pectoris  1  1/282 (0.35%)  0/289 (0.00%)  0/290 (0.00%)  0/292 (0.00%) 
Myocardial fibrosis  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Sick sinus syndrome  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Silent myocardial infarction  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Ear and labyrinth disorders         
Neurosensory hypoacusis  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Gastrointestinal disorders         
Gastrointestinal haemorrhage  1  1/282 (0.35%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Abdominal discomfort  1  1/282 (0.35%)  0/289 (0.00%)  0/290 (0.00%)  0/292 (0.00%) 
Anal fissure  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Colitis  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Food poisoning  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Hepatobiliary disorders         
Cholelithiasis  1  1/282 (0.35%)  1/289 (0.35%)  1/290 (0.34%)  0/292 (0.00%) 
Biliary dyskinesia  1  1/282 (0.35%)  0/289 (0.00%)  0/290 (0.00%)  0/292 (0.00%) 
Immune system disorders         
Anaphylactic reaction  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Infections and infestations         
Pneumonia  1  1/282 (0.35%)  4/289 (1.38%)  1/290 (0.34%)  1/292 (0.34%) 
Cellulitis  1  0/282 (0.00%)  1/289 (0.35%)  1/290 (0.34%)  2/292 (0.68%) 
Appendicitis  1  0/282 (0.00%)  0/289 (0.00%)  3/290 (1.03%)  0/292 (0.00%) 
Bronchopneumonia  1  1/282 (0.35%)  1/289 (0.35%)  1/290 (0.34%)  0/292 (0.00%) 
Urinary tract infection  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  1/292 (0.34%) 
Appendicitis perforated  1  1/282 (0.35%)  0/289 (0.00%)  0/290 (0.00%)  0/292 (0.00%) 
Arthritis bacterial  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Erysipelas  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Gastroenteritis  1  0/282 (0.00%)  0/289 (0.00%)  0/290 (0.00%)  1/292 (0.34%) 
Herpes zoster  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Lower respiratory tract infection  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Lung infection  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Lyme disease  1  0/282 (0.00%)  0/289 (0.00%)  0/290 (0.00%)  1/292 (0.34%) 
Pneumococcal infection  1  0/282 (0.00%)  0/289 (0.00%)  0/290 (0.00%)  1/292 (0.34%) 
Pneumonia bacterial  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Pneumonia influenzal  1  1/282 (0.35%)  0/289 (0.00%)  0/290 (0.00%)  0/292 (0.00%) 
Sepsis  1  1/282 (0.35%)  0/289 (0.00%)  0/290 (0.00%)  0/292 (0.00%) 
Staphylococcal infection  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Tuberculosis  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Upper respiratory tract infection  1  1/282 (0.35%)  0/289 (0.00%)  0/290 (0.00%)  0/292 (0.00%) 
Viral infection  1  0/282 (0.00%)  0/289 (0.00%)  0/290 (0.00%)  1/292 (0.34%) 
Injury, poisoning and procedural complications         
Femur fracture  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  1/292 (0.34%) 
Ankle fracture  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Contusion  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Fall  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Fibula fracture  1  0/282 (0.00%)  0/289 (0.00%)  0/290 (0.00%)  1/292 (0.34%) 
Infusion related reaction  1  0/282 (0.00%)  0/289 (0.00%)  0/290 (0.00%)  1/292 (0.34%) 
Intentional overdose  1  1/282 (0.35%)  0/289 (0.00%)  0/290 (0.00%)  0/292 (0.00%) 
Meniscus lesion  1  1/282 (0.35%)  0/289 (0.00%)  0/290 (0.00%)  0/292 (0.00%) 
Tendon rupture  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Tibia fracture  1  0/282 (0.00%)  0/289 (0.00%)  0/290 (0.00%)  1/292 (0.34%) 
Investigations         
Alanine aminotransferase increased  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Aspartate aminotransferase increased  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Blood bilirubin increased  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Transaminases increased  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Metabolism and nutrition disorders         
Diabetes mellitus  1  1/282 (0.35%)  0/289 (0.00%)  0/290 (0.00%)  0/292 (0.00%) 
Diabetes mellitus inadequate control  1  1/282 (0.35%)  0/289 (0.00%)  0/290 (0.00%)  0/292 (0.00%) 
Hypoglycaemia  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Musculoskeletal and connective tissue disorders         
Rheumatoid arthritis  1  2/282 (0.71%)  0/289 (0.00%)  0/290 (0.00%)  0/292 (0.00%) 
Back pain  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Gouty arthritis  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Intervertebral disc protrusion osteoarthritis  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Osteonecrosis  1  0/282 (0.00%)  0/289 (0.00%)  0/290 (0.00%)  1/292 (0.34%) 
Oteoarthritis  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Breast cancer  1  1/282 (0.35%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Colon cancer  1  1/282 (0.35%)  0/289 (0.00%)  0/290 (0.00%)  0/292 (0.00%) 
Endometrial cancer  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Endometrial cancer stage I  1  0/282 (0.00%)  0/289 (0.00%)  0/290 (0.00%)  1/292 (0.34%) 
Hepatic neoplasm malignant  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Lung neoplasm  1  0/282 (0.00%)  0/289 (0.00%)  0/290 (0.00%)  1/292 (0.34%) 
