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A Study of Tocilizumab in Comparison to Etanercept in Participants With Rheumatoid Arthritis and Cardiovascular Disease Risk Factors

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ClinicalTrials.gov Identifier: NCT01331837
Recruitment Status : Completed
First Posted : April 8, 2011
Results First Posted : July 13, 2017
Last Update Posted : July 13, 2017
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Rheumatoid Arthritis
Interventions Drug: Etanercept
Drug: Tocilizumab
Enrollment 3080
Recruitment Details  
Pre-assignment Details A total of 3080 patients were enrolled from 353 sites, across 31 countries
Arm/Group Title Tocilizumab Etanercept
Hide Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Period Title: Overall Study
Started 1538 1542
Completed 1482 1475
Not Completed 56 67
Reason Not Completed
Death             30             34
Lost to Follow-up             3             1
Info not recorded             10             16
Withdrawal by Subject             13             16
Arm/Group Title Tocilizumab Etanercept Total
Hide Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years. Total of all reporting groups
Overall Number of Baseline Participants 1538 1542 3080
Hide Baseline Analysis Population Description
Analysis was conducted on the Intention to treat (ITT) population, i.e. all patients randomized who have taken at least one dose of study medication.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 1538 participants 1542 participants 3080 participants
60.7  (7.4) 60.7  (7.6) 60.7  (7.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1538 participants 1542 participants 3080 participants
Female
1193
  77.6%
1202
  78.0%
2395
  77.8%
Male
345
  22.4%
340
  22.0%
685
  22.2%
1.Primary Outcome
Title Time to First Cardiovascular (CV) Events Adjudication Committee (EAC) (CV-EAC) Adjudicated Event
Hide Description Prospective comparison of time to first occurrence of any component of the composite of CV death (including events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke.
Time Frame From baseline up to 4.9 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was conducted on the Intention to treat (ITT) population, i.e. all patients randomized who have taken at least one dose of study medication
Arm/Group Title Tocilizumab Etanercept
Hide Arm/Group Description:
Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Overall Number of Participants Analyzed 1538 1542
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab, Etanercept
Comments

The analysis assessed in the ITT population the hazard ratio of the primary endpoint in TCZ compared to ETA patients. This was done through a comparison of the hazard functions between TCZ and ETA patients.

A stratified Cox proportional hazards regression model was used in evaluating the relative CV event rate of TCZ over ETA, with the following randomization factors used as strata:

  • Previous exposure to anti-TNF (Yes/No)
  • History of CV events (Yes/No)
Type of Statistical Test Non-Inferiority or Equivalence
Comments In order to reject the null hypothesis and claim non-inferiority of TCZ compared to ETA, a HR point estimate of ≤ 1.278 and upper limit of 95% CI <1.8 was required.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.05
Confidence Interval (2-Sided) 95%
0.77 to 1.43
Estimation Comments [Not Specified]
2.Primary Outcome
Title Percentage of Patients Reporting a Cardiovascular (CV) Events Adjudication Committee (EAC) (CV-EAC) Adjudicated Event
Hide Description Percentage of patients reporting any component of the composite of CV death (including events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke
Time Frame From baseline up to 4.9 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was conducted on the Intention to treat (ITT) population, i.e. all patients randomized who have taken at least one dose of study medication
Arm/Group Title Tocilizumab Etanercept
Hide Arm/Group Description:
Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Overall Number of Participants Analyzed 1538 1542
Measure Type: Number
Unit of Measure: Percentage of patients with event
5.4 5.1
3.Primary Outcome
Title Time to First CV-EAC Adjudicated Event - Sensitivity Analysis
Hide Description Prospective comparison of time to first occurrence of any component of the composite of CV death (including events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke - Sensitivity Analysis
Time Frame From Baseline up to 4.9 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analyses was conducted on the On-treatment (OT) population, i.e. patients who switched from randomized treatment were censored at the time of treatment switching.
Arm/Group Title Tocilizumab Etanercept
Hide Arm/Group Description:
Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Overall Number of Participants Analyzed 1538 1542
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab, Etanercept
Comments

The analysis assessed in the OT population the hazard ratio of the primary endpoint in TCZ compared to ETA patients. This was done through a comparison of the hazard functions between TCZ and ETA patients.

A stratified Cox proportional hazards regression model was used in evaluating the relative CV event rate of TCZ over ETA, with the following randomization factors used as strata:

  • Previous exposure to anti-TNF (Yes/No)
  • History of CV events (Yes/No)
Type of Statistical Test Non-Inferiority or Equivalence
Comments The non-inferiority margin was only formally tested for the primary ITT analysis'
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.11
Confidence Interval (2-Sided) 95%
0.76 to 1.62
Estimation Comments [Not Specified]
4.Primary Outcome
Title Percentage of Patients With a CV-EAC Adjudicated Event - Sensitivity Analysis
Hide Description Percentage of patients with any component of the composite of CV death (including events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke - Sensitivity Analysis
Time Frame From Baseline up to 4.9 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analyses was conducted on the On-treatment (OT) population, i.e. patients who switched from randomized treatment were censored at the time of treatment switching.
Arm/Group Title Tocilizumab Etanercept
Hide Arm/Group Description:
Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Overall Number of Participants Analyzed 1538 1542
Measure Type: Number
Unit of Measure: Percentage of patients with event
3.7 3.4
5.Primary Outcome
Title Time to First CV-EAC Adjudicated Event Excluding Undetermined Cause of Death - Sensitivity Analysis
Hide Description Prospective comparison of time to first occurrence of any component of the composite of CV death (excluding events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke - Sensitivity Analyses
Time Frame From baseline up to 4.9 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was conducted on the ITT population
Arm/Group Title Tocilizumab Etanercept
Hide Arm/Group Description:
Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Overall Number of Participants Analyzed 1538 1542
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab, Etanercept
Comments

The analysis assessed in the ITT population the hazard ratio of the primary endpoint in TCZ compared to ETA patients. This was done through a comparison of the hazard functions between TCZ and ETA patients.

A stratified Cox proportional hazards regression model was used in evaluating the relative CV event rate of TCZ over ETA, with the following randomization factors used as strata:

  • Previous exposure to anti-TNF (Yes/No)
  • History of CV events (Yes/No)
Type of Statistical Test Non-Inferiority or Equivalence
Comments The non-inferiority margin was only formally tested for the primary ITT analysis and not for the sensitivity analysis.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.01
Confidence Interval (2-Sided) 95%
0.73 to 1.40
Estimation Comments [Not Specified]
6.Primary Outcome
Title Percentage of Patients With a CV-EAC Adjudicated Event Excluding Undetermined Cause of Death - Sensitivity Analysis
Hide Description Percentage of patients with any component of the composite of CV death (excluding events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke - Sensitivity Analyses
Time Frame From baseline up to 4.9 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was conducted on the ITT population
Arm/Group Title Tocilizumab Etanercept
Hide Arm/Group Description:
Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Overall Number of Participants Analyzed 1538 1542
Measure Type: Number
Unit of Measure: Percentage of patients with event
4.8 4.7
7.Primary Outcome
Title Time to First CV-EAC Adjudicated Event Before Last Direct Contact Date
Hide Description Prospective comparison of time to first occurrence of any component of the composite of CV death (including events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke before last direct contact date (i.e., latest date of visit, IVRS call, or site call).
Time Frame From Baseline up to 4.9 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was conducted on the ITT population
Arm/Group Title Tocilizumab Etanercept
Hide Arm/Group Description:
Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Overall Number of Participants Analyzed 1538 1542
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab, Etanercept
Comments

The analysis assessed in the ITT population the hazard ratio of the primary endpoint in TCZ compared to ETA patients. This was done through a comparison of the hazard functions between TCZ and ETA patients.

A stratified Cox proportional hazards regression model was used in evaluating the relative CV event rate of TCZ over ETA, with the following randomization factors used as strata:

  • Previous exposure to anti-TNF (Yes/No)
  • History of CV events (Yes/No)
Type of Statistical Test Non-Inferiority or Equivalence
Comments The non-inferiority margin was only formally tested for the primary ITT analysis and not for the sensitivity analysis.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.04
Confidence Interval (2-Sided) 95%
0.70 to 1.56
Estimation Comments [Not Specified]
8.Primary Outcome
Title Percentage of Participants With a CV-EAC Adjudicated Event Before Last Direct Contact Date
Hide Description Percentage of participants with any component of the composite of CV death (including events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke before last direct contact date (i.e., latest date of visit, IVRS call, or site call).
Time Frame From Baseline up to 4.9 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was conducted on the ITT population
Arm/Group Title Tocilizumab Etanercept
Hide Arm/Group Description:
Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Overall Number of Participants Analyzed 1538 1542
Measure Type: Number
Unit of Measure: Percentage of participants with event
3.2 3.0
9.Secondary Outcome
Title The Time to First Occurrence of an Expanded CV Composite Endpoint
Hide Description Prospective comparison of the time to first ccurrence of the expanded composite endpoint. The expanded composite endpoint is defined as the CV composite of the primary endpoint with the addition of non-elective coronary revascularization procedures and hospitalization for unstable angina.
Time Frame From baseline up to 4.9 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was conducted on the ITT population.
Arm/Group Title Tocilizumab Etanercept
Hide Arm/Group Description:
Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Overall Number of Participants Analyzed 1538 1542
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab, Etanercept
Comments

The analysis assessed in the ITT population the hazard ratio of the secondary endpoint in TCZ compared to ETA patients. This was done through a comparison of the hazard functions between TCZ and ETA patients.

