<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03288584</url>
  </required_header>
  <id_info>
    <org_study_id>RA-IL6-ATTIKON</org_study_id>
    <nct_id>NCT03288584</nct_id>
  </id_info>
  <brief_title>Effects of Interleukin-6 Inhibition on Vascular, Endothelial and Left Ventricular Function in Rheumatoid Arthritis</brief_title>
  <official_title>The Effect of Inhibition of Interleukin-6 Activity on Vascular, Endothelial and Left Ventricular Function in Patients With Rheumatoid Arthritis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Athens</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Athens</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Recent studies show beneficial effect of the inhibition of interleukin-6 (IL-6) activity on&#xD;
      vascular and left ventricular (LV) function. The purpose of this study is to investigate&#xD;
      whether anakinra, an IL-6 receptor antagonist, improves vascular, endothelial and LV function&#xD;
      in patients with rheumatoid arthritis (RA).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The inflammatory processes observed in patients with rheumatoid arthritis (RA) are strongly&#xD;
      linked to enhanced interleukin-6 (IL-6) activity. Increased IL-6 activity causes myocardial&#xD;
      cell damage and endothelial dysfunction. The adverse effects of IL-6 on myocardial and&#xD;
      endothelial cells are mediated by an enhanced nitrooxidative stress and the promotion of&#xD;
      apoptotic cardiomyocyte death through increased nitrooxidative stress and inflammation.&#xD;
      Tocilizumab, a recombinant form of human IL-6 receptor antagonist, is commonly used for the&#xD;
      treatment of RA. However it has not been defined whether inhibition of IL-6 activity by&#xD;
      tocilizumab shows beneficial effects on endothelial, coronary, arterial and LV systolic and&#xD;
      diastolic function in patients with RA.&#xD;
&#xD;
      For this purpose, we studied 60 patients with RA (American Rheumatism Association criteria).&#xD;
      All the above subjects had an inadequate response to disease modifying antirheumatic drugs&#xD;
      (DMARDs) and corticosteroids and were going to initiate treatment with IL-6 activity&#xD;
      inhibitor (tocilizumab). All patients were on treatment with statins and cardioactive&#xD;
      medications respectively, for the last 6 months.&#xD;
&#xD;
      All patients were randomized to receive a single injection of tocilizumab (150 mg s.c.), or&#xD;
      other biological agent (TNFa inhibitor, abatacept, rituximab, IL-1Ra) or enhanced treatment&#xD;
      with corticosteroid and non-biological agents.&#xD;
&#xD;
      Twenty asymptomatic subjects matched for age and sex as the RA patients and with a normal&#xD;
      ECG, echocardiogram, and treadmill test were selected as healthy control subjects among&#xD;
      subjects attending the cardiology outpatients' clinic.&#xD;
&#xD;
      At baseline in all RA subjects and controls as well as 3 months after the single injection of&#xD;
      tocilizumab in RA subjects, we assessed the following parameters a)carotid-femoral pulse wave&#xD;
      velocity (PWV), b) the LV dimensions,fractional shortening and wall motion score index (WMSI)&#xD;
      c) the systolic (Sm), early diastolic (Em) and late diastolic (Am) myocardial velocities of&#xD;
      the mitral annulus by using of tissue Doppler (TDI) as well as the ratio of E wave of the&#xD;
      mitral inflow measured by pulsed wave Doppler to the mean Em as an index of LV diastolic&#xD;
      filling pressures d) the LV longitudinal, circumferential and radial strain and strain rate,&#xD;
      as well as Global Longitudinal strain and Torsion using speckle tracking echocardiography e)&#xD;
      the coronary flow reserve (CFR)after adenosine infusion to assess coronary vasomotor function&#xD;
      f) the flow-mediated endothelial-dependent dilation of the brachial artery (FMD) to assess&#xD;
      peripheral endothelial function g) the diameters of aorta at systole and diastole to&#xD;
      calculate the aortic strain as an index of local aortic properties, h) perfused boundary&#xD;
      region (PBR) of the sublingual arterial microvessels (ranged from 5-25μm) using Sideview,&#xD;
      Darkfield imaging (Microscan, Glycocheck). Increased PBR is considered an accurate index of&#xD;
      reduced endothelial glucocalyx thickness because of a deeper red blood cells (RBC)&#xD;
      penetration in the glucocalyx. At the same time periods, we measured in blood samples a)&#xD;
      nitrotyrosine (NT), protein carbonyls (PC) and malondialdehyde (MDA) to assess oxidative&#xD;
      stress, b) soluble Fas and Fas-ligand to assess apoptosis, and c) interleukin-6 and tumor&#xD;
