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

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).

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.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Tocilizumab; Drug: Methotrexate; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 132
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Quebec, Canada, G1W 4R4
    • Centre Re Recherche Saint-Louis
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2S2
      • The Governors of the Uni of Alberta; Heritage Medical Research Centre
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 3Y1
      • Laurel Medical Clinic
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1M3
      • Manitoba Clinic
  • Newfoundland and Labrador
    • St John's, Newfoundland and Labrador, Canada, A1A 5E8
      • Nexus Clinical Research Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8N 1Y2
      • Dr. William G. Bensen Medicine Professional Corporation
    • Mississauga, Ontario, Canada, L5M 2V8
      • Credit Valley, Rheumatology
    • Ottawa, Ontario, Canada, K1H 1A2
      • Rheumatology Research Associates
    • Toronto, Ontario, Canada, M4K 1N2
      • Private Practice
  • Quebec
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • CHUS Hopital Fleurimont
• Puerto Rico
  • Ponce, Puerto Rico, 00716
    • Ponce School of Medicine; Caimed Center
• United Kingdom
  • Glasgow, United Kingdom, G4 0SF
    • Glasgow Royal Infirmary; Centre For Rheumatic Diseases
  • Manchester, United Kingdom, M41 5SL
    • Trafford General Hospital; Rheumatology
  • Newcastle Upon Tyne, United Kingdom, NE1 4LP
    • Royal Victoria Infirmary; Clinical Research Facility
• United States
  • Alabama
    • Anniston, Alabama, United States, 36207
      • Pinnacle Research Group; Llc, Central
    • Huntsville, Alabama, United States, 35801
      • Rheumatology Associates of North Alabama
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • Advanced Arthritis Care & Research
    • Tucson, Arizona, United States, 85704
      • Catalina Pointe Clinical Research, Inc.
  • California
    • Los Angeles, California, United States, 90045
      • Pacific Arthritis Care Center
  • Florida
    • Aventura, Florida, United States, 33180
      • Arthritis & Rheumatism; Disease Specialities
    • Jupiter, Florida, United States, 33458
      • Science and Research Institute, Inc.
    • Palm Harbor, Florida, United States, 34684
      • Arthritis Center Palm Harbor
    • Palm Harbor, Florida, United States, 34684
      • Arthritis Rsrch of Florida, Inc.
    • Sarasota, Florida, United States, 34239
      • Sarasota Arthritis Center; Research Dept
    • Tampa, Florida, United States, 33614
      • Burnette & Silverfield, MDS
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Arthritis & Rheumatology of Georgia
  • Illinois
    • Vernon Hills, Illinois, United States, 60061
      • Deerbrook Medical Associates
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins Uni
  • Michigan
    • Kalamazoo, Michigan, United States, 49048
      • Borgess Research Institute
  • Mississippi
    • Flowood, Mississippi, United States, 39232
      • Jackson Arthritis Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63131
      • Physicians Group, LC DBA Rheumatology & Internal Medicine Associates
  • New Jersey
    • Clifton, New Jersey, United States, 07012
      • NJP Clinical Research
  • North Carolina
    • Asheville, North Carolina, United States, 28803
      • Asheville Arthritis & Osteoporosis Center, PA
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73103
      • Health Research of Oklahoma, Llc
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Lehigh Valley Hospital; Dept of Medicine
    • Duncansville, Pennsylvania, United States, 16635
      • Altoona Center for Clinical Research
    • Wyomissing, Pennsylvania, United States, 19610
      • Clinical Research Center of Reading
  • Texas
    • Houston, Texas, United States, 77074
      • Houston Inst. For Clinical Research
    • Sugar Land, Texas, United States, 77479
      • Texas Research Center
  • Washington
    • Olympia, Washington, United States, 98502
      • South Puget Sound Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TCZ + MTX; 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; Administered by intravenous infusion, 8 mg/kg every 4 weeks.; Other Names: RoActemra; Actemra; Drug: Methotrexate; Administered orally or parenterally, 7.5-25 mg weekly.
Placebo Comparator: Placebo + MTX; 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; Administered by intravenous infusion, 8 mg/kg every 4 weeks.; Other Names: RoActemra; Actemra; Drug: Methotrexate; Administered orally or parenterally, 7.5-25 mg weekly.; Drug: Placebo; Placebo to tocilizumab administered by intravenous infusion every 4 weeks.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Wang J, Bansal AT, Martin M, Germer S, Benayed R, Essioux L, Lee JS, Begovich A, Hemmings A, Kenwright A, Taylor KE, Upmanyu R, Cutler P, Harari O, Marchini J, Criswell LA, Platt A. Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis. Pharmacogenomics J. 2013 Jun;13(3):235-41. doi: 10.1038/tpj.2012.8. Epub 2012 Apr 10.

Study record dates

Study Major Dates

• Study Start (Actual): October 31, 2007
• Primary Completion (Actual): September 30, 2008
• Study Completion (Actual): January 31, 2011

Study Registration Dates

• First Submitted: September 24, 2007
• First Submitted That Met QC Criteria: September 24, 2007
• First Posted (Estimate): September 26, 2007

Study Record Updates

• Last Update Posted (Actual): July 26, 2017
• Last Update Submitted That Met QC Criteria: June 28, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methotrexate
• Other Study ID Numbers: WA19923; 2007-001114-17