A stratified Cox proportional hazards regression model was used in evaluating the relative CV event rate of TCZ over ETA, with the following randomization factors used as strata:

  • Previous exposure to anti-TNF (Yes/No)
  • History of CV events (Yes/No)
Type of Statistical Test Non-Inferiority or Equivalence
Comments The non-inferiority margin was only formally tested for the primary ITT analysis.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.99
Confidence Interval (2-Sided) 95%
0.73 to 1.34
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Percentages of Participants With an Expanded CV Composite Endpoint
Hide Description Percentages of participants with the expanded CV composite endpoint. The expanded composite endpoint is defined as the CV composite of the primary endpoint with the addition of non-elective coronary revascularization procedures and hospitalization for unstable angina.
Time Frame From baseline up to 4.9 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was conducted on the ITT population.
Arm/Group Title Tocilizumab Etanercept
Hide Arm/Group Description:
Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Overall Number of Participants Analyzed 1538 1542
Measure Type: Number
Unit of Measure: Percentages of participants
5.5 5.4
11.Secondary Outcome
Title Time to First Occurrence of Individual Component of Primary Endpoint: Non-fatal Myocardial Infarction
Hide Description Prospective comparison of time to first occurrence of Individual component of primary endpoint: non-fatal Myocardial Infarction
Time Frame From baseline up to 4.9 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Anlysis was conducted on the ITT population.
Arm/Group Title Tocilizumab Etanercept
Hide Arm/Group Description:
Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Overall Number of Participants Analyzed 1538 1542
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab, Etanercept
Comments

The analysis assessed in the ITT population the hazard ratio of the secondary endpoint in TCZ compared to ETA patients. This was done through a comparison of the hazard functions between TCZ and ETA patients.

A stratified Cox proportional hazards regression model was used in evaluating the relative CV event rate of TCZ over ETA, with the following randomization factors used as strata:

  • Previous exposure to anti-TNF (Yes/No)
  • History of CV events (Yes/No)
Type of Statistical Test Non-Inferiority or Equivalence
Comments 'The non-inferiority margin was only formally tested for the primary ITT analysis'
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.89
Confidence Interval (2-Sided) 95%
0.54 to 1.49
Estimation Comments [Not Specified]
12.Secondary Outcome
Title Percentage of Patients With Individual Component of Primary Endpoint: Non-fatal Myocardial Infarction
Hide Description Percentage of patients reporting Individual component of primary endpoint: non-fatal Myocardial Infarction
Time Frame From baseline up to 4.9 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Anlysis was conducted on the ITT population
Arm/Group Title Tocilizumab Etanercept
Hide Arm/Group Description:
Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Overall Number of Participants Analyzed 1538 1542
Measure Type: Number
Unit of Measure: Percentage of patients
1.8 2.0
13.Secondary Outcome
Title Time to First Occurrence of Individual Component of Primary Endpoint: Cardiovascular Death
Hide Description Prospective comparison of time to first occurrence of Individual component of primary endpoint: cardiovascular death
Time Frame From baseline up to 4.9 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was conducted on the ITT population
Arm/Group Title Tocilizumab Etanercept
Hide Arm/Group Description:
Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Overall Number of Participants Analyzed 1538 1542
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab, Etanercept
Comments

The analysis assessed in the ITT population the hazard ratio of the secondary endpoint in TCZ compared to ETA patients. This was done through a comparison of the hazard functions between TCZ and ETA patients.

A stratified Cox proportional hazards regression model was used in evaluating the relative CV event rate of TCZ over ETA, with the following randomization factors used as strata:

  • Previous exposure to anti-TNF (Yes/No)
  • History of CV events (Yes/No)
Type of Statistical Test Non-Inferiority or Equivalence
Comments The non-inferiority margin was only formally tested for the primary ITT analysis.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.03
Confidence Interval (2-Sided) 95%
0.64 to 1.63
Estimation Comments [Not Specified]
14.Secondary Outcome
Title Percentage of Patients With Individual Component of Primary Endpoint: Cardiovascular Death
Hide Description Percentage of patients reporting Individual component of primary endpoint: cardiovascular death
Time Frame From baseline up to 4.9 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was conducted on the ITT population
Arm/Group Title Tocilizumab Etanercept
Hide Arm/Group Description:
Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Overall Number of Participants Analyzed 1538 1542
Measure Type: Number
Unit of Measure: Percentage of patients
2.3 2.3
15.Secondary Outcome
Title Time to First Occurrence of Individual Component of Primary Endpoint: Non-fatal Stroke
Hide Description Prospective comparison of time to first occurrence of Individual component of primary endpoint: non-fatal stroke
Time Frame From baseline up to 4.9 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was conducted on the ITT population
Arm/Group Title Tocilizumab Etanercept
Hide Arm/Group Description:
Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Overall Number of Participants Analyzed 1538 1542
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab, Etanercept
Comments

The analysis assessed in the ITT population the hazard ratio of the secondary endpoint in TCZ compared to ETA patients. This was done through a comparison of the hazard functions between TCZ and ETA patients.

A stratified Cox proportional hazards regression model was used in evaluating the relative CV event rate of TCZ over ETA, with the following randomization factors used as strata:

  • Previous exposure to anti-TNF (Yes/No)
  • History of CV events (Yes/No)
Type of Statistical Test Non-Inferiority or Equivalence
Comments The non-inferiority margin was only formally tested for the primary ITT analysis.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.53
Confidence Interval (2-Sided) 95%
0.80 to 2.92
Estimation Comments [Not Specified]
16.Secondary Outcome
Title Percentage of Patients With Individual Component of Primary Endpoint: Non-fatal Stroke
Hide Description [Not Specified]
Time Frame From baseline up to 4.9 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was conducted on the ITT population
Arm/Group Title Tocilizumab Etanercept
Hide Arm/Group Description:
Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Overall Number of Participants Analyzed 1538 1542
Measure Type: Number
Unit of Measure: Percentage of patients
1.6 1.0
17.Secondary Outcome
Title Time to First Occurrence of Individual Component of Primary Endpoint: All-cause Mortality
Hide Description Prospective comparison of time to first occurrence of Individual component of primary endpoint: All-cause mortality
Time Frame From baseline up to 4.9 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was conducted on the ITT population.
Arm/Group Title Tocilizumab Etanercept
Hide Arm/Group Description:
Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Overall Number of Participants Analyzed 1538 1542
Median (95% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab, Etanercept
Comments

The analysis assessed in the ITT population the hazard ratio of the secondary endpoint in TCZ compared to ETA patients. This was done through a comparison of the hazard functions between TCZ and ETA patients.

A stratified Cox proportional hazards regression model was used in evaluating the relative CV event rate of TCZ over ETA, with the following randomization factors used as strata:

  • Previous exposure to anti-TNF (Yes/No)
  • History of CV events (Yes/No)
Type of Statistical Test Non-Inferiority or Equivalence
Comments The non-inferiority margin was only formally tested for the primary ITT analysis.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.99
Confidence Interval (2-Sided) 95%
0.70 to 1.41
Estimation Comments [Not Specified]
18.Secondary Outcome
Title Percentage of Patients With Individual Component of Primary Endpoint: All-cause Mortality
Hide Description Percentage of patients reporting Individual component of primary endpoint: All-cause mortality
Time Frame From baseline up to 4.9 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was conducted on the ITT population.
Arm/Group Title Tocilizumab Etanercept
Hide Arm/Group Description:
Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Overall Number of Participants Analyzed 1538 1542
Measure Type: Number
Unit of Measure: Percentage of patients
4.2 4.2
Time Frame Adverse events were collected throughout the entire course of the study.
Adverse Event Reporting Description Analyses were conducted on the On treatment safety (OTS) population, i.e. all patients randomized who have taken at lease one dose of study medication, with patients censored at time of treatment switch. Patients are presented according to treatment received.
 
