Effect of Monoclonal Anti-IL6 Antibody (Tocilizumab) on the Cardiovascular Risk in Patients With Rheumatoid Arthritis (TOCRIVAR)

The purpose of this study is to determine whether tocilizumab changes the cardiovascular risk factors on patients with arthritis rheumatoid.

Study hypothesis: the IL-6 contributes to increase the cardiovascular risk factors of patients with rheumatoid arthritis because it produces systemic effects as increasing weight and atherogenic body fat, changing energy homeostasis and inducing the adipokines production and the insulin resistence.

Study Overview

• Status: Unknown
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Other: Braquial ecography

• Study Type: Interventional
• Enrollment (Anticipated): 28
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • Santa Cruz de Tenerife
    • La Laguna, Santa Cruz de Tenerife, Spain, 38320
      • Hospital Universitario de Canarias

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 18 and <70 years.
2. Diagnosis of active Rheumatoid Arthritis, moderate to severe (≥ 3.2 DAS28) of ≥ 6 months duration.
3. Patients with an inadequate clinical response to a stable dose of non-biological DMARDs or anti-TNF treatment for a period ≥ 8 weeks before treatment.
4. If patients are receiving oral corticosteroids, the dose should have been ≤ 10 mg predinosona and stable for at least one month before the start of treatment (day 1).
5. Patients who are able and wish to sign the informed consent and comply with the requirements of the study protocol.

Exclusion Criteria:

1. Major surgery (including joints surgery) within eight weeks prior to the screening visit or major surgery scheduled for six months after first infusion.
2. Other Rheumatic autoimmune diseases, including systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), scleroderma, polymyositis or systemic involvement secondary to AR (such as vasculitis, pulmonary fibrosis or Felty's syndrome). It's allowed the inclusion of patients with interstitial pulmonary fibrosis and be still able to tolerate treatment with MTX. Sjögren's syndrome with RA is not considered exclusion criterion.
3. Rheumatoid arthritis with Functional Class IV as defined in the RA Classification of the ACR (complete or significant disability of patients, confined to bed or to the wheelchair and without possibilities to take care themselves).

4. Prior or actual inflammatory joint disease different of RA (eg, gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease).

   Specific drug criteria

5. Treatment with any investigational agent in the four weeks before the screening visit (or time equivalent to five half-lives of the investigational drug, whichever is longer).
6. Immunization with a live vaccine / attenuated in the four weeks prior to the baseline visit.
7. Pretreatment with TCZ Laboratory Tests (at the screening visit)
8. Serum creatinine> 142 mmol / l (1.6 mg / dL) in women and> 168 mmol / l (1.9 mg / dl) in men and absence of active renal disease.
9. ALT (SGPT) and AST (SGOT)> 1.5 ULN (if the initial sample of ALT [SGPT] or AST [SGOT] gives a value> 1.5 times ULN, you can take and analyze a second sample during the selection period).
10. Platelet count <100 x 109 / l (100.000/mm3).
11. Hemoglobin <85 g / dl (<8.5 g / l, 5.3 mmol / l).
12. Leukocytes <1.0 x 109 / l (1000/mm3), ANC <0.5 x 109 / L (500/mm3).
13. RAL <0.5 x 109 / L (500/mm3).
14. Positivity for surface antigen of hepatitis B (HBsAg) and antibodies to hepatitis C.
15. Total bilirubin> ULN (if the initial sample of bilirubin> ULN, you can take and analyze a second sample during the selection period).
16. Triglycerides> 10 mmol / l (> 900 mg / dl) at the screening visit (non fasting).
17. Pregnant or lactating women.
18. not use of reliable means of contraception, such as a physical barrier (patient and partner), pill or contraceptive patch, spermicide and barrier or IUD.
19. Background of serious allergic or anaphylactic reactions to human monoclonal antibodies, humanized or murine.
20. RXT evidence of clinically significant abnormality.
21. Evidence of uncontrolled concomitant serious illness, cardiovascular, nervous system, lung (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus), or gastrointestinal.
22. history of diverticulitis, diverticulosis in antibiotic treatment, the physician should consider the benefit-risk ratio.
23. Background of lower GI ulcer disease as the Crohn's disease, ulcerative colitis or other symptomatic conditions predisposed to perforations lower GI
24. Uncontrolled diseases such as asthma, psoriasis or inflammatory bowel disease,... treated normally with corticosteroids orally or parenterally.
25. Ongoing liver disease as determined by the principal investigator. (Patients with a history of elevated ALT (SGPT) will not be excluded)
26. Active infections or recurrent infections in the past by mycobacteria, fungus, virus or bacteria (for example: tuberculosis, atypical mycobacterial disease, clinically significant abnormalities in RXT, hepatitis B and C, herpes zoster), or any major episode infection that required hospitalization or IV antibiotic treatment in the 4 weeks preceding the screening visit or oral antibiotic in the 2 weeks prior to the screening visit.
27. Primary or secondary immunodeficiency.
28. Evidence of active malignancy diagnosed within 5 years before the inclusion(including solid tumors and hematological), or breast cancer diagnosed in the previous 5 years.
29. Active tuberculosis (TB) requiring treatment within 3 years above. Patients with a positive skin test tuberculin purified protein derivative (PPD) at the screening visit. Patients treated for tuberculosis no recurrence in the last three years will not be excluded.
30. HIV positive patients.
31. History of alcoholism, drug addiction or drug abuse in the six months before the screening visit.
32. Painful neuropathies or other conditions that may interfere with the pain assessment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: tocilizumab; All the patients are treated with tocilizumab before inclusion. The doses, frequency and duration are in acordance with the Summary of Characteristics of the Product authorised by EMA. Usually 8mg/kg (not minor than 480 mg), once each 4 weeks.	Other: Braquial ecography; At the moment of the ecography, the clinician evaluates the endothelial responses via applying braquial ischemia and administering sublingual nitroglicerin spray to evaluate vasodilation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Framingham Point Scores	Proportion of changes in Framingham Point Scores	Baseline and 52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Liver enzymes	Number of patients with liver enzymes elevated.	Baseline, 12, 24 and 52 weeks
Lipoprotein levels	Number of patients with elevated lipoprotein levels	Baseline, 12, 24 and 52 weeks
DAS28 score	Variation in DAS28 score after tocilizumab	Baseline and 52 week
Number of patients with Adverse Drug Reactions	Number of patients with Adverse Drug Reactions as a measure of safety	up to 52 weeks
Insulinemia	Change in insulinemia 52 weeks later.	Baseline and 52 week

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of brachial artery vasodilation	To evaluate the endothelial responses to ischemia and vasodilatation by ecography	Baseline, 24 and 52 weeks
cytokines, adipokines and adhesion molecules levels	To evaluate changes in cytokines, adipokines and adhesion molecules	Baseline and 52 week

Collaborators and Investigators

• Sponsor: Hospital Universitario de Canarias
• Collaborators: Roche Pharma AG
• Investigators: Principal Investigator: Federico Díaz González, MD, PhD, Hospital Universitario de Canarias

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (Anticipated): March 1, 2017
• Study Completion (Anticipated): March 1, 2017

Study Registration Dates

• First Submitted: December 3, 2012
• First Submitted That Met QC Criteria: December 18, 2012
• First Posted (Estimate): December 19, 2012

Study Record Updates

• Last Update Posted (Estimate): February 9, 2017
• Last Update Submitted That Met QC Criteria: February 7, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: Rheumatoid Arthritis, tocilizumab, cardiovascular risk factors
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid
• Other Study ID Numbers: FRC-TOC-2009-01; 2010-018658-12 (EudraCT Number)