      necrosis factor-a to assess inflammation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">October 27, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2020</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Reduction of pulse wave velocity after treatment with tocilizumab</measure>
    <time_frame>3 months after treatment</time_frame>
    <description>Reduction of pulse wave velocity (PWV, m/sec) using tonometry after administration of tocilizumab</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Increase of global longitudinal strain after treatment with tocilizumab</measure>
    <time_frame>3 months after treatment</time_frame>
    <description>Increase of left ventricular global longitudinal strain (GLS, %) using speckle tracking echocardiography after administration of tocilizumab</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Reduction of malondialdehyde after treatment with tocilizumab</measure>
    <time_frame>3 months after treatment</time_frame>
    <description>Reduction of malondialdehyde (MDA, nmol/L) using spectrophotometry after treatment with tocilizumab</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Reduction of protein carbonyls after treatment with tocilizumab</measure>
    <time_frame>3 months after treatment</time_frame>
    <description>Reduction of protein carbonyls (PCs, nmol/mg protein) using spectrophotometry after treatment with tocilizumab</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Increased of endothelial glycocalyx thickness after treatment with tocilizumab</measure>
    <time_frame>3 months after treatment</time_frame>
    <description>Increased of endothelial glycocalyx thickness as assessed by perfused boundary region (PBR, micrometers) of the sublingual arterial microvessels after treatment with tocilizumab</description>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Rheumatoid Arthritis</condition>
  <condition>Inflammation</condition>
  <arm_group>
    <arm_group_label>Tocilizumab</arm_group_label>
    <description>Inhibition of Interleukin-6 activity by tocilizumab (Actemra®) 150mg od, sc injection</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Other biological agent</arm_group_label>
    <description>Other biological agent (TNFa inhibitor, abatacept, rituximab, IL-1Ra)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Corticosteroid and non-biological agents.</arm_group_label>
    <description>Enhanced treatment with corticosteroid and non-biological agents.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tocilizumab (Actemra®)</intervention_name>
    <description>Inhibition of Interleukin-6 activity by tocilizumab (Actemra®) 150mg od, sc injection</description>
    <arm_group_label>Tocilizumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Other biological agent</intervention_name>
    <description>Other biological agent (TNFa inhibitor, abatacept, rituximab, IL-1Ra)</description>
    <arm_group_label>Other biological agent</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Corticosteroid and non-biological agents.</intervention_name>
    <description>Enhanced treatment with corticosteroid and non-biological agents.</description>
    <arm_group_label>Corticosteroid and non-biological agents.</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Patients with rheumatoid arthritis who had an inadequate response to disease modifying&#xD;
        antirheumatic drugs (DMARDs) and corticosteroids and were going to initiate treatment with&#xD;
        interleukin-6 inhibitor.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with rheumatoid arthritis who had an inadequate response to disease modifying&#xD;
             antirheumatic drugs (DMARDs) and corticosteroids and were going to initiate treatment&#xD;
             with interleukin-6 inhibitor.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Familiar hyperlipidemia&#xD;
&#xD;
          -  Diabetes mellitus&#xD;
&#xD;
          -  Chronic obstructive pulmonary disease or asthma&#xD;
&#xD;
          -  Moderate or severe valvular heart disease&#xD;
&#xD;
          -  Primary cardiomyopathies&#xD;
&#xD;
          -  Malignant tumors&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ignatios Ikonomidis, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>National and Kapodistrain University of Athens</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Ignatios Ikonomidis, MD</last_name>
    <phone>00302105832187</phone>
    <email>ignoik@otenet.gr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>John Lekakis, MD</last_name>
    <phone>00302105832187</phone>
    <email>lekakisster@gmail.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Attikon Hospital</name>
      <address>
        <city>Athens</city>
        <state>Haidari</state>
        <zip>12462</zip>
        <country>Greece</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ignatios Ikonomidis, MD</last_name>
      <phone>00302105832187</phone>
      <email>ignoik@otenet.gr</email>
    </contact>
    <investigator>