Arm/Group Title Etanercept Tocilizumab
Hide Arm/Group Description Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years. Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
All-Cause Mortality
Etanercept Tocilizumab
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Etanercept Tocilizumab
Affected / at Risk (%) Affected / at Risk (%)
Total   422/1542 (27.37%)   479/1538 (31.14%) 
Blood and lymphatic system disorders     
ANAEMIA * 1  9/1542 (0.58%)  5/1538 (0.33%) 
AUTOIMMUNE HAEMOLYTIC ANAEMIA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
COAGULOPATHY * 1  1/1542 (0.06%)  0/1538 (0.00%) 
GRANULOCYTOPENIA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
LEUKOCYTOSIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
MICROCYTIC ANAEMIA * 1  2/1542 (0.13%)  0/1538 (0.00%) 
PANCYTOPENIA * 1  4/1542 (0.26%)  1/1538 (0.07%) 
THROMBOCYTOPENIA * 1  0/1542 (0.00%)  2/1538 (0.13%) 
LEUKOPENIA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
Cardiac disorders     
ACUTE CORONARY SYNDROME * 1  1/1542 (0.06%)  1/1538 (0.07%) 
ACUTE MYOCARDIAL INFARCTION * 1  9/1542 (0.58%)  7/1538 (0.46%) 
ADAMS−STOKES SYNDROME * 1  1/1542 (0.06%)  0/1538 (0.00%) 
ANGINA PECTORIS * 1  2/1542 (0.13%)  8/1538 (0.52%) 
ANGINA UNSTABLE * 1  7/1542 (0.45%)  4/1538 (0.26%) 
ATRIAL FIBRILLATION * 1  18/1542 (1.17%)  14/1538 (0.91%) 
ATRIAL FLUTTER * 1  0/1542 (0.00%)  2/1538 (0.13%) 
ATRIOVENTRICULAR BLOCK SECOND DEGREE * 1  2/1542 (0.13%)  0/1538 (0.00%) 
BRADYARRHYTHMIA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
BRADYCARDIA * 1  2/1542 (0.13%)  1/1538 (0.07%) 
BUNDLE BRANCH BLOCK LEFT * 1  0/1542 (0.00%)  1/1538 (0.07%) 
CARDIAC ARREST * 1  4/1542 (0.26%)  1/1538 (0.07%) 
CARDIAC FAILURE * 1  3/1542 (0.19%)  11/1538 (0.72%) 
CARDIAC FAILURE CHRONIC * 1  1/1542 (0.06%)  0/1538 (0.00%) 
CARDIAC FAILURE CONGESTIVE * 1  8/1542 (0.52%)  7/1538 (0.46%) 
CARDIAC FIBRILLATION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
CARDIAC TAMPONADE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
CARDIOGENIC SHOCK * 1  1/1542 (0.06%)  0/1538 (0.00%) 
CARDIOMYOPATHY * 1  1/1542 (0.06%)  0/1538 (0.00%) 
CARDIOPULMONARY FAILURE * 1  1/1542 (0.06%)  4/1538 (0.26%) 
CORONARY ARTERY DISEASE * 1  3/1542 (0.19%)  9/1538 (0.59%) 
CORONARY ARTERY OCCLUSION * 1  1/1542 (0.06%)  1/1538 (0.07%) 
CORONARY ARTERY STENOSIS * 1  2/1542 (0.13%)  0/1538 (0.00%) 
HYPERTENSIVE HEART DISEASE * 1  0/1542 (0.00%)  3/1538 (0.20%) 
ISCHAEMIC CARDIOMYOPATHY * 1  2/1542 (0.13%)  0/1538 (0.00%) 
LEFT VENTRICULAR FAILURE * 1  2/1542 (0.13%)  0/1538 (0.00%) 
MITRAL VALVE INCOMPETENCE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
MITRAL VALVE STENOSIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
MYOCARDIAL INFARCTION * 1  15/1542 (0.97%)  10/1538 (0.65%) 
MYOCARDIAL ISCHAEMIA * 1  3/1542 (0.19%)  1/1538 (0.07%) 
PALPITATIONS * 1  1/1542 (0.06%)  1/1538 (0.07%) 
POSTINFARCTION ANGINA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
SILENT MYOCARDIAL INFARCTION * 1  2/1542 (0.13%)  0/1538 (0.00%) 
SINOATRIAL BLOCK * 1  1/1542 (0.06%)  0/1538 (0.00%) 
SINUS BRADYCARDIA * 1  1/1542 (0.06%)  1/1538 (0.07%) 
SINUS NODE DYSFUNCTION * 1  1/1542 (0.06%)  0/1538 (0.00%) 
SUPRAVENTRICULAR TACHYCARDIA * 1  1/1542 (0.06%)  1/1538 (0.07%) 
TACHYCARDIA * 1  1/1542 (0.06%)  1/1538 (0.07%) 
VENTRICULAR DYSFUNCTION * 1  1/1542 (0.06%)  0/1538 (0.00%) 
VENTRICULAR FIBRILLATION * 1  1/1542 (0.06%)  0/1538 (0.00%) 
VENTRICULAR TACHYCARDIA * 1  2/1542 (0.13%)  0/1538 (0.00%) 
CARDIO−RESPIRATORY ARREST * 1  3/1542 (0.19%)  1/1538 (0.07%) 
Congenital, familial and genetic disorders     
ATRIAL SEPTAL DEFECT * 1  0/1542 (0.00%)  1/1538 (0.07%) 
HYDROCELE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
Ear and labyrinth disorders     
DEAFNESS UNILATERAL * 1  1/1542 (0.06%)  1/1538 (0.07%) 
VERTIGO * 1  1/1542 (0.06%)  1/1538 (0.07%) 
Endocrine disorders     
GOITRE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
HYPERTHYROIDISM * 1  0/1542 (0.00%)  1/1538 (0.07%) 
HYPOTHYROIDISM * 1  0/1542 (0.00%)  1/1538 (0.07%) 
Eye disorders     
CATARACT * 1  2/1542 (0.13%)  2/1538 (0.13%) 
CORNEAL PERFORATION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
KERATITIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
RETINAL ARTERY OCCLUSION * 1  1/1542 (0.06%)  1/1538 (0.07%) 
RETINAL DETACHMENT * 1  1/1542 (0.06%)  0/1538 (0.00%) 
SCLERITIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
ULCERATIVE KERATITIS * 1  1/1542 (0.06%)  2/1538 (0.13%) 
Gastrointestinal disorders     
ABDOMINAL ADHESIONS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
ABDOMINAL HERNIA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
ABDOMINAL PAIN * 1  4/1542 (0.26%)  3/1538 (0.20%) 
ABDOMINAL PAIN UPPER * 1  0/1542 (0.00%)  2/1538 (0.13%) 
ACID PEPTIC DISEASE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
ACUTE ABDOMEN * 1  0/1542 (0.00%)  1/1538 (0.07%) 
ASCITES * 1  0/1542 (0.00%)  1/1538 (0.07%) 
COLITIS * 1  1/1542 (0.06%)  1/1538 (0.07%) 
COLITIS ISCHAEMIC * 1  1/1542 (0.06%)  0/1538 (0.00%) 
COLITIS ULCERATIVE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
CONSTIPATION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
CROHN’S DISEASE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
DIAPHRAGMATIC HERNIA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
DIARRHOEA * 1  4/1542 (0.26%)  2/1538 (0.13%) 
DIVERTICULAR PERFORATION * 1  1/1542 (0.06%)  6/1538 (0.39%) 
DIVERTICULUM * 1  0/1542 (0.00%)  1/1538 (0.07%) 
DIVERTICULUM INTESTINAL * 1  2/1542 (0.13%)  1/1538 (0.07%) 
DIVERTICULUM INTESTINAL HAEMORRHAGIC * 1  0/1542 (0.00%)  1/1538 (0.07%) 
DUODENAL ULCER * 1  1/1542 (0.06%)  0/1538 (0.00%) 
ENTERITIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
ENTEROCOLITIS * 1  0/1542 (0.00%)  2/1538 (0.13%) 
FEMORAL HERNIA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
GASTRIC ULCER * 1  1/1542 (0.06%)  2/1538 (0.13%) 
GASTRIC ULCER HAEMORRHAGE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
GASTRIC ULCER PERFORATION * 1  1/1542 (0.06%)  0/1538 (0.00%) 
GASTRITIS * 1  2/1542 (0.13%)  4/1538 (0.26%) 
GASTRITIS HAEMORRHAGIC * 1  1/1542 (0.06%)  0/1538 (0.00%) 
GASTROINTESTINAL HAEMORRHAGE * 1  4/1542 (0.26%)  4/1538 (0.26%) 
GASTROINTESTINAL INFLAMMATION * 1  1/1542 (0.06%)  0/1538 (0.00%) 
GASTROINTESTINAL ULCER HAEMORRHAGE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
GASTROOESOPHAGEAL REFLUX DISEASE * 1  1/1542 (0.06%)  1/1538 (0.07%) 
HAEMATEMESIS * 1  0/1542 (0.00%)  2/1538 (0.13%) 
HAEMATOCHEZIA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
HAEMORRHOIDS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
INCARCERATED HIATUS HERNIA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
