Effects of Interleukin-6 Inhibition on Vascular, Endothelial and Left Ventricular Function in Rheumatoid Arthritis

• ClinicalTrials.gov Identifier: NCT03288584
• Recruitment Status: Recruiting
• First Posted: September 20, 2017
• Last Update Posted: July 9, 2018
• Sponsor: University of Athens
• Information provided by (Responsible Party): Ignatios Ikonomidis, University of Athens

Tracking Information

• First Submitted Date: September 16, 2017
• First Posted Date: September 20, 2017
• Last Update Posted Date: July 9, 2018
• Actual Study Start Date: January 2017
• Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 4, 2017)

• Reduction of pulse wave velocity after treatment with tocilizumab [ Time Frame: 3 months after treatment ]
  Reduction of pulse wave velocity (PWV, m/sec) using tonometry after administration of tocilizumab
• Increase of global longitudinal strain after treatment with tocilizumab [ Time Frame: 3 months after treatment ]
  Increase of left ventricular global longitudinal strain (GLS, %) using speckle tracking echocardiography after administration of tocilizumab

Original Primary Outcome Measures (submitted: September 16, 2017)

Improvement in vascular and left ventricular function after tocilizumab [ Time Frame: 3 months after treatment ]

Improvement in vascular and left ventricular function after administration of tocilizumab

• Change History: Complete list of historical versions of study NCT03288584 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: October 4, 2017)

• Reduction of malondialdehyde after treatment with tocilizumab [ Time Frame: 3 months after treatment ]
  Reduction of malondialdehyde (MDA, nmol/L) using spectrophotometry after treatment with tocilizumab
• Reduction of protein carbonyls after treatment with tocilizumab [ Time Frame: 3 months after treatment ]
  Reduction of protein carbonyls (PCs, nmol/mg protein) using spectrophotometry after treatment with tocilizumab
• Increased of endothelial glycocalyx thickness after treatment with tocilizumab [ Time Frame: 3 months after treatment ]
  Increased of endothelial glycocalyx thickness as assessed by perfused boundary region (PBR, micrometers) of the sublingual arterial microvessels after treatment with tocilizumab

Original Secondary Outcome Measures (submitted: September 16, 2017)

Reduction of oxidative stress and apoptosis after tocilizumab treatment [ Time Frame: 3 months after treatment ]

Reduction of oxidative stress and apoptosis after tocilizumab treatment

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Effects of Interleukin-6 Inhibition on Vascular, Endothelial and Left Ventricular Function in Rheumatoid Arthritis
• Official Title: The Effect of Inhibition of Interleukin-6 Activity on Vascular, Endothelial and Left Ventricular Function in Patients With Rheumatoid Arthritis
• Brief Summary: Recent studies show beneficial effect of the inhibition of interleukin-6 (IL-6) activity on vascular and left ventricular (LV) function. The purpose of this study is to investigate whether anakinra, an IL-6 receptor antagonist, improves vascular, endothelial and LV function in patients with rheumatoid arthritis (RA).

Detailed Description

The inflammatory processes observed in patients with rheumatoid arthritis (RA) are strongly linked to enhanced interleukin-6 (IL-6) activity. Increased IL-6 activity causes myocardial cell damage and endothelial dysfunction. The adverse effects of IL-6 on myocardial and endothelial cells are mediated by an enhanced nitrooxidative stress and the promotion of apoptotic cardiomyocyte death through increased nitrooxidative stress and inflammation. Tocilizumab, a recombinant form of human IL-6 receptor antagonist, is commonly used for the treatment of RA. However it has not been defined whether inhibition of IL-6 activity by tocilizumab shows beneficial effects on endothelial, coronary, arterial and LV systolic and diastolic function in patients with RA.

For this purpose, we studied 60 patients with RA (American Rheumatism Association criteria). All the above subjects had an inadequate response to disease modifying antirheumatic drugs (DMARDs) and corticosteroids and were going to initiate treatment with IL-6 activity inhibitor (tocilizumab). All patients were on treatment with statins and cardioactive medications respectively, for the last 6 months.

All patients were randomized to receive a single injection of tocilizumab (150 mg s.c.), or other biological agent (TNFa inhibitor, abatacept, rituximab, IL-1Ra) or enhanced treatment with corticosteroid and non-biological agents.

Twenty asymptomatic subjects matched for age and sex as the RA patients and with a normal ECG, echocardiogram, and treadmill test were selected as healthy control subjects among subjects attending the cardiology outpatients' clinic.

