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

Study Overview
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Brief Summary
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This randomized, open-label, parallel-group, multicenter study will evaluate the rate of cardiovascular events with tocilizumab in comparison to etanercept in participants with rheumatoid arthritis (RA). Participants will be randomized to receive intravenous (IV) 8 milligrams per kilogram (mg/kg) tocilizumab every 4 weeks or subcutaneous 50 milligrams (mg) etanercept weekly, with or without non-biologic disease-modifying anti-rheumatic drug (DMARD).

Official Title
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A Clinical Outcomes Study to Evaluate the Effects of IL-6 Receptor Blockade With Tocilizumab (TCZ) in Comparison With Etanercept (ETA) on the Rate of Cardiovascular Events in Patients With Moderate to Severe Rheumatoid Arthritis (RA)

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Etanercept
* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with moderate to severe RA of greater than or equal to (>=6) months duration Inadequate response to at least one non-biologic DMARD Positive for Rheumatoid Factor (RF) and/or anti-cyclic citrullinated peptide (CCP) antibodies at screening Have C-reactive protein (CRP) greater than (>) 0.3 milligrams per deciliter (mg/dL) at screening or at the baseline visit Swollen joint count (SJC) >=8 (66 joint count) and tender joint count (TJC) >= 8 (68 joint count) during screening or at the baseline visit History of Coronary Heart Disease (CHD) or presence of one or more additional CHD risk factors, including current cigarette smoking, hypertension, low High Density Lipoprotein (HDL) cholesterol, family history of premature CHD, diabetes, presence of extra-articular disease associated with rheumatoid arthritis At the time of randomization, will have discontinued infliximab, adalimumab, golimumab, or certolizumab for >= 4 weeks Exclusion Criteria: Major surgery (including joint surgery or coronary revascularization) within 8 weeks prior to screening or planned major surgery within 1 year of study start Rheumatic autoimmune disease other than RA History of or current inflammatory joint disease other than RA Current or recent (within past 3 months) evidence of serious uncontrolled concomitant cardiovascular or cerebrovascular disease (myocardial infarction, revascularization, stroke, transient ischemic attack, or acute coronary syndrome) Current or previous (within the past 2 years) evidence of serious uncontrolled concomitant pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus) or gastrointestinal disease Uncontrolled disease states, such as asthma or inflammatory bowel disease where flares are commonly treated with oral or parenteral corticosteroids Pre-existing central nervous system demyelinating or seizure disorders History of diverticulitis, diverticulosis requiring treatment or other lower gastrointestinal tract conditions that might predispose to perforations Current liver disease as determined by the investigator; a history of asymptomatic elevations in liver function tests (LFTs) is not considered an exclusion Active current infection or history of recurrent bacterial, viral, fungal, mycobacterial or other infections, including but not limited to tuberculosis and atypical mycobacterial disease, hepatitis B and C, and herpes zoster, but excluding fungal infections of nail beds Any major episode of infection requiring hospitalization or treatment with IV antibiotics within four weeks of screening or oral antibiotics within two weeks prior to screening visit Active tuberculosis (TB) requiring treatment within 3 years prior to baseline Latent TB diagnosed during screening that has not been appropriately treated Primary or secondary immunodeficiency (history of or currently active) Moderate to severe heart failure Evidence of active malignant disease, malignancies diagnosed within the previous 10 years (including hematologic malignancies and solid tumors, except basal cell carcinoma of the skin that has been excised and cured), or breast cancer diagnosed within the previous 20 years Breast feeding mothers History of alcohol, drug or chemical abuse within the 6 months prior to screening Participants with lack of peripheral venous access Participants with a history of allergic reactions to latex Previous treatment with non-tumor necrosis factor (non-TNF)-inhibitor biologic therapy Treatment with any investigational agent within 4 weeks of screening visit Treatment with any cell depleting therapies within 1 year of baseline Treatment with IV gamma globulin, plasmapheresis or Prosorba column within 6 months of baseline visit Immunization with a live/attenuated vaccine within 4 weeks prior to baseline visit Any previous treatment with alkylating agents, such as cyclophosphamide or chlorambucil, or with total lymphoid irradiation

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Etanercept<br> | Drug: Etanercept<br>* Participants will receive 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.<br>|
| Experimental: Tocilizumab<br> | Drug: Tocilizumab<br>* Participants will receive 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.<br>* Other names: Actemra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Cardiovascular (CV) Events Adjudication Committee (EAC) (CV-EAC) Adjudicated Event | 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. | From baseline up to 4.9 years | 
| Percentage of Patients Reporting a Cardiovascular (CV) Events Adjudication Committee (EAC) (CV-EAC) Adjudicated Event | 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 | From baseline up to 4.9 years | 
| Time to First CV-EAC Adjudicated Event - Sensitivity Analysis | 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 | From Baseline up to 4.9 years | 
| Percentage of Patients With a CV-EAC Adjudicated Event - Sensitivity Analysis | 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 | From Baseline up to 4.9 years | 
| Time to First CV-EAC Adjudicated Event Excluding Undetermined Cause of Death - Sensitivity Analysis | 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 | From baseline up to 4.9 years | 
| Percentage of Patients With a CV-EAC Adjudicated Event Excluding Undetermined Cause of Death - Sensitivity Analysis | 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 | From baseline up to 4.9 years | 
| Time to First CV-EAC Adjudicated Event Before Last Direct Contact Date | 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). | From Baseline up to 4.9 years | 
| Percentage of Participants With a CV-EAC Adjudicated Event Before Last Direct Contact Date | 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). | From Baseline up to 4.9 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Time to First Occurrence of an Expanded CV Composite Endpoint | 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. | From baseline up to 4.9 years | 
| Percentages of Participants With an Expanded CV Composite Endpoint | 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. | From baseline up to 4.9 years | 
| Time to First Occurrence of Individual Component of Primary Endpoint: Non-fatal Myocardial Infarction | Prospective comparison of time to first occurrence of Individual component of primary endpoint: non-fatal Myocardial Infarction | From baseline up to 4.9 years | 
| Percentage of Patients With Individual Component of Primary Endpoint: Non-fatal Myocardial Infarction | Percentage of patients reporting Individual component of primary endpoint: non-fatal Myocardial Infarction | From baseline up to 4.9 years | 
| Time to First Occurrence of Individual Component of Primary Endpoint: Cardiovascular Death | Prospective comparison of time to first occurrence of Individual component of primary endpoint: cardiovascular death | From baseline up to 4.9 years | 
| Percentage of Patients With Individual Component of Primary Endpoint: Cardiovascular Death | Percentage of patients reporting Individual component of primary endpoint: cardiovascular death | From baseline up to 4.9 years | 
| Time to First Occurrence of Individual Component of Primary Endpoint: Non-fatal Stroke | Prospective comparison of time to first occurrence of Individual component of primary endpoint: non-fatal stroke | From baseline up to 4.9 years | 
| Percentage of Patients With Individual Component of Primary Endpoint: Non-fatal Stroke |  | From baseline up to 4.9 years | 
| Time to First Occurrence of Individual Component of Primary Endpoint: All-cause Mortality | Prospective comparison of time to first occurrence of Individual component of primary endpoint: All-cause mortality | From baseline up to 4.9 years | 
| Percentage of Patients With Individual Component of Primary Endpoint: All-cause Mortality | Percentage of patients reporting Individual component of primary endpoint: All-cause mortality | From baseline up to 4.9 years |