Effects of Interleukin-1 Inhibition on Vascular and Left Ventricular Function in Rheumatoid Arthritis Patients With Coronary Artery Disease

The recruitment status of this study is unknown because the information has not been verified recently.
Verified March 2012 by University of Athens.
Recruitment status was  Active, not recruiting
Sponsor:
Information provided by (Responsible Party):
Ignatios Ikonomidis, University of Athens
ClinicalTrials.gov Identifier:
NCT01566201
First received: March 27, 2012
Last updated: March 28, 2012
Last verified: March 2012
  Purpose

Inhibition of interleukin-1 (IL-1) activity in patients with RA without CAD ameliorates vascular and LV function. Moreover, data from species shows beneficial effect of this treatment on LV function after experimental myocardial infarction. The purpose of this study is to investigate whether anakinra, an IL-1 receptor antagonist, improves vascular and left ventricular (LV) function in patients with coronary artery disease (CAD) and coexistent rheumatoid arthritis (RA).


Condition Intervention
Rheumatoid Arthritis
Coronary Artery Disease
Inflammation
Drug: anakinra
Drug: placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: The Effect of Inhibition of Interleukin-1 Activity on Vascular and Left Ventricular Function in Patients With Coronary Artery Disease and Coexistent Rheumatoid Arthritis

Resource links provided by NLM:


Further study details as provided by University of Athens:

Primary Outcome Measures:
  • Improvement in vascular and left ventricular function after anakinra [ Time Frame: 3 hours after treatment ] [ Designated as safety issue: No ]
    Improvement in vascular and left ventricular function after administration of anakinra compared to placebo


Secondary Outcome Measures:
  • Reduction of nitrooxidative stress and apoptosis after anakinra treatment [ Time Frame: 3 hours after treatment ] [ Designated as safety issue: No ]

Estimated Enrollment: 80
Study Start Date: March 2011
Estimated Study Completion Date: June 2012
Estimated Primary Completion Date: April 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: anakinra Drug: anakinra
Inhibition of Interleukin-1 activity by anakinra (Kineret®) 100mg od, sc injection
Other Name: Kineret® (anakinra)
Placebo Comparator: placebo Drug: placebo
water for injection
Other Name: water for injection

Detailed Description:

The inflammatory processes observed in patients with rheumatoid arthritis (RA) are strongly linked to enhanced interleukin-1 (IL-1) activity. Increased IL-1 activity causes myocardial cell damage and endothelial dysfunction. The adverse effects of IL-1 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. Anakinra, a recombinant form of human IL-1 receptor antagonist, is commonly used for the treatment of RA. Experimental data indicates that administration of anakinra after acute myocardial infarction ameliorates cardiac remodeling by reducing cardiomyocyte apoptosis. Moreover, in our previous studies we have shown that treatment with anakinra reduces IL-1-mediated nitrooxidative stress and apoptotic markers leading to an improvement in Tissue Doppler and speckle tracking-derived parameters of left ventricular (LV) function in RA patients. However it has not been defined whether inhibition of IL-1 activity by anakinra shows beneficial effects on endothelial, coronary, arterial and LV systolic and diastolic function in patients with coronary artery disease (CAD).

For this purpose, we studied 60 patients with CAD and coexistent RA (American Rheumatism Association criteria) as well as 20 patients with RA and without CAD. All the above subjects had an inadequate response to disease modifying antirheumatic drugs (DMARDs) and corticosteroids and were going to initiate treatment with IL-1 activity inhibitor (anakinra). All patients were on treatment with statins and cardioactive medications respectively, for the last 6 months. In the 20 patients with only RA, the presence of CAD was excluded with a non-invasive test and/or a negative recent coronary arteriogram.

In a double-blind, placebo-controlled fashion, all patients were randomized to receive a single injection of anakinra(100 mg s.c.) or placebo. After 48-hours patients were crossed over to the alternate treatment (placebo or anakinra) and measurement of the examined markers was repeated. The 48h interval between the 2 consecutive studies was decided to secure a sufficient wash-out period of anakinra in accordance to the drug's half-life time.

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-hours after the single injection of anakinra in RA subjects, we assessed by means of echocardiography the following parameters a) the LV dimensions,fractional shortening and wall motion score index (WMSI) b) 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 c) the LV longitudinal, circumferential and radial strain and strain rate, as well as Global Longitudinal strain and Torsion using speckle tracking echocardiography d) the coronary flow reserve (CFR)after adenosine infusion to assess coronary vasomotor function e) the flow-mediated endothelial-dependent dilation of the brachial artery (FMD) to assess peripheral endothelial function f) the diameters of aorta at systole and diastole to calculate the aortic strain as an index of local aortic properties. At the same time periods, we measured in blood samples a) nitrotyrosine (NT), protein carbonyls (PC)and malondialdehyde(MDA)to assess nitrooxidative stress b)soluble Fas and Fas-ligand )to assess apoptosis c) interleukin-1b and tumor necrosis factor-a to assess inflammation

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Patients with rheumatoid arthritis and coexistent coronary artery disease or without CAD who had an inadequate response to disease modifying antirheumatic drugs (DMARDs) and corticosteroids and were going to initiate treatment with interleukin-1 inhibitor.

Exclusion Criteria:

  • Familiar hyperlipidemia
  • Diabetes mellitus
  • Chronic obstructive pulmonary disease or asthma, moderate or severe valvular heart disease, primary cardiomyopathies,malignant tumors
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01566201

Locations
Greece
"Attikon" University General Hospital
Haidari, Athens, Attiki, Greece, 12462
Sponsors and Collaborators
University of Athens
Investigators
Principal Investigator: Ignatios Ikonomidis, MD 2nd Cardiology Department, University of Athens, Greece
Principal Investigator: Stavros Tzortzis, MD 2nd Cardiology Department, University of Athens, Greece
Principal Investigator: John P. Lekakis, MD 2nd Cardiology Department, University of Athens, Greece
Principal Investigator: Ioanna Andreadou, Dr Department of Pharmaceutical Chemistry, University of Athens Medical School, Greece
Principal Investigator: Ioannis Paraskevaidis, MD 2nd Cardiology Department, University of Athens, Greece
Principal Investigator: Maria Anastasiou-Nana, MD 2nd Cardiology Department, University of Athens, Greece
  More Information

No publications provided by University of Athens

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Ignatios Ikonomidis, Assistant Professor in Cardiology, University of Athens
ClinicalTrials.gov Identifier: NCT01566201     History of Changes
Other Study ID Numbers: RCT-RACAD-ATTIKON-01
Study First Received: March 27, 2012
Last Updated: March 28, 2012
Health Authority: Greece: Ethics Committee

Keywords provided by University of Athens:
Arterial stiffness
Endothelial function
Left ventricular function
Apoptosis
Nitrooxidative stress

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Inflammation
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Pathologic Processes
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases

ClinicalTrials.gov processed this record on September 30, 2014