INCARCERATED UMBILICAL HERNIA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
INGUINAL HERNIA * 1  1/1542 (0.06%)  1/1538 (0.07%) 
INTESTINAL OBSTRUCTION * 1  1/1542 (0.06%)  1/1538 (0.07%) 
LARGE INTESTINAL STENOSIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
LARGE INTESTINE PERFORATION * 1  0/1542 (0.00%)  4/1538 (0.26%) 
LARGE INTESTINE POLYP * 1  2/1542 (0.13%)  0/1538 (0.00%) 
LOWER GASTROINTESTINAL HAEMORRHAGE * 1  2/1542 (0.13%)  0/1538 (0.00%) 
MALLORY−WEISS SYNDROME * 1  0/1542 (0.00%)  1/1538 (0.07%) 
MELAENA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
NAUSEA * 1  0/1542 (0.00%)  2/1538 (0.13%) 
OESOPHAGITIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
PALATAL DISORDER * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PANCREATITIS * 1  1/1542 (0.06%)  4/1538 (0.26%) 
PANCREATITIS ACUTE * 1  3/1542 (0.19%)  5/1538 (0.33%) 
PEPTIC ULCER * 1  1/1542 (0.06%)  1/1538 (0.07%) 
PEPTIC ULCER HAEMORRHAGE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
RETROPERITONEAL FIBROSIS * 1  1/1542 (0.06%)  1/1538 (0.07%) 
UPPER GASTROINTESTINAL HAEMORRHAGE * 1  2/1542 (0.13%)  2/1538 (0.13%) 
VOMITING * 1  0/1542 (0.00%)  1/1538 (0.07%) 
General disorders     
CHEST PAIN * 1  10/1542 (0.65%)  3/1538 (0.20%) 
COMPLICATION ASSOCIATED WITH DEVICE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
DEATH * 1  4/1542 (0.26%)  3/1538 (0.20%) 
GENERAL PHYSICAL HEALTH DETERIORATION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
IMPAIRED HEALING * 1  0/1542 (0.00%)  1/1538 (0.07%) 
LOCAL SWELLING * 1  0/1542 (0.00%)  1/1538 (0.07%) 
MULTIPLE ORGAN DYSFUNCTION SYNDROME * 1  0/1542 (0.00%)  2/1538 (0.13%) 
NON−CARDIAC CHEST PAIN * 1  1/1542 (0.06%)  5/1538 (0.33%) 
OEDEMA PERIPHERAL * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PAIN * 1  0/1542 (0.00%)  1/1538 (0.07%) 
PYREXIA * 1  3/1542 (0.19%)  3/1538 (0.20%) 
SUDDEN DEATH * 1  1/1542 (0.06%)  3/1538 (0.20%) 
SWELLING * 1  0/1542 (0.00%)  1/1538 (0.07%) 
Hepatobiliary disorders     
BILE DUCT OBSTRUCTION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
CHOLANGITIS ACUTE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
CHOLECYSTITIS * 1  0/1542 (0.00%)  3/1538 (0.20%) 
CHOLECYSTITIS ACUTE * 1  2/1542 (0.13%)  1/1538 (0.07%) 
CHOLECYSTITIS CHRONIC * 1  1/1542 (0.06%)  1/1538 (0.07%) 
CHOLELITHIASIS * 1  6/1542 (0.39%)  14/1538 (0.91%) 
HEPATIC VEIN THROMBOSIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
HEPATITIS * 1  0/1542 (0.00%)  2/1538 (0.13%) 
HEPATITIS ACUTE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
POST CHOLECYSTECTOMY SYNDROME * 1  0/1542 (0.00%)  1/1538 (0.07%) 
Immune system disorders     
DRUG HYPERSENSITIVITY * 1  0/1542 (0.00%)  1/1538 (0.07%) 
HYPERSENSITIVITY * 1  0/1542 (0.00%)  1/1538 (0.07%) 
OVERLAP SYNDROME * 1  1/1542 (0.06%)  0/1538 (0.00%) 
SARCOIDOSIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
Infections and infestations     
ABSCESS * 1  1/1542 (0.06%)  1/1538 (0.07%) 
ABSCESS LIMB * 1  0/1542 (0.00%)  6/1538 (0.39%) 
ABSCESS ORAL * 1  0/1542 (0.00%)  1/1538 (0.07%) 
ABSCESS RUPTURE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
ACUTE SINUSITIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
ANAL ABSCESS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
APPENDICITIS * 1  0/1542 (0.00%)  3/1538 (0.20%) 
ARTHRITIS BACTERIAL * 1  6/1542 (0.39%)  9/1538 (0.59%) 
ARTHRITIS INFECTIVE * 1  1/1542 (0.06%)  2/1538 (0.13%) 
ASPERGILLUS INFECTION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
ATYPICAL PNEUMONIA * 1  2/1542 (0.13%)  0/1538 (0.00%) 
BILIARY SEPSIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
BRONCHITIS * 1  4/1542 (0.26%)  5/1538 (0.33%) 
BRONCHITIS VIRAL * 1  1/1542 (0.06%)  0/1538 (0.00%) 
BRONCHOPULMONARY ASPERGILLOSIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
BURSITIS INFECTIVE * 1  0/1542 (0.00%)  2/1538 (0.13%) 
CELLULITIS * 1  8/1542 (0.52%)  24/1538 (1.56%) 
CELLULITIS STAPHYLOCOCCAL * 1  1/1542 (0.06%)  0/1538 (0.00%) 
CELLULITIS STREPTOCOCCAL * 1  0/1542 (0.00%)  1/1538 (0.07%) 
CERVICITIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
CHRONIC TONSILLITIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
CLOSTRIDIUM DIFFICILE COLITIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
CLOSTRIDIUM DIFFICILE INFECTION * 1  1/1542 (0.06%)  0/1538 (0.00%) 
COLONIC ABSCESS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
DENGUE FEVER * 1  0/1542 (0.00%)  1/1538 (0.07%) 
DEVICE RELATED INFECTION * 1  1/1542 (0.06%)  1/1538 (0.07%) 
DEVICE RELATED SEPSIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
DISSEMINATED TUBERCULOSIS * 1  1/1542 (0.06%)  1/1538 (0.07%) 
DIVERTICULITIS * 1  1/1542 (0.06%)  10/1538 (0.65%) 
EMPYEMA * 1  1/1542 (0.06%)  1/1538 (0.07%) 
ENDOPHTHALMITIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
ENTERITIS INFECTIOUS * 1  2/1542 (0.13%)  0/1538 (0.00%) 
EPIDIDYMITIS * 1  1/1542 (0.06%)  1/1538 (0.07%) 
EPIGLOTTITIS * 1  0/1542 (0.00%)  2/1538 (0.13%) 
ERYSIPELAS * 1  2/1542 (0.13%)  11/1538 (0.72%) 
ESCHERICHIA PYELONEPHRITIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
ESCHERICHIA SEPSIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
ESCHERICHIA URINARY TRACT INFECTION * 1  1/1542 (0.06%)  0/1538 (0.00%) 
FUNGAL SKIN INFECTION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
GASTROENTERITIS * 1  6/1542 (0.39%)  3/1538 (0.20%) 
GASTROENTERITIS NOROVIRUS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
GASTROENTERITIS VIRAL * 1  1/1542 (0.06%)  1/1538 (0.07%) 
GROIN ABSCESS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
HAEMATOMA INFECTION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
HAEMOPHILUS SEPSIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
HERPANGINA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
HERPES ZOSTER * 1  4/1542 (0.26%)  2/1538 (0.13%) 
INFECTED DERMAL CYST * 1  1/1542 (0.06%)  1/1538 (0.07%) 
INFECTION * 1  1/1542 (0.06%)  0/1538 (0.00%) 
INFECTIOUS COLITIS * 1  2/1542 (0.13%)  0/1538 (0.00%) 
INFECTIOUS PLEURAL EFFUSION * 1  1/1542 (0.06%)  3/1538 (0.20%) 
INFECTIVE ANEURYSM * 1  0/1542 (0.00%)  1/1538 (0.07%) 
INFLUENZA * 1  1/1542 (0.06%)  1/1538 (0.07%) 
INJECTION SITE ABSCESS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
INTERVERTEBRAL DISCITIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
LOCALISED INFECTION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
LOWER RESPIRATORY TRACT INFECTION * 1  2/1542 (0.13%)  1/1538 (0.07%) 
LUDWIG ANGINA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
LUNG ABSCESS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
LUNG INFECTION * 1  1/1542 (0.06%)  0/1538 (0.00%) 
LUNG INFECTION PSEUDOMONAL * 1  0/1542 (0.00%)  1/1538 (0.07%) 
MASTOIDITIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
