Trial Outcomes & Findings for A Study of Tocilizumab in Comparison to Etanercept in Participants With Rheumatoid Arthritis and Cardiovascular Disease Risk Factors (NCT NCT01331837)

Last Updated: 2017-07-13

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

3080 participants

Primary outcome timeframe

From baseline up to 4.9 years

Results posted on

2017-07-13

Participant Flow

A total of 3080 patients were enrolled from 353 sites, across 31 countries

Participant milestones

Participant milestones
Measure	Tocilizumab Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.	Etanercept Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Overall Study STARTED	1538	1542
Overall Study COMPLETED	1482	1475
Overall Study NOT COMPLETED	56	67

Reasons for withdrawal

Reasons for withdrawal
Measure	Tocilizumab Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.	Etanercept Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Overall Study Death	30	34
Overall Study Lost to Follow-up	3	1
Overall Study Info not recorded	10	16
Overall Study Withdrawal by Subject	13	16

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tocilizumab n=1538 Participants Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.	Etanercept n=1542 Participants Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.	Total n=3080 Participants Total of all reporting groups
Age, Continuous	60.7 Years STANDARD_DEVIATION 7.4 • n=5 Participants	60.7 Years STANDARD_DEVIATION 7.6 • n=7 Participants	60.7 Years STANDARD_DEVIATION 7.5 • n=5 Participants
Sex: Female, Male Female	1193 Participants n=5 Participants	1202 Participants n=7 Participants	2395 Participants n=5 Participants
Sex: Female, Male Male	345 Participants n=5 Participants	340 Participants n=7 Participants	685 Participants n=5 Participants

PRIMARY outcome

Timeframe: From baseline up to 4.9 years

Population: 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

Outcome measures

Outcome measures
Measure	Tocilizumab n=1538 Participants Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.	Etanercept n=1542 Participants Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Time to First Cardiovascular (CV) Events Adjudication Committee (EAC) (CV-EAC) Adjudicated Event	NA Months Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event	NA Months Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event

PRIMARY outcome

Timeframe: From baseline up to 4.9 years

Population: 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

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

Outcome measures

Outcome measures
Measure	Tocilizumab n=1538 Participants Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.	Etanercept n=1542 Participants Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Percentage of Patients Reporting a Cardiovascular (CV) Events Adjudication Committee (EAC) (CV-EAC) Adjudicated Event	5.4 Percentage of patients with event	5.1 Percentage of patients with event

PRIMARY outcome

Timeframe: From Baseline up to 4.9 years

Population: 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.

Outcome measures

Outcome measures
Measure	Tocilizumab n=1538 Participants Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.	Etanercept n=1542 Participants Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Time to First CV-EAC Adjudicated Event - Sensitivity Analysis	NA Months Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event	NA Months Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event

PRIMARY outcome

Timeframe: From Baseline up to 4.9 years

Population: 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.

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

Outcome measures

Outcome measures
Measure	Tocilizumab n=1538 Participants Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.	Etanercept n=1542 Participants Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Percentage of Patients With a CV-EAC Adjudicated Event - Sensitivity Analysis	3.7 Percentage of patients with event	3.4 Percentage of patients with event

PRIMARY outcome

Timeframe: From baseline up to 4.9 years

Population: Analysis was conducted on the ITT population

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

Outcome measures

Outcome measures
Measure	Tocilizumab n=1538 Participants Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.	Etanercept n=1542 Participants Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Time to First CV-EAC Adjudicated Event Excluding Undetermined Cause of Death - Sensitivity Analysis	NA Months 95% Confidence Interval NA Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event	NA Months 95% Confidence Interval NA Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event

PRIMARY outcome

Timeframe: From baseline up to 4.9 years

Population: Analysis was conducted on the ITT population

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

Outcome measures

Outcome measures
Measure	Tocilizumab n=1538 Participants Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.	Etanercept n=1542 Participants Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Percentage of Patients With a CV-EAC Adjudicated Event Excluding Undetermined Cause of Death - Sensitivity Analysis	4.8 Percentage of patients with event	4.7 Percentage of patients with event

PRIMARY outcome

Timeframe: From Baseline up to 4.9 years

Population: Analysis was conducted on the ITT population

Outcome measures

Outcome measures
Measure	Tocilizumab n=1538 Participants Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.	Etanercept n=1542 Participants Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Time to First CV-EAC Adjudicated Event Before Last Direct Contact Date	NA Months 95% Confidence Interval NA Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event	NA Months 95% Confidence Interval NA Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event

PRIMARY outcome

Timeframe: From Baseline up to 4.9 years

Population: Analysis was conducted on the ITT population

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).

