Rheumatoid ArthritisNCT03288584
Effects of Interleukin-6 Inhibition on Vascular, Endothelial and Left Ventricular Function in Rheumatoid Arthritis
An observational study of Rheumatoid Arthritis and Inflammation, run by University of Athens at 1 site in Greece.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 80 yearsHealthy volunteers can take part
- Conditions the study is for
- Rheumatoid Arthritis, Inflammation
- What is being tested?
- Tocilizumab (Actemra®), Other biological agent and Corticosteroid and non-biological agents.
- Type of treatment
- Injection or infusion
- How many people
- 60 participants
- Where
- 1 siteGreece
- Study dates
- 27 Oct 2017to 31 Dec 2020
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
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.
Who may be able to join
- 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.
Who cannot join
- Familiar hyperlipidemia
- Diabetes mellitus
- Chronic obstructive pulmonary disease or asthma
- Moderate or severe valvular heart disease
- Primary cardiomyopathies
- Malignant tumors
Trial locations and contacts
1 site in 1 country.
Greece1 site, 1 recruiting
- Recruiting
Attikon Hospital
Athens, Haidari, 12462
Ignatios Ikonomidis, MD, 00302105832187, ignoik@otenet.gr
Ignatios Ikonomidis, MD
About this study
Official title: The Effect of Inhibition of Interleukin-6 Activity on Vascular, Endothelial and Left Ventricular Function in Patients With Rheumatoid Arthritis
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).
Read the 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.
- Conditions
- Rheumatoid Arthritis, Inflammation
- Being tested
- Tocilizumab (Actemra®), Other biological agent, Corticosteroid and non-biological agents.
- Keywords
- Arterial stiffness, Endothelial function, Endothelial glycocalyx, Left ventricular function, Apoptosis, Oxidative stress
- Medical subject headings
- Arthritis, Rheumatoid, Inflammation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Tocilizumab (Actemra®)Drug
Inhibition of Interleukin-6 activity by tocilizumab (Actemra®) 150mg od, sc injection
Other biological agentDrug
Other biological agent (TNFa inhibitor, abatacept, rituximab, IL-1Ra)
Corticosteroid and non-biological agents.Drug
Enhanced treatment with corticosteroid and non-biological agents.
| Study group | Role | What they receive |
|---|---|---|
| Tocilizumab | Inhibition of Interleukin-6 activity by tocilizumab (Actemra®) 150mg od, sc injection Receives: Drug: Tocilizumab (Actemra®) | |
| Other biological agent | Other biological agent (TNFa inhibitor, abatacept, rituximab, IL-1Ra) Receives: Drug: Other biological agent | |
| Corticosteroid and non-biological agents. | Enhanced treatment with corticosteroid and non-biological agents. Receives: Drug: Corticosteroid and non-biological agents. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Reduction of pulse wave velocity after treatment with tocilizumab
Reduction of pulse wave velocity (PWV, m/sec) using tonometry after administration of tocilizumab
Measured: 3 months after treatment
Increase of global longitudinal strain after treatment with tocilizumab
Increase of left ventricular global longitudinal strain (GLS, %) using speckle tracking echocardiography after administration of tocilizumab
Measured: 3 months after treatment
Secondary outcomes (3)
Reduction of malondialdehyde after treatment with tocilizumab
Reduction of malondialdehyde (MDA, nmol/L) using spectrophotometry after treatment with tocilizumab
Measured: 3 months after treatment
Reduction of protein carbonyls after treatment with tocilizumab
Reduction of protein carbonyls (PCs, nmol/mg protein) using spectrophotometry after treatment with tocilizumab
Measured: 3 months after treatment
Increased of endothelial glycocalyx thickness after treatment with tocilizumab
Increased of endothelial glycocalyx thickness as assessed by perfused boundary region (PBR, micrometers) of the sublingual arterial microvessels after treatment with tocilizumab
Measured: 3 months after treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Sep 2017
- Study start27 Oct 2017
- Primary completion31 Dec 2020 (estimated)
- Study completion31 Dec 2020 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Rheumatoid ArthritisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Athens
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Ignatios Ikonomidis, University of Athens
- Investigators
- Ignatios Ikonomidis, MD, Principal investigator, National and Kapodistrain University of Athens
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03288584
- Sponsor's protocol ID
- RA-IL6-ATTIKON
- Status last verified
- Apr 2020
- First submitted
- 16 Sep 2017
- Last updated
- 3 Apr 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Ikonomidis I, Pavlidis G, Katsimbri P, Lambadiari V, Parissis J, Andreadou I, Tsoumani M, Boumpas D, Kouretas D, Iliodromitis E. Tocilizumab improves oxidative stress and endothelial glycocalyx: A mechanism that may explain the effects of biological treatment on COVID-19. Food Chem Toxicol. 2020 Nov;145:111694. doi: 10.1016/j.fct.2020.111694. Epub 2020 Aug 18.