MENINGITIS * 1  0/1542 (0.00%)  2/1538 (0.13%) 
MUSCLE ABSCESS * 1  1/1542 (0.06%)  1/1538 (0.07%) 
NASAL ABSCESS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
NEUROSYPHILIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
OESOPHAGEAL CANDIDIASIS * 1  2/1542 (0.13%)  0/1538 (0.00%) 
OPHTHALMIC HERPES SIMPLEX * 1  1/1542 (0.06%)  0/1538 (0.00%) 
OPHTHALMIC HERPES ZOSTER * 1  1/1542 (0.06%)  2/1538 (0.13%) 
OSTEOMYELITIS * 1  2/1542 (0.13%)  2/1538 (0.13%) 
OSTEOMYELITIS CHRONIC * 1  1/1542 (0.06%)  0/1538 (0.00%) 
OTITIS EXTERNA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
PAPILLOMA VIRAL INFECTION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
PERIHEPATIC ABSCESS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PERITONITIS * 1  0/1542 (0.00%)  3/1538 (0.20%) 
PERITONSILLAR ABSCESS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PHARYNGITIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PNEUMOCYSTIS JIROVECII PNEUMONIA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PNEUMONIA * 1  41/1542 (2.66%)  47/1538 (3.06%) 
PNEUMONIA BACTERIAL * 1  1/1542 (0.06%)  1/1538 (0.07%) 
PNEUMONIA INFLUENZAL * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PNEUMONIA MYCOPLASMAL * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PNEUMONIA PNEUMOCOCCAL * 1  0/1542 (0.00%)  1/1538 (0.07%) 
PNEUMONIA STAPHYLOCOCCAL * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PNEUMONIA VIRAL * 1  1/1542 (0.06%)  0/1538 (0.00%) 
POST PROCEDURAL INFECTION * 1  0/1542 (0.00%)  2/1538 (0.13%) 
POSTOPERATIVE WOUND INFECTION * 1  4/1542 (0.26%)  1/1538 (0.07%) 
PSEUDOMONAS INFECTION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
PULMONARY TUBERCULOMA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PULMONARY TUBERCULOSIS * 1  1/1542 (0.06%)  1/1538 (0.07%) 
PYELONEPHRITIS * 1  1/1542 (0.06%)  5/1538 (0.33%) 
RECTAL ABSCESS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
RESPIRATORY TRACT INFECTION * 1  2/1542 (0.13%)  2/1538 (0.13%) 
SALPINGITIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
SCROTAL ABSCESS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
SEPSIS * 1  7/1542 (0.45%)  6/1538 (0.39%) 
SEPTIC SHOCK * 1  3/1542 (0.19%)  3/1538 (0.20%) 
SINUSITIS * 1  2/1542 (0.13%)  0/1538 (0.00%) 
SOFT TISSUE INFECTION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
STAPHYLOCOCCAL INFECTION * 1  1/1542 (0.06%)  1/1538 (0.07%) 
STAPHYLOCOCCAL SEPSIS * 1  0/1542 (0.00%)  2/1538 (0.13%) 
STREPTOCOCCAL BACTERAEMIA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
SUBCUTANEOUS ABSCESS * 1  3/1542 (0.19%)  2/1538 (0.13%) 
TONGUE ABSCESS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
TONSILLITIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
TOXIC SHOCK SYNDROME STREPTOCOCCAL * 1  0/1542 (0.00%)  1/1538 (0.07%) 
TRACHEITIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
TUBERCULOSIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
UPPER RESPIRATORY TRACT INFECTION * 1  1/1542 (0.06%)  1/1538 (0.07%) 
URINARY TRACT INFECTION * 1  12/1542 (0.78%)  7/1538 (0.46%) 
URINARY TRACT INFECTION BACTERIAL * 1  0/1542 (0.00%)  1/1538 (0.07%) 
UROSEPSIS * 1  2/1542 (0.13%)  1/1538 (0.07%) 
VIRAL INFECTION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
VIRAL PHARYNGITIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
WEST NILE VIRAL INFECTION * 1  1/1542 (0.06%)  0/1538 (0.00%) 
WOUND INFECTION * 1  1/1542 (0.06%)  1/1538 (0.07%) 
Injury, poisoning and procedural complications     
ACCIDENT AT WORK * 1  0/1542 (0.00%)  1/1538 (0.07%) 
ANAEMIA POSTOPERATIVE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
ANKLE FRACTURE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
ARTHROPOD STING * 1  1/1542 (0.06%)  0/1538 (0.00%) 
COMMINUTED FRACTURE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
CONTUSION * 1  1/1542 (0.06%)  1/1538 (0.07%) 
DISLOCATION OF VERTEBRA * 1  2/1542 (0.13%)  0/1538 (0.00%) 
FALL * 1  1/1542 (0.06%)  2/1538 (0.13%) 
FEMORAL NECK FRACTURE * 1  3/1542 (0.19%)  0/1538 (0.00%) 
FEMUR FRACTURE * 1  6/1542 (0.39%)  5/1538 (0.33%) 
FOOT FRACTURE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
FRACTURE DISPLACEMENT * 1  1/1542 (0.06%)  0/1538 (0.00%) 
GUN SHOT WOUND * 1  1/1542 (0.06%)  0/1538 (0.00%) 
HAND FRACTURE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
HIP FRACTURE * 1  12/1542 (0.78%)  4/1538 (0.26%) 
HUMERUS FRACTURE * 1  4/1542 (0.26%)  3/1538 (0.20%) 
INFUSION RELATED REACTION * 1  0/1542 (0.00%)  2/1538 (0.13%) 
JOINT DISLOCATION * 1  2/1542 (0.13%)  3/1538 (0.20%) 
JOINT INJURY * 1  1/1542 (0.06%)  0/1538 (0.00%) 
LIGAMENT INJURY * 1  1/1542 (0.06%)  0/1538 (0.00%) 
LOWER LIMB FRACTURE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
OVERDOSE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PATELLA FRACTURE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PNEUMOTHORAX TRAUMATIC * 1  0/1542 (0.00%)  1/1538 (0.07%) 
POST PROCEDURAL FISTULA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
POST PROCEDURAL HAEMATOMA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
RADIUS FRACTURE * 1  0/1542 (0.00%)  2/1538 (0.13%) 
RESPIRATORY FUME INHALATION DISORDER * 1  0/1542 (0.00%)  1/1538 (0.07%) 
RIB FRACTURE * 1  4/1542 (0.26%)  1/1538 (0.07%) 
SPINAL COMPRESSION FRACTURE * 1  1/1542 (0.06%)  1/1538 (0.07%) 
SPINAL FRACTURE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
STOMAL HERNIA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
STRESS FRACTURE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
SUBCUTANEOUS HAEMATOMA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
SUBDURAL HAEMATOMA * 1  0/1542 (0.00%)  2/1538 (0.13%) 
SYNOVIAL RUPTURE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
TENDON RUPTURE * 1  2/1542 (0.13%)  1/1538 (0.07%) 
THORACIC VERTEBRAL FRACTURE * 1  2/1542 (0.13%)  0/1538 (0.00%) 
ULNA FRACTURE * 1  1/1542 (0.06%)  2/1538 (0.13%) 
UPPER LIMB FRACTURE * 1  0/1542 (0.00%)  2/1538 (0.13%) 
WOUND * 1  0/1542 (0.00%)  1/1538 (0.07%) 
WOUND DEHISCENCE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
WRIST FRACTURE * 1  2/1542 (0.13%)  0/1538 (0.00%) 
Investigations     
EOSINOPHIL COUNT INCREASED * 1  1/1542 (0.06%)  0/1538 (0.00%) 
HAEMATOCRIT ABNORMAL * 1  0/1542 (0.00%)  1/1538 (0.07%) 
HAEMOGLOBIN ABNORMAL * 1  0/1542 (0.00%)  1/1538 (0.07%) 
LIVER FUNCTION TEST INCREASED * 1  1/1542 (0.06%)  0/1538 (0.00%) 
STAPHYLOCOCCUS TEST POSITIVE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
SYNOVIAL FLUID WHITE BLOOD CELLS POSITIVE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
TRANSAMINASES INCREASED * 1  1/1542 (0.06%)  0/1538 (0.00%) 
TROPONIN INCREASED * 1  2/1542 (0.13%)  0/1538 (0.00%) 
Metabolism and nutrition disorders     