At baseline in all RA subjects and controls as well as 3 months after the single injection of tocilizumab in RA subjects, we assessed the following parameters a)carotid-femoral pulse wave velocity (PWV), b) the LV dimensions,fractional shortening and wall motion score index (WMSI) c) the systolic (Sm), early diastolic (Em) and late diastolic (Am) myocardial velocities of the mitral annulus by using of tissue Doppler (TDI) as well as the ratio of E wave of the mitral inflow measured by pulsed wave Doppler to the mean Em as an index of LV diastolic filling pressures d) the LV longitudinal, circumferential and radial strain and strain rate, as well as Global Longitudinal strain and Torsion using speckle tracking echocardiography e) the coronary flow reserve (CFR)after adenosine infusion to assess coronary vasomotor function f) the flow-mediated endothelial-dependent dilation of the brachial artery (FMD) to assess peripheral endothelial function g) the diameters of aorta at systole and diastole to calculate the aortic strain as an index of local aortic properties, h) perfused boundary region (PBR) of the sublingual arterial microvessels (ranged from 5-25μm) using Sideview, Darkfield imaging (Microscan, Glycocheck). Increased PBR is considered an accurate index of reduced endothelial glucocalyx thickness because of a deeper red blood cells (RBC) penetration in the glucocalyx. At the same time periods, we measured in blood samples a) nitrotyrosine (NT), protein carbonyls (PC) and malondialdehyde (MDA) to assess oxidative stress, b) soluble Fas and Fas-ligand to assess apoptosis, and c) interleukin-6 and tumor necrosis factor-a to assess inflammation.

• Study Type: Observational
• Study Design: Observational Model: Case-Control; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided
• Biospecimen: Not Provided
• Sampling Method: Probability Sample
• Study Population: Patients with rheumatoid arthritis who had an inadequate response to disease modifying antirheumatic drugs (DMARDs) and corticosteroids and were going to initiate treatment with interleukin-6 inhibitor.

Condition

• Rheumatoid Arthritis
• Inflammation

Intervention

• Drug: Tocilizumab (Actemra®)
  Inhibition of Interleukin-6 activity by tocilizumab (Actemra®) 150mg od, sc injection
• Drug: Other biological agent
  Other biological agent (TNFa inhibitor, abatacept, rituximab, IL-1Ra)
• Drug: Corticosteroid and non-biological agents.
  Enhanced treatment with corticosteroid and non-biological agents.

Study Groups/Cohorts

• Tocilizumab
  Inhibition of Interleukin-6 activity by tocilizumab (Actemra®) 150mg od, sc injection
  Intervention: Drug: Tocilizumab (Actemra®)
• Other biological agent
  Other biological agent (TNFa inhibitor, abatacept, rituximab, IL-1Ra)
  Intervention: Drug: Other biological agent
• Corticosteroid and non-biological agents.
  Enhanced treatment with corticosteroid and non-biological agents.
  Intervention: Drug: Corticosteroid and non-biological agents.

• Publications *: Ikonomidis I, Pavlidis G, Katsimbri P, Andreadou I, Triantafyllidi H, Tsoumani M, Varoudi M, Vlastos D, Makavos G, Kostelli G, Βenas D, Lekakis J, Parissis J, Boumpas D, Alexopoulos D, Iliodromitis E. Differential effects of inhibition of interleukin 1 and 6 on myocardial, coronary and vascular function. Clin Res Cardiol. 2019 Oct;108(10):1093-1101. doi: 10.1007/s00392-019-01443-9. Epub 2019 Mar 11.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 16, 2017): 60
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 2019
• Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients with rheumatoid arthritis who had an inadequate response to disease modifying antirheumatic drugs (DMARDs) and corticosteroids and were going to initiate treatment with interleukin-6 inhibitor.

Exclusion Criteria:

• Familiar hyperlipidemia
• Diabetes mellitus
• Chronic obstructive pulmonary disease or asthma
• Moderate or severe valvular heart disease
• Primary cardiomyopathies
• Malignant tumors

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Ignatios Ikonomidis, MD; 00302105832187; ignoik@otenet.gr

Contact: John Lekakis, MD; 00302105832187; lekakisster@gmail.com

• Listed Location Countries: Greece

Administrative Information

• NCT Number: NCT03288584
• Other Study ID Numbers: RA-IL6-ATTIKON
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Ignatios Ikonomidis, University of Athens
• Study Sponsor: University of Athens
• Collaborators: Not Provided

Investigators

• Principal Investigator: Ignatios Ikonomidis, MD; National and Kapodistrain University of Athens

• PRS Account: University of Athens
• Verification Date: July 2018