PubMed 32822775Ikonomidis I, Pavlidis G, Katsimbri P, Andreadou I, Triantafyllidi H, Tsoumani M, Varoudi M, Vlastos D, Makavos G, Kostelli G, Betaenas 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.
PubMed 30859382
Study at a glance
From the registry record, last updated by the sponsor on 3 Apr 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of Inhibition of Interleukin-6 Activity on Vascular, Endothelial and Left Ventricular Function in Patients With Rheumatoid Arthritis
- ClinicalTrials.gov ID
- NCT03288584
- Acronym / sponsor ID
- RA-IL6-ATTIKON
- Conditions
- Rheumatoid Arthritis, Inflammation
- Keywords
- Arterial stiffness, Endothelial function, Endothelial glycocalyx, Left ventricular function, Apoptosis, Oxidative stress
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 60 participants (estimated)
- Lead sponsor
- University of AthensUniversity, hospital or other
- Study start
- 27 Oct 2017 (actual)
- Primary completion
- 31 Dec 2020 (estimated)
- Study completion
- 31 Dec 2020 (estimated)
- First posted
- 20 Sep 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Tocilizumab | – | Drug: Tocilizumab (Actemra®)Inhibition of Interleukin-6 activity by tocilizumab (Actemra®) 150mg od, sc injection |
| Other biological agent | – | Drug: Other biological agentOther biological agent (TNFa inhibitor, abatacept, rituximab, IL-1Ra) |
| Corticosteroid and non-biological agents. | – | Drug: Corticosteroid and non-biological agents.Enhanced treatment with corticosteroid and non-biological agents. |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- 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.
Key inclusion criteria (1 listed)
- 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.
Key exclusion criteria (6 listed)
- Familiar hyperlipidemia
- Diabetes mellitus
- Chronic obstructive pulmonary disease or asthma
- Moderate or severe valvular heart disease
- Primary cardiomyopathies
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Tocilizumab (Actemra®)Inhibition of Interleukin-6 activity by tocilizumab (Actemra®) 150mg od, sc injection | Drug | Tocilizumab |
| Other biological agentOther biological agent (TNFa inhibitor, abatacept, rituximab, IL-1Ra) | Drug | Other biological agent |
| Corticosteroid and non-biological agents.Enhanced treatment with corticosteroid and non-biological agents. | Drug | Corticosteroid and non-biological agents. |
Primary outcome
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
3 secondary outcomes
Reduction of malondialdehyde after treatment with tocilizumab
Time frame: 3 months after treatment
Reduction of protein carbonyls after treatment with tocilizumab
Time frame: 3 months after treatment
Increased of endothelial glycocalyx thickness after treatment with tocilizumab
Time frame: 3 months after treatment
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Apr 2020.
- Derived from this study: PubMed 32822775Ikonomidis I, Pavlidis G, Katsimbri P, Lambadiari V, Parissis J, Andreadou I, Tsoumani M, Boumpas D, Kouretas D, Iliodromitis E. Tocilizumab improves oxidative stress and endothelial glycocalyx: A mechanism that may explain the effects of biological treatment on COVID-19. Food Chem Toxicol. 2020 Nov;145:111694. doi: 10.1016/j.fct.2020.111694. Epub 2020 Aug 18.
- Derived from this study: PubMed 30859382Ikonomidis I, Pavlidis G, Katsimbri P, Andreadou I, Triantafyllidi H, Tsoumani M, Varoudi M, Vlastos D, Makavos G, Kostelli G, Betaenas 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ignatios Ikonomidis, MD principal investigator
National and Kapodistrain University of Athens
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Rheumatoid Arthritis and Inflammation, run by University of Athens at 1 site in Greece.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 3 Apr 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Greece. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Ignatios Ikonomidis, MD (00302105832187, ignoik@otenet.gr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Reduction of pulse wave velocity after treatment with tocilizumab (time frame: 3 months after treatment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03288584, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Apr 2020.