DEHYDRATION * 1  4/1542 (0.26%)  5/1538 (0.33%) 
DIABETES MELLITUS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
DIABETIC COMPLICATION * 1  1/1542 (0.06%)  0/1538 (0.00%) 
ELECTROLYTE IMBALANCE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
HYPERGLYCAEMIA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
HYPERKALAEMIA * 1  3/1542 (0.19%)  0/1538 (0.00%) 
HYPOKALAEMIA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
HYPONATRAEMIA * 1  3/1542 (0.19%)  1/1538 (0.07%) 
METABOLIC ACIDOSIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
TYPE 2 DIABETES MELLITUS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
Musculoskeletal and connective tissue disorders     
ARTHRALGIA * 1  1/1542 (0.06%)  1/1538 (0.07%) 
ARTHRITIS * 1  1/1542 (0.06%)  1/1538 (0.07%) 
BACK PAIN * 1  6/1542 (0.39%)  0/1538 (0.00%) 
BURSITIS * 1  2/1542 (0.13%)  2/1538 (0.13%) 
COSTOCHONDRITIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
FASCIITIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
FINGER DEFORMITY * 1  0/1542 (0.00%)  1/1538 (0.07%) 
FISTULA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
FOOT DEFORMITY * 1  3/1542 (0.19%)  2/1538 (0.13%) 
HAEMARTHROSIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
INTERVERTEBRAL DISC DISORDER * 1  0/1542 (0.00%)  3/1538 (0.20%) 
INTERVERTEBRAL DISC PROTRUSION * 1  6/1542 (0.39%)  5/1538 (0.33%) 
KNEE DEFORMITY * 1  0/1542 (0.00%)  1/1538 (0.07%) 
LIMB DEFORMITY * 1  1/1542 (0.06%)  0/1538 (0.00%) 
LUMBAR SPINAL STENOSIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
MORPHOEA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
MUSCLE SPASMS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
MUSCULOSKELETAL CHEST PAIN * 1  1/1542 (0.06%)  0/1538 (0.00%) 
MYALGIA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
NECK PAIN * 1  0/1542 (0.00%)  1/1538 (0.07%) 
OSTEOARTHRITIS * 1  22/1542 (1.43%)  14/1538 (0.91%) 
OSTEONECROSIS * 1  4/1542 (0.26%)  2/1538 (0.13%) 
OSTEONECROSIS OF JAW * 1  1/1542 (0.06%)  0/1538 (0.00%) 
OSTEOPOROSIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
OSTEOPOROTIC FRACTURE * 1  2/1542 (0.13%)  1/1538 (0.07%) 
PAIN IN EXTREMITY * 1  1/1542 (0.06%)  1/1538 (0.07%) 
PERIARTHRITIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
RHEUMATOID ARTHRITIS * 1  15/1542 (0.97%)  12/1538 (0.78%) 
RHEUMATOID NODULE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
ROTATOR CUFF SYNDROME * 1  1/1542 (0.06%)  0/1538 (0.00%) 
SPINAL OSTEOARTHRITIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
SPONDYLOLISTHESIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
SYNOVIAL CYST * 1  0/1542 (0.00%)  1/1538 (0.07%) 
SYNOVITIS * 1  1/1542 (0.06%)  1/1538 (0.07%) 
TENOSYNOVITIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
ADENOCARCINOMA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
ADENOCARCINOMA OF COLON * 1  2/1542 (0.13%)  0/1538 (0.00%) 
ANAL SQUAMOUS CELL CARCINOMA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
BASAL CELL CARCINOMA * 1  3/1542 (0.19%)  1/1538 (0.07%) 
BENIGN ANORECTAL NEOPLASM * 1  0/1542 (0.00%)  1/1538 (0.07%) 
BENIGN NEOPLASM OF CERVIX UTERI * 1  0/1542 (0.00%)  1/1538 (0.07%) 
BLADDER CANCER * 1  1/1542 (0.06%)  0/1538 (0.00%) 
BLADDER TRANSITIONAL CELL CARCINOMA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
BRAIN NEOPLASM * 1  0/1542 (0.00%)  1/1538 (0.07%) 
BREAST CANCER * 1  3/1542 (0.19%)  3/1538 (0.20%) 
CARCINOID TUMOUR OF THE GASTROINTESTINAL TRACT * 1  0/1542 (0.00%)  1/1538 (0.07%) 
CARCINOID TUMOUR PULMONARY * 1  1/1542 (0.06%)  0/1538 (0.00%) 
CARDIAC MYXOMA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
CENTRAL NERVOUS SYSTEM LYMPHOMA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
CEREBRAL HAEMANGIOMA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
CHOLANGIOCARCINOMA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
COLON ADENOMA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
COLON CANCER * 1  1/1542 (0.06%)  0/1538 (0.00%) 
COLON CANCER METASTATIC * 1  1/1542 (0.06%)  0/1538 (0.00%) 
COLORECTAL CANCER * 1  1/1542 (0.06%)  0/1538 (0.00%) 
DIFFUSE LARGE B−CELL LYMPHOMA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
ENDOMETRIAL ADENOCARCINOMA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
GLIOBLASTOMA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
HAEMANGIOMA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
INTESTINAL ADENOCARCINOMA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
INTRADUCTAL PROLIFERATIVE BREAST LESION * 1  1/1542 (0.06%)  0/1538 (0.00%) 
LARYNGEAL CANCER * 1  0/1542 (0.00%)  1/1538 (0.07%) 
LUNG ADENOCARCINOMA * 1  1/1542 (0.06%)  3/1538 (0.20%) 
LUNG ADENOCARCINOMA STAGE IV * 1  1/1542 (0.06%)  0/1538 (0.00%) 
LUNG CANCER METASTATIC * 1  2/1542 (0.13%)  2/1538 (0.13%) 
LUNG NEOPLASM * 1  1/1542 (0.06%)  1/1538 (0.07%) 
LUNG NEOPLASM MALIGNANT * 1  4/1542 (0.26%)  3/1538 (0.20%) 
MALIGNANT MELANOMA STAGE II * 1  1/1542 (0.06%)  0/1538 (0.00%) 
MARJOLIN’S ULCER * 1  1/1542 (0.06%)  0/1538 (0.00%) 
METASTASES TO BONE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
METASTATIC GASTRIC CANCER * 1  1/1542 (0.06%)  0/1538 (0.00%) 
METASTATIC NEOPLASM * 1  1/1542 (0.06%)  0/1538 (0.00%) 
NEOPLASM MALIGNANT * 1  0/1542 (0.00%)  1/1538 (0.07%) 
NON−HODGKIN’S LYMPHOMA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
OVARIAN ADENOMA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
OVARIAN CANCER * 1  0/1542 (0.00%)  2/1538 (0.13%) 
PANCREATIC CARCINOMA METASTATIC * 1  0/1542 (0.00%)  1/1538 (0.07%) 
PANCREATIC NEOPLASM * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PAPILLARY THYROID CANCER * 1  0/1542 (0.00%)  1/1538 (0.07%) 
PARAPROTEINAEMIA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PARATHYROID TUMOUR BENIGN * 1  0/1542 (0.00%)  1/1538 (0.07%) 
PHARYNGEAL NEOPLASM BENIGN * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PITUITARY TUMOUR BENIGN * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PLASMA CELL MYELOMA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PROSTATE CANCER * 1  1/1542 (0.06%)  3/1538 (0.20%) 
RENAL CANCER * 1  0/1542 (0.00%)  1/1538 (0.07%) 
RENAL CELL CARCINOMA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
SMALL CELL LUNG CANCER * 1  1/1542 (0.06%)  0/1538 (0.00%) 
SQUAMOUS CELL CARCINOMA OF LUNG * 1  1/1542 (0.06%)  0/1538 (0.00%) 
SQUAMOUS CELL CARCINOMA OF THE TONGUE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
SQUAMOUS ENDOMETRIAL CARCINOMA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
THYROID ADENOMA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
TONGUE NEOPLASM MALIGNANT STAGE UNSPECIFIED * 1  1/1542 (0.06%)  1/1538 (0.07%) 
TUMOUR INVASION * 1  1/1542 (0.06%)  0/1538 (0.00%) 
UTERINE CANCER * 1  0/1542 (0.00%)  3/1538 (0.20%) 