Metastatic bronchial carcinoma  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Ovarian germ cell teratoma benign  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Renal cancer stage II  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Renal cell carcinoma  1  1/282 (0.35%)  0/289 (0.00%)  0/290 (0.00%)  0/292 (0.00%) 
Uterine leiomyoma  1  0/282 (0.00%)  0/289 (0.00%)  0/290 (0.00%)  1/292 (0.34%) 
Nervous system disorders         
Cerebral ischaemia  1  1/282 (0.35%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Cerebral haemorrhage  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Convulsion  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Hypoglycaemic coma  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Peroneal nerve palsy  1  1/282 (0.35%)  0/289 (0.00%)  0/290 (0.00%)  0/292 (0.00%) 
Syncope  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Transient ischaemic attack  1  1/282 (0.35%)  0/289 (0.00%)  0/290 (0.00%)  0/292 (0.00%) 
VIth nerve paralysis  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Pregnancy, puerperium and perinatal conditions         
Pregnancy  1  0/282 (0.00%)  0/289 (0.00%)  2/290 (0.69%)  4/292 (1.37%) 
Psychiatric disorders         
Suicide attempt  1  0/282 (0.00%)  0/289 (0.00%)  0/290 (0.00%)  1/292 (0.34%) 
Renal and urinary disorders         
Renal cyst  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Renal failure acute  1  1/282 (0.35%)  0/289 (0.00%)  0/290 (0.00%)  0/292 (0.00%) 
Reproductive system and breast disorders         
Endometrial hyperplasia  1  0/282 (0.00%)  0/289 (0.00%)  0/290 (0.00%)  1/292 (0.34%) 
Epididymal cyst  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Metrorrhagia  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Asthma  1  0/282 (0.00%)  0/289 (0.00%)  0/290 (0.00%)  2/292 (0.68%) 
Chronic obstructive pulmonary disease  1  0/282 (0.00%)  2/289 (0.69%)  0/290 (0.00%)  0/292 (0.00%) 
Pulmonary embolism  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  1/292 (0.34%) 
Pulmonary fibrosis  1  1/282 (0.35%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Acute respiratory distress syndrome  1  1/282 (0.35%)  0/289 (0.00%)  0/290 (0.00%)  0/292 (0.00%) 
Haemothorax  1  0/282 (0.00%)  0/289 (0.00%)  0/290 (0.00%)  1/292 (0.34%) 
Pneumonitis  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Pneumothorax  1  0/282 (0.00%)  0/289 (0.00%)  1/290 (0.34%)  0/292 (0.00%) 
Vascular disorders         
Deep vein thrombosis  1  0/282 (0.00%)  1/289 (0.35%)  1/290 (0.34%)  0/292 (0.00%) 
Arteriosclerosis  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Hypertension  1  0/282 (0.00%)  0/289 (0.00%)  0/290 (0.00%)  1/292 (0.34%) 
Peripheral ischaemia  1  1/282 (0.35%)  0/289 (0.00%)  0/290 (0.00%)  0/292 (0.00%) 
Peripheral vascular disorder  1  0/282 (0.00%)  1/289 (0.35%)  0/290 (0.00%)  0/292 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (15.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo to Tocilizumab + Methotrexate Tocilizumab 4 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Methotrexate Tocilizumab 8 mg/kg + Placebo to Methotrexate
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   177/282 (62.77%)   182/289 (62.98%)   201/290 (69.31%)   163/292 (55.82%) 
Gastrointestinal disorders         
Nausea  1  46/282 (16.31%)  41/289 (14.19%)  43/290 (14.83%)  19/292 (6.51%) 
Diarrhoea  1  18/282 (6.38%)  16/289 (5.54%)  19/290 (6.55%)  18/292 (6.16%) 
Dyspepsia  1  16/282 (5.67%)  17/289 (5.88%)  11/290 (3.79%)  14/292 (4.79%) 
Infections and infestations         
Upper respiratory tract infection  1  40/282 (14.18%)  37/289 (12.80%)  30/290 (10.34%)  39/292 (13.36%) 
Nasopharyngitis  1  38/282 (13.48%)  40/289 (13.84%)  28/290 (9.66%)  27/292 (9.25%) 
Urinary tract infection  1  13/282 (4.61%)  18/289 (6.23%)  14/290 (4.83%)  10/292 (3.42%) 
Bronchitis  1  6/282 (2.13%)  18/289 (6.23%)  20/290 (6.90%)  8/292 (2.74%) 
Investigations         
Alanine aminotransferase increased  1  29/282 (10.28%)  39/289 (13.49%)  55/290 (18.97%)  22/292 (7.53%) 
Transaminases increased  1  23/282 (8.16%)  35/289 (12.11%)  40/290 (13.79%)  22/292 (7.53%) 
Aspartate aminotransferase increased  1  8/282 (2.84%)  8/289 (2.77%)  17/290 (5.86%)  11/292 (3.77%) 
Musculoskeletal and connective tissue disorders         
Rheumatoid arthritis  1  21/282 (7.45%)  9/289 (3.11%)  16/290 (5.52%)  10/292 (3.42%) 
Back pain  1  7/282 (2.48%)  10/289 (3.46%)  8/290 (2.76%)  19/292 (6.51%) 
Nervous system disorders         
Headache  1  12/282 (4.26%)  20/289 (6.92%)  18/290 (6.21%)  20/292 (6.85%) 
Skin and subcutaneous tissue disorders         
Rash  1  3/282 (1.06%)  18/289 (6.23%)  12/290 (4.14%)  8/292 (2.74%) 
Vascular disorders         
Hypertension  1  21/282 (7.45%)  16/289 (5.54%)  23/290 (7.93%)  25/292 (8.56%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (15.0)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Results Point of Contact
Name/Title: Medical Communications
Organization: Hoffmann-La Roche
Phone: 800 821-8590
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01007435     History of Changes
Other Study ID Numbers: WA19926
2009-012759-12
First Submitted: November 3, 2009
First Posted: November 4, 2009
Results First Submitted: May 23, 2013
Results First Posted: July 12, 2013
Last Update Posted: July 26, 2017