Outcome measures

Outcome measures
Measure	Tocilizumab n=1538 Participants Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.	Etanercept n=1542 Participants Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Percentage of Participants With a CV-EAC Adjudicated Event Before Last Direct Contact Date	3.2 Percentage of participants with event	3.0 Percentage of participants with event

SECONDARY outcome

Timeframe: From baseline up to 4.9 years

Population: Analysis was conducted on the ITT population.

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.

Outcome measures

Outcome measures
Measure	Tocilizumab n=1538 Participants Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.	Etanercept n=1542 Participants Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
The Time to First Occurrence of an Expanded CV Composite Endpoint	NA Months 95% Confidence Interval NA Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event	NA Months 95% Confidence Interval NA Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event

SECONDARY outcome

Timeframe: From baseline up to 4.9 years

Population: Analysis was conducted on the ITT population.

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.

Outcome measures

Outcome measures
Measure	Tocilizumab n=1538 Participants Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.	Etanercept n=1542 Participants Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Percentages of Participants With an Expanded CV Composite Endpoint	5.5 Percentages of participants	5.4 Percentages of participants

SECONDARY outcome

Timeframe: From baseline up to 4.9 years

Population: Anlysis was conducted on the ITT population.

Prospective comparison of time to first occurrence of Individual component of primary endpoint: non-fatal Myocardial Infarction

Outcome measures

Outcome measures
Measure	Tocilizumab n=1538 Participants Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.	Etanercept n=1542 Participants Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Time to First Occurrence of Individual Component of Primary Endpoint: Non-fatal Myocardial Infarction	NA Months 95% Confidence Interval NA Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event	NA Months 95% Confidence Interval NA Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event

SECONDARY outcome

Timeframe: From baseline up to 4.9 years

Population: Anlysis was conducted on the ITT population

Percentage of patients reporting Individual component of primary endpoint: non-fatal Myocardial Infarction

Outcome measures

Outcome measures
Measure	Tocilizumab n=1538 Participants Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.	Etanercept n=1542 Participants Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Percentage of Patients With Individual Component of Primary Endpoint: Non-fatal Myocardial Infarction	1.8 Percentage of patients	2.0 Percentage of patients

SECONDARY outcome

Timeframe: From baseline up to 4.9 years

Population: Analysis was conducted on the ITT population

Prospective comparison of time to first occurrence of Individual component of primary endpoint: cardiovascular death

Outcome measures

Outcome measures
Measure	Tocilizumab n=1538 Participants Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.	Etanercept n=1542 Participants Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Time to First Occurrence of Individual Component of Primary Endpoint: Cardiovascular Death	NA Months 95% Confidence Interval NA Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event	NA Months 95% Confidence Interval NA Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event

SECONDARY outcome

Timeframe: From baseline up to 4.9 years

Population: Analysis was conducted on the ITT population

Percentage of patients reporting Individual component of primary endpoint: cardiovascular death

Outcome measures

Outcome measures
Measure	Tocilizumab n=1538 Participants Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.	Etanercept n=1542 Participants Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Percentage of Patients With Individual Component of Primary Endpoint: Cardiovascular Death	2.3 Percentage of patients	2.3 Percentage of patients

SECONDARY outcome

Timeframe: From baseline up to 4.9 years

Population: Analysis was conducted on the ITT population

Prospective comparison of time to first occurrence of Individual component of primary endpoint: non-fatal stroke

Outcome measures

Outcome measures
Measure	Tocilizumab n=1538 Participants Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.	Etanercept n=1542 Participants Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Time to First Occurrence of Individual Component of Primary Endpoint: Non-fatal Stroke	NA Months 95% Confidence Interval NA Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event	NA Months 95% Confidence Interval NA Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event

SECONDARY outcome

Timeframe: From baseline up to 4.9 years

Population: Analysis was conducted on the ITT population

Outcome measures

Outcome measures
Measure	Tocilizumab n=1538 Participants Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.	Etanercept n=1542 Participants Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Percentage of Patients With Individual Component of Primary Endpoint: Non-fatal Stroke	1.6 Percentage of patients	1.0 Percentage of patients

SECONDARY outcome

Timeframe: From baseline up to 4.9 years

Population: Analysis was conducted on the ITT population.

Prospective comparison of time to first occurrence of Individual component of primary endpoint: All-cause mortality

Outcome measures

Outcome measures
Measure	Tocilizumab n=1538 Participants Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.	Etanercept n=1542 Participants Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Time to First Occurrence of Individual Component of Primary Endpoint: All-cause Mortality	NA Months 95% Confidence Interval NA Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event	NA Months 95% Confidence Interval NA Median time to event and 95% confidence intervals could not be estimated due to less than 50% of patients experiencing an event

SECONDARY outcome

Timeframe: From baseline up to 4.9 years

Population: Analysis was conducted on the ITT population.