Nervous system disorders     
AMYOTROPHIC LATERAL SCLEROSIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
BALANCE DISORDER * 1  1/1542 (0.06%)  0/1538 (0.00%) 
BRAIN STEM INFARCTION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
CAROTID ARTERY DISEASE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
CAROTID ARTERY STENOSIS * 1  1/1542 (0.06%)  1/1538 (0.07%) 
CEREBRAL HAEMATOMA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
CEREBRAL INFARCTION * 1  2/1542 (0.13%)  1/1538 (0.07%) 
CEREBRAL ISCHAEMIA * 1  2/1542 (0.13%)  1/1538 (0.07%) 
CEREBROVASCULAR ACCIDENT * 1  8/1542 (0.52%)  14/1538 (0.91%) 
CEREBROVASCULAR DISORDER * 1  1/1542 (0.06%)  1/1538 (0.07%) 
CERVICAL CORD COMPRESSION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
CERVICAL RADICULOPATHY * 1  1/1542 (0.06%)  0/1538 (0.00%) 
COMA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
DEMENTIA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
DEMENTIA ALZHEIMER’S TYPE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
DIABETIC COMA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
DYSARTHRIA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
DYSKINESIA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
EMBOLIC STROKE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
ENCEPHALOPATHY * 1  1/1542 (0.06%)  0/1538 (0.00%) 
EPILEPSY * 1  0/1542 (0.00%)  3/1538 (0.20%) 
FACIAL PARALYSIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
GENERALISED TONIC−CLONIC SEIZURE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
HAEMORRHAGIC STROKE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
HEMIPARESIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
HEPATIC ENCEPHALOPATHY * 1  0/1542 (0.00%)  1/1538 (0.07%) 
HYPERTENSIVE ENCEPHALOPATHY * 1  0/1542 (0.00%)  1/1538 (0.07%) 
INTRACRANIAL ANEURYSM * 1  0/1542 (0.00%)  1/1538 (0.07%) 
ISCHAEMIC STROKE * 1  5/1542 (0.32%)  5/1538 (0.33%) 
LOSS OF CONSCIOUSNESS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
LUMBAR RADICULOPATHY * 1  2/1542 (0.13%)  0/1538 (0.00%) 
METABOLIC ENCEPHALOPATHY * 1  1/1542 (0.06%)  0/1538 (0.00%) 
MIGRAINE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
MYASTHENIA GRAVIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PARAESTHESIA * 1  1/1542 (0.06%)  1/1538 (0.07%) 
PARKINSON’S DISEASE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PRESYNCOPE * 1  2/1542 (0.13%)  0/1538 (0.00%) 
REVERSIBLE ISCHAEMIC NEUROLOGICAL DEFICIT * 1  1/1542 (0.06%)  0/1538 (0.00%) 
RUPTURED CEREBRAL ANEURYSM * 1  0/1542 (0.00%)  1/1538 (0.07%) 
SCIATICA * 1  3/1542 (0.19%)  1/1538 (0.07%) 
SEIZURE * 1  1/1542 (0.06%)  1/1538 (0.07%) 
SPINAL CORD COMPRESSION * 1  0/1542 (0.00%)  2/1538 (0.13%) 
SUBARACHNOID HAEMORRHAGE * 1  3/1542 (0.19%)  1/1538 (0.07%) 
SYNCOPE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
TRANSIENT GLOBAL AMNESIA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
TRANSIENT ISCHAEMIC ATTACK * 1  3/1542 (0.19%)  9/1538 (0.59%) 
VASCULAR DEMENTIA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
Product Issues     
DEVICE BREAKAGE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
DEVICE DISLOCATION * 1  0/1542 (0.00%)  3/1538 (0.20%) 
DEVICE FAILURE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
DEVICE LOOSENING * 1  0/1542 (0.00%)  1/1538 (0.07%) 
Psychiatric disorders     
BURNOUT SYNDROME * 1  1/1542 (0.06%)  0/1538 (0.00%) 
CONFUSIONAL STATE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
DELIRIUM * 1  0/1542 (0.00%)  1/1538 (0.07%) 
DELIRIUM TREMENS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
DEPRESSION * 1  2/1542 (0.13%)  0/1538 (0.00%) 
MAJOR DEPRESSION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
MENTAL DISORDER * 1  1/1542 (0.06%)  0/1538 (0.00%) 
MENTAL STATUS CHANGES * 1  0/1542 (0.00%)  1/1538 (0.07%) 
PSYCHOTIC DISORDER * 1  0/1542 (0.00%)  1/1538 (0.07%) 
SCHIZOAFFECTIVE DISORDER BIPOLAR TYPE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
SUICIDAL IDEATION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
SUICIDE ATTEMPT * 1  0/1542 (0.00%)  1/1538 (0.07%) 
MANIA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
Renal and urinary disorders     
ACUTE KIDNEY INJURY * 1  5/1542 (0.32%)  3/1538 (0.20%) 
CALCULUS BLADDER * 1  0/1542 (0.00%)  1/1538 (0.07%) 
CALCULUS URINARY * 1  2/1542 (0.13%)  1/1538 (0.07%) 
CHRONIC KIDNEY DISEASE * 1  1/1542 (0.06%)  1/1538 (0.07%) 
CYSTITIS HAEMORRHAGIC * 1  1/1542 (0.06%)  0/1538 (0.00%) 
END STAGE RENAL DISEASE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
GLOMERULONEPHRITIS CHRONIC * 1  0/1542 (0.00%)  1/1538 (0.07%) 
HYDRONEPHROSIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
NEPHROLITHIASIS * 1  3/1542 (0.19%)  3/1538 (0.20%) 
OBSTRUCTIVE NEPHROPATHY * 1  0/1542 (0.00%)  1/1538 (0.07%) 
PELVI−URETERIC OBSTRUCTION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
RENAL COLIC * 1  0/1542 (0.00%)  1/1538 (0.07%) 
RENAL FAILURE * 1  3/1542 (0.19%)  2/1538 (0.13%) 
TUBULOINTERSTITIAL NEPHRITIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
URETERIC OBSTRUCTION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
URETEROLITHIASIS * 1  1/1542 (0.06%)  2/1538 (0.13%) 
URETHRAL STENOSIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
URINARY RETENTION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
Reproductive system and breast disorders     
ACQUIRED PHIMOSIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
BREAST FIBROSIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
CERVICAL DYSPLASIA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
CERVICAL POLYP * 1  0/1542 (0.00%)  1/1538 (0.07%) 
CYSTOCELE * 1  0/1542 (0.00%)  2/1538 (0.13%) 
GENITAL PROLAPSE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
METRORRHAGIA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
OVARIAN CYST * 1  0/1542 (0.00%)  0/1538 (0.00%) 
OVARIAN CYST TORSION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
RECTOCELE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
SPERMATOCELE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
UTERINE POLYP * 1  1/1542 (0.06%)  0/1538 (0.00%) 
UTERINE PROLAPSE * 1  1/1542 (0.06%)  1/1538 (0.07%) 
VAGINAL HAEMATOMA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
Respiratory, thoracic and mediastinal disorders     
ACUTE PULMONARY OEDEMA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
ACUTE RESPIRATORY DISTRESS SYNDROME * 1  0/1542 (0.00%)  1/1538 (0.07%) 
ACUTE RESPIRATORY FAILURE * 1  1/1542 (0.06%)  1/1538 (0.07%) 
ALVEOLITIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
ASTHMA * 1  5/1542 (0.32%)  2/1538 (0.13%) 
ASTHMATIC CRISIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
ATELECTASIS * 1  1/1542 (0.06%)  1/1538 (0.07%) 