      <last_name>Ignatios Ikonomidis, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Pelagia Katsimbri, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Ioanna Andreadou, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>George Pavlidis, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Dimitrios Boumpas, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>John Lekakis, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Efstathios Iliodromitis, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Greece</country>
  </location_countries>
  <verification_date>April 2020</verification_date>
  <study_first_submitted>September 16, 2017</study_first_submitted>
  <study_first_submitted_qc>September 16, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 20, 2017</study_first_posted>
  <last_update_submitted>April 1, 2020</last_update_submitted>
  <last_update_submitted_qc>April 1, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">April 3, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Athens</investigator_affiliation>
    <investigator_full_name>Ignatios Ikonomidis</investigator_full_name>
    <investigator_title>Associate Professor of Cardiology</investigator_title>
  </responsible_party>
  <keyword>Arterial stiffness</keyword>
  <keyword>Endothelial function</keyword>
  <keyword>Endothelial glycocalyx</keyword>
  <keyword>Left ventricular function</keyword>
  <keyword>Apoptosis</keyword>
  <keyword>Oxidative stress</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Arthritis</mesh_term>
    <mesh_term>Arthritis, Rheumatoid</mesh_term>
    <mesh_term>Inflammation</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03288584
org study id: RA-IL6-ATTIKON
nct id: NCT03288584
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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).
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.
observational model: Case-Control
time perspective: Prospective
measure: Reduction of pulse wave velocity after treatment with tocilizumab
time frame: 3 months after treatment
description: Reduction of pulse wave velocity (PWV, m/sec) using tonometry after administration of tocilizumab
measure: Increase of global longitudinal strain after treatment with tocilizumab
time frame: 3 months after treatment
description: Increase of left ventricular global longitudinal strain (GLS, %) using speckle tracking echocardiography after administration of tocilizumab
measure: Reduction of malondialdehyde after treatment with tocilizumab
time frame: 3 months after treatment
description: Reduction of malondialdehyde (MDA, nmol/L) using spectrophotometry after treatment with tocilizumab
measure: Reduction of protein carbonyls after treatment with tocilizumab
time frame: 3 months after treatment
description: Reduction of protein carbonyls (PCs, nmol/mg protein) using spectrophotometry after treatment with tocilizumab
measure: Increased of endothelial glycocalyx thickness after treatment with tocilizumab
time frame: 3 months after treatment
description: Increased of endothelial glycocalyx thickness as assessed by perfused boundary region (PBR, micrometers) of the sublingual arterial microvessels after treatment with tocilizumab
arm group label: Tocilizumab
description: Inhibition of Interleukin-6 activity by tocilizumab (Actemra®) 150mg od, sc injection
arm group label: Other biological agent
description: Other biological agent (TNFa inhibitor, abatacept, rituximab, IL-1Ra)
arm group label: Corticosteroid and non-biological agents.
description: Enhanced treatment with corticosteroid and non-biological agents.
intervention type: Drug
intervention name: Tocilizumab (Actemra®)
description: Inhibition of Interleukin-6 activity by tocilizumab (Actemra®) 150mg od, sc injection
arm group label: Tocilizumab
intervention type: Drug
intervention name: Other biological agent
description: Other biological agent (TNFa inhibitor, abatacept, rituximab, IL-1Ra)
arm group label: Other biological agent
intervention type: Drug
intervention name: Corticosteroid and non-biological agents.
description: Enhanced treatment with corticosteroid and non-biological agents.
arm group label: Corticosteroid and non-biological agents.
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Ignatios Ikonomidis, MD
role: Principal Investigator
affiliation: National and Kapodistrain University of Athens
last name: Ignatios Ikonomidis, MD
phone: 00302105832187
email: ignoik@otenet.gr
last name: John Lekakis, MD
phone: 00302105832187
email: lekakisster@gmail.com
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
country: Greece
responsible party type: Principal Investigator
investigator affiliation: University of Athens
investigator full name: Ignatios Ikonomidis
investigator title: Associate Professor of Cardiology
mesh term: Arthritis
mesh term: Arthritis, Rheumatoid
mesh term: Inflammation
sharing ipd: No