A Study of the Effect of Tocilizumab on Markers of Atherogenic Risk in Patients With Moderate to Severe Rheumatoid Arthritis

Study Overview
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Brief Summary
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This 2 arm study will investigate the effects of tocilizumab on lipids, arterial stiffness, and markers of atherogenic risk in patients with moderate to severe active rheumatoid arthritis. In Part 1 of the study, patients will be randomized to receive either tocilizumab 8mg/kg intravenously or placebo every 4 weeks, in combination with methotrexate 7.5-25 mg weekly. In Part 2, all patients will receive open-label treatment with tocilizumab plus methotrexate.

Official Title
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A Mechanism of Action Study to Evaluate the Effects of IL-6 Receptor Blockade With Tocilizumab (TCZ) on Lipids, Arterial Stiffness, and Markers of Atherogenic Risk in Patients With Moderate to Severe Active Rheumatoid Arthritis (RA).

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Tocilizumab
* Drug: Placebo
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients, 18-75 years of age rheumatoid arthritis (RA) of >6 months duration able to receive outpatient treatment on methotrexate for at least 12 weeks before entering study, at a stable dose of 7.5-25 mg/week for the last 8 weeks oral corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDS) permitted, if at a stable dose for 4 weeks before study start Exclusion Criteria major surgery (including joint surgery) within 8 weeks prior to screening, or planned surgery within 6 months after entering study history of, or current inflammatory joint disease or rheumatic autoimmune disease other than RA inadequate response to anti-tumor necrosis factor (TNF) agent during the 6 months prior to baseline, or inadequate response to >2 anti-TNF agents initiation of treatment with lipid lowering agents within 12 weeks prior to baseline

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TCZ + MTX<br>Participants received 8 mg/kg tocilizumab (TCZ) by intravenous infusion (IV) every 4 weeks plus methotrexate (MTX) 7.5-25 mg (oral or parenteral) weekly for the first 24 weeks. From Week 24 to Week 104, participants received open-label TCZ 8 mg/kg every 4 weeks plus 7.5-25 mg MTX weekly. | Drug: Tocilizumab<br>* Administered by intravenous infusion, 8 mg/kg every 4 weeks.<br>* Other names: Actemra;Drug: Methotrexate<br>* Administered orally or parenterally, 7.5-25 mg weekly.<br>|
| Placebo Comparator: Placebo + MTX<br>Participants received placebo intravenous infusion (IV) every 4 weeks plus methotrexate (MTX) 7.5-25 mg (oral or parenteral) weekly for the first 24 weeks. From Week 24 to 104, participants received open-label tocilizumab (TCZ) 8 mg/kg every 4 weeks plus 7.5-25 mg MTX. | Drug: Tocilizumab<br>* Administered by intravenous infusion, 8 mg/kg every 4 weeks.<br>* Other names: Actemra;Drug: Placebo<br>* Placebo to tocilizumab administered by intravenous infusion every 4 weeks.<br>Drug: Methotrexate<br>* Administered orally or parenterally, 7.5-25 mg weekly.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Small Low Density Lipoprotein (sLDL) Particle Numbers | Small LDL particles are associated with an increased risk of cardiovascular disease: more of these small particles lead to a greater risk. The concentration of fasting small LDL particles was determined using the Nuclear Magnetic Resonance (NMR) methodology. | Baseline and Week 12 | 
| Change From Baseline to Week 12 in Aortic Pulse Wave Velocity (PWV) | Aortic (central) arterial stiffness was assessed with Pulse Wave Analysis (PWA) of the radial artery and carotid-femoral PWV using applanation tonometry after the patient had rested in a supine position for at least 10 minutes. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 24 in Small Low Density Lipoprotein (sLDL) Particle Numbers | Small LDL particles are associated with an increased risk of cardiovascular disease: more of these small particles lead to a greater risk. The concentration of fasting small LDL particles was determined using the Nuclear Magnetic Resonance (NMR) methodology. | Baseline and Week 24 | 
| Change From Baseline to Week 24 in Aortic Pulse Wave Velocity (PWV) | Aortic (central) arterial stiffness was assessed with Pulse Wave Analysis (PWA) of the radial artery and carotid-femoral PWV using applanation tonometry after the patient had rested in a supine position for at least 10 minutes. | Baseline and Week 24 | 
| Number of Participants Experiencing Adverse Events (AEs) | A severe AE is an event in which the intensity of the event results in an inability to work or perform normal daily activity. A Serious AE is fatal, life-threatening, requires in-patient hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant or requires intervention to prevent one of the above outcomes. AEs of special interest include infection, gastrointestinal, infusion reaction (occurring during or within 24 hours of infusion), hepatic disorder, myocardial infarction and stroke. | Up to Week 24 |