Percentage of patients reporting Individual component of primary endpoint: All-cause mortality

Outcome measures

Outcome measures
Measure	Tocilizumab n=1538 Participants Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.	Etanercept n=1542 Participants Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Percentage of Patients With Individual Component of Primary Endpoint: All-cause Mortality	4.2 Percentage of patients	4.2 Percentage of patients

Adverse Events

Etanercept

Serious events: 422 serious events

Other events: 910 other events

Deaths: 0 deaths

Tocilizumab

Serious events: 479 serious events

Other events: 1090 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

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

Restriction type: OTHER

Measure	Etanercept n=1542 participants at risk Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.	Tocilizumab n=1538 participants at risk Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
Blood and lymphatic system disorders LEUKOPENIA	1.4% 21/1542 • Adverse events were collected throughout the entire course of the study. 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.	5.5% 85/1538 • Adverse events were collected throughout the entire course of the study. 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.
Blood and lymphatic system disorders NEUTROPENIA	2.1% 33/1542 • Adverse events were collected throughout the entire course of the study. 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.	6.0% 92/1538 • Adverse events were collected throughout the entire course of the study. 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.
Gastrointestinal disorders DIARRHOEA	5.4% 84/1542 • Adverse events were collected throughout the entire course of the study. 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.	9.1% 140/1538 • Adverse events were collected throughout the entire course of the study. 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.
Infections and infestations BRONCHITIS	12.0% 185/1542 • Adverse events were collected throughout the entire course of the study. 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.	15.9% 244/1538 • Adverse events were collected throughout the entire course of the study. 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.
Infections and infestations NASOPHARYNGITIS	9.1% 141/1542 • Adverse events were collected throughout the entire course of the study. 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.	15.5% 239/1538 • Adverse events were collected throughout the entire course of the study. 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.
Infections and infestations PHARYNGITIS	4.9% 76/1542 • Adverse events were collected throughout the entire course of the study. 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.	7.3% 113/1538 • Adverse events were collected throughout the entire course of the study. 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.
Infections and infestations SINUSITIS	5.1% 78/1542 • Adverse events were collected throughout the entire course of the study. 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.	5.7% 88/1538 • Adverse events were collected throughout the entire course of the study. 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.
Infections and infestations UPPER RESPIRATORY TRACT INFECTION	12.5% 193/1542 • Adverse events were collected throughout the entire course of the study. 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.	15.8% 243/1538 • Adverse events were collected throughout the entire course of the study. 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.
Infections and infestations URINARY TRACT INFECTION	9.7% 150/1542 • Adverse events were collected throughout the entire course of the study. 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.	11.3% 174/1538 • Adverse events were collected throughout the entire course of the study. 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.
Investigations ALANINE AMINOTRANSFERASE INCREASED	2.9% 44/1542 • Adverse events were collected throughout the entire course of the study. 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.	7.8% 120/1538 • Adverse events were collected throughout the entire course of the study. 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.
Metabolism and nutrition disorders HYPERCHOLESTEROLAEMIA	3.4% 52/1542 • Adverse events were collected throughout the entire course of the study. 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.	9.3% 143/1538 • Adverse events were collected throughout the entire course of the study. 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.
Musculoskeletal and connective tissue disorders ARTHRALGIA	6.9% 106/1542 • Adverse events were collected throughout the entire course of the study. 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.	9.3% 143/1538 • Adverse events were collected throughout the entire course of the study. 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.
Musculoskeletal and connective tissue disorders BACK PAIN	6.0% 92/1542 • Adverse events were collected throughout the entire course of the study. 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.	9.6% 147/1538 • Adverse events were collected throughout the entire course of the study. 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.
Musculoskeletal and connective tissue disorders RHEUMATOID ARTHRITIS	8.6% 132/1542 • Adverse events were collected throughout the entire course of the study. 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.	9.9% 152/1538 • Adverse events were collected throughout the entire course of the study. 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.
Nervous system disorders HEADACHE	4.4% 68/1542 • Adverse events were collected throughout the entire course of the study. 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.	6.7% 103/1538 • Adverse events were collected throughout the entire course of the study. 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.
Respiratory, thoracic and mediastinal disorders COUGH	4.9% 76/1542 • Adverse events were collected throughout the entire course of the study. 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.	8.3% 127/1538 • Adverse events were collected throughout the entire course of the study. 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.
Vascular disorders HYPERTENSION	10.2% 158/1542 • Adverse events were collected throughout the entire course of the study. 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.	13.0% 200/1538 • Adverse events were collected throughout the entire course of the study. 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.