BRONCHIAL HYPERREACTIVITY * 1  0/1542 (0.00%)  1/1538 (0.07%) 
BRONCHIAL OBSTRUCTION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
BRONCHITIS CHRONIC * 1  0/1542 (0.00%)  1/1538 (0.07%) 
BRONCHOSPASM * 1  1/1542 (0.06%)  0/1538 (0.00%) 
BRONCHOSTENOSIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
CHRONIC OBSTRUCTIVE PULMONARY DISEASE * 1  7/1542 (0.45%)  10/1538 (0.65%) 
CHRONIC RESPIRATORY FAILURE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
DYSPNOEA * 1  4/1542 (0.26%)  5/1538 (0.33%) 
EMPHYSEMA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
EPISTAXIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
HYDROTHORAX * 1  0/1542 (0.00%)  1/1538 (0.07%) 
HYPOXIA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
INTERSTITIAL LUNG DISEASE * 1  3/1542 (0.19%)  5/1538 (0.33%) 
LUNG DISORDER * 1  0/1542 (0.00%)  1/1538 (0.07%) 
LUNG INFILTRATION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
PLEURAL EFFUSION * 1  5/1542 (0.32%)  6/1538 (0.39%) 
PNEUMONIA ASPIRATION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
PNEUMONITIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
PNEUMOTHORAX * 1  2/1542 (0.13%)  1/1538 (0.07%) 
PULMONARY EMBOLISM * 1  11/1542 (0.71%)  1/1538 (0.07%) 
PULMONARY FIBROSIS * 1  1/1542 (0.06%)  1/1538 (0.07%) 
PULMONARY GRANULOMA * 1  0/1542 (0.00%)  1/1538 (0.07%) 
PULMONARY HYPERTENSION * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PULMONARY MASS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PULMONARY OEDEMA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PULMONARY SARCOIDOSIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PULMONARY THROMBOSIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
RESPIRATORY DISTRESS * 1  1/1542 (0.06%)  2/1538 (0.13%) 
RESPIRATORY FAILURE * 1  1/1542 (0.06%)  1/1538 (0.07%) 
Skin and subcutaneous tissue disorders     
ANGIOEDEMA * 1  2/1542 (0.13%)  1/1538 (0.07%) 
BLISTER * 1  0/1542 (0.00%)  1/1538 (0.07%) 
DECUBITUS ULCER * 1  1/1542 (0.06%)  0/1538 (0.00%) 
DERMAL CYST * 1  1/1542 (0.06%)  1/1538 (0.07%) 
DERMATITIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
DIABETIC FOOT * 1  1/1542 (0.06%)  0/1538 (0.00%) 
HYPERSENSITIVITY VASCULITIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
PEMPHIGOID * 1  1/1542 (0.06%)  0/1538 (0.00%) 
RASH * 1  0/1542 (0.00%)  1/1538 (0.07%) 
RASH ERYTHEMATOUS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
SKIN DISORDER * 1  1/1542 (0.06%)  0/1538 (0.00%) 
SKIN NECROSIS * 1  0/1542 (0.00%)  2/1538 (0.13%) 
SKIN ULCER * 1  1/1542 (0.06%)  4/1538 (0.26%) 
URTICARIA * 1  2/1542 (0.13%)  0/1538 (0.00%) 
VASCULITIC ULCER * 1  0/1542 (0.00%)  1/1538 (0.07%) 
Surgical and medical procedures     
ABDOMINAL HERNIA REPAIR * 1  1/1542 (0.06%)  0/1538 (0.00%) 
ANAL FISTULA EXCISION * 1  1/1542 (0.06%)  0/1538 (0.00%) 
ANGIOPLASTY * 1  0/1542 (0.00%)  1/1538 (0.07%) 
APPENDICECTOMY * 1  0/1542 (0.00%)  1/1538 (0.07%) 
CARDIAC PACEMAKER REPLACEMENT * 1  0/1542 (0.00%)  1/1538 (0.07%) 
COLOSTOMY CLOSURE * 1  1/1542 (0.06%)  0/1538 (0.00%) 
HIP ARTHROPLASTY * 1  1/1542 (0.06%)  1/1538 (0.07%) 
IMPLANTABLE DEFIBRILLATOR INSERTION * 1  1/1542 (0.06%)  0/1538 (0.00%) 
KNEE ARTHROPLASTY * 1  0/1542 (0.00%)  1/1538 (0.07%) 
LARGE INTESTINE ANASTOMOSIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
MITRAL VALVE REPLACEMENT * 1  1/1542 (0.06%)  0/1538 (0.00%) 
SEQUESTRECTOMY * 1  0/1542 (0.00%)  1/1538 (0.07%) 
UMBILICAL HERNIA REPAIR * 1  0/1542 (0.00%)  1/1538 (0.07%) 
Vascular disorders     
AORTIC ANEURYSM * 1  4/1542 (0.26%)  3/1538 (0.20%) 
AORTIC ANEURYSM RUPTURE * 1  0/1542 (0.00%)  1/1538 (0.07%) 
AORTIC CALCIFICATION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
AORTIC DISSECTION * 1  1/1542 (0.06%)  1/1538 (0.07%) 
AORTIC STENOSIS * 1  0/1542 (0.00%)  1/1538 (0.07%) 
DEEP VEIN THROMBOSIS * 1  8/1542 (0.52%)  6/1538 (0.39%) 
EMBOLISM ARTERIAL * 1  1/1542 (0.06%)  0/1538 (0.00%) 
FEMORAL ARTERY EMBOLISM * 1  1/1542 (0.06%)  0/1538 (0.00%) 
HAEMATOMA * 1  1/1542 (0.06%)  0/1538 (0.00%) 
HYPERTENSION * 1  6/1542 (0.39%)  4/1538 (0.26%) 
HYPERTENSIVE CRISIS * 1  2/1542 (0.13%)  1/1538 (0.07%) 
HYPERTENSIVE EMERGENCY * 1  1/1542 (0.06%)  0/1538 (0.00%) 
HYPOTENSION * 1  1/1542 (0.06%)  2/1538 (0.13%) 
INFARCTION * 1  1/1542 (0.06%)  0/1538 (0.00%) 
ORTHOSTATIC HYPOTENSION * 1  0/1542 (0.00%)  1/1538 (0.07%) 
PERIPHERAL ARTERIAL OCCLUSIVE DISEASE * 1  2/1542 (0.13%)  1/1538 (0.07%) 
PERIPHERAL ISCHAEMIA * 1  2/1542 (0.13%)  3/1538 (0.20%) 
PERIPHERAL VENOUS DISEASE * 1  1/1542 (0.06%)  2/1538 (0.13%) 
RHEUMATOID VASCULITIS * 1  1/1542 (0.06%)  0/1538 (0.00%) 
SUBCLAVIAN ARTERY OCCLUSION * 1  1/1542 (0.06%)  0/1538 (0.00%) 
THROMBOSIS * 1  1/1542 (0.06%)  2/1538 (0.13%) 
VARICOSE VEIN * 1  0/1542 (0.00%)  1/1538 (0.07%) 
VENOUS THROMBOSIS LIMB * 1  1/1542 (0.06%)  1/1538 (0.07%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA version 19.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Etanercept Tocilizumab
Affected / at Risk (%) Affected / at Risk (%)
Total   910/1542 (59.01%)   1090/1538 (70.87%) 
Blood and lymphatic system disorders     
LEUKOPENIA * 1  21/1542 (1.36%)  85/1538 (5.53%) 
NEUTROPENIA * 1  33/1542 (2.14%)  92/1538 (5.98%) 
Gastrointestinal disorders     
DIARRHOEA * 1  84/1542 (5.45%)  140/1538 (9.10%) 
Infections and infestations     
BRONCHITIS * 1  185/1542 (12.00%)  244/1538 (15.86%) 
NASOPHARYNGITIS * 1  141/1542 (9.14%)  239/1538 (15.54%) 
PHARYNGITIS * 1  76/1542 (4.93%)  113/1538 (7.35%) 
SINUSITIS * 1  78/1542 (5.06%)  88/1538 (5.72%) 
UPPER RESPIRATORY TRACT INFECTION * 1  193/1542 (12.52%)  243/1538 (15.80%) 
URINARY TRACT INFECTION * 1  150/1542 (9.73%)  174/1538 (11.31%) 
Investigations     
ALANINE AMINOTRANSFERASE INCREASED * 1  44/1542 (2.85%)  120/1538 (7.80%) 
Metabolism and nutrition disorders     
HYPERCHOLESTEROLAEMIA * 1  52/1542 (3.37%)  143/1538 (9.30%) 
Musculoskeletal and connective tissue disorders     
ARTHRALGIA * 1  106/1542 (6.87%)  143/1538 (9.30%) 
BACK PAIN * 1  92/1542 (5.97%)  147/1538 (9.56%) 
RHEUMATOID ARTHRITIS * 1  132/1542 (8.56%)  152/1538 (9.88%) 
Nervous system disorders     
HEADACHE * 1  68/1542 (4.41%)  103/1538 (6.70%) 
Respiratory, thoracic and mediastinal disorders     
COUGH * 1  76/1542 (4.93%)  127/1538 (8.26%) 
Vascular disorders     
HYPERTENSION * 1  158/1542 (10.25%)  200/1538 (13.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA version 19.0
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: NCT01331837     History of Changes
Other Study ID Numbers: WA25204
2010-020065-24 ( EudraCT Number )
First Submitted: April 7, 2011
First Posted: April 8, 2011
Results First Submitted: March 24, 2017
Results First Posted: July 13, 2017
Last Update Posted